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US20030181668A1 - Secreted and transmembrane polypeptides and nucleic acids encoding the same - Google Patents

Secreted and transmembrane polypeptides and nucleic acids encoding the same Download PDF

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Publication number
US20030181668A1
US20030181668A1 US10/063,568 US6356802A US2003181668A1 US 20030181668 A1 US20030181668 A1 US 20030181668A1 US 6356802 A US6356802 A US 6356802A US 2003181668 A1 US2003181668 A1 US 2003181668A1
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US
United States
Prior art keywords
seq
acid sequence
pro
amino acid
alternatively
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/063,568
Inventor
Dan Eaton
Ellen Filvaroff
Mary Gerritsen
Audrey Goddard
Paul Godowski
J. Grimaldi
Austin Gurney
Colin Watanabe
William Wood
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Genentech Inc
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Genentech Inc
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Priority claimed from PCT/US1999/005028 external-priority patent/WO1999046281A2/en
Priority claimed from PCT/US1999/010733 external-priority patent/WO1999060127A2/en
Priority claimed from PCT/US1999/031274 external-priority patent/WO2000053752A2/en
Priority claimed from PCT/US2000/004341 external-priority patent/WO2000053756A2/en
Priority claimed from PCT/US2000/005601 external-priority patent/WO2000056889A2/en
Priority claimed from PCT/US2000/005841 external-priority patent/WO2000053758A2/en
Priority claimed from PCT/US2000/007532 external-priority patent/WO2000070050A1/en
Priority claimed from PCT/US2000/014042 external-priority patent/WO2000077037A2/en
Priority claimed from PCT/US2000/015264 external-priority patent/WO2000073452A2/en
Priority claimed from PCT/US2000/023328 external-priority patent/WO2001016318A2/en
Priority claimed from PCT/US2000/030873 external-priority patent/WO2001040465A2/en
Priority claimed from PCT/US2000/032678 external-priority patent/WO2001040466A2/en
Priority claimed from PCT/US2000/034956 external-priority patent/WO2001046420A2/en
Priority claimed from US09/747,259 external-priority patent/US6569645B2/en
Priority claimed from PCT/US2001/006520 external-priority patent/WO2001068848A2/en
Priority claimed from US09/816,744 external-priority patent/US6579520B2/en
Priority claimed from US09/870,574 external-priority patent/US6551799B2/en
Priority claimed from PCT/US2001/017800 external-priority patent/WO2001093983A1/en
Priority claimed from US09/874,503 external-priority patent/US20020177188A1/en
Priority claimed from US09/908,827 external-priority patent/US20030054442A1/en
Priority claimed from US10/006,867 external-priority patent/US7160985B2/en
Application filed by Genentech Inc filed Critical Genentech Inc
Priority to US10/063,568 priority Critical patent/US20030181668A1/en
Publication of US20030181668A1 publication Critical patent/US20030181668A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
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    • C07—ORGANIC CHEMISTRY
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    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/82—Translation products from oncogenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3023—Lung
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3038—Kidney, bladder
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3046—Stomach, Intestines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3053—Skin, nerves, brain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C—CHEMISTRY; METALLURGY
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    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424—Serine endopeptidases (3.4.21)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P21/00—Preparation of peptides or proteins
    • C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/866—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof involving immunoglobulin or antibody fragment, e.g. fab', fab, fv, fc, heavy chain or light chain

Definitions

  • the present invention relates generally to the identification and isolation of novel DNA and to the recombinant production of novel polypeptides.
  • Extracellular proteins play important roles in, among other things, the formation, differentiation and maintenance of multicellular organisms.
  • secreted polypeptides for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones
  • secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment.
  • Secreted proteins have various industrial applications, including as pharmaceuticals, diagnostics, biosensors and bioreactors.
  • Most protein drugs available at present, such as thrombolytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins.
  • Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents.
  • Efforts are being undertaken by both industry and proficient to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci. 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].
  • Membrane-bound proteins and receptors can play important roles in, among other things, the formation, differentiation and maintenance of multicellular organisms.
  • membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
  • Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents.
  • Receptor immunoadhesins for instance, can be employed as therapeutic agents to block receptor-ligand interactions.
  • the membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction.
  • the invention provides an isolated nucleic acid molecule comprising a nucleotide sequence that encodes a PRO polypeptide.
  • the isolated nucleic acid molecule comprises a nucleotide sequence having at least about 80% nucleic acid sequence identity, alternatively at least about 81% nucleic acid sequence identity, alternatively at least about 82% nucleic acid sequence identity, alternatively at least about 83% nucleic acid sequence identity, alternatively at least about 84% nucleic acid sequence identity, alternatively at least about 85% nucleic acid sequence identity, alternatively at least about 86% nucleic acid sequence identity, alternatively at least about 87% nucleic acid sequence identity, alternatively at least about 88% nucleic acid sequence identity, alternatively at least about 89% nucleic acid sequence identity, alternatively at least about 90% nucleic acid sequence identity, alternatively at least about 91% nucleic acid sequence identity, alternatively at least about 92% nucleic acid sequence identity, alternatively at least about 93% nucleic acid sequence identity, alternatively at least about 94% nucleic acid sequence identity, alternatively at least about 95% nucleic acid sequence identity, alternatively at least about 96% nu
  • the isolated nucleic acid molecule comprises a nucleotide sequence having at least about 80% nucleic acid sequence identity, alternatively at least about 81% nucleic acid sequence identity, alternatively at least about 82% nucleic acid sequence identity, alternatively at least about 83% nucleic acid sequence identity, alternatively at least about 84% nucleic acid sequence identity, alternatively at least about 85% nucleic acid sequence identity, alternatively at least about 86% nucleic acid sequence identity, alternatively at least about 87% nucleic acid sequence identity, alternatively at least about 88% nucleic acid sequence identity, alternatively at least about 89% nucleic acid sequence identity, alternatively at least about 90% nucleic acid sequence identity, alternatively at least about 91% nucleic acid sequence identity, alternatively at least about 92% nucleic acid sequence identity, alternatively at least about 93% nucleic acid sequence identity, alternatively at least about 94% nucleic acid sequence identity, alternatively at least about 95% nucleic acid sequence identity, alternatively at least about 96% nu
  • the invention concerns an isolated nucleic acid molecule comprising a nucleotide sequence having at least about 80% nucleic acid sequence identity, alternatively at least about 81% nucleic acid sequence identity, alternatively at least about 82% nucleic acid sequence identity, alternatively at least about 83% nucleic acid sequence identity, alternatively at least about 84% nucleic acid sequence identity, alternatively at least about 85% nucleic acid sequence identity, alternatively at least about 86% nucleic acid sequence identity, alternatively at least about 87% nucleic acid sequence identity, alternatively at least about 88% nucleic acid sequence identity, alternatively at least about 89% nucleic acid sequence identity, alternatively at least about 90% nucleic acid sequence identity, alternatively at least about 91% nucleic acid sequence identity, alternatively at least about 92% nucleic acid sequence identity, alternatively at least about 93% nucleic acid sequence identity, alternatively at least about 94% nucleic acid sequence identity, alternatively at least about 95% nucleic acid sequence identity, alternatively
  • Another aspect the invention provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding a PRO polypeptide which is either transmembrane domain-deleted or transmembrane domain-inactivated, or is complementary to such encoding nucleotide sequence, wherein the transmembrane domain(s) of such polypeptide are disclosed herein. Therefore, soluble extracellular domains of the herein described PRO polypeptides are contemplated.
  • Another embodiment is directed to fragments of a PRO polypeptide coding sequence, or the complement thereof, that may find use as, for example, hybridization probes, for encoding fragments of a PRO polypeptide that may optionally encode a polypeptide comprising a binding site for an anti-PRO antibody or as antisense oligonucleotide probes.
  • nucleic acid fragments are usually at least about 20 nucleotides in length, alternatively at least about 30 nucleotides in length, alternatively at least about 40 nucleotides in length, alternatively at least about 50 nucleotides in length, alternatively at least about 60 nucleotides in length, alternatively at least about 70 nucleotides in length, alternatively at least about 80 nucleotides in length, alternatively at least about 90 nucleotides in length, alternatively at least about 100 nucleotides in length, alternatively at least about 110 nucleotides in length, alternatively at least about 120 nucleotides in length, alternatively at least about 130 nucleotides in length, alternatively at least about 140 nucleotides in length, alternatively at least about 150 nucleotides in length, alternatively at least about 160 nucleotides in length, alternatively at least about 170 nucleotides in length, alternatively at least about 180 nucleotides in length, alternatively at least about 190 nucle
  • novel fragments of a PRO polypeptide-encoding nucleotide sequence may be determined in a routine manner by aligning the PRO polypeptide-encoding nucleotide sequence with other known nucleotide sequences using any of a number of well known sequence alignment programs and determining which PRO polypeptide-encoding nucleotide sequence fragment(s) are novel. All of such PRO polypeptide-encoding nucleotide sequences are contemplated herein. Also contemplated are the PRO polypeptide fragments encoded by these nucleotide molecule fragments, preferably those PRO polypeptide fragments that comprise a binding site for an anti-PRO antibody.
  • the invention provides isolated PRO polypeptide encoded by any of the isolated nucleic acid sequences hereinabove identified.
  • the invention concerns an isolated PRO polypeptide, comprising an amino acid sequence having at least about 80% amino acid sequence identity, alternatively at least about 81% amino acid sequence identity, alternatively at least about 82% amino acid sequence identity, alternatively at least about 83% amino acid sequence identity, alternatively at least about 84% amino acid sequence identity, alternatively at least about 85% amino acid sequence identity, alternatively at least about 86% amino acid sequence identity, alternatively at least about 87% amino acid sequence identity, alternatively at least about 88% amino acid sequence identity, alternatively at least about 89% amino acid sequence identity, alternatively at least about 90% amino acid sequence identity, alternatively at least about 91% amino acid sequence identity, alternatively at least about 92% amino acid sequence identity, alternatively at least about 93% amino acid sequence identity, alternatively at least about 94% amino acid sequence identity, alternatively at least about 95% amino acid sequence identity, alternatively at least about 96% amino acid sequence identity, alternatively at least about 97% amino acid sequence identity, alternatively at least about 98% amino acid sequence identity and alternatively at
  • the invention concerns an isolated PRO polypeptide comprising an amino acid sequence having at least about 80% amino acid sequence identity, alternatively at least about 81% amino acid sequence identity, alternatively at least about 82% amino acid sequence identity, alternatively at least about 83% amino acid sequence identity, alternatively at least about 84% amino acid sequence identity, alternatively at least about 85% amino acid sequence identity, alternatively at least about 86% amino acid sequence identity, alternatively at least about 87% amino acid sequence identity, alternatively at least about 88% amino acid sequence identity, alternatively at least about 89% amino acid sequence identity, alternatively at least about 90% amino acid sequence identity, alternatively at least about 91% amino acid sequence identity, alternatively at least about 92% amino acid sequence identity, alternatively at least about 93% amino acid sequence identity, alternatively at least about 94% amino acid sequence identity, alternatively at least about 95% amino acid sequence identity, alternatively at least about 96% amino acid sequence identity, alternatively at least about 97% amino acid sequence identity, alternatively at least about 98% amino acid sequence identity and alternatively at least
  • the invention provides an isolated PRO polypeptide without the N-terminal signal sequence and/or the initiating methionine and is encoded by a nucleotide sequence that encodes such an amino acid sequence as hereinbefore described.
  • Processes for producing the same are also herein described, wherein those processes comprise culturing a host cell comprising a vector which comprises the appropriate encoding nucleic acid molecule under conditions suitable for expression of the PRO polypeptide and recovering the PRO polypeptide from the cell culture.
  • Another aspect the invention provides an isolated PRO polypeptide which is either transmembrane domain-deleted or transmembrane domain-inactivated.
  • Processes for producing the same are also herein described, wherein those processes comprise culturing a host cell comprising a vector which comprises the appropriate encoding nucleic acid molecule under conditions suitable for expression of the PRO polypeptide and recovering the PRO polypeptide from the cell culture.
  • the invention concerns agonists and antagonists of a native PRO polypeptide as defined herein.
  • the agonist or antagonist is an anti-PRO antibody or a small molecule.
  • the invention concerns a method of identifying agonists or antagonists to a PRO polypeptide which comprise contacting the PRO polypeptide with a candidate molecule and monitoring a biological activity mediated by said PRO polypeptide.
  • the PRO polypeptide is a native PRO polypeptide.
  • the invention concerns a composition of matter comprising a PRO polypeptide, or an agonist or antagonist of a PRO polypeptide as herein described, or an anti-PRO antibody, in combination with a carrier.
  • the carrier is a pharmaceutically acceptable carrier.
  • Another embodiment of the present invention is directed to the use of a PRO polypeptide, or an agonist or antagonist thereof as hereinbefore described, or an anti-PRO antibody, for the preparation of a medicament useful in the treatment of a condition which is responsive to the PRO polypeptide, an agonist or antagonist thereof or an anti-PRO antibody.
  • the invention provides vectors comprising DNA encoding any of the herein described polypeptides.
  • Host cell comprising any such vector are also provided.
  • the host cells may be CHO cells, E. coli, or yeast.
  • a process for producing any of the herein described polypeptides is further provided and comprises culturing host cells under conditions suitable for expression of the desired polypeptide and recovering the desired polypeptide from the cell culture.
  • the invention provides chimeric molecules comprising any of the herein described polypeptides fused to a heterologous polypeptide or amino acid sequence.
  • Example of such chimeric molecules comprise any of the herein described polypeptides fused to an epitope tag sequence or a Fc region of an immunoglobulin.
  • the invention provides an antibody which binds, preferably specifically, to any of the above or below described polypeptides.
  • the antibody is a monoclonal antibody, humanized antibody, antibody fragment or single-chain antibody.
  • the invention provides oligonucleotide probes useful for isolating genomic and cDNA nucleotide sequences or as antisense probes, wherein those probes may be derived from any of the above or below described nucleotide sequences.
  • the present invention is directed to methods of using the PRO polypeptides of the present invention for a variety of uses based upon the functional biological assay data presented in the Examples below.
  • FIG. 1 shows a nucleotide sequence (SEQ ID NO:1) of a native sequence PRO180 cDNA, wherein SEQ ID NO:1 is a clone designated herein as “DNA26843-1389”.
  • FIG. 2 shows the amino acid sequence (SEQ ID NO:2) derived from the coding sequence of SEQ ID NO:1 shown in FIG. 1.
  • FIG. 3 shows a nucleotide sequence (SEQ ID NO:3) of a native sequence PRO218 cDNA, wherein SEQ ID NO:3 is a clone designated herein as “DNA30867-1335”.
  • FIG. 4 shows the amino acid sequence (SEQ ID NO:4) derived from the coding sequence of SEQ ID NO:3 shown in FIG. 3.
  • FIG. 5 shows a nucleotide sequence (SEQ ID NO:5) of a native sequence PRO263 cDNA, wherein SEQ ID NO:5 is a clone designated herein as “DNA34431-1177”.
  • FIG. 6 shows the amino acid sequence (SEQ ID NO:6) derived from the coding sequence of SEQ ID NO:5 shown in FIG. 5.
  • FIG. 7 shows a nucleotide sequence (SEQ ID NO:7) of a native sequence PRO295 cDNA, wherein SEQ ID NO:7 is a clone designated herein as “DNA38268-1188”.
  • FIG. 8 shows the amino acid sequence (SEQ ID NO:8) derived from the coding sequence of SEQ ID NO:7 shown in FIG. 7.
  • FIG. 9 shows a nucleotide sequence (SEQ ID NO:9) of a native sequence PRO874 cDNA, wherein SEQ ID NO:9 is a clone designated herein as “DNA40621-1440”.
  • FIG. 10 shows the amino acid sequence (SEQ ID NO:10) derived from the coding sequence of SEQ ID NO:9 shown in FIG. 9.
  • FIG. 11 shows a nucleotide sequence (SEQ ID NO:11) of a native sequence PRO300 cDNA, wherein SEQ ID NO:11 is a clone designated herein as “DNA40625-1189”.
  • FIG. 12 shows the amino acid sequence (SEQ ID NO:12) derived from the coding sequence of SEQ ID NO:11 shown in FIG. 11.
  • FIG. 13 shows a nucleotide sequence (SEQ ID NO:13) of a native sequence PRO1864 cDNA, wherein SEQ ID NO:13 is a clone designated herein as “DNA45409-2511”.
  • FIG. 14 shows the amino acid sequence (SEQ ID NO:14) derived from the coding sequence of SEQ ID NO:13 shown in FIG. 13.
  • FIG. 15 shows a nucleotide sequence (SEQ ID NO:15) of a native sequence PRO1282 cDNA, wherein SEQ ID NO:15 is a clone designated herein as “DNA45495-1550”.
  • FIG. 16 shows the amino acid sequence (SEQ ID NO:16) derived from the coding sequence of SEQ ID NO:15 shown in FIG. 15.
  • FIG. 17 shows a nucleotide sequence (SEQ ID NO:17) of a native sequence PRO1063 cDNA, wherein SEQ ID NO:17 is a clone designated herein as “DNA49820-1427”.
  • FIG. 18 shows the amino acid sequence (SEQ ID NO:18) derived from the coding sequence of SEQ ID NO:17 shown in FIG. 17.
  • FIG. 19 shows a nucleotide sequence (SEQ ID NO:19) of a native sequence PRO1773 cDNA, wherein SEQ ID NO:19 is a clone designated herein as “DNA56406-1704”.
  • FIG. 20 shows the amino acid sequence (SEQ ID NO:20) derived from the coding sequence of SEQ ID NO:19 shown in FIG. 19.
  • FIG. 21 shows a nucleotide sequence (SEQ ID NO:21) of a native sequence PRO1013 cDNA, wherein SEQ ID NO:21 is a clone designated herein as “DNA56410-1414”.
  • FIG. 22 shows the amino acid sequence (SEQ ID NO:22) derived from the coding sequence of SEQ ID NO:21 shown in FIG. 21.
  • FIG. 23 shows a nucleotide sequence (SEQ ID NO:23) of a native sequence PRO937 cDNA, wherein SEQ ID NO:23 is a clone designated herein as “DNA56436-1448”.
  • FIG. 24 shows the amino acid sequence (SEQ ID NO:24) derived from the coding sequence of SEQ ID NO:23 shown in FIG. 23.
  • FIG. 25 shows a nucleotide sequence (SEQ ID NO:25) of a native sequence PRO842 cDNA, wherein SEQ ID NO:25 is a clone designated herein as “DNA56855-1447”.
  • FIG. 26 shows the amino acid sequence (SEQ ID NO:26) derived from the coding sequence of SEQ ID NO:25 shown in FIG. 25.
  • FIG. 27 shows a nucleotide sequence (SEQ ID NO:27) of a native sequence PRO1180 cDNA, wherein SEQ ID NO:27 is a clone designated herein as “DNA56860-1510”.
  • FIG. 28 shows the amino acid sequence (SEQ ID NO:28) derived from the coding sequence of SEQ ID NO:27 shown in FIG. 27.
  • FIG. 29 shows a nucleotide sequence (SEQ ID NO:29) of a native sequence PRO831 cDNA, wherein SEQ ID NO:29 is a clone designated herein as “DNA56862-1343”.
  • FIG. 30 shows the amino acid sequence (SEQ ID NO:30) derived from the coding sequence of SEQ ID NO:29 shown in FIG. 29.
  • FIG. 31 shows a nucleotide sequence (SEQ ID NO:31) of a native sequence PRO1115 cDNA, wherein SEQ ID NO:31 is a clone designated herein as “DNA56868-1478”.
  • FIG. 32 shows the amino acid sequence (SEQ ID NO:32) derived from the coding sequence of SEQ ID NO:31 shown in FIG. 31.
  • FIG. 33 shows a nucleotide sequence (SEQ ID NO:33) of a native sequence PRO1277 cDNA, wherein SEQ ID NO:33 is a clone designated herein as “DNA56869-1545”.
  • FIG. 34 shows the amino acid sequence (SEQ ID NO:34) derived from the coding sequence of SEQ ID NO:33 shown in FIG. 33.
  • FIG. 35 shows a nucleotide sequence (SEQ ID NO:35) of a native sequence PRO1074 cDNA, wherein SEQ ID NO:35 is a clone designated herein as “DNA57704-1452”.
  • FIG. 36 shows the amino acid sequence (SEQ ID NO:36) derived from the coding sequence of SEQ ID NO:35 shown in FIG. 35.
  • FIG. 37 shows a nucleotide sequence (SEQ ID NO:37) of a native sequence PRO1344 cDNA, wherein SEQ ID NO:37 is a clone designated herein as “DNA58723-1588”.
  • FIG. 38 shows the amino acid sequence (SEQ ID NO:38) derived from the coding sequence of SEQ ID NO:37 shown in FIG. 37.
  • FIG. 39 shows a nucleotide sequence (SEQ ID NO:39) of a native sequence PRO1136 cDNA, wherein SEQ ID NO:39 is a clone designated herein as “DNA57827-1493”.
  • FIG. 40 shows the amino acid sequence (SEQ ID NO:40) derived from the coding sequence of SEQ ID NO:39 shown in FIG. 39.
  • FIG. 41 shows a nucleotide sequence (SEQ ID NO:41) of a native sequence PRO1109 cDNA, wherein SEQ ID NO:41 is a clone designated herein as “DNA58737-1473”.
  • FIG. 42 shows the amino acid sequence (SEQ ID NO:42) derived from the coding sequence of SEQ ID NO:41 shown in FIG. 41.
  • FIG. 43 shows a nucleotide sequence (SEQ ID NO:43) of a native sequence PRO1003 cDNA, wherein SEQ ID NO:43 is a clone designated herein as “DNA58846-1409”.
  • FIG. 44 shows the amino acid sequence (SEQ ID NO:44) derived from the coding sequence of SEQ ID NO:43 shown in FIG. 43.
  • FIG. 45 shows a nucleotide sequence (SEQ ID NO:45) of a native sequence PRO1138 cDNA, wherein SEQ ID NO:45 is a clone designated herein as “DNA58850-1495”.
  • FIG. 46 shows the amino acid sequence (SEQ ID NO:46) derived from the coding sequence of SEQ ID NO:45 shown in FIG. 45.
  • FIG. 47 shows a nucleotide sequence (SEQ ID NO:47) of a native sequence PRO994 cDNA, wherein SEQ ID NO:47 is a clone designated herein as “DNA58855-1422”.
  • FIG. 48 shows the amino acid sequence (SEQ ID NO:48) derived from the coding sequence of SEQ ID NO:47 shown in FIG. 47.
  • FIG. 49 shows a nucleotide sequence (SEQ ID NO:49) of a native sequence PRO1069 cDNA, wherein SEQ ID NO:49 is a clone designated herein as “DNA59211-1450”.
  • FIG. 50 shows the amino acid sequence (SEQ ID NO:50) derived from the coding sequence of SEQ ID NO:49 shown in FIG. 49.
  • FIG. 51 shows a nucleotide sequence (SEQ ID NO:51) of a native sequence PRO1411 cDNA, wherein SEQ ID NO:51 is a clone designated herein as “DNA59212-1627”.
  • FIG. 52 shows the amino acid sequence (SEQ ID NO:52) derived from the coding sequence of SEQ ID NO:51 shown in FIG. 51.
  • FIG. 53 shows a nucleotide sequence (SEQ ID NO:53) of a native sequence PRO1129 cDNA, wherein SEQ ID NO:53 is a clone designated herein as “DNA59213-1487”.
  • FIG. 54 shows the amino acid sequence (SEQ ID NO:54) derived from the coding sequence of SEQ ID NO:53 shown in FIG. 53.
  • FIG. 55 shows a nucleotide sequence (SEQ ID NO:55) of a native sequence PRO1027 cDNA, wherein SEQ ID NO:55 is a clone designated herein as “DNA59605-1418”.
  • FIG. 56 shows the amino acid sequence (SEQ ID NO:56) derived from the coding sequence of SEQ ID NO:55 shown in FIG. 55.
  • FIG. 57 shows a nucleotide sequence (SEQ ID NO:57) of a native sequence PRO1106 cDNA, wherein SEQ ID NO:57 is a clone designated herein as “DNA59609-1470”.
  • FIG. 58 shows the amino acid sequence (SEQ ID NO:58) derived from the coding sequence of SEQ ID NO:57 shown in FIG. 57.
  • FIG. 59 shows a nucleotide sequence (SEQ ID NO:59) of a native sequence PRO1291 cDNA, wherein SEQ ID NO:59 is a clone designated herein as “DNA59610-1556”.
  • FIG. 60 shows the amino acid sequence (SEQ ID NO:60) derived from the coding sequence of SEQ ID NO:59 shown in FIG. 59.
  • FIG. 61 shows a nucleotide sequence (SEQ ID NO:61) of a native sequence PRO3573 cDNA, wherein SEQ ID NO:61 is a clone designated herein as “DNA59837-2545”.
  • FIG. 62 shows the amino acid sequence (SEQ ID NO:62) derived from the coding sequence of SEQ ID NO:61 shown in FIG. 61.
  • FIG. 63 shows a nucleotide sequence (SEQ ID NO:63) of a native sequence PRO3566 cDNA, wherein SEQ ID NO:63 is a clone designated herein as “DNA59844-2542”.
  • FIG. 64 shows the amino acid sequence (SEQ ID NO:64) derived from the coding sequence of SEQ ID NO:63 shown in FIG. 63.
  • FIG. 65 shows a nucleotide sequence (SEQ ID NO:65) of a native sequence PRO1098 cDNA, wherein SEQ ID NO:65 is a clone designated herein as “DNA59854-1459”.
  • FIG. 66 shows the amino acid sequence (SEQ ID NO:66) derived from the coding sequence of SEQ ID NO:65 shown in FIG. 65.
  • FIG. 67 shows a nucleotide sequence (SEQ ID NO:67) of a native sequence PRO1158 cDNA, wherein SEQ ID NO:67 is a clone designated herein as “DNA60625-1507”.
  • FIG. 68 shows the amino acid sequence (SEQ ID NO:68) derived from the coding sequence of SEQ ID NO:67 shown in FIG. 67.
  • FIG. 69 shows a nucleotide sequence (SEQ ID NO:69) of a native sequence PRO1124 cDNA, wherein SEQ ID NO:69 is a clone designated herein as “DNA60629-1481”.
  • FIG. 70 shows the amino acid sequence (SEQ ID NO:70) derived from the coding sequence of SEQ ID NO:69 shown in FIG. 69.
  • FIG. 71 shows a nucleotide sequence (SEQ ID NO:71) of a native sequence PRO1287 cDNA, wherein SEQ ID NO:71 is a clone designated herein as “DNA61755-1554”.
  • FIG. 72 shows the amino acid sequence (SEQ ID NO:72) derived from the coding sequence of SEQ ID NO:71 shown in FIG. 71.
  • FIG. 73 shows a nucleotide sequence (SEQ ID NO:73) of a native sequence PRO1335 cDNA, wherein SEQ ID NO:73 is a clone designated herein as “DNA62812-1594”.
  • FIG. 74 shows the amino acid sequence (SEQ ID NO:74) derived from the coding sequence of SEQ ID NO:73 shown in FIG. 73.
  • FIG. 75 shows a nucleotide sequence (SEQ ID NO:75) of a native sequence PRO1315 cDNA, wherein SEQ ID NO:75 is a clone designated herein as “DNA62815-1576”.
  • FIG. 76 shows the amino acid sequence (SEQ ID NO:76) derived from the coding sequence of SEQ ID NO:75 shown in FIG. 75.
  • FIG. 77 shows a nucleotide sequence (SEQ ID NO:77) of a native sequence PRO1357 cDNA, wherein SEQ ID NO:77 is a clone designated herein as “DNA64881-1602”.
  • FIG. 78 shows the amino acid sequence (SEQ ID NO:78) derived from the coding sequence of SEQ ID NO:77 shown in FIG. 77.
  • FIG. 79 shows a nucleotide sequence (SEQ ID NO:79) of a native sequence PRO1356 cDNA, wherein SEQ ID NO:79 is a clone designated herein as “DNA64886-1601”.
  • FIG. 80 shows the amino acid sequence (SEQ ID NO:80) derived from the coding sequence of SEQ ID NO:79 shown in FIG. 79.
  • FIG. 81 shows a nucleotide sequence (SEQ ID NO:81) of a native sequence PRO1557 cDNA, wherein SEQ ID NO:81 is a clone designated herein as “DNA64902-1667”.
  • FIG. 82 shows the amino acid sequence (SEQ ID NO:82) derived from the coding sequence of SEQ ID NO:81 shown in FIG. 81.
  • FIG. 83 shows a nucleotide sequence (SEQ ID NO:83) of a native sequence PRO1347 cDNA, wherein SEQ ID NO:83 is a clone designated herein as “DNA64950-1590”.
  • FIG. 84 shows the amino acid sequence (SEQ ID NO:84) derived from the coding sequence of SEQ ID NO:83 shown in FIG. 83.
  • FIG. 85 shows a nucleotide sequence (SEQ ID NO:85) of a native sequence PRO1302 cDNA, wherein SEQ ID NO:85 is a clone designated herein as “DNA65403-1565”.
  • FIG. 86 shows the amino acid sequence (SEQ ID NO:86) derived from the coding sequence of SEQ ID NO:85 shown in FIG. 85.
  • FIG. 87 shows a nucleotide sequence (SEQ ID NO:87) of a native sequence PRO1270 cDNA, wherein SEQ ID NO:87 is a clone designated herein as “DNA66308-1537”.
  • FIG. 88 shows the amino acid sequence (SEQ ID NO:88) derived from the coding sequence of SEQ ID NO:87 shown in FIG. 87.
  • FIG. 89 shows a nucleotide sequence (SEQ ID NO:89) of a native sequence PRO1268 cDNA, wherein SEQ ID NO:89 is a clone designated herein as “DNA66519-1535”.
  • FIG. 90 shows the amino acid sequence (SEQ ID NO:90) derived from the coding sequence of SEQ ID NO:89 shown in FIG. 89.
  • FIG. 91 shows a nucleotide sequence (SEQ ID NO:91) of a native sequence PRO1327 cDNA, wherein SEQ ID NO:91 is a clone designated herein as “DNA66521-1583”.
  • FIG. 92 shows the amino acid sequence (SEQ ID NO:92) derived from the coding sequence of SEQ ID NO:91 shown in FIG. 91.
  • FIG. 93 shows a nucleotide sequence (SEQ ID NO:93) of a native sequence PRO1328 cDNA, wherein SEQ ID NO:93 is a clone designated herein as “DNA66658-1584”.
  • FIG. 94 shows the amino acid sequence (SEQ ID NO:94) derived from the coding sequence of SEQ ID NO:93 shown in FIG. 93.
  • FIG. 95 shows a nucleotide sequence (SEQ ID NO:95) of a native sequence PRO1329 cDNA, wherein SEQ ID NO:95 is a clone designated herein as “DNA66660-1585”.
  • FIG. 96 shows the amino acid sequence (SEQ ID NO:96) derived from the coding sequence of SEQ ID NO:95 shown in FIG. 95.
  • FIG. 97 shows a nucleotide sequence (SEQ ID NO:97) of a native sequence PRO1340 cDNA, wherein SEQ ID NO:97 is a clone designated herein as “DNA66663-1598”.
  • FIG. 98 shows the amino acid sequence (SEQ ID NO:98) derived from the coding sequence of SEQ ID NO:97 shown in FIG. 97.
  • FIG. 99 shows a nucleotide sequence (SEQ ID NO:99) of a native sequence PRO1342 cDNA, wherein SEQ ID NO:99 is a clone designated herein as “DNA66674-1599”.
  • FIG. 100 shows the amino acid sequence (SEQ ID NO:100) derived from the coding sequence of SEQ ID NO:99 shown in FIG. 99.
  • FIG. 101 shows a nucleotide sequence (SEQ ID NO:101) of a native sequence PRO3579 cDNA, wherein SEQ ID NO:101 is a clone designated herein as “DNA68862-2546”.
  • FIG. 102 shows the amino acid sequence (SEQ ID NO:102) derived from the coding sequence of SEQ ID NO:101 shown in FIG. 101.
  • FIG. 103 shows a nucleotide sequence (SEQ ID NO:103) of a native sequence PRO1472 cDNA, wherein SEQ ID NO:103 is a clone designated herein as “DNA68866-1644”.
  • FIG. 104 shows the amino acid sequence (SEQ ID NO:104) derived from the coding sequence of SEQ ID NO:103 shown in FIG. 103.
  • FIG. 105 shows a nucleotide sequence (SEQ ID NO:105) of a native sequence PRO1461 cDNA, wherein SEQ ID NO:105 is a clone designated herein as “DNA68871-1638”.
  • FIG. 106 shows the amino acid sequence (SEQ ID NO:106) derived from the coding sequence of SEQ ID NO:105 shown in FIG. 105.
  • FIG. 107 shows a nucleotide sequence (SEQ ID NO:107) of a native sequence PRO1568 cDNA, wherein SEQ ID NO:107 is a clone designated herein as “DNA68880-1676”.
  • FIG. 108 shows the amino acid sequence (SEQ ID NO:108) derived from the coding sequence of SEQ ID NO:107 shown in FIG. 107.
  • FIG. 109 shows a nucleotide sequence (SEQ ID NO:109) of a native sequence PRO1753 cDNA, wherein SEQ ID NO:109 is a clone designated herein as “DNA68883-1691”.
  • FIG. 110 shows the amino acid sequence (SEQ ID NO:110) derived from the coding sequence of SEQ ID NO:109 shown in FIG. 109.
  • FIG. 111 shows a nucleotide sequence (SEQ ID NO:111) of a native sequence PRO1570 cDNA, wherein SEQ ID NO:111 is a clone designated herein as “DNA68885-1678”.
  • FIG. 112 shows the amino acid sequence (SEQ ID NO:112) derived from the coding sequence of SEQ ID NO:111 shown in FIG. 111.
  • FIG. 113 shows a nucleotide sequence (SEQ ID NO:113) of a native sequence PRO1446 cDNA, wherein SEQ ID NO:113 is a clone designated herein as “DNA71277-1636”.
  • FIG. 114 shows the amino acid sequence (SEQ ID NO:114) derived from the coding sequence of SEQ ID NO:113 shown in FIG. 113.
  • FIG. 115 shows a nucleotide sequence (SEQ ID NO:115) of a native sequence PRO1565 cDNA, wherein SEQ ID NO:115 is a clone designated herein as “DNA73727-1673”.
  • FIG. 116 shows the amino acid sequence (SEQ ID NO:116) derived from the coding sequence of SEQ ID NO:115 shown in FIG. 115.
  • FIG. 117 shows a nucleotide sequence (SEQ ID NO:117) of a native sequence PRO1572 cDNA, wherein SEQ ID NO:117 is a clone designated herein as “DNA73734-1680”.
  • FIG. 118 shows the amino acid sequence (SEQ ID NO:118) derived from the coding sequence of SEQ ID NO:117 shown in FIG. 117.
  • FIG. 119 shows a nucleotide sequence (SEQ ID NO:119) of a native sequence PRO1573 cDNA, wherein SEQ ID NO:119 is a clone designated herein as “DNA73735-1681”.
  • FIG. 120 shows the amino acid sequence (SEQ ID NO:120) derived from the coding sequence of SEQ ID NO:119 shown in FIG. 119.
  • FIG. 121 shows a nucleotide sequence (SEQ ID NO:121) of a native sequence PRO1550 cDNA, wherein SEQ ID NO:121 is a clone designated herein as “DNA76393-1664”.
  • FIG. 122 shows the amino acid sequence (SEQ ID NO:122) derived from the coding sequence of SEQ ID NO:121 shown in FIG. 121.
  • FIG. 123 shows a nucleotide sequence (SEQ ID NO:123) of a native sequence PRO1693 cDNA, wherein SEQ ID NO:123 is a clone designated herein as “DNA77301-1708”.
  • FIG. 124 shows the amino acid sequence (SEQ ID NO:124) derived from the coding sequence of SEQ ID NO:123 shown in FIG. 123.
  • FIG. 125 shows a nucleotide sequence (SEQ ID NO:125) of a native sequence PRO1566 cDNA, wherein SEQ ID NO:125 is a clone designated herein as “DNA77568-1626”.
  • FIG. 126 shows the amino acid sequence (SEQ ID NO:126) derived from the coding sequence of SEQ ID NO:125 shown in FIG. 125.
  • FIG. 127 shows a nucleotide sequence (SEQ ID NO:127) of a native sequence PRO1774 cDNA, wherein SEQ ID NO:127 is a clone designated herein as “DNA77626-1705”.
  • FIG. 128 shows the amino acid sequence (SEQ ID NO:128) derived from the coding sequence of SEQ ID NO:127 shown in FIG. 127.
  • FIG. 129 shows a nucleotide sequence (SEQ ID NO:129) of a native sequence PRO1928 cDNA, wherein SEQ ID NO:129 is a clone designated herein as “DNA81754-2532”.
  • FIG. 130 shows the amino acid sequence (SEQ ID NO:130) derived from the coding sequence of SEQ ID NO:129 shown in FIG. 129.
  • FIG. 131 shows a nucleotide sequence (SEQ ID NO:131) of a native sequence PRO1865 cDNA, wherein SEQ ID NO:131 is a clone designated herein as “DNA81757-2512”.
  • FIG. 132 shows the amino acid sequence (SEQ ID NO:132) derived from the coding sequence of SEQ ID NO:131 shown in FIG. 131.
  • FIG. 133 shows a nucleotide sequence (SEQ ID NO:133) of a native sequence PRO1925 cDNA, wherein SEQ ID NO:133 is a clone designated herein as “DNA82302-2529”.
  • FIG. 134 shows the amino acid sequence (SEQ ID NO:134) derived from the coding sequence of SEQ ID NO:133 shown in FIG. 133.
  • FIG. 135 shows a nucleotide sequence (SEQ ID NO:135) of a native sequence PRO1926 cDNA, wherein SEQ ID NO:135 is a clone designated herein as “DNA82340-2530”.
  • FIG. 136 shows the amino acid sequence (SEQ ID NO:136) derived from the coding sequence of SEQ ID NO:135 shown in FIG. 135.
  • FIG. 137 shows a nucleotide sequence (SEQ ID NO:137) of a native sequence PRO1801 cDNA, wherein SEQ ID NO:137 is a clone designated herein as “DNA83500-2506”.
  • FIG. 138 shows the amino acid sequence (SEQ ID NO:138) derived from the coding sequence of SEQ ID NO:137 shown in FIG. 137.
  • FIG. 139 shows a nucleotide sequence (SEQ ID NO:139) of a native sequence PRO4405 cDNA, wherein SEQ ID NO:139 is a clone designated herein as “DNA84920-2614”.
  • FIG. 140 shows the amino acid sequence (SEQ ID NO:140) derived from the coding sequence of SEQ ID NO:139 shown in FIG. 139.
  • FIG. 141 shows a nucleotide sequence (SEQ ID NO:141) of a native sequence PRO3435 cDNA, wherein SEQ ID NO:141 is a clone designated herein as “DNA85066-2534”.
  • FIG. 142 shows the amino acid sequence (SEQ ID NO:142) derived from the coding sequence of SEQ ID NO:141 shown in FIG. 141.
  • FIG. 143 shows a nucleotide sequence (SEQ ID NO:143) of a native sequence PRO3543 cDNA, wherein SEQ ID NO:143 is a clone designated herein as “DNA86571-2551”.
  • FIG. 144 shows the amino acid sequence (SEQ ID NO:144) derived from the coding sequence of SEQ ID NO:143 shown in FIG. 143.
  • FIG. 145 shows a nucleotide sequence (SEQ ID NO:145) of a native sequence PRO3443 cDNA, wherein SEQ ID NO:145 is a clone designated herein as “DNA87991-2540”.
  • FIG. 146 shows the amino acid sequence (SEQ ID NO:146) derived from the coding sequence of SEQ ID NO:145 shown in FIG. 145.
  • FIG. 147 shows a nucleotide sequence (SEQ ID NO:147) of a native sequence PRO3442 cDNA, wherein SEQ ID NO:147 is a clone designated herein as “DNA92238-2539”.
  • FIG. 148 shows the amino acid sequence (SEQ ID NO:148) derived from the coding sequence of SEQ ID NO:147 shown in FIG. 147.
  • FIG. 149 shows a nucleotide sequence (SEQ ID NO:149) of a native sequence PRO5990 cDNA, wherein SEQ ID NO:149 is a clone designated herein as “DNA96042-2682”.
  • FIG. 150 shows the amino acid sequence (SEQ ID NO:150) derived from the coding sequence of SEQ ID NO:149 shown in FIG. 149.
  • FIG. 151 shows a nucleotide sequence (SEQ ID NO:151) of a native sequence PRO4342 cDNA, wherein SEQ ID NO:151 is a clone designated herein as “DNA96787-2534”.
  • FIG. 152 shows the amino acid sequence (SEQ ID NO:152) derived from the coding sequence of SEQ ID NO:151 shown in FIG. 151.
  • FIG. 153 shows a nucleotide sequence (SEQ ID NO:153) of a native sequence PRO10096 cDNA, wherein SEQ ID NO:153 is a clone designated herein as “DNA125185-2806”.
  • FIG. 154 shows the amino acid sequence (SEQ ID NO:154) derived from the coding sequence of SEQ ID NO:153 shown in FIG. 153.
  • FIG. 155 shows a nucleotide sequence (SEQ ID NO:155) of a native sequence PRO10272 cDNA, wherein SEQ ID NO:155 is a clone designated herein as “DNA147531-2821”.
  • FIG. 156 shows the amino acid sequence (SEQ ID NO:156) derived from the coding sequence of SEQ ID NO:155 shown in FIG. 155.
  • FIG. 157 shows a nucleotide sequence (SEQ ID NO:157) of a native sequence PRO5801 cDNA, wherein SEQ ID NO:157 is a clone designated herein as “DNA115291-2681”.
  • FIG. 158 shows the amino acid sequence (SEQ ID NO:158) derived from the coding sequence of SEQ ID NO:157 shown in FIG. 157.
  • FIG. 159 shows a nucleotide sequence (SEQ ID NO:159) of a native sequence PRO20110 cDNA, wherein SEQ ID NO:159 is a clone designated herein as “DNA166819”.
  • FIG. 160 shows the amino acid sequence (SEQ ID NO:160) derived from the coding sequence of SEQ ID NO:159 shown in FIG. 159.
  • FIG. 161 shows a nucleotide sequence (SEQ ID NO:161) of a native sequence PRO20040 cDNA, wherein SEQ ID NO:161 is a clone designated herein as “DNA164625-2890”.
  • FIG. 162 shows the amino acid sequence (SEQ ID NO:162) derived from the coding sequence of SEQ ID NO:161 shown in FIG. 161.
  • FIG. 163 shows a nucleotide sequence (SEQ ID NO:163) of a native sequence PRO20233 cDNA, wherein SEQ ID NO:163 is a clone designated herein as “DNA165608”.
  • FIG. 164 shows the amino acid sequence (SEQ ID NO:164) derived from the coding sequence of SEQ ID NO:163 shown in FIG. 163.
  • FIG. 165 shows a nucleotide sequence (SEQ ID NO:165) of a native sequence PRO19670 cDNA, wherein SEQ ID NO:165 is a clone designated herein as “DNA131639-2874”.
  • FIG. 166 shows the amino acid sequence (SEQ ID NO:166) derived from the coding sequence of SEQ ID NO:165 shown in FIG. 165.
  • FIG. 167 shows a nucleotide sequence (SEQ ID NO:167) of a native sequence PRO1890 cDNA, wherein SEQ ID NO:167 is a clone designated herein as “DNA79230-2525”.
  • FIG. 168 shows the amino acid sequence (SEQ ID NO:168) derived from the coding sequence of SEQ ID NO:167 shown in FIG. 167.
  • PRO polypeptide and “PRO” as used herein and when immediately followed by a numerical designation refer to various polypeptides, wherein the complete designation (i.e., PRO/number) refers to specific polypeptide sequences as described herein.
  • the terms “PRO/number polypeptide” and “PRO/number” wherein the term “number” is provided as an actual numerical designation as used herein encompass native sequence polypeptides and polypeptide variants (which are further defined herein).
  • the PRO polypeptides described herein may be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods.
  • PRO polypeptide refers to each individual PRO/number polypeptide disclosed herein.
  • PRO polypeptide refers to each of the polypeptides individually as well as jointly. For example, descriptions of the preparation of, purification of, derivation of, formation of antibodies to or against, administration of, compositions containing, treatment of a disease with, etc., pertain to each polypeptide of the invention individually.
  • the term “PRO polypeptide” also includes variants of the PRO/number polypeptides disclosed herein.
  • a “native sequence PRO polypeptide” comprises a polypeptide having the same amino acid sequence as the corresponding PRO polypeptide derived from nature. Such native sequence PRO polypeptides can be isolated from nature or can be produced by recombinant or synthetic means.
  • the term “native sequence PRO polypeptide” specifically encompasses naturally-occurring truncated or secreted forms of the specific PRO polypeptide (e.g., an extracellular domain sequence), naturally-occurring variant forms (e.g., alternatively spliced forms) and naturally-occurring allelic variants of the polypeptide.
  • the native sequence PRO polypeptides disclosed herein are mature or full-length native sequence polypeptides comprising the full-length amino acids sequences shown in the accompanying figures. Start and stop codons are shown in bold font and underlined in the figures. However, while the PRO polypeptide disclosed in the accompanying figures are shown to begin with methionine residues designated herein as amino acid position 1 in the figures, it is conceivable and possible that other methionine residues located either upstream or downstream from the amino acid position 1 in the figures may be employed as the starting amino acid residue for the PRO polypeptides.
  • the PRO polypeptide “extracellular domain” or “ECD” refers to a form of the PRO polypeptide which is essentially free of the transmembrane and cytoplasmic domains. Ordinarily, a PRO polypeptide ECD will have less than 1% of such transmembrane and/or cytoplasmic domains and preferably, will have less than 0.5% of such domains. It will be understood that any transmembrane domains identified for the PRO polypeptides of the present invention are identified pursuant to criteria routinely employed in the art for identifying that type of hydrophobic domain. The exact boundaries of a transmembrane domain may vary but most likely by no more than about 5 amino acids at either end of the domain as initially identified herein.
  • an extracellular domain of a PRO polypeptide may contain from about 5 or fewer amino acids on either side of the transmembrane domain/extracellular domain boundary as identified in the Examples or specification and such polypeptides, with or without the associated signal peptide, and nucleic acid encoding them, are comtemplated by the present invention.
  • cleavage of a signal sequence from a secreted polypeptide is not entirely uniform, resulting in more than one secreted species.
  • These mature polypeptides, where the signal peptide is cleaved within no more than about 5 amino acids on either side of the C-terminal boundary of the signal peptide as identified herein, and the polynucleotides encoding them, are contemplated by the present invention.
  • PRO polypeptide variant means an active PRO polypeptide as defined above or below having at least about 80% amino acid sequence identity with a full-length native sequence PRO polypeptide sequence as disclosed herein, a PRO polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO polypeptide, with or without the signal peptide, as disclosed herein or any other fragment of a full-length PRO polypeptide sequence as disclosed herein.
  • Such PRO polypeptide variants include, for instance, PRO polypeptides wherein one or more amino acid residues are added, or deleted, at the N- or C-terminus of the full-length native amino acid sequence.
  • a PRO polypeptide variant will have at least about 80% amino acid sequence identity, alternatively at least about 81% amino acid sequence identity, alternatively at least about 82% amino acid sequence identity, alternatively at least about 83% amino acid sequence identity, alternatively at least about 84% amino acid sequence identity, alternatively at least about 85% amino acid sequence identity, alternatively at least about 86% amino acid sequence identity, alternatively at least about 87% amino acid sequence identity, alternatively at least about 88% amino acid sequence identity, alternatively at least about 89% amino acid sequence identity, alternatively at least about 90% amino acid sequence identity, alternatively at least about 91% amino acid sequence identity, alternatively at least about 92% amino acid sequence identity, alternatively at least about 93% amino acid sequence identity, alternatively at least about 94% amino acid sequence identity, alternatively at least about 95% amino acid sequence identity, alternatively at least about 96% amino acid sequence identity, alternatively at least about 97% amino acid sequence identity, alternatively at least about 98% amino acid sequence identity and alternatively at least about 99% amino acid sequence identity to a full-length
  • PRO variant polypeptides are at least about 10 amino acids in length, alternatively at least about 20 amino acids in length, alternatively at least about 30 amino acids in length, alternatively at least about 40 amino acids in length, alternatively at least about 50 amino acids in length, alternatively at least about 60 amino acids in length, alternatively at least about 70 amino acids in length, alternatively at least about 80 amino acids in length, alternatively at least about 90 amino acids in length, alternatively at least about 100 amino acids in length, alternatively at least about 150 amino acids in length, alternatively at least about 200 amino acids in length, alternatively at least about 300 amino acids in length, or more.
  • Percent (%) amino acid sequence identity with respect to the PRO polypeptide sequences identified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific PRO polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2, wherein the complete source code for the ALIGN-2 program is provided in Table 1 below.
  • the ALIGN-2 sequence comparison computer program was authored by Genentech, Inc. and the source code shown in Table 1 below has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087.
  • the ALIGN-2 program is publicly available through Genentech, Inc., South San Francisco, Calif. or may be compiled from the source code provided in Table 1 below.
  • the ALIGN-2 program should be compiled for use on a UNIX operating system, preferably digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.
  • % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows:
  • Tables 2 and 3 demonstrate how to calculate the % amino acid sequence identity of the amino acid sequence designated “Comparison Protein” to the amino acid sequence designated “PRO”, wherein “PRO” represents the amino acid sequence of a hypothetical PRO polypeptide of interest, “Comparison Protein” represents the amino acid sequence of a polypeptide against which the “PRO” polypeptide of interest is being compared, and “X”, “Y” and “Z” each represent different hypothetical amino acid residues.
  • a % amino acid sequence identity value is determined by dividing (a) the number of matching identical amino acid residues between the amino acid sequence of the PRO polypeptide of interest having a sequence derived from the native PRO polypeptide and the comparison amino acid sequence of interest (i.e., the sequence against which the PRO polypeptide of interest is being compared which may be a PRO variant polypeptide) as determined by WU-BLAST-2 by (b) the total number of amino acid residues of the PRO polypeptide of interest.
  • amino acid sequence A is the comparison amino acid sequence of interest and the amino acid sequence B is the amino acid sequence of the PRO polypeptide of interest.
  • Percent amino acid sequence identity may also be determined using the sequence comparison program NCBI-BLAST2 (Altschul et al., Nucleic Acids Res. 25:3389-3402 (1997)).
  • NCBI-BLAST2 sequence comparison program may be downloaded from http://www.ncbi.nlm.nih.gov or otherwise obtained from the National Institute of Health, Bethesda, Md.
  • % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows:
  • PRO variant polynucleotide or “PRO variant nucleic acid sequence” means a nucleic acid molecule which encodes an active PRO polypeptide as defined below and which has at least about 80% nucleic acid sequence identity with a nucleotide acid sequence encoding a full-length native sequence PRO polypeptide sequence as disclosed herein, a full-length native sequence PRO polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO polypeptide, with or without the signal peptide, as disclosed herein or any other fragment of a full-length PRO polypeptide sequence as disclosed herein.
  • a PRO variant polynucleotide will have at least about 80% nucleic acid sequence identity, alternatively at least about 81% nucleic acid sequence identity, alternatively at least about 82% nucleic acid sequence identity, alternatively at least about 83% nucleic acid sequence identity, alternatively at least about 84% nucleic acid sequence identity, alternatively at least about 85% nucleic acid sequence identity, alternatively at least about 86% nucleic acid sequence identity, alternatively at least about 87% nucleic acid sequence identity, alternatively at least about 88% nucleic acid sequence identity, alternatively at least about 89% nucleic acid sequence identity, alternatively at least about 90% nucleic acid sequence identity, alternatively at least about 91% nucleic acid sequence identity, alternatively at least about 92% nucleic acid sequence identity, alternatively at least about 93% nucleic acid sequence identity, alternatively at least about 94% nucleic acid sequence identity, alternatively at least about 95% nucleic acid sequence identity, alternatively at least about 96% nucleic acid sequence identity, alternatively at least about 9
  • PRO variant polynucleotides are at least about 30 nucleotides in length, alternatively at least about 60 nucleotides in length, alternatively at least about 90 nucleotides in length, alternatively at least about 120 nucleotides in length, alternatively at least about 150 nucleotides in length, alternatively at least about 180 nucleotides in length, alternatively at least about 210 nucleotides in length, alternatively at least about 240 nucleotides in length, alternatively at least about 270 nucleotides in length, alternatively at least about 300 nucleotides in length, alternatively at least about 450 nucleotides in length, alternatively at least about 600 nucleotides in length, alternatively at least about 900 nucleotides in length, or more.
  • Percent (%) nucleic acid sequence identity with respect to PRO-encoding nucleic acid sequences identified herein is defined as the percentage of nucleotides in a candidate sequence that are identical with the nucleotides in the PRO nucleic acid sequence of interest, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software.
  • % nucleic acid sequence identity values are generated using the sequence comparison computer program ALIGN-2, wherein the complete source code for the ALIGN-2 program is provided in Table 1 below.
  • the ALIGN-2 sequence comparison computer program was authored by Genentech, Inc. and the source code shown in Table 1 below has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087.
  • the ALIGN-2 program is publicly available through Genentech, Inc., South San Francisco, Calif. or may be compiled from the source code provided in Table 1 below.
  • the ALIGN-2 program should be compiled for use on a UNIX operating system, preferably digital UNIX V4.OD. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.
  • the % nucleic acid sequence identity of a given nucleic acid sequence C to, with, or against a given nucleic acid sequence D is calculated as follows:
  • W is the number of nucleotides scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of C and D
  • Z is the total number of nucleotides in D. It will be appreciated that where the length of nucleic acid sequence C is not equal to the length of nucleic acid sequence D, the % nucleic acid sequence identity of C to D will not equal the % nucleic acid sequence identity of D to C.
  • Tables 4 and 5 demonstrate how to calculate the % nucleic acid sequence identity of the nucleic acid sequence designated “Comparison DNA” to the nucleic acid sequence designated “PRO-DNA”, wherein “PRO-DNA” represents a hypothetical PRO-encoding nucleic acid sequence of interest, “Comparison DNA” represents the nucleotide sequence of a nucleic acid molecule against which the “PRO-DNA” nucleic acid molecule of interest is being compared, and “N”, “L” and “V” each represent different hypothetical nucleotides.
  • a % nucleic acid sequence identity value is determined by dividing (a) the number of matching identical nucleotides between the nucleic acid sequence of the PRO polypeptide-encoding nucleic acid molecule of interest having a sequence derived from the native sequence PRO polypeptide-encoding nucleic acid and the comparison nucleic acid molecule of interest (i.e., the sequence against which the PRO polypeptide-encoding nucleic acid molecule of interest is being compared which may be a variant PRO polynucleotide) as determined by WU-BLAST-2 by (b) the total number of nucleotides of the PRO polypeptide-encoding nucleic acid molecule of interest.
  • nucleic acid sequence A is the comparison nucleic acid molecule of interest and the nucleic acid sequence B is the nucleic acid sequence of the PRO polypeptide-encoding nucleic acid molecule of interest.
  • Percent nucleic acid sequence identity may also be determined using the sequence comparison program NCBI-BLAST2 (Altschul et al., Nucleic Acids Res. 25:3389-3402 (1997)).
  • NCBI-BLAST2 sequence comparison program may be downloaded from http://www.ncbi.nlm.nih.gov or otherwise obtained from the National Institute of Health, Bethesda, Md.
  • % nucleic acid sequence identity of a given nucleic acid sequence C to, with, or against a given nucleic acid sequence D is calculated as follows:
  • W is the number of nucleotides scored as identical matches by the sequence alignment program NCBI-BLAST2 in that program's alignment of C and D
  • Z is the total number of nucleotides in D. It will be appreciated that where the length of nucleic acid sequence C is not equal to the length of nucleic acid sequence D, the % nucleic acid sequence identity of C to D will not equal the % nucleic acid sequence identity of D to C.
  • PRO variant polynucleotides are nucleic acid molecules that encode an active PRO polypeptide and which are capable of hybridizing, preferably under stringent hybridization and wash conditions, to nucleotide sequences encoding a full-length PRO polypeptide as disclosed herein.
  • PRO variant polypeptides may be those that are encoded by a PRO variant polynucleotide.
  • Isolated when used to describe the various polypeptides disclosed herein, means polypeptide that has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes.
  • the polypeptide will be purified (1) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain.
  • Isolated polypeptide includes polypeptide in situ within recombinant cells, since at least one component of the PRO polypeptide natural environment will not be present. Ordinarily, however, isolated polypeptide will be prepared by at least one purification step.
  • An “isolated” PRO polypeptide-encoding nucleic acid or other polypeptide-encoding nucleic acid is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the natural source of the polypeptide-encoding nucleic acid.
  • An isolated polypeptide-encoding nucleic acid molecule is other than in the form or setting in which it is found in nature. Isolated polypeptide-encoding nucleic acid molecules therefore are distinguished from the specific polypeptide-encoding nucleic acid molecule as it exists in natural cells.
  • an isolated polypeptide-encoding nucleic acid molecule includes polypeptide-encoding nucleic acid molecules contained in cells that ordinarily express the polypeptide where, for example, the nucleic acid molecule is in a chromosomal location different from that of natural cells.
  • control sequences refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism.
  • the control sequences that are suitable for prokaryotes include a promoter, optionally an operator sequence, and a ribosome binding site.
  • Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.
  • Nucleic acid is “operably linked” when it is placed into a functional relationship with another nucleic acid sequence.
  • DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide;
  • a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or
  • a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation.
  • “operably linked” means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.
  • antibody is used in the broadest sense and specifically covers, for example, single anti-PRO monoclonal antibodies (including agonist, antagonist, and neutralizing antibodies), anti-PRO antibody compositions with polyepitopic specificity, single chain anti-PRO antibodies, and fragments of anti-PRO antibodies (see below).
  • monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts.
  • “Stringency” of hybridization reactions is readily determinable by one of ordinary skill in the art, and generally is an empirical calculation dependent upon probe length, washing temperature, and salt concentration. In general, longer probes require higher temperatures for proper annealing, while shorter probes need lower temperatures. Hybridization generally depends on the ability of denatured DNA to reanneal when complementary strands are present in an environment below their melting temperature. The higher the degree of desired homology between the probe and hybridizable sequence, the higher the relative temperature which can be used. As a result, it follows that higher relative temperatures would tend to make the reaction conditions more stringent, while lower temperatures less so. For additional details and explanation of stringency of hybridization reactions, see Ausubel et al., Current Protocols in Molecular Biology, Wiley lnterscience Publishers, (1995).
  • “Stringent conditions” or “high stringency condition”, as defined herein, may be identified by those that: (1) employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50° C.; (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42° C.; or (3) employ 50% formamide, 5 ⁇ SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5 ⁇ Denhardt's solution, sonicated salmon sperm DNA (50 ⁇ g/ml), 0.1% SDS, and 10% dex
  • Modely stringent conditions may be identified as described by Sambrook et al., Molecular Cloning: A Laboratory Manual, New York: Cold Spring Harbor Press, 1989, and include the use of washing solution and hybridization conditions (e.g., temperature, ionic strength and % SDS) less stringent that those described above.
  • washing solution and hybridization conditions e.g., temperature, ionic strength and % SDS
  • An example of moderately stringent conditions is overnight incubation at 37° C.
  • epitope tagged when used herein refers to a chimeric polypeptide comprising a PRO polypeptide fused to a “tag polypeptide”.
  • the tag polypeptide has enough residues to provide an epitope against which an antibody can be made, yet is short enough such that it does not interfere with activity of the polypeptide to which it is fused.
  • the tag polypeptide preferably also is fairly unique so that the antibody does not substantially cross-react with other epitopes.
  • Suitable tag polypeptides generally have at least six amino acid residues and usually between about 8 and 50 amino acid residues (preferably, between about 10 and 20 amino acid residues).
  • immunoadhesin designates antibody-like molecules which combine the binding specificity of a heterologous protein (an “adhesin”) with the effector functions of immunoglobulin constant domains.
  • the immunoadhesins comprise a fusion of an amino acid sequence with the desired binding specificity which is other than the antigen recognition and binding site of an antibody (i.e., is “heterologous”), and an immunoglobulin constant domain sequence.
  • the adhesin part of an immunoadhesin molecule typically is a contiguous amino acid sequence comprising at least the binding site of a receptor or a ligand.
  • the immunoglobulin constant domain sequence in the immunoadhesin may be obtained from any immunoglobulin, such as IgG-1, IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE, IgD or IgM.
  • immunoglobulin such as IgG-1, IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE, IgD or IgM.
  • “Active” or “activity” for the purposes herein refers to form(s) of a PRO polypeptide which retain a biological and/or an immunological activity of native or naturally-occurring PRO, wherein “biological” activity refers to a biological function (either inhibitory or stimulatory) caused by a native or naturally-occurring PRO other than the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally-occurring PRO and an “immunological” activity refers to the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally-occurring PRO.
  • the term “antagonist” is used in the broadest sense, and includes any molecule that partially or fully blocks, inhibits, or neutralizes a biological activity of a native PRO polypeptide disclosed herein.
  • the term “agonist” is used in the broadest sense and includes any molecule that mimics a biological activity of a native PRO polypeptide disclosed herein.
  • Suitable agonist or antagonist molecules specifically include agonist or antagonist antibodies or antibody fragments, fragments or amino acid sequence variants of native PRO polypeptides, peptides, antisense oligonucleotides, small organic molecules, etc.
  • Methods for identifying agonists or antagonists of a PRO polypeptide may comprise contacting a PRO polypeptide with a candidate agonist or antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the PRO polypeptide.
  • Treatment refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder.
  • Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented.
  • “Chronic” administration refers to administration of the agent(s) in a continuous mode as opposed to an acute mode, so as to maintain the initial therapeutic effect (activity) for an extended period of time. “Intermittent” administration is treatment that is not consecutively done without interruption, but rather is cyclic in nature.
  • “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats, rabbits, etc. Preferably, the mammal is human.
  • Administration “in combination with” one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order.
  • Carriers as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers which are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution.
  • physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEENTM, polyethylene glycol (PEG), and PLURONICSTM.
  • buffers such as phosphate, citrate, and other organic acids
  • antioxidants including ascorbic acid
  • proteins such as serum albumin,
  • Antibody fragments comprise a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody.
  • antibody fragments include Fab, Fab′, F(ab′) 2 and Fv fragments; diabodies; linear antibodies (Zapata et al., Protein Eng. 8(10): 1057-1062[1995]); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
  • Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual “Fc” fragment, a designation reflecting the ability to crystallize readily Pepsin treatment yields an F(ab′) 2 fragment that has two antigen-combining sites and is still capable of cross-linking antigen.
  • Fv is the minimum antibody fragment which contains a complete antigen-recognition and—binding site. This region consists of a dimer of one heavy—and one light-chain variable domain in tight, non-covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the V H -V L dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
  • the Fab fragment also contains the constant domain of the light chain and the first constant domain (CH1) of the heavy chain.
  • Fab fragments differ from Fab′ fragments by the addition of a few residues at the carboxy terminus of the heavy chain CH1 domain including one or more cysteines from the antibody hinge region.
  • Fab′-SH is the designation herein for Fab′ in which the cysteine residue(s) of the constant domains bear a free thiol group.
  • F(ab′) 2 antibody fragments originally were produced as pairs of Fab′ fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
  • the “light chains” of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains.
  • immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2.
  • Single-chain Fv or “sFv” antibody fragments comprise the V H and V L domains of antibody, wherein these domains are present in a single polypeptide chain.
  • the Fv polypeptide further comprises a polypeptide linker between the V H and V L domains which enables the sFv to form the desired structure for antigen binding.
  • diabodies refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (V H ) connected to a light-chain variable domain (V L ) in the same polypeptide chain (V H -V L ).
  • V H heavy-chain variable domain
  • V L light-chain variable domain
  • the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites.
  • Diabodies are described more fully in, for example, EP 404,097; WO 93/11161; and Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).
  • an “isolated” antibody is one which has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes.
  • the antibody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain.
  • Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step.
  • An antibody that “specifically binds to” or is “specific for” a particular polypeptide or an epitope on a particular polypeptide is one that binds to that particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.
  • label when used herein refers to a detectable compound or composition which is conjugated directly or indirectly to the antibody so as to generate a “labeled” antibody.
  • the label may be detectable by itself (e.g. radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition which is detectable.
  • solid phase is meant a non-aqueous matrix to which the antibody of the present invention can adhere.
  • solid phases encompassed herein include those formed partially or entirely of glass (e.g., controlled pore glass), polysaccharides (e.g., agarose), polyacrylamides, polystyrene, polyvinyl alcohol and silicones.
  • the solid phase can comprise the well of an assay plate; in others it is a purification column (e.g., an affinity chromatography column). This term also includes a discontinuous solid phase of discrete particles, such as those described in U.S. Pat. No. 4,275,149.
  • a “liposome” is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as a PRO polypeptide or antibody thereto) to a mammal.
  • a drug such as a PRO polypeptide or antibody thereto
  • the components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.
  • the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO polypeptides.
  • cDNAs encoding various PRO polypeptides have been identified and isolated, as disclosed in further detail in the Examples below. It is noted that proteins produced in separate expression rounds may be given different PRO numbers but the UNQ number is unique for any given DNA and the encoded protein, and will not be changed.
  • PRO/number the protein encoded by the full length native nucleic acid molecules disclosed herein as well as all further native homologues and variants included in the foregoing definition of PRO, will be referred to as “PRO/number”, regardless of their origin or mode of preparation.
  • PRO variants can be prepared.
  • PRO variants can be prepared by introducing appropriate nucleotide changes into the PRO DNA, and/or by synthesis of the desired PRO polypeptide.
  • amino acid changes may alter post-translational processes of the PRO, such as changing the number or position of glycosylation sites or altering the membrane anchoring characteristics.
  • Variations in the native full-length sequence PRO or in various domains of the PRO described herein can be made, for example, using any of the techniques and guidelines for conservative and non-conservative mutations set forth, for instance, in U.S. Pat. No. 5,364,934.
  • Variations may be a substitution, deletion or insertion of one or more codons encoding the PRO that results in a change in the amino acid sequence of the PRO as compared with the native sequence PRO.
  • the variation is by substitution of at least one amino acid with any other amino acid in one or more of the domains of the PRO.
  • Guidance in determining which amino acid residue may be inserted, substituted or deleted without adversely affecting the desired activity may be found by comparing the sequence of the PRO with that of homologous known protein molecules and minimizing the number of amino acid sequence changes made in regions of high homology.
  • Amino acid substitutions can be the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, such as the replacement of a leucine with a serine, i.e., conservative amino acid replacements.
  • Insertions or deletions may optionally be in the range of about 1 to 5 amino acids. The variation allowed may be determined by systematically making insertions, deletions or substitutions of amino acids in the sequence and testing the resulting variants for activity exhibited by the full-length or mature native sequence.
  • PRO polypeptide fragments are provided herein. Such fragments may be truncated at the N-terminus or C-terminus, or may lack internal residues, for example, when compared with a full length native protein. Certain fragments lack amino acid residues that are not essential for a desired biological activity of the PRO polypeptide.
  • PRO fragments may be prepared by any of a number of conventional techniques. Desired peptide fragments may be chemically synthesized. An alternative approach involves generating PRO fragments by enzymatic digestion, e.g., by treating the protein with an enzyme known to cleave proteins at sites defined by particular amino acid residues, or by digesting the DNA with suitable restriction enzymes and isolating the desired fragment. Yet another suitable technique involves isolating and amplifying a DNA fragment encoding a desired polypeptide fragment, by polymerase chain reaction (PCR). Oligonucleotides that define the desired termini of the DNA fragment are employed at the 5′ and 3′ primers in the PCR. Preferably, PRO polypeptide fragments share at least one biological and/or immunological activity with the native PRO polypeptide disclosed herein.
  • PCR polymerase chain reaction
  • Substantial modifications in function or immunological identity of the PRO polypeptide are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain.
  • Non-conservative substitutions will entail exchanging a member of one of these classes for another class. Such substituted residues also may be introduced into the conservative substitution sites or, more preferably, into the remaining (non-conserved) sites.
  • the variations can be made using methods known in the art such as oligonucleotide-mediated (site-directed) mutagenesis, alanine scanning, and PCR mutagenesis.
  • Site-directed mutagenesis [Carter et al., Nucl. Acids Res., 13:4331 (1986); Zoller et al., Nucl. Acids Res., 10:6487 (1987)]
  • cassette mutagenesis [Wells et al., Gene, 34:315 (1985)]
  • restriction selection mutagenesis [Wells et al., Philos. Trans. R. Soc. London SerA, 317:415 (1986)] or other known techniques can be performed on the cloned DNA to produce the PRO variant DNA.
  • Scanning amino acid analysis can also be employed to identify one or more amino acids along a contiguous sequence.
  • preferred scanning amino acids are relatively small, neutral amino acids.
  • amino acids include alanine, glycine, serine, and cysteine.
  • Alanine is typically a preferred scanning amino acid among this group because it eliminates the side-chain beyond the beta-carbon and is less likely to alter the main-chain conformation of the variant [Cunningham and Wells, Science, 244:1081-1085 (1989)].
  • Alanine is also typically preferred because it is the most common amino acid. Further, it is frequently found in both buried and exposed positions [Creighton, The Proteins, (W. H. Freeman & Co., N.Y.); Chothia, J. Mol. Biol., 150:1 (1976)]. If alanine substitution does not yield adequate amounts of variant, an isoteric amino acid can be used.
  • Covalent modifications of PRO are included within the scope of this invention.
  • One type of covalent modification includes reacting targeted amino acid residues of a PRO -polypeptide with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C- terminal residues of the PRO.
  • Derivatization with bifunctional agents is useful, for instance, for crosslinking PRO to a water-insoluble support matrix or surface for use in the method for purifying anti-PRO antibodies, and vice-versa.
  • crosslinking agents include, e.g., 1,1-bis (diazoacetyl)-2-phenylethane, glutaraldehyde, N-hydroxysuccinimide esters, for example, esters with 4-azidosalicylic acid, homobifunctional imidoesters, including disuccinimidyl esters such as 3,3′-dithiobis(succinimidylpropionate), bifunctional maleimides such as bis-N-maleimido-1,8-octane and agents such as methyl-3-[(p-azidophenyl)dithio]propioimidate.
  • 1,1-bis (diazoacetyl)-2-phenylethane glutaraldehyde
  • N-hydroxysuccinimide esters for example, esters with 4-azidosalicylic acid
  • homobifunctional imidoesters including disuccinimidyl esters such as 3,3′-dithiobis(s
  • Another type of covalent modification of the PRO polypeptide included within the scope of this invention comprises altering the native glycosylation pattern of the polypeptide.
  • “Altering the native glycosylation pattern” is intended for purposes herein to mean deleting one or more carbohydrate moieties found in native sequence PRO (either by removing the underlying glycosylation site or by deleting the glycosylation by chemical and/or enzymatic means), and/or adding one or more glycosylation sites that are not present in the native sequence PRO.
  • the phrase includes qualitative changes in the glycosylation of the native proteins, involving a change in the nature and proportions of the various carbohydrate moieties present.
  • Addition of glycosylation sites to the PRO polypeptide may be accomplished by altering the amino acid sequence.
  • the alteration may be made, for example, by the addition of, or substitution by, one or more serine or threonine residues to the native sequence PRO (for O-linked glycosylation sites).
  • the PRO amino acid sequence may optionally be altered through changes at the DNA level, particularly by mutating the DNA encoding the PRO polypeptide at preselected bases such that codons are generated that will translate into the desired amino acids.
  • Another means of increasing the number of carbohydrate moieties on the PRO polypeptide is by chemical or enzymatic coupling of glycosides to the polypeptide. Such methods are described in the art, e.g., in WO 87/05330 published Sep. 11, 1987, and in Aplin and Wriston, CRC Crit. Rev. Biochem., pp. 259-306 (1981).
  • Removal of carbohydrate moieties present on the PRO polypeptide may be accomplished chemically or enzymatically or by mutational substitution of codons encoding for amino acid residues that serve as targets for glycosylation.
  • Chemical deglycosylation techniques are known in the art and described, for instance, by Hakimuddin, et al., Arch. Biochem. Biophys., 259:52 (1987) and by Edge et al., Anal. Biochem., 118:131 (1981).
  • Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al., Meth. Enzymol., 138:350 (1987).
  • PRO polypeptide comprises linking the PRO polypeptide to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol (PEG), polypropylene glycol, or polyoxyalkylenes, in the manner set forth in U.S. Pat. Nos. 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192 or 4,179,337.
  • PEG polyethylene glycol
  • polypropylene glycol polypropylene glycol
  • polyoxyalkylenes polyoxyalkylenes
  • the PRO of the present invention may also be modified in a way to form a chimeric molecule comprising PRO fused to another, heterologous polypeptide or amino acid sequence.
  • such a chimeric molecule comprises a fusion of the PRO with a tag polypeptide which provides an epitope to which an anti-tag antibody can selectively bind.
  • the epitope tag is generally placed at the amino- or carboxyl-terminus of the PRO. The presence of such epitope-tagged forms of the PRO can be detected using an antibody against the tag polypeptide. Also, provision of the epitope tag enables the PRO to be readily purified by affinity purification using an anti-tag antibody or another type of affinity matrix that binds to the epitope tag.
  • tag polypeptides and their respective antibodies are well known in the art.
  • poly-histidine poly-his
  • poly-histidine-glycine poly-his-glycine tags
  • flu HA tag polypeptide and its antibody 12CA5 [Field et al., Mol. Cell. Biol., 8:21 59-2165 (1988)]
  • c-myc tag and the 8F9, 3C7, 6E10, G4, B7 and 9E10 antibodies thereto [Evan et al., Molecular and Cellular Biology, 5:3610-3616 (1985)]
  • Herpes Simplex virus glycoprotein D (gD) tag and its antibody [Paborsky et al., Protein Engineering, 3(6):547-553 (1990)].
  • tag polypeptides include the Flag-peptide [Hopp et al., BioTechnology, 6:1204-1210 (1988)]; the KT3 epitope peptide [Martin et al., Science, 255:192-194 (1992)]; an ⁇ -tubulin epitope peptide [Skinner et al., J. Biol. Chem., 266:15163-15166 (1991)]; and the T7 gene 10 protein peptide tag [Lutz-Freyermuth et al., Proc. Natl. Acad. Sci. USA, 87:6393-6397 (1990)].
  • the chimeric molecule may comprise a fusion of the PRO with an immunoglobulin or a particular region of an immunoglobulin.
  • an immunoglobulin also referred to as an “immunoadhesin”
  • a fusion could be to the Fc region of an IgG molecule.
  • the Ig fusions preferably include the substitution of a soluble (transmembrane domain deleted or inactivated) form of a PRO polypeptide in place of at least one variable region within an Ig molecule.
  • the immunoglobulin fusion includes the hinge, CH2 and CH3, or the hinge, CH1, CH2 and CH3 regions of an IgG1 molecule.
  • PRO sequence may be produced by direct peptide synthesis using solid-phase techniques [see, e.g., Stewart et al., Solid-Phase Peptide Synthesis, W. H. Freeman Co., San Francisco, Calif. (1969); Merrifield, J. Am. Chem. Soc., 85:2149-2154 (1963)].
  • In vitro protein synthesis may be performed using manual techniques or by automation.
  • Automated synthesis may be accomplished, for instance, using an Applied Biosystems Peptide Synthesizer (Foster City, Calif.) using manufacturer's instructions.
  • Various portions of the PRO may be chemically synthesized separately and combined using chemical or enzymatic methods to produce the full-length PRO.
  • DNA encoding PRO may be obtained from a cDNA library prepared from tissue believed to possess the PRO mRNA and to express it at a detectable level. Accordingly, human PRO DNA can be conveniently obtained from a cDNA library prepared from human tissue, such as described in the Examples.
  • the PRO-encoding gene may also be obtained from a genomic library or by known synthetic procedures (e.g., automated nucleic acid synthesis).
  • Libraries can be screened with probes (such as antibodies to the PRO or oligonucleotides of at least about 20-80 bases) designed to identify the gene of interest or the protein encoded by it. Screening the cDNA or genomic library with the selected probe may be conducted using standard procedures, such as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989). An alternative means to isolate the gene encoding PRO is to use PCR methodology [Sambrook et al., supra; Dieffenbach et al., PCR Primer: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 1995)].
  • the oligonucleotide sequences selected as probes should be of sufficient length and sufficiently unambiguous that false positives are minimized.
  • the oligonucleotide is preferably labeled such that it can be detected upon hybridization to DNA in the library being screened. Methods of labeling are well known in the art, and include the use of radiolabels like 32 P-labeled ATP, biotinylation or enzyme labeling. Hybridization conditions, including moderate stringency and high stringency, are provided in Sambrook et al., supra.
  • Sequences identified in such library screening methods can be compared and aligned to other known sequences deposited and available in public databases such as GenBank or other private sequence databases. Sequence identity (at either the amino acid or nucleotide level) within defined regions of the molecule or across the full-length sequence can be determined using methods known in the art and as described herein.
  • Nucleic acid having protein coding sequence may be obtained by screening selected cDNA or genomic libraries using the deduced amino acid sequence disclosed herein for the first time, and, if necessary, using conventional primer extension procedures as described in Sambrook et al., supra, to detect precursors and processing intermediates of mRNA that may not have been reverse-transcribed into cDNA.
  • Host cells are transfected or transformed with expression or cloning vectors described herein for PRO production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences.
  • the culture conditions such as media, temperature, pH and the like, can be selected by the skilled artisan without undue experimentation. In general, principles, protocols, and practical techniques for maximizing the productivity of cell cultures can be found in Mammalian Cell Biotechnology: a Practical Approach, M. Butler, ed. (IRL Press, 1991) and Sambrook et al., supra.
  • Methods of eukaryotic cell transfection and prokaryotic cell transformation are known to the ordinarily skilled artisan, for example, CaCl 2 , CaPO 4 , liposome-mediated and electroporation. Depending on the host cell used, transformation is performed using standard techniques appropriate to such cells.
  • the calcium treatment employing calcium chloride, as described in Sambrook et al., supra, or electroporation is generally used for prokaryotes.
  • Infection with Agrobacterium tumefaciens is used for transformation of certain plant cells, as described by Shaw et al., Gene, 23:315 (1983) and WO 89/05859 published Jun. 29, 1989.
  • DNA into cells such as by nuclear microinjection, electroporation, bacterial protoplast fusion with intact cells, or polycations, e.g., polybrene, polyornithine, may also be used.
  • polycations e.g., polybrene, polyornithine.
  • Suitable host cells for cloning or expressing the DNA in the vectors herein include prokaryote, yeast, or higher eukaryote cells.
  • Suitable prokaryotes include but are not limited to eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae such as E. coli.
  • Various E. coli strains are publicly available, such as E coli K12 strain MM294 (ATCC 31,446); E coli X1776 (ATCC 31,537); E. coli strain W3110 (ATCC 27,325) and K5 772 (ATCC 53,635).
  • suitable prokaryotic host cells include Enterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter, Erwlinla, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium, Serratia, e.g., Serratia marcescans, and Shigella, as well as Bacili such as B. subtilis and B. licheniformis (e.g., B. licheniformis 41 P disclosed in DD 266,710 published Apr. 12, 1989), Pseudomonas such as P. aeruginosa, and Streptomyces. These examples are illustrative rather than limiting.
  • Strain W3110 is one particularly preferred host or parent host because it is a common host strain for recombinant DNA product fermentations. Preferably, the host cell secretes minimal amounts of proteolytic enzymes.
  • strain W3110 may be modified to effect a genetic mutation in the genes encoding proteins endogenous to the host, with examples of such hosts including E. coli W3110 strain 1A2, which has the complete genotype tonA; E coli W3110 strain 9E4, which has the complete genotype tonA ptr3; E.
  • coli W3110 strain 27C7 (ATCC 55,244), which has the complete genotype tonA ptr3 phoA E15 (argF-lac)769 degP ompT kan r ;
  • E. coli W3110 strain 37D6 which has the complete genotype tonA ptr3 phoA E15 (argF-lac)169 degP ompT rbs7 ilvG kan r ;
  • E. coli W3110 strain 40B4 which is strain 37D6 with a non-kanamycin resistant degP deletion mutation; and an E. coli strain having mutant periplasmic protease disclosed in U.S. Pat. No. 4,946,783 issued Aug. 7, 1990.
  • in vitro methods of cloning e.g., PCR or other nucleic acid polymerase reactions, are suitable.
  • eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for PRO-encoding vectors.
  • Saccharomyces cerevisiae is a commonly used lower eukaryotic host microorganism.
  • Others include Schizosaccharomyces pombe (Beach and Nurse, Nature, 290: 140 [1981]; EP 139,383 published May 2, 1985); Kluyveromyces hosts (U.S. Pat. No. 4,943,529; Fleer et al., Bio/Technology, 9:968-975 (1991)) such as, e.g., K.
  • lactis (MW98-8C, CBS683, CBS4574; Louvencourt et al., J. Bacteriol., 154(2):737-742 [1983]), K. fragilis (ATCC 12,424), K. bulgaricus (ATCC 16,045), K. wickeramii (ATCC 24,178), K. waltii (ATCC 56,500), K. drosophilarum (ATCC 36,906; Van den Berg et al., Bio/Technology, 8:135 (1990)), K. thermotolerans, and K. marxianus; yarrowia (EP 402,226); Pichia pastoris (EP 183,070; Sreekrishna et al., J.
  • Candida Trichoderma reesia (EP 244,234); Neurospora crassa (Case et al., Proc. Natl. Acad. Sci. USA, 76:5259-5263 [1979]); Schwanniomyces such as Schwanniomyces occidentalis (EP 394,538 published Oct. 31, 1990); and filamentous fungi such as, e.g., Neurospora, Penicilium, Tolypocladium(WO 91/00357 published Jan. 10, 1991), and Aspergillus hosts such as A. nidulans (Ballance et al., Biochem. Biophys. Res.
  • Methylotropic yeasts are suitable herein and include, but are not limited to, yeast capable of growth on methanol selected from the genera consisting of Hansenula, Candida, Kloeckera, Pichia, Saccharomyces, Torulopsis, and Rhodotorula. A list of specific species that are exemplary of this class of yeasts may be found in C. Anthony, The Biochemistry of Methylotrophs, 269 (1982).
  • Suitable host cells for the expression of glycosylated PRO are derived from multicellular organisms.
  • invertebrate cells include insect cells such as Drosophila S2 and Spodoptera Sf9, as well as plant cells.
  • useful mammalian host cell lines include Chinese hamster ovary (CHO) and COS cells. More specific examples include monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture, Graham et al., J. Gen Virol., 36:59 (1977)); Chinese hamster ovary cells/-DHFR (CHO, Urlaub and Chasin, Proc. Natl. Acad. Sci.
  • mice sertoli cells TM4, Mather, Biol. Reprod., 23:243-251 (1980)
  • human lung cells W138, ATCC CCL 75
  • human liver cells Hep G2, HB 8065
  • mouse mammary tumor MMT 060562, ATCC CCL51. The selection of the appropriate host cell is deemed to be within the skill in the art.
  • the nucleic acid (e.g., cDNA or genomic DNA) encoding PRO may be inserted into a replicable vector for cloning (amplification of the DNA) or for expression.
  • a replicable vector for cloning (amplification of the DNA) or for expression.
  • the vector may, for example, be in the form of a plasmid, cosmid, viral particle, or phage.
  • the appropriate nucleic acid sequence may be inserted into the vector by a variety of procedures. In general, DNA is inserted into an appropriate restriction endonuclease site(s) using techniques known in the art.
  • Vector components generally include, but are not limited to, one or more of a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. Construction of suitable vectors containing one or more of these components employs standard ligation techniques which are known to the skilled artisan.
  • the PRO may be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, which may be a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide.
  • a heterologous polypeptide which may be a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide.
  • the signal sequence may be a component of the vector, or it may be a part of the PRO-encoding DNA that is inserted into the vector.
  • the signal sequence may be a prokaryotic signal sequence selected, for example, from the group of the alkaline phosphatase, penicillinase, lpp, or heat-stable enterotoxin II leaders.
  • the signal sequence may be, e.g., the yeast invertase leader, alpha factor leader (including Saccharomyces and Kluyveromyces ⁇ -factor leaders, the latter described in U.S. Pat. No. 5,010,182), or acid phosphatase leader, the C. albicans glucoamylase leader (EP 362,179 published Apr. 4, 1990), or the signal described in WO 90/13646 published Nov. 15, 1990.
  • mammalian signal sequences may be used to direct secretion of the protein, such as signal sequences from secreted polypeptides of the same or related species, as well as viral secretory leaders.
  • Both expression and cloning vectors contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells. Such sequences are well known for a variety of bacteria, yeast, and viruses.
  • the origin of replication from the plasmid pBR322 is suitable for most Gram-negative bacteria, the 2 ⁇ plasmid origin is suitable for yeast, and various viral origins (SV40, polyoma, adenovirus, VSV or BPV) are useful for cloning vectors in mammalian cells.
  • Selection genes will typically contain a selection gene, also termed a selectable marker.
  • Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g., ampicillin, neomycin, methotrexate, or tetracycline, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media, e.g., the gene encoding D-alanine racemase for Bacilli.
  • Suitable selectable markers for mammalian cells are those that enable the identification of cells competent to take up the PRO-encoding nucleic acid, such as DHFR or thymidine kinase.
  • An appropriate host cell when wild-type DHFR is employed is the CHO cell line deficient in DHFR activity, prepared and propagated as described by Urlaub et al., Proc. Natl. Acad. Sci. USA, 77:4216 (1980).
  • a suitable selection gene for use in yeast is the trp 1 gene present in the yeast plasmid YRp7 [Stinchcomb et al., Nature, 282:39 (1979); Kingsman et al., Gene, 7:141 (1979); Tschemper et al., Gene, 10:157 (1980)].
  • the trp 1 gene provides a selection marker for a mutant strain of yeast lacking the ability to grow in tryptophan, for example, ATCC No. 44076 or PEP4-1 [Jones, Genetics, 85:12 (1977)].
  • Expression and cloning vectors usually contain a promoter operably linked to the PRO-encoding nucleic acid sequence to direct mRNA synthesis. Promoters recognized by a variety of potential host cells are well known. Promoters suitable for use with prokaryotic hosts include the ⁇ -lactamase and lactose promoter systems [Chang et al., Nature, 275:615 (1978); Goeddel et al., Nature, 281:544 (1979)], alkaline phosphatase, a tryptophan (trp) promoter system [Goeddel, Nucleic Acids Res., 8:4057 (1980); EP 36,776], and hybrid promoters such as the tac promoter [deBoer et al., Proc. Natl. Acad. Sci. USA, 80:21-25 (1983)]. Promoters for use in bacterial systems also will contain a Shine-Dalgarno (S.D.) sequence operably linked to the DNA en
  • Suitable promoting sequences for use with yeast hosts include the promoters for 3-phosphoglycerate kinase [Hitzeman et al., J. Biol. Chem., 255:2073 (1980)] or other glycolytic enzymes [Hess et al., J. Adv.
  • yeast promoters which are inducible promoters having the additional advantage of transcription controlled by growth conditions, are the promoter regions for alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, degradative enzymes associated with nitrogen metabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase, and enzymes responsible for maltose and galactose utilization. Suitable vectors and promoters for use in yeast expression are further described in EP 73,657.
  • PRO transcription from vectors in mammalian host cells is controlled, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowipox virus (UK 2,211,504 published Jul. 5, 1989), adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus and Simian Virus 40 (SV40), from heterologous mammalian promoters, e.g., the actin promoter or an immunoglobulin promoter, and from heat-shock promoters, provided such promoters are compatible with the host cell systems.
  • viruses such as polyoma virus, fowipox virus (UK 2,211,504 published Jul. 5, 1989), adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus,
  • Enhancers are cis-acting elements of DNA, usually about from 10 to 300 bp, that act on a promoter to increase its transcription.
  • Many enhancer sequences are now known from mammalian genes (globin, elastase, albumin, ⁇ -fetoprotein, and insulin). Typically, however, one will use an enhancer from a eukaryotic cell virus.
  • Examples include the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers.
  • the enhancer may be spliced into the vector at a position 5′ or 3′ to the PRO coding sequence, but is preferably located at a site 5′ from the promoter.
  • Expression vectors used in eukaryotic host cells will also contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are commonly available from the 5′ and, occasionally 3′, untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA encoding PRO.
  • Gene amplification and/or expression may be measured in a sample directly, for example, by conventional Southern blotting, Northern blotting to quantitate the transcription of mRNA [Thomas, Proc. Natl. Acad. Sci. USA, 77:5201(1980)], dot blotting (DNA analysis), or in situ hybridization, using an appropriately labeled probe, based on the sequences provided herein.
  • antibodies may be employed that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. The antibodies in turn may be labeled and the assay may be carried out where the duplex is bound to a surface, so that upon the formation of duplex on the surface, the presence of antibody bound to the duplex can be detected.
  • Gene expression may be measured by immunological methods, such as immunohistochemical staining of cells or tissue sections and assay of cell culture or body fluids, to quantitate directly the expression of gene product.
  • Antibodies useful for immunohistochemical staining and/or assay of sample fluids may be either monoclonal or polyclonal, and may be prepared in any mammal. Conveniently, the antibodies may be prepared against a native sequence PRO polypeptide or against a synthetic peptide based on the DNA sequences provided herein or against exogenous sequence fused to PRO DNA and encoding a specific antibody epitope.
  • Forms of PRO may be recovered from culture medium or from host cell lysates. If membrane-bound, it can be released from the membrane using a suitable detergent solution (e.g. Triton-X 100) or by enzymatic cleavage. Cells employed in expression of PRO can be disrupted by various physical or chemical means, such as freeze-thaw cycling, sonication, mechanical disruption, or cell lysing agents.
  • a suitable detergent solution e.g. Triton-X 100
  • Cells employed in expression of PRO can be disrupted by various physical or chemical means, such as freeze-thaw cycling, sonication, mechanical disruption, or cell lysing agents.
  • PRO may be desired to purify PRO from recombinant cell proteins or polypeptides.
  • the following procedures are exemplary of suitable purification procedures: by fractionation on an ion-exchange column; ethanol precipitation; reverse phase HPLC; chromatography on silica or on a cation-exchange resin such as DEAE; chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gel filtration using, for example, Sephadex G-75; protein A Sepharose columns to remove contaminants such as IgG; and metal chelating columns to bind epitope-tagged forms of the PRO.
  • Nucleotide sequences (or their complement) encoding PRO have various applications in the art of molecular biology, including uses as hybridization probes, in chromosome and gene mapping and in the generation of anti-sense RNA and DNA.
  • PRO nucleic acid will also be useful for the preparation of PRO polypeptides by the recombinant techniques described herein.
  • the full-length native sequence PRO gene, or portions thereof, may be used as hybridization probes for a cDNA library to isolate the full-length PRO cDNA or to isolate still other cDNAs (for instance, those encoding naturally-occurring variants of PRO or PRO from other species) which have a desired sequence identity to the native PRO sequence disclosed herein.
  • the length of the probes will be about 20 to about 50 bases.
  • the hybridization probes may be derived from at least partially novel regions of the full length native nucleotide sequence wherein those regions may be determined without undue experimentation or from genomic sequences including promoters, enhancer elements and introns of native sequence PRO.
  • a screening method will comprise isolating the coding region of the PRO gene using the known DNA sequence to synthesize a selected probe of about 40 bases.
  • Hybridization probes may be labeled by a variety of labels, including radionucleotides such as 32 P or 35 S, or enzymatic labels such as alkaline phosphatase coupled to the probe via avidin/biotin coupling systems. Labeled probes having a sequence complementary to that of the PRO gene of the present invention can be used to screen libraries of human cDNA, genomic DNA or mRNA to determine which members of such libraries the probe hybridizes to. Hybridization techniques are described in further detail in the Examples below.
  • antisense or sense oligonucleotides comprising a singe-stranded nucleic acid sequence (either RNA or DNA) capable of binding to target PRO mRNA (sense) or PRO DNA (antisense) sequences.
  • Antisense or sense oligonucleotides comprise a fragment of the coding region of PRO DNA. Such a fragment generally comprises at least about 14 nucleotides, preferably from about 14 to 30 nucleotides.
  • Stein and Cohen Cancer Res. 48:2659, 1988
  • van der Krol et al. BioTechniques 6:958, 1988.
  • binding of antisense or sense oligonucleotides to target nucleic acid sequences results in the formation of duplexes that block transcription or translation of the target sequence by one of several means, including enhanced degradation of the duplexes, premature termination of transcription or translation, or by other means.
  • the antisense oligonucleotides thus may be used to block expression of PRO proteins.
  • Antisense or sense oligonucleotides further comprise oligonucleotides having modified sugar-phosphodiester backbones (or other sugar linkages, such as those described in WO 91/06629) and wherein such sugar linkages are resistant to endogenous nucleases.
  • Such oligonucleotides with resistant sugar linkages are stable in vivo (i.e., capable of resisting enzymatic degradation) but retain sequence specificity to be able to bind to target nucleotide sequences.
  • sense or antisense oligonucleotides include those oligonucleotides which are covalently linked to organic moieties, such as those described in WO 90/10048, and other moieties that increases affinity of the oligonucleotide for a target nucleic acid sequence, such as poly-(L-lysine).
  • intercalating agents such as ellipticine, and alkylating agents or metal complexes may be attached to sense or antisense oligonucleotides to modify binding specificities of the antisense or sense oligonucleotide for the target nucleotide sequence.
  • Antisense or sense oligonucleotides may be introduced into a cell containing the target nucleic acid sequence by any gene transfer method, including, for example, CaPO 4- mediated DNA transfection, electroporation, or by using gene transfer vectors such as Epstein-Barr virus.
  • an antisense or sense oligonucleotide is inserted into a suitable retroviral vector.
  • a cell containing the target nucleic acid sequence is contacted with the recombinant retroviral vector, either in vivo or ex vivo.
  • Suitable retroviral vectors include, but are not limited to, those derived from the murine retrovirus M-MuLV, N2 (a retrovirus derived from M-MuLV), or the double copy vectors designated DCT5A, DCT5B and DCT5C (see WO 90/13641).
  • Sense or antisense oligonucleotides also may be introduced into a cell containing the target nucleotide sequence by formation of a conjugate with a ligand binding molecule, as described in WO 91/04753.
  • Suitable ligand binding molecules include, but are not limited to, cell surface receptors, growth factors, other cytokines, or other ligands that bind to cell surface receptors.
  • conjugation of the ligand binding molecule does not substantially interfere with the ability of the ligand binding molecule to bind to its corresponding molecule or receptor, or block entry of the sense or antisense oligonucleotide or its conjugated version into the cell.
  • a sense or an antisense oligonucleotide may be introduced into a cell containing the target nucleic acid sequence by formation of an oligonucleotide-lipid complex, as described in WO 90/10448.
  • the sense or antisense oligonucleotide-lipid complex is preferably dissociated within the cell by an endogenous lipase.
  • Antisense or sense RNA or DNA molecules are generally at least about 5 bases in length, about 10 bases in length, about 15 bases in length, about 20 bases in length, about 25 bases in length, about 30 bases in length, about 35 bases in length, about 40 bases in length, about 45 bases in length, about 50 bases in length, about 55 bases in length, about 60 bases in length, about 65 bases in length, about 70 bases in length, about 75 bases in length, about 80 bases in length, about 85 bases in length, about 90 bases in length, about 95 bases in length, about 100 bases in length, or more.
  • the probes may also be employed in PCR techniques to generate a pool of sequences for identification of closely related PRO coding sequences.
  • Nucleotide sequences encoding a PRO can also be used to construct hybridization probes for mapping the gene which encodes that PRO and for the genetic analysis of individuals with genetic disorders.
  • the nucleotide sequences provided herein may be mapped to a chromosome and specific regions of a chromosome using known techniques, such as in situ hybridization, linkage analysis against known chromosomal markers, and hybridization screening with libraries.
  • the coding sequences for PRO encode a protein which binds to another protein (example, where the PRO is a receptor)
  • the PRO can be used in assays to identify the other proteins or molecules involved in the binding interaction. By such methods, inhibitors of the receptor/ligand binding interaction can be identified. Proteins involved in such binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction. Also, the receptor PRO can be used to isolate correlative ligand(s). Screening assays can be designed to find lead compounds that mimic the biological activity of a native PRO or a receptor for PRO.
  • screening assays will include assays amenable to high-throughput screening of chemical libraries, making them particularly suitable for identifying small molecule drug candidates.
  • Small molecules contemplated include synthetic organic or inorganic compounds.
  • the assays can be performed in a variety of formats, including protein-protein binding assays, biochemical screening assays, immunoassays and cell based assays, which are well characterized in the art.
  • Nucleic acids which encode PRO or its modified forms can also be used to generate either transgenic animals or “knock out” animals which, in turn, are useful in the development and screening of therapeutically useful reagents.
  • a transgenic animal e.g., a mouse or rat
  • a transgenic animal is an animal having cells that contain a transgene, which transgene was introduced into the animal or an ancestor of the animal at a prenatal, e.g., an embryonic stage.
  • a transgene is a DNA which is integrated into the genome of a cell from which a transgenic animal develops.
  • cDNA encoding PRO can be used to clone genomic DNA encoding PRO in accordance with established techniques and the genomic sequences used to generate transgenic animals that contain cells which express DNA encoding PRO.
  • Methods for generating transgenic animals, particularly animals such as mice or rats, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009.
  • particular cells would be targeted for PRO transgene incorporation with tissue-specific enhancers.
  • Transgenic animals that include a copy of a transgene encoding PRO introduced into the germ line of the animal at an embryonic stage can be used to examine the effect of increased expression of DNA encoding PRO.
  • Such animals can be used as tester animals for reagents thought to confer protection from, for example, pathological conditions associated with its overexpression.
  • an animal is treated with the reagent and a reduced incidence of the pathological condition, compared to untreated animals bearing the transgene, would indicate a potential therapeutic intervention for the pathological condition.
  • non-human homologues of PRO can be used to construct a PRO “knock out” animal which has a defective or altered gene encoding PRO as a result of homologous recombination between the endogenous gene encoding PRO and altered genomic DNA encoding PRO introduced into an embryonic stem cell of the animal.
  • cDNA encoding PRO can be used to clone genomic DNA encoding PRO in accordance with established techniques. A portion of the genomic DNA encoding PRO can be deleted or replaced with another gene, such as a gene encoding a selectable marker which can be used to monitor integration.
  • flanking DNA typically, several kilobases of unaltered flanking DNA (both at the 5′ and 3′ ends) are included in the vector [see e.g., Thomas and Capecchi, Cell, 51:503 (1987) for a description of homologous recombination vectors].
  • the vector is introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced DNA has homologously recombined with the endogenous DNA are selected [see e.g., Li et al., Cell, 69:915 (1992)].
  • the selected cells are then injected into a blastocyst of an animal (e.g., a mouse or rat) to form aggregation chimeras [see e.g., Bradley, in Teratocarcinomas and Embryonic Stem Cells: A Practical Approach, E. J. Robertson, ed. (IRL, Oxford, 1987), pp. 113-152].
  • a chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term to create a “knock out” animal.
  • Progeny harboring the homologously recombined DNA in their germ cells can be identified by standard techniques and used to breed animals in which all cells of the animal contain the homologously recombined DNA.
  • Knockout animals can be characterized for instance, for their ability to defend against certain pathological conditions and for their development of pathological conditions due to absence of the PRO polypeptide.
  • Nucleic acid encoding the PRO polypeptides may also be used in gene therapy.
  • genes are introduced into cells in order to achieve in vivo synthesis of a therapeutically effective genetic product, for example for replacement of a defective gene.
  • Gene therapy includes both conventional gene therapy where a lasting effect is achieved by a single treatment, and the administration of gene therapeutic agents, which involves the one time or repeated administration of a therapeutically effective DNA or mRNA.
  • Antisense RNAs and DNAs can be used as therapeutic agents for blocking the expression of certain genes in vivo. It has already been shown that short antisense oligonucleotides can be imported into cells where they act as inhibitors, despite their low intracellular concentrations caused by their restricted uptake by the cell membrane.
  • oligonucleotides can be modified to enhance their uptake, e.g. by substituting their negatively charged phosphodiester groups by uncharged groups.
  • nucleic acids there are a variety of techniques available for introducing nucleic acids into viable cells.
  • the techniques vary depending upon whether the nucleic acid is transferred into cultured cells in vitro, or in vivo in the cells of the intended host.
  • Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, microinjection, cell fusion, DEAE-dextran, the calcium phosphate precipitation method, etc.
  • the currently preferred in vivo gene transfer techniques include transfection with viral (typically retroviral) vectors and viral coat protein-liposome mediated transfection (Dzau et al., Trends in Biotechnology 11, 205-210 [1993]).
  • the nucleic acid source with an agent that targets the target cells, such as an antibody specific for a cell surface membrane protein or the target cell, a ligand for a receptor on the target cell, etc.
  • an agent that targets the target cells such as an antibody specific for a cell surface membrane protein or the target cell, a ligand for a receptor on the target cell, etc.
  • proteins which bind to a cell surface membrane protein associated with endocytosis may be used for targeting and/or to facilitate uptake, e.g. capsid proteins or fragments thereof tropic for a particular cell type, antibodies for proteins which undergo internalization in cycling, proteins that target intracellular localization and enhance intracellular half-life.
  • the technique of receptor-mediated endocytosis is described, for example, by Wu et al., J. Biol. Chem.
  • PRO polypeptides described herein may also be employed as molecular weight markers for protein electrophoresis purposes and the isolated nucleic acid sequences may be used for recombinantly expressing those markers.
  • nucleic acid molecules encoding the PRO polypeptides or fragments thereof described herein are useful for chromosome identification.
  • Each PRO nucleic acid molecule of the present invention can be used as a chromosome marker.
  • PRO polypeptides and nucleic acid molecules of the present invention may also be used diagnostically for tissue typing, wherein the PRO polypeptides of the present invention may be differentially expressed in one tissue as compared to another, preferably in a diseased tissue as compared to a normal tissue of the same tissue type.
  • PRO nucleic acid molecules will find use for generating probes for PCR, Northern analysis, Southern analysis and Western analysis.
  • PRO polypeptides described herein may also be employed as therapeutic agents.
  • the PRO polypeptides of the present invention can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby the PRO product hereof is combined in admixture with a pharmaceutically acceptable carrier vehicle.
  • Therapeutic formulations are prepared for storage by mixing the active ingredient having the desired degree of purity with optional physiologically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions.
  • Acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEENTM, PLURONICSTM or PEG.
  • buffers such as phosphate, citrate and other organic acids
  • antioxidants including ascorbic acid
  • formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes, prior to or following lyophilization and reconstitution.
  • Therapeutic compositions herein generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
  • the route of administration is in accord with known methods, e.g. injection or infusion by intravenous, intraperitoneal, intracerebral, intramuscular, intraocular, intraarterial or intralesional routes, topical administration, or by sustained release systems.
  • Dosages and desired drug concentrations of pharmaceutical compositions of the present invention may vary depending on the particular use envisioned. The determination of the appropriate dosage or route of administration is well within the skill of an ordinary physician. Animal experiments provide reliable guidance for the determination of effective doses for human therapy. Interspecies scaling of effective doses can be performed following the principles laid down by Mordenti, J. and Chappell, W. “The use of interspecies scaling in toxicokinetics” In Toxicokinetics and New Drug Development, Yacobi et al., Eds., Pergamon Press, New York 1989, pp. 42-96.
  • a PRO polypeptide or agonist or antagonist thereof When in vivo administration of a PRO polypeptide or agonist or antagonist thereof is employed, normal dosage amounts may vary from about 10 ng/kg to up to 100 mg/kg of mammal body weight or more per day, preferably about 1 ⁇ g/kg/day to 10 mg/kg/day, depending upon the route of administration.
  • Guidance as to particular dosages and methods of delivery is provided in the literature; see, for example, U.S. Pat. Nos. 4,657,760; 5,206,344; or 5,225,212. It is anticipated that different formulations will be effective for different treatment compounds and different disorders, that administration targeting one organ or tissue, for example, may necessitate delivery in a manner different from that to another organ or tissue.
  • microencapsulation of the PRO polypeptide is contemplated. Microencapsulation of recombinant proteins for sustained release has been successfully performed with human growth hormone (rhGH), interferon- (rhlFN-), interleukin-2, and MN rgp120. Johnson et al., Nat. Med., 2:795-799 (1996); Yasuda, Biomed.
  • rhGH human growth hormone
  • rhlFN- interferon-
  • interleukin-2 interleukin-2
  • MN rgp120 MN rgp120
  • the sustained-release formulations of these proteins were developed using poly-lactic-coglycolic acid (PLGA) polymer due to its biocompatibility and wide range of biodegradable properties.
  • PLGA poly-lactic-coglycolic acid
  • the degradation products of PLGA, lactic and glycolic acids, can be cleared quickly within the human body.
  • the degradability of this polymer can be adjusted from months to years depending on its molecular weight and composition.
  • Lewis “Controlled release of bioactive agents from lactide/glycolide polymer,” in: M. Chasin and R. Langer (Eds.), Biodegradable Polymers as Drug Delivery Systems (Marcel Dekker: New York, 1990), pp.1-41.
  • This invention encompasses methods of screening compounds to identify those that mimic the PRO polypeptide (agonists) or prevent the effect of the PRO polypeptide (antagonists).
  • Screening assays for antagonist drug candidates are designed to identify compounds that bind or complex with the PRO polypeptides encoded by the genes identified herein, or otherwise interfere with the interaction of the encoded polypeptides with other cellular proteins.
  • Such screening assays will include assays amenable to high-throughput screening of chemical libraries, making them particularly suitable for identifying small molecule drug candidates.
  • the assays can be performed in a variety of formats, including protein-protein binding assays, biochemical screening assays, immunoassays, and cell-based assays, which are well characterized in the art.
  • the interaction is binding and the complex formed can be isolated or detected in the reaction mixture.
  • the PRO polypeptide encoded by the gene identified herein or the drug candidate is immobilized on a solid phase, e.g., on a microtiter plate, by covalent or non-covalent attachments.
  • Non-covalent attachment generally is accomplished by coating the solid surface with a solution of the PRO polypeptide and drying.
  • an immobilized antibody e.g., a monoclonal antibody, specific for the PRO polypeptide to be immobilized can be used to anchor it to a solid surface.
  • the assay is performed by adding the non-immobilized component, which may be labeled by a detectable label, to the immobilized component, e.g., the coated surface containing the anchored component.
  • the non-reacted components are removed, e.g., by washing, and complexes anchored on the solid surface are detected.
  • the detection of label immobilized on the surface indicates that complexing occurred.
  • complexing can be detected, for example, by using a labeled antibody specifically binding the immobilized complex.
  • the candidate compound interacts with but does not bind to a particular PRO polypeptide encoded by a gene identified herein, its interaction with that polypeptide can be assayed by methods well known for detecting protein-protein interactions.
  • assays include traditional approaches, such as, e.g., cross-linking, co-immunoprecipitation, and co-purification through gradients or chromatographic columns.
  • protein-protein interactions can be monitored by using a yeast-based genetic system described by Fields and co-workers (Fields and Song, Nature (London), 340:245-246 (1989); Chien et al., Proc. Natl. Acad. Sci.
  • yeast GAL4 Many transcriptional activators, such as yeast GAL4, consist of two physically discrete modular domains, one acting as the DNA-binding domain, the other one functioning as the transcription-activation domain.
  • yeast expression system described in the foregoing publications (generally referred to as the “two-hybrid system”) takes advantage of this property, and employs two hybrid proteins, one in which the target protein is fused to the DNA-binding domain of GAL4, and another, in which candidate activating proteins are fused to the activation domain.
  • GAL1- lacZ reporter gene under control of a GAL4-activated promoter depends on reconstitution of GAL4 activity via protein-protein interaction. Colonies containing interacting polypeptides are detected with a chromogenic substrate for ⁇ -galactosidase.
  • a complete kit (MATCHMAKERTM) for identifying protein-protein interactions between two specific proteins using the two-hybrid technique is commercially available from Clontech. This system can also be extended to map protein domains involved in specific protein interactions as well as to pinpoint amino acid residues that are crucial for these interactions.
  • the PRO polypeptide may be added to a cell along with the compound to be screened for a particular activity and the ability of the compound to inhibit the activity of interest in the presence of the PRO polypeptide indicates that the compound is an antagonist to the PRO polypeptide.
  • antagonists may be detected by combining the PRO polypeptide and a potential antagonist with membrane-bound PRO polypeptide receptors or recombinant receptors under appropriate conditions for a competitive inhibition assay.
  • the PRO polypeptide can be labeled, such as by radioactivity, such that the number of PRO polypeptide molecules bound to the receptor can be used to determine the effectiveness of the potential antagonist.
  • the gene encoding the receptor can be identified by numerous methods known to those of skill in the art, for example, ligand panning and FACS sorting. Coligan et al., Current Protocols in Immun., 1(2): Chapter 5 (1991).
  • expression cloning is employed wherein polyadenylated RNA is prepared from a cell responsive to the PRO polypeptide and a cDNA library created from this RNA is divided into pools and used to transfect COS cells or other cells that are not responsive to the PRO polypeptide. Transfected cells that are grown on glass slides are exposed to labeled PRO polypeptide.
  • the PRO polypeptide can be labeled by a variety of means including iodination or inclusion of a recognition site for a site-specific protein kinase. Following fixation and incubation, the slides are subjected to autoradiographic analysis. Positive pools are identified and sub-pools are prepared and re-transfected using an interactive sub-pooling and re-screening process, eventually yielding a single clone that encodes the putative receptor.
  • labeled PRO polypeptide can be photoaffinity-linked with cell membrane or extract preparations that express the receptor molecule. Cross-linked material is resolved by PAGE and exposed to X-ray film. The labeled complex containing the receptor can be excised, resolved into peptide fragments, and subjected to protein micro-sequencing. The amino acid sequence obtained from micro- sequencing would be used to design a set of degenerate oligonucleotide probes to screen a cDNA library to identify the gene encoding the putative receptor.
  • mammalian cells or a membrane preparation expressing the receptor would be incubated with labeled PRO polypeptide in the presence of the candidate compound. The ability of the compound to enhance or block this interaction could then be measured.
  • potential antagonists include an oligonucleotide that binds to the fusions of immunoglobulin with PRO polypeptide, and, in particular, antibodies including, without limitation, poly- and monoclonal antibodies and antibody fragments, single-chain antibodies, anti-idiotypic antibodies, and chimeric or humanized versions of such antibodies or fragments, as well as human antibodies and antibody fragments.
  • a potential antagonist may be a closely related protein, for example, a mutated form of the PRO polypeptide that recognizes the receptor but imparts no effect, thereby competitively inhibiting the action of the PRO polypeptide.
  • Another potential PRO polypeptide antagonist is an antisense RNA or DNA construct prepared using antisense technology, where, e.g., an antisense RNA or DNA molecule acts to block directly the translation of mRNA by hybridizing to targeted mRNA and preventing protein translation.
  • Antisense technology can be used to control gene expression through triple-helix formation or antisense DNA or RNA, both of which methods are based on binding of a polynucleotide to DNA or RNA.
  • the 5′ coding portion of the polynucleotide sequence, which encodes the mature PRO polypeptides herein is used to design an antisense RNA oligonucleotide of from about 10 to 40 base pairs in length.
  • a DNA oligonucleotide is designed to be complementary to a region of the gene involved in transcription (triple helix—see Lee et al., Nucl. Acids Res., 6:3073 (1979); Cooney et al., Science, 241: 456 (1988); Dervan et al., Science, 251:1360 (1991)), thereby preventing transcription and the production of the PRO polypeptide.
  • the antisense RNA oligonucleotide hybridizes to the mRNA in vivo and blocks translation of the mRNA molecule into the PRO polypeptide (antisense—Okano, Neurochem., 56:560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression (CRC Press: Boca Raton, Fla., 1988).
  • the oligonucleotides described above can also be delivered to cells such that the antisense RNA or DNA may be expressed in vivo to inhibit production of the PRO polypeptide.
  • antisense DNA is used, oligodeoxyribonucleotides derived from the translation-initiation site, e.g., between about ⁇ 10 and +10 positions of the target gene nucleotide sequence, are preferred.
  • Potential antagonists include small molecules that bind to the active site, the receptor binding site, or growth factor or other relevant binding site of the PRO polypeptide, thereby blocking the normal biological activity of the PRO polypeptide.
  • small molecules include, but are not limited to, small peptides or peptide-like molecules, preferably soluble peptides, and synthetic non-peptidyl organic or inorganic compounds.
  • Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA. Ribozymes act by sequence-specific hybridization to the complementary target RNA, followed by endonucleolytic cleavage. Specific ribozyme cleavage sites within a potential RNA target can be identified by known techniques. For further details see, e.g., Rossi, Current Biology, 4:469-471 (1994), and PCT publication No. WO 97/33551 (published Sep. 18, 1997).
  • Nucleic acid molecules in triple-helix formation used to inhibit transcription should be single-stranded and composed of deoxynucleotides.
  • the base composition of these oligonucleotides is designed such that it promotes triple-helix formation via Hoogsteen base-pairing rules, which generally require sizeable stretches of purines or pyrimidines on one strand of a duplex.
  • Hoogsteen base-pairing rules which generally require sizeable stretches of purines or pyrimidines on one strand of a duplex.
  • Diagnostic and therapeutic uses of the herein disclosed molecules may also be based upon the positive functional assay hits disclosed and described below.
  • the present invention further provides anti-PRO antibodies.
  • Exemplary antibodies include polyclonal, monoclonal, humanized, bispecific, and heteroconjugate antibodies.
  • the anti-PRO antibodies may comprise polyclonal antibodies. Methods of preparing polyclonal antibodies are known to the skilled artisan. Polyclonal antibodies can be raised in a mammal, for example, by one or more injections of an immunizing agent and, if desired, an adjuvant. Typically, the immunizing agent and/or adjuvant will be injected in the mammal by multiple subcutaneous or intraperitoneal injections.
  • the immunizing agent may include the PRO polypeptide or a fusion protein thereof. It may be useful to conjugate the immunizing agent to a protein known to be immunogenic in the mammal being immunized.
  • immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor.
  • adjuvants which may be employed include Freund's complete adjuvant and MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).
  • the immunization protocol may be selected by one skilled in the art without undue experimentation.
  • the anti-PRO antibodies may, alternatively, be monoclonal antibodies.
  • Monoclonal antibodies may be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975).
  • a hybridoma method a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent.
  • the lymphocytes may be immunized in vitro.
  • the immunizing agent will typically include the PRO polypeptide or a fusion protein thereof.
  • PBLs peripheral blood lymphocytes
  • spleen cells or lymph node cells are used if non-human mammalian sources are desired.
  • the lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell [Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-103].
  • Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin.
  • rat or mouse myeloma cell lines are employed.
  • the hybridoma cells may be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells.
  • a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells.
  • the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (“HAT medium”), which substances prevent the growth of HGPRT-deficient cells.
  • Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, California and the American Type Culture Collection, Manassas, Va. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies [Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51-63].
  • the culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against PRO.
  • the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA).
  • RIA radioimmunoassay
  • ELISA enzyme-linked immunoabsorbent assay
  • the binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107:220 (1980).
  • the clones may be subcloned by limiting dilution procedures and grown by standard methods [Goding, supra]. Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI -1640 medium. Alternatively, the hybridoma cells may be grown in vivo as ascites in a mammal.
  • the monoclonal antibodies secreted by the subclones may be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
  • the monoclonal antibodies may also be made by recombinant DNA methods, such as those described in U.S. Pat. No. 4,816,567.
  • DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies).
  • the hybridoma cells of the invention serve as a preferred source of such DNA.
  • the DNA may be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells.
  • host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells.
  • the DNA also may be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences [U.S. Pat. No. 4,816,567; Morrison et al., supra] or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide.
  • non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.
  • the antibodies may be monovalent antibodies.
  • Methods for preparing monovalent antibodies are well known in the art. For example, one method involves recombinant expression of immunoglobulin light chain and modified heavy chain.
  • the heavy chain is truncated generally at any point in the Fc region so as to prevent heavy chain crosslinking.
  • the relevant cysteine residues are substituted with another amino acid residue or are deleted so as to prevent crosslinking.
  • the anti-PRO antibodies of the invention may further comprise humanized antibodies or human antibodies.
  • Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab′, F(ab′) 2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin.
  • Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity.
  • CDR complementary determining region
  • Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence.
  • the humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin [ones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992)].
  • Fc immunoglobulin constant region
  • a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain.
  • Humanization can be essentially performed following the method of Winter and co-workers [ones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1 534-1536 (1988)], by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody.
  • rodent CDRs or CDR sequences for the corresponding sequences of a human antibody.
  • such “humanized” antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species.
  • humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
  • Human antibodies can also be produced using various techniques known in the art, including phage display libraries [Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)].
  • the techniques of Cole et al. and Boerner et al. are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boerner et al., J. Immunol., 147(1):86-95 (1991)].
  • human antibodies can be made by introducing of human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Pat. Nos.
  • the antibodies may also be affinity matured using known selection and/or mutagenesis methods as described above.
  • Preferred affinity matured antibodies have an affinity which is five times, more preferably 10 times, even more preferably 20 or 30 times greater than the starting antibody (generally murine, humanized or human) from which the matured antibody is prepared.
  • Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens.
  • one of the binding specificities is for the PRO, the other one is for any other antigen, and preferably for a cell-surface protein or receptor or receptor subunit.
  • bispecific antibodies Methods for making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities [Milstein and Cuello, Nature, 305:537-539 (1983)]. Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO 93/08829, published May 13, 1993, and in Traunecker et al., EMBO J., 10:3655-3659 (1991).
  • Antibody variable domains with the desired binding specificities can be fused to immunoglobulin constant domain sequences.
  • the fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region (CH1) containing the site necessary for light-chain binding present in at least one of the fusions.
  • DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain are inserted into separate expression vectors, and are co-transfected into a suitable host organism.
  • the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture.
  • the preferred interface comprises at least a part of the CH3 region of an antibody constant domain.
  • one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g. tyrosine or tryptophan).
  • Compensatory “cavities” of identical or similar size to the large side chain (s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers.
  • Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g. F(ab′) 2 bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al., Science 229:81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab′) 2 fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab′ fragments generated are then converted to thionitrobenzoate (TNB) derivatives.
  • TAB thionitrobenzoate
  • One of the Fab′-TNB derivatives is then reconverted to the Fab′-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab′-TNB derivative to form the bispecific antibody.
  • the bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.
  • Fab′ fragments may be directly recovered from E. coli and chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175:217(1992) describe the production of a fully humanized bispecific antibody F(ab′) 2 molecule. Each Fab′ fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger-the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.
  • bispecific antibodies have been produced using leucine zippers.
  • the leucine zipper peptides from the Fos and Jun proteins were linked to the Fab′ portions of two different antibodies by gene fusion.
  • the antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers.
  • the fragments comprise a heavy-chain variable domain (V H ) connected to a light-chain variable domain (V L ) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the V H and V L domains of one fragment are forced to pair with the complementary V L and V H domains of another fragment, thereby forming two antigen-binding sites.
  • V H and V L domains of one fragment are forced to pair with the complementary V L and V H domains of another fragment, thereby forming two antigen-binding sites.
  • sFv single-chain Fv
  • Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See, Gruber et al., J. Immunol. 152:5368 (1994). Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991).
  • bispecific antibodies may bind to two different epitopes on a given PRO polypeptide herein.
  • an anti-PRO polypeptide arm may be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2, CD3, CD28, or B7), or Fc receptors for IgG (Fc y R), such as Fc y RI (CD64), Fc y RII (CD32) and Fc y RIII (CD16) so as to focus cellular defense mechanisms to the cell expressing the particular PRO polypeptide.
  • Bispecific antibodies may also be used to localize cytotoxic agents to cells which express a particular PRO polypeptide.
  • These antibodies possess a PRO-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA.
  • a cytotoxic agent or a radionuclide chelator such as EOTUBE, DPTA, DOTA, or TETA.
  • Another bispecific antibody of interest binds the PRO polypeptide and further binds tissue factor (TF).
  • Heteroconjugate antibodies are also within the scope of the present invention.
  • Heteroconjugate antibodies are composed of two covalentlyjoined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells [U.S. Pat. No. 4,676,980], and for treatment of HIV infection [WO 91/00360; WO 92/200373; EP 03089].
  • the antibodies may be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents.
  • immunotoxins may be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S. Pat. No. 4,676,980.
  • cysteine residue(s) may be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region.
  • the homodimeric antibody thus generated may have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et al., J. Exp Med., 176: 1191-1195 (1992) and Shopes, J. Immunol., 148: 2918-2922 (1992).
  • Homodimeric antibodies with enhanced anti-tumor activity may also be prepared using heterobifunctional cross-linkers as described in Wolff et al. Cancer Research, 53: 2560-2565 (1993).
  • an antibody can be engineered that has dual Fc regions and may thereby have enhanced complement lysis and ADCC capabilities. See Stevenson et al., Anti-Cancer Drug Design, 3: 219-230 (1989).
  • the invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).
  • a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).
  • Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa ), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.
  • radionuclides are available for the production of radioconjugated antibodies. Examples include 212 Bi, 131 I, 131 In, 90 Y, and 186 Re. Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyidithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis
  • a ricin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987).
  • Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyidiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO 94/11026.
  • the antibody may be conjugated to a “receptor” (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a “ligand” (e.g., avidin) that is conjugated to a cytotoxic agent (e.g., a radionucleotide).
  • a receptor such streptavidin
  • a ligand e.g., avidin
  • cytotoxic agent e.g., a radionucleotide
  • the antibodies disclosed herein may also be formulated as immunoliposomes.
  • Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., Proc. Natl Acad. Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Pat. No. 5,013,556.
  • Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.
  • Fab′ fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin et al., J. Biol. Chem., 257: 286-288 (1982) via a disulfide-interchange reaction.
  • a chemotherapeutic agent such as Doxorubicin is optionally contained within the liposome. See Gabizon et al., J. National Cancer Inst., 81(19): 1484 (1989).
  • Antibodies specifically binding a PRO polypeptide identified herein, as well as other molecules identified by the screening assays disclosed hereinbefore, can be administered for the treatment of various disorders in the form of pharmaceutical compositions.
  • the PRO polypeptide is intracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred.
  • lipofections or liposomes can also be used to deliver the antibody, or an antibody fragment, into cells.
  • the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred.
  • peptide molecules can be designed that retain the ability to bind the target protein sequence.
  • Such peptides can be synthesized chemically and/or produced by recombinant DNA technology. See, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA, 90: 7889-7893 (1993).
  • the formulation herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other.
  • the composition may comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent.
  • cytotoxic agent such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent.
  • Such molecules are suitably present in combination in amounts that are effective for the purpose intended.
  • the active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methyl methacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules
  • formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.
  • Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No.
  • copolymers of L-glutamic acid and y ethyl-L-glutamate non-degradable ethylene-vinyl acetate
  • degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate)
  • poly-D-( ⁇ )-3-hydroxybutyric acid While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods.
  • encapsulated antibodies When encapsulated antibodies remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37° C., resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies can be devised for stabilization depending on the mechanism involved. For example, if the aggregation mechanism is discovered to be intermolecular S-S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.
  • anti-PRO antibodies of the invention have various utilities.
  • anti-PRO antibodies may be used in diagnostic assays for PRO, e.g., detecting its expression (and in some cases, differential expression) in specific cells, tissues, or serum.
  • diagnostic assay techniques known in the art may be used, such as competitive binding assays, direct or indirect sandwich assays and immunoprecipitation assays conducted in either heterogeneous or homogeneous phases [Zola, Monoclonal Antibodies: A Manual of Techniques, CRC Press, Inc. (1987) pp.147-158].
  • the antibodies used in the diagnostic assays can be labeled with a detectable moiety.
  • the detectable moiety should be capable of producing, either directly or indirectly, a detectable signal.
  • the detectable moiety may be a radioisotope, such as 3 H, 14 C, 32 P, 35 S, or 125 I, a fluorescent or chemiluminescent compound, such as fluorescein isothiocyanate, rhodamine, or luciferin, or an enzyme, such as alkaline phosphatase, beta-galactosidase or horseradish peroxidase.
  • a radioisotope such as 3 H, 14 C, 32 P, 35 S, or 125 I
  • a fluorescent or chemiluminescent compound such as fluorescein isothiocyanate, rhodamine, or luciferin
  • an enzyme such as alkaline phosphatase, beta-galactosidase or horseradish peroxidase.
  • Any method known in the art for conjugating the antibody to the detectable moiety may be employed, including those methods described by Hunter et al., Nature, 144:945 (1962); David et
  • Anti-PRO antibodies also are useful for the affinity purification of PRO from recombinant cell culture or natural sources.
  • the antibodies against PRO are immobilized on a suitable support, such as Sephadex resin or filter paper, using methods well known in the art.
  • the immobilized antibody then is contacted with a sample containing the PRO to be purified, and thereafter the support is washed with a suitable solvent that will remove substantially all the material in the sample except the PRO, which is bound to the immobilized antibody. Finally, the support is washed with another suitable solvent that will release the PRO from the antibody.
  • the extracellular domain (ECD) sequences (including the secretion signal sequence, if any) from about 950 known secreted proteins from the Swiss-Prot public database were used to search EST databases.
  • the EST databases included public databases (e.g., Dayhoff, GenBank), and proprietary databases (e.g. LIFESEQTM, Incyte Pharmaceuticals, Palo Alto, Calif.).
  • the search was performed using the computer program BLAST or BLAST-2 (Altschul et al., Methods in Enzymology 266:460-480 (1996)) as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequences. Those comparisons with a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program “phrap” (Phil Green, University of Washington, Seattle, Wash.).
  • oligonucleotides were then synthesized and used to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for a PRO polypeptide.
  • Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length.
  • the probe sequences are typically 40-55 bp in length.
  • additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-1.5 kbp.
  • DNA from the libraries was screened by PCR amplification, as per Ausubel et al., Current Protocols in Molecular Biology, with the PCR primer pair. A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pairs.
  • the cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif.
  • the cDNA was primed with oligo dT containing a NotI site, linked with blunt to SalI hemikinased adaptors, cleaved with NotI, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and NotI sites.
  • a suitable cloning vector such as pRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes
  • mRNA was isolated from a human tissue of interest using reagents and protocols from Invitrogen, San Diego, Calif. (Fast Track 2). This RNA was used to generate an oligo dT primed cDNA library in the vector pRK5D using reagents and protocols from Life Technologies, Gaithersburg, Md. (Super Script Plasmid System). In this procedure, the double stranded cDNA was sized to greater than 1000 bp and the SalI/NotI linkered cDNA was cloned into XhoI/NotI cleaved vector.
  • pRK5D is a cloning vector that has an sp6 transcription initiation site followed by an SfiI restriction enzyme site preceding the XhoI/NotI cDNA cloning sites.
  • a secondary cDNA library was generated in order to preferentially represent the 5′ ends of the primary cDNA clones.
  • Sp6 RNA was generated from the primary library (described above), and this RNA was used to generate a random primed cDNA library in the vector pSST-AMY.0 using reagents and protocols from Life Technologies (Super Script Plasmid System, referenced above). In this procedure the double stranded cDNA was sized to 500-1000 bp, Tinkered with blunt to NotI adaptors, cleaved with SfiI, and cloned into SfiI/NotI cleaved vector.
  • pSST-AMY.0 is a cloning vector that has a yeast alcohol dehydrogenase promoter preceding the cDNA cloning sites and the mouse amylase sequence (the mature sequence without the secretion signal) followed by the yeast alcohol dehydrogenase terminator, after the cloning sites.
  • cDNAs cloned into this vector that are fused in frame with amylase sequence will lead to the secretion of amylase from appropriately transfected yeast colonies.
  • DNA from the library described in paragraph 2 above was chilled on ice to which was added electrocompetent DH10B bacteria (Life Technologies, 20 ml). The bacteria and vector mixture was then electroporated as recommended by the manufacturer. Subsequently, SOC media (Life Technologies, 1 ml) was added and the mixture was incubated at 37° C. for 30 minutes. The transformants were then plated onto 20 standard 150 mm LB plates containing ampicillin and incubated for 16 hours (37° C.). Positive colonies were scraped off the plates and the DNA was isolated from the bacterial pellet using standard protocols, e.g. CsCl-gradient. The purified DNA was then carried on to the yeast protocols below.
  • yeast methods were divided into three categories: (1) Transformation of yeast with the plasmid/cDNA combined vector; (2) Detection and isolation of yeast clones secreting amylase; and (3) PCR amplification of the insert directly from the yeast colony and purification of the DNA for sequencing and further analysis.
  • yeast strain used was HD56-5A (ATCC-90785). This strain has the following genotype: MAT alpha, ura3-52, leu2-3, leu2-112, his3-11, his3-15, MAL + , SUC + , GAL + .
  • yeast mutants can be employed that have deficient post-translational pathways. Such mutants may have translocation deficient alleles in sec 71, sec72, sec62, with truncated sec71 being most preferred.
  • antagonists including antisense nucleotides and/or ligands which interfere with the normal operation of these genes, other proteins implicated in this post translation pathway (e.g., SEC61 p, SEC72p, SEC62p, SEC63p, TDJ1 p or SSA1p-4p) or the complex formation of these proteins may also be preferably employed in combination with the amylase-expressing yeast.
  • other proteins implicated in this post translation pathway e.g., SEC61 p, SEC72p, SEC62p, SEC63p, TDJ1 p or SSA1p-4p
  • the complex formation of these proteins may also be preferably employed in combination with the amylase-expressing yeast.
  • the cells were then harvested and prepared for transformation by transfer into GS3 rotor bottles in a Sorval GS3 rotor at 5,000 rpm for 5 minutes, the supernatant discarded, and then resuspended into sterile water, and centrifuged again in 50 ml falcon tubes at 3,500 rpm in a Beckman GS-6KR centrifuge. The supernatant was discarded and the cells were subsequently washed with LiAc/TE (10 ml, 10 mM Tris-HCl, 1 mM EDTA pH 7.5, 100 mM Li 2 OOCCH 3 ), and resuspended into LiAc/TE (2.5 ml).
  • LiAc/TE 10 ml, 10 mM Tris-HCl, 1 mM EDTA pH 7.5, 100 mM Li 2 OOCCH 3
  • Transformation took place by mixing the prepared cells (100 ⁇ l) with freshly denatured single stranded salmon testes DNA (Lofstrand Labs, Gaithersburg, Md.) and transforming DNA (1 ⁇ g, vol. ⁇ 10 ⁇ l) in microfuge tubes. The mixture was mixed briefly by vortexing, then 40% PEG/TE (600 ⁇ l, 40% polyethylene glycol-4000, 10 mM Tris-HCl, 1 mM EDTA, 100 mM Li 2 OOCCH 3 , pH 7.5) was added. This mixture was gently mixed and incubated at 30° C. while agitating for 30 minutes. The cells were then heat shocked at 42° C.
  • TE 500 ⁇ l, 10 mM Tris-HCl, 1 mM EDTA pH 7.5
  • the cells were then diluted into TE (1 ml) and aliquots (200 ⁇ l) were spread onto the selective media previously prepared in 150 mm growth plates (VWR).
  • the selective media used was a synthetic complete dextrose agar lacking uracil (SCD-Ura) prepared as described in Kaiser et al., Methods in Yeast Genetics, Cold Spring Harbor Press, Cold Spring Harbor, N.Y., p. 208-210 (1994). Transformants were grown at 30° C. for 2-3 days.
  • the detection of colonies secreting amylase was performed by including red starch in the selective growth media.
  • Starch was coupled to the red dye (Reactive Red-120, Sigma) as per the procedure described by Biely et al., Anal. Biochem., 172:1 76-179 (1988).
  • the coupled starch was incorporated into the SCD-Ura agar plates at a final concentration of 0.15% (w/v), and was buffered with potassium phosphate to a pH of 7.0 (50-100 mM final concentration).
  • the positive colonies were picked and streaked across fresh selective media (onto 150 mm plates) in order to obtain well isolated and identifiable single colonies.
  • Well isolated single colonies positive for amylase secretion were detected by direct incorporation of red starch into buffered SCD-Ura agar. Positive colonies were determined by their ability to break down starch resulting in a clear halo around the positive colony visualized directly.
  • the sequence of the forward oligonucleotide 1 was: 5′-TGTAAAACGACGGCCAGTTAAATAGACCTGCAATTATTAATCT-3′ (SEQ ID NO:170)
  • the sequence of reverse oligonucleotide 2 was: 5′-CAGGAAACAGCTATGACCACCTGCACACCTGCAAATCCATT-3′
  • PCR was then performed as follows: a. Denature 92° C., 5 minutes b. 3 cycles of: Denature 92° C., 30 seconds Anneal 59° C., 30 seconds Extend 72° C., 60 seconds c. 3 cycles of: Denature 92° C., 30 seconds Anneal 57° C., 30 seconds Extend 72° C., 60 seconds d. 25 cycles of: Denature 92° C., 30 seconds Anneal 55° C., 30 seconds Extend 72° C., 60 seconds e. Hold 4° C.
  • the underlined regions of the oligonucleotides annealed to the ADH promoter region and the amylase region, respectively, and amplified a 307 bp region from vector pSST-AMY.0 when no insert was present.
  • the first 18 nucleotides of the 5′ end of these oligonucleotides contained annealing sites for the sequencing primers.
  • the total product of the PCR reaction from an empty vector was 343 bp.
  • signal sequence-fused cDNA resulted in considerably longer nucleotide sequences.
  • Various polypeptide-encoding nucleic acid sequences were identified by applying a proprietary signal sequence finding algorithm developed by Genentech, Inc. (South San Francisco, Calif.) upon ESTs as well as clustered and assembled EST fragments from public (e.g., GenBank) and/or private (LIFESEQ®, Incyte Pharmaceuticals, Inc., Palo Alto, Calif.) databases.
  • the signal sequence algorithm computes a secretion signal score based on the character of the DNA nucleotides surrounding the first and optionally the second methionine codon(s) (ATG) at the 5′-end of the sequence or sequence fragment under consideration.
  • the nucleotides following the first ATG must code for at least 35 unambiguous amino acids without any stop codons. If the first ATG has the required amino acids, the second is not examined. If neither meets the requirement, the candidate sequence is not scored.
  • the DNA and corresponding amino acid sequences surrounding the ATG codon are scored using a set of seven sensors (evaluation parameters) known to be associated with secretion signals. Use of this algorithm resulted in the identification of numerous polypeptide-encoding nucleic acid sequences.
  • the following method describes use of a nucleotide sequence encoding PRO as a hybridization probe.
  • DNA comprising the coding sequence of full-length or mature PRO as disclosed herein is employed as a probe to screen for homologous DNAs (such as those encoding naturally-occurring variants of PRO) in human tissue cDNA libraries or human tissue genomic libraries.
  • Hybridization and washing of filters containing either library DNAs is performed under the following high stringency conditions.
  • Hybridization of radiolabeled PRO-derived probe to the filters is performed in a solution of 50% formamide, 5 ⁇ SSC, 0.1% SDS, 0.1% sodium pyrophosphate, 50 mM sodium phosphate, pH 6.8, 2 ⁇ Denhardt's solution, and 10% dextran sulfate at 42° C. for 20 hours. Washing of the filters is performed in an aqueous solution of 0.1 ⁇ SSC and 0.1% SDS at 42° C.
  • DNAs having a desired sequence identity with the DNA encoding full-length native sequence PRO can then be identified using standard techniques known in the art.
  • This example illustrates preparation of an unglycosylated form of PRO by recombinant expression in E. coli.
  • the DNA sequence encoding PRO is initially amplified using selected PCR primers.
  • the primers should contain restriction enzyme sites which correspond to the restriction enzyme sites on the selected expression vector.
  • restriction enzyme sites which correspond to the restriction enzyme sites on the selected expression vector.
  • a variety of expression vectors may be employed.
  • An example of a suitable vector is pBR322 (derived from E. coli; see Bolivar et al., Gene, 2:95 (1977)) which contains genes for ampicillin and tetracycline resistance.
  • the vector is digested with restriction enzyme and dephosphorylated.
  • the PCR amplified sequences are then ligated into the vector.
  • the vector will preferably include sequences which encode for an antibiotic resistance gene, a trp promoter, a polyhis leader (including the first six STII codons, polyhis sequence, and enterokinase cleavage site), the PRO coding region, lambda transcriptional terminator, and an argU gene.
  • the ligation mixture is then used to transform a selected E. coli strain using the methods described in Sambrook et al., supra. Transformants are identified by their ability to grow on LB plates and antibiotic resistant colonies are then selected. Plasmid DNA can be isolated and confirmed by restriction analysis and DNA sequencing.
  • Selected clones can be grown overnight in liquid culture medium such as LB broth supplemented with antibiotics.
  • the overnight culture may subsequently be used to inoculate a larger scale culture.
  • the cells are then grown to a desired optical density, during which the expression promoter is turned on.
  • the cells After culturing the cells for several more hours, the cells can be harvested by centrifugation.
  • the cell pellet obtained by the centrifugation can be solubilized using various agents known in the art, and the solubilized PRO protein can then be purified using a metal chelating column under conditions that allow tight binding of the protein.
  • PRO may be expressed in E. coli in a poly-His tagged form, using the following procedure.
  • the DNA encoding PRO is initially amplified using selected PCR primers.
  • the primers will contain restriction enzyme sites which correspond to the restriction enzyme sites on the selected expression vector, and other useful sequences providing for efficient and reliable translation initiation, rapid purification on a metal chelation column, and proteolytic removal with enterokinase.
  • the PCR-amplified, poly-His tagged sequences are then ligated into an expression vector, which is used to transform an E. coli host based on strain 52 (W3110 fuhA(tonA) Ion galE rpoHts (htpRts) cIpP(laclq).
  • Transformants are first grown in LB containing 50 mg/ml carbenicillin at 30° C. with shaking until an O.D.600 of 3-5 is reached. Cultures are then diluted 50-100 fold into CRAP media (prepared by mixing 3.57 g (NH 4 ) 2 SO 4 , 0.71 g sodium citrate-2H2O, 1.07 g KCl, 5.36 g Difco yeast extract, 5.36 g Sheffield hycase SF in 500 mL water, as well as 110 mM MPOS, pH 7.3, 0.55% (w/v) glucose and 7 mM MgSO 4 ) and grown for approximately 20-30 hours at 30° C. with shaking. Samples are removed to verify expression by SDS-page analysis, and the bulk culture is centrifuged to pellet the cells. Cell pellets are frozen until purification and refolding.
  • CRAP media prepared by mixing 3.57 g (NH 4 ) 2 SO 4 , 0.71 g sodium citrate-2H2O, 1.07 g KCl,
  • E. coli paste from 0.5 to 1 L fermentations (6-10 g pellets) is resuspended in 10 volumes (w/v) in 7 M guanidine, 20 mM Tris, pH 8 buffer.
  • Solid sodium sulfite and sodium tetrathionate is added to make final concentrations of 0.1 M and 0.02 M, respectively, and the solution is stirred overnight at 4° C. This step results in a denatured protein with all cysteine residues blocked by sulfitolization.
  • the solution is centrifuged at 40,000 rpm in a Beckman Ultracentifuge for 30 min.
  • the supernatant is diluted with 3-5 volumes of metal chelate column buffer (6 M guanidine, 20 mM Tris, pH 7.4) and filtered through 0.22 micron filters to clarify.
  • the clarified extract is loaded onto a 5 ml Qiagen Ni-NTA metal chelate column equilibrated in the metal chelate column buffer.
  • the column is washed with additional buffer containing 50 mM imidazole (Calbiochem, Utrol grade), pH 7.4.
  • the protein is eluted with buffer containing 250 mM imidazole. Fractions containing the desired protein are pooled and stored at 4° C. Protein concentration is estimated by its absorbance at 280 nm using the calculated extinction coefficient based on its amino acid sequence.
  • the proteins are refolded by diluting the sample slowly into freshly prepared refolding buffer consisting of: 20 mM Tris, pH 8.6, 0.3 M NaCl, 2.5 M urea, 5 mM cysteine, 20 mM glycine and 1 mM EDTA. Refolding volumes are chosen so that the final protein concentration is between 50 to 100 micrograms/ml.
  • the refolding solution is stirred gently at 4° C. for 12-36 hours.
  • the refolding reaction is quenched by the addition of TFA to a final concentration of 0.4% (pH of approximately 3).
  • the solution is filtered through a 0.22 micron filter and acetonitrile is added to 2-10% final concentration.
  • the refolded protein is chromatographed on a Poros R1/H reversed phase column using a mobile buffer of 0.1% TFA with elution with a gradient of acetonitrile from 10 to 80%. Aliquots of fractions with A280 absorbance are analyzed on SDS polyacrylamide gels and fractions containing homogeneous refolded protein are pooled. Generally, the properly refolded species of most proteins are eluted at the lowest concentrations of acetonitrile since those species are the most compact with their hydrophobic interiors shielded from interaction with the reversed phase resin. Aggregated species are usually eluted at higher acetonitrile concentrations. In addition to resolving misfolded forms of proteins from the desired form, the reversed phase step also removes endotoxin from the samples.
  • Fractions containing the desired folded PRO polypeptide are pooled and the acetonitrile removed using a gentle stream of nitrogen directed at the solution. Proteins are formulated into 20 mM Hepes, pH 6.8 with 0.14 M sodium chloride and 4% mannitol by dialysis or by gel filtration using G25 Superfine (Pharmacia) resins equilibrated in the formulation buffer and sterile filtered.
  • This example illustrates preparation of a potentially glycosylated form of PRO by recombinant expression in mammalian cells.
  • the vector, pRK5 (see EP 307,247, published Mar. 15, 1989), is employed as the expression vector.
  • the PRO DNA is ligated into pRK5 with selected restriction enzymes to allow insertion of the PRO DNA using ligation methods such as described in Sambrook et al., supra.
  • the resulting vector is called pRK5-PRO.
  • the selected host cells may be 293 cells.
  • Human 293 cells (ATCC CCL 1573) are grown to confluence in tissue culture plates in medium such as DMEM supplemented with fetal calf serum and optionally, nutrient components and/or antibiotics.
  • About 10 ⁇ g pRK5-PRO DNA is mixed with about 1 ⁇ g DNA encoding the VA RNA gene [Thimmappaya et al., Cell, 31:543 (1982)] and dissolved in 500 ⁇ l of 1 mM Tris-HCl, 0.1 mM EDTA, 0.227 M CaCl 2 .
  • the culture medium is removed and replaced with culture medium (alone) or culture medium containing 200 ⁇ Ci/ml 35 S-cysteine and 200 ⁇ Ci/ml 35 S-methionine.
  • culture medium alone
  • culture medium containing 200 ⁇ Ci/ml 35 S-cysteine and 200 ⁇ Ci/ml 35 S-methionine After a 12 hour incubation, the conditioned medium is collected, concentrated on a spin filter, and loaded onto a 1 5% SDS gel. The processed gel may be dried and exposed to film for a selected period of time to reveal the presence of PRO polypeptide.
  • the cultures containing transfected cells may undergo further incubation (in serum free medium) and the medium is tested in selected bioassays.
  • PRO may be introduced into 293 cells transiently using the dextran sulfate method described by Somparyrac et al., Proc. Natl. Acad. Sci., 12:7575 (1981). 293 cells are grown to maximal density in a spinner flask and 700 ⁇ g pRK5-PRO DNA is added. The cells are first concentrated from the spinner flask by centrifugation and washed with PBS. The DNA-dextran precipitate is incubated on the cell pellet for four hours.
  • the cells are treated with 20% glycerol for 90 seconds, washed with tissue culture medium, and re-introduced into the spinner flask containing tissue culture medium, 5 ⁇ g/ml bovine insulin and 0.1 ⁇ g/ml bovine transferrin. After about four days, the conditioned media is centrifuged and filtered to remove cells and debris. The sample containing expressed PRO can then be concentrated and purified by any selected method, such as dialysis and/or column chromatography.
  • PRO can be expressed in CHO cells.
  • the pRKS-PRO can be transfected into CHO cells using known reagents such as CaPO 4 or DEAE-dextran.
  • the cell cultures can be incubated, and the medium replaced with culture medium (alone) or medium containing a radiolabel such as 35 S-methionine.
  • the culture medium may be replaced with serum free medium.
  • the cultures are incubated for about 6 days, and then the conditioned medium is harvested.
  • the medium containing the expressed PRO can then be concentrated and purified by any selected method.
  • Epitope-tagged PRO may also be expressed in host CHO cells.
  • the PRO may be subcloned out of the pRK5 vector.
  • the subclone insert can undergo PCR to fuse in frame with a selected epitope tag such as a poly-his tag into a Baculovirus expression vector.
  • the poly-his tagged PRO insert can then be subcloned into a SV40 driven vector containing a selection marker such as DHFR for selection of stable clones.
  • the CHO cells can be transfected (as described above) with the SV40 driven vector. Labeling may be performed, as described above, to verify expression.
  • the culture medium containing the expressed poly-His tagged PRO can then be concentrated and purified by any selected method, such as by Ni 2+ -chelate affinity chromatography.
  • PRO may also be expressed in CHO and/or COS cells by a transient expression procedure or in CHO cells by another stable expression procedure.
  • Stable expression in CHO cells is performed using the following procedure.
  • the proteins are expressed as an IgG construct (immunoadhesin), in which the coding sequences for the soluble forms (e.g. extracellular domains) of the respective proteins are fused to an IgG1 constant region sequence containing the hinge, CH2 and CH2 domains and/or is a poly-His tagged form.
  • CHO expression vectors are constructed to have compatible restriction sites 5′ and 3′ of the DNA of interest to allow the convenient shuttling of cDNA's.
  • the vector used expression in CHO cells is as described in Lucas et al., Nucl. Acids Res. 24:9 (1774-1779 (1996), and uses the SV40 early promoter/enhancer to drive expression of the cDNA of interest and dihydrofolate reductase (DHFR).
  • DHFR expression permits selection for stable maintenance of the plasmid following transfection.
  • the ampules containing the plasmid DNA are thawed by placement into water bath and mixed by vortexing.
  • the contents are pipetted into a centrifuge tube containing 10 mLs of media and centrifuged at 1000 rpm for 5 minutes.
  • the supernatant is aspirated and the cells are resuspended in 10 mL of selective media (0.2 ⁇ m filtered PS20 with 5% 0.2 ⁇ m diafiltered fetal bovine serum).
  • the cells are then aliquoted into a 100 mL spinner containing 90 mL of selective media. After 1-2 days, the cells are transferred into a 250 mL spinner filled with 150 mL selective growth medium and incubated at 37° C.
  • spinners After another 2-3 days, 250 mL, 500 mL and 2000 mL spinners are seeded with 3 ⁇ 10 5 cells/mL.
  • the cell media is exchanged with fresh media by centrifugation and resuspension in production medium.
  • any suitable CHO media may be employed, a production medium described in U.S. Pat. No. 5,122,469, issued Jun. 16, 1992 may actually be used.
  • a 3L production spinner is seeded at 1.2 ⁇ 10 6 cells/mL. On day 0, the cell number pH is determined. On day 1, the spinner is sampled and sparging with filtered air is commenced.
  • the spinner On day 2, the spinner is sampled, the temperature shifted to 33° C., and 30 mL of 500 g/L glucose and 0.6 mL of 10% antifoam (e.g., 35% polydimethylsiloxane emulsion, Dow Corning 365 Medical Grade Emulsion) taken. Throughout the production, the pH is adjusted as necessary to keep it at around 7.2. After 10 days, or until the viability dropped below 70%, the cell culture is harvested by centrifugation and filtering through a 0.22 ⁇ m filter. The filtrate was either stored at 4° C. or immediately loaded onto columns for purification.
  • 10% antifoam e.g., 35% polydimethylsiloxane emulsion, Dow Corning 365 Medical Grade Emulsion
  • the proteins are purified using a Ni-NTA column (Qiagen). Before purification, imidazole is added to the conditioned media to a concentration of 5 mM. The conditioned media is pumped onto a 6 ml Ni-NTA column equilibrated in 20 mM Hepes, pH 7.4, buffer containing 0.3 M NaCl and 5 mM imidazole at a flow rate of 4-5 ml/min. at 4° C. After loading, the column is washed with additional equilibration buffer and the protein eluted with equilibration buffer containing 0.25 M imidazole.
  • the highly purified protein is subsequently desalted into a storage buffer containing 10 mM Hepes, 0.14 M NaCl and 4% mannitol, pH 6.8, with a 25 ml G25 Superfine (Pharmacia) column and stored at ⁇ 80° C.
  • Immunoadhesin (Fc-containing) constructs are purified from the conditioned media as follows.
  • the conditioned medium is pumped onto a 5 ml Protein A column (Pharmacia) which had been equilibrated in 20 mM Na phosphate buffer, pH 6.8. After loading, the column is washed extensively with equilibration buffer before elution with 100 mM citric acid, pH 3.5.
  • the eluted protein is immediately neutralized by collecting 1 ml fractions into tubes containing 275 ⁇ L of 1 M Tris buffer, pH 9.
  • the highly purified protein is subsequently desalted into storage buffer as described above for the poly-His tagged proteins. The homogeneity is assessed by SDS polyacrylamide gels and by N-terminal amino acid sequencing by Edman degradation.
  • yeast expression vectors are constructed for intracellular production or secretion of PRO from the ADH2/GAPDH promoter.
  • DNA encoding PRO and the promoter is inserted into suitable restriction enzyme sites in the selected plasmid to direct intracellular expression of PRO.
  • DNA encoding PRO can be cloned into the selected plasmid, together with DNA encoding the ADH2/GAPDH promoter, a native PRO signal peptide or other mammalian signal peptide, or, for example, a yeast alpha-factor or invertase secretory signal/leader sequence, and linker sequences (if needed) for expression of PRO.
  • yeast cells such as yeast strain AB110
  • yeast cells can then be transformed with the expression plasmids described above and cultured in selected fermentation media.
  • the transformed yeast supernatants can be analyzed by precipitation with 10% trichloroacetic acid and separation by SDS-PAGE, followed by staining of the gels with Coomassie Blue stain.
  • Recombinant PRO can subsequently be isolated and purified by removing the yeast cells from the fermentation medium by centrifugation and then concentrating the medium using selected cartridge filters.
  • the concentrate containing PRO may further be purified using selected column chromatography resins.
  • sequence coding for PRO is fused upstream of an epitope tag contained within a baculovirus expression vector.
  • epitope tags include poly-his tags and immunoglobulin tags (like Fc regions of IgG).
  • a variety of plasmids may be employed, including plasmids derived from commercially available plasmids such as pVL1393 (Novagen).
  • the sequence encoding PRO or the desired portion of the coding sequence of PRO such as the sequence encoding the extracellular domain of a transmembrane protein or the sequence encoding the mature protein if the protein is extracellular is amplified by PCR with primers complementary to the 5′ and 3′ regions.
  • the 5′ primer may incorporate flanking (selected) restriction enzyme sites.
  • the product is then digested with those selected restriction enzymes and subcloned into the expression vector.
  • Recombinant baculovirus is generated by co-transfecting the above plasmid and BaculoGoldTM virus DNA (Pharmingen) into Spodoptera frugiperda (“Sf9”) cells (ATCC CRL 1711) using lipofectin (commercially available from GIBCO-BRL). After 4-5 days of incubation at 28° C., the released viruses are harvested and used for further amplifications. Viral infection and protein expression are performed as described by O'Reilley et al., Baculovirus expression vectors: A Laboratory Manual, Oxford: Oxford University Press (1994).
  • Expressed poly-his tagged PRO can then be purified, for example, by Ni 2+ -chelate affinity chromatography as follows. Extracts are prepared from recombinant virus-infected Sf9 cells as described by Rupert et al., Nature, 362:175-179 (1993). Briefly, Sf9 cells are washed, resuspended in sonication buffer (25 mL Hepes, pH 7.9; 12.5 mM MgCl 2 ; 0.1 mM EDTA; 10% glycerol; 0.1% NP-40; 0.4 M KCl), and sonicated twice for 20 seconds on ice.
  • sonication buffer 25 mL Hepes, pH 7.9; 12.5 mM MgCl 2 ; 0.1 mM EDTA; 10% glycerol; 0.1% NP-40; 0.4 M KCl
  • the sonicates are cleared by centrifugation, and the supernatant is diluted 50-fold in loading buffer (50 mM phosphate, 300 mM NaCl, 10% glycerol, pH 7.8) and filtered through a 0.45 ⁇ m filter.
  • loading buffer 50 mM phosphate, 300 mM NaCl, 10% glycerol, pH 7.8
  • a Ni 2+ -NTA agarose column (commercially available from Qiagen) is prepared with a bed volume of 5 mL, washed with 25 mL of water and equilibrated with 25 mL of loading buffer.
  • the filtered cell extract is loaded onto the column at 0.5 mL per minute.
  • the column is washed to baseline A 280 with loading buffer, at which point fraction collection is started.
  • the column is washed with a secondary wash buffer (50 mM phosphate; 300 mM NaCl, 10% glycerol, pH 6.0), which elutes nonspecifically bound protein.
  • a secondary wash buffer 50 mM phosphate; 300 mM NaCl, 10% glycerol, pH 6.0
  • the column is developed with a 0 to 500 mM Imidazole gradient in the secondary wash buffer.
  • One mL fractions are collected and analyzed by SDS-PAGE and silver staining or Western blot with Ni 2+ -NTA-conjugated to alkaline phosphatase (Qiagen). Fractions containing the eluted His 10 -tagged PRO are pooled and dialyzed against loading buffer.
  • purification of the IgG tagged (or Fc tagged) PRO can be performed using known chromatography techniques, including for instance, Protein A or protein G column chromatography.
  • This example illustrates preparation of monoclonal antibodies which can specifically bind PRO.
  • Immunogens that may be employed include purified PRO, fusion proteins containing PRO, and cells expressing recombinant PRO on the cell surface. Selection of the immunogen can be made by the skilled artisan without undue experimentation.
  • mice such as Balb/c are immunized with the PRO immunogen emulsified in complete Freund's adjuvant and injected subcutaneously or intraperitoneally in an amount from 1-100 micrograms.
  • the immunogen is emulsified in MPL-TDM adjuvant (Ribi Immunochemical Research, Hamilton, Mont.) and injected into the animal's hind foot pads.
  • MPL-TDM adjuvant Ribi Immunochemical Research, Hamilton, Mont.
  • the immunized mice are then boosted 10 to 12 days later with additional immunogen emulsified in the selected adjuvant. Thereafter, for several weeks, the mice may also be boosted with additional immunization injections. Serum samples may be periodically obtained from the mice by retro-orbital bleeding for testing in ELISA assays to detect anti-PRO antibodies.
  • the animals “positive” for antibodies can be injected with a final intravenous injection of PRO.
  • the mice Three to four days later, the mice are sacrificed and the spleen cells are harvested.
  • the spleen cells are then fused (using 35% polyethylene glycol) to a selected murine myeloma cell line such as P3X63AgU.1, available from ATCC, No. CRL 1597.
  • the fusions generate hybridoma cells which can then be plated in 96 well tissue culture plates containing HAT (hypoxanthine, aminopterin, and thymidine) medium to inhibit proliferation of non-fused cells, myeloma hybrids, and spleen cell hybrids.
  • HAT hyperxanthine, aminopterin, and thymidine
  • hybridoma cells will be screened in an ELISA for reactivity against PRO. Determination of “positive” hybridoma cells secreting the desired monoclonal antibodies against PRO is within the skill in the art.
  • the positive hybridoma cells can be injected intraperitoneally into syngeneic Balb/c mice to produce ascites containing the anti-PRO monoclonal antibodies.
  • the hybridoma cells can be grown in tissue culture flasks or roller bottles. Purification of the monoclonal antibodies produced in the ascites can be accomplished using ammonium sulfate precipitation, followed by gel exclusion chromatography. Alternatively, affinity chromatography based upon binding of antibody to protein A or protein G can be employed.
  • Native or recombinant PRO polypeptides may be purified by a variety of standard techniques in the art of protein purification. For example, pro-PRO polypeptide, mature PRO polypeptide, or pre-PRO polypeptide is purified by immunoaffinity chromatography using antibodies specific for the PRO polypeptide of interest. In general, an immunoaffinity column is constructed by covalently coupling the anti-PRO polypeptide antibody to an activated chromatographic resin.
  • Polyclonal immunoglobulins are prepared from immune sera either by precipitation with ammonium sulfate or by purification on immobilized Protein A (Pharmacia LKB Biotechnology, Piscataway, N.J.). Likewise, monoclonal antibodies are prepared from mouse ascites fluid by ammonium sulfate precipitation or chromatography on immobilized Protein A. Partially purified immunoglobulin is covalently attached to a chromatographic resin such as CnBr-activated SEPHAROSETM (Pharmacia LKB Biotechnology). The antibody is coupled to the resin, the resin is blocked, and the derivative resin is washed according to the manufacturer's instructions.
  • a chromatographic resin such as CnBr-activated SEPHAROSETM (Pharmacia LKB Biotechnology). The antibody is coupled to the resin, the resin is blocked, and the derivative resin is washed according to the manufacturer's instructions.
  • Such an immunoaffinity column is utilized in the purification of PRO polypeptide by preparing a fraction from cells containing PRO polypeptide in a soluble form. This preparation is derived by solubilization of the whole cell or of a subcellular fraction obtained via differential centrifugation by the addition of detergent or by other methods well known in the art. Alternatively, soluble PRO polypeptide containing a signal sequence may be secreted in useful quantity into the medium in which the cells are grown.
  • a soluble PRO polypeptide-containing preparation is passed over the immunoaffinity column, and the column is washed under conditions that allow the preferential absorbance of PRO polypeptide (e.g. , high ionic strength buffers in the presence of detergent). Then, the column is eluted under conditions that disrupt antibody/PRO polypeptide binding (e.g., a low pH buffer such as approximately pH 2-3, or a high concentration of a chaotrope such as urea or thiocyanate ion), and PRO polypeptide is collected.
  • a low pH buffer such as approximately pH 2-3
  • a chaotrope such as urea or thiocyanate ion
  • This invention is particularly useful for screening compounds by using PRO polypeptides or binding fragment thereof in any of a variety of drug screening techniques.
  • the PRO polypeptide or fragment employed in such a test may either be free in solution, affixed to a solid support, borne on a cell surface, or located intracellularly.
  • One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the PRO polypeptide or fragment. Drugs are screened against such transformed cells in competitive binding assays. Such cells, either in viable or fixed form, can be used for standard binding assays.
  • One may measure, for example, the formation of complexes between PRO polypeptide or a fragment and the agent being tested. Alternatively, one can examine the diminution in complex formation between the PRO polypeptide and its target cell or target receptors caused by the agent being tested.
  • the present invention provides methods of screening for drugs or any other agents which can affect a PRO polypeptide-associated disease or disorder. These methods comprise contacting such an agent with a PRO polypeptide or fragment thereof and assaying (i) for the presence of a complex between the agent and the PRO polypeptide or fragment, or (ii) for the presence of a complex between the PRO polypeptide or fragment and the cell, by methods well known in the art. In such competitive binding assays, the PRO polypeptide or fragment is typically labeled.
  • free PRO polypeptide or fragment is separated from that present in bound form, and the amount of free or uncomplexed label is a measure of the ability of the particular agent to bind to PRO polypeptide or to interfere with the PRO polypeptide/cell complex.
  • Another technique for drug screening provides high throughput screening for compounds having suitable binding affinity to a polypeptide and is described in detail in WO 84/03564, published on Sep. 13, 1984. Briefly stated, large numbers of different small peptide test compounds are synthesized on a solid substrate, such as plastic pins or some other surface. As applied to a PRO polypeptide, the peptide test compounds are reacted with PRO polypeptide and washed. Bound PRO polypeptide is detected by methods well known in the art. Purified PRO polypeptide can also be coated directly onto plates for use in the aforementioned drug screening techniques. In addition, non-neutralizing antibodies can be used to capture the peptide and immobilize it on the solid support.
  • This invention also contemplates the use of competitive drug screening assays in which neutralizing antibodies capable of binding PRO polypeptide specifically compete with a test compound for binding to PRO polypeptide or fragments thereof. In this manner, the antibodies can be used to detect the presence of any peptide which shares one or more antigenic determinants with PRO polypeptide.
  • the goal of rational drug design is to produce structural analogs of biologically active polypeptide of interest (i.e., a PRO polypeptide) or of small molecules with which they interact, e.g., agonists, antagonists, or inhibitors. Any of these examples can be used to fashion drugs which are more active or stable forms of the PRO polypeptide or which enhance or interfere with the function of the PRO polypeptide in vivo (c.f., Hodgson, Bio/Technology, 9: 19-21(1991)).
  • the three-dimensional structure of the PRO polypeptide, or of a PRO polypeptide-inhibitor complex is determined by X-ray crystallography, by computer modeling or, most typically, by a combination of the two approaches. Both the shape and charges of the PRO polypeptide must be ascertained to elucidate the structure and to determine active site(s) of the molecule. Less often, useful information regarding the structure of the PRO polypeptide may be gained by modeling based on the structure of homologous proteins. In both cases, relevant structural information is used to design analogous PRO polypeptide-like molecules or to identify efficient inhibitors.
  • Useful examples of rational drug design may include molecules which have improved activity or stability as shown by Braxton and Wells, Biochemistry, 31:7796-7801(1992) or which act as inhibitors, agonists, or antagonists of native peptides as shown by Athauda et al., J. Biochem., 113:742-746(1993).
  • a target-specific antibody selected by functional assay, as described above, and then to solve its crystal structure.
  • This approach in principle, yields a pharmacore upon which subsequent drug design can be based. It is possible to bypass protein crystallography altogether by generating anti-idiotypic antibodies (anti-ids) to a functional, pharmacologically active antibody. As a mirror image of a mirror image, the binding site of the anti-ids would be expected to be an analog of the original receptor. The anti-id could then be used to identify and isolate peptides from banks of chemically or biologically produced peptides. The isolated peptides would then act as the pharmacore.
  • anti-ids anti-idiotypic antibodies
  • PRO polypeptide may be made available to perform such analytical studies as X-ray crystallography.
  • knowledge of the PRO polypeptide amino acid sequence provided herein will provide guidance to those employing computer modeling techniques in place of or in addition to X-ray crystallography.
  • This assay shows that certain polypeptides of the invention act to induce the expression of c-fos in pericyte cells and, therefore, are useful not only as diagnostic markers for particular types of pericyte-associated tumors but also for giving rise to antagonists which would be expected to be useful for the therapeutic treatment of pericyte-associated tumors.
  • Induction of c-fos expression in pericytes is also indicative of the induction of angiogenesis and, as such, PRO polypeptides capable of inducing the expression of c-fos would be expected to be useful for the treatment of conditions where induced angiogenesis would be beneficial including, for example, wound healing, and the like.
  • pericytes are received from VEC Technologies and all but 5 ml of media is removed from flask.
  • the pericytes are trypsinized, washed, spun and then plated onto 96 well plates.
  • Replicates are averaged and SD/CV are determined.
  • Fold increase over Protein 32 (buffer control) value indicated by chemiluminescence units (RLU) luminometer reading verses frequency is plotted on a histogram. Two-fold above Protein 32 value is considered positive for the assay.
  • Assay Media low glucose DMEM +5% FBS.
  • PRO polypeptides were then added at 1% either alone or in combination with 18 ng/ml interleukin-1 ⁇ , a known stimulator of proteoglycan release from cartilage tissue. The supernatant was then harvested and assayed for the amount of proteoglycans using the 1,9-dimethyl-methylene blue (DMB) colorimetric assay (Farndale and Buttle, Biochem. Biophys. Acta 883:173-177 (1985)). A positive result in this assay indicates that the test polypeptide will find use, for example, in the treatment of sports-related joint problems, articular cartilage defects, osteoarthritis or rheumatoid arthritis.
  • DMB 1,9-dimethyl-methylene blue
  • PRO polypeptides When various PRO polypeptides were tested in the above assay, the polypeptides demonstrated a marked ability to stimulate release of proteoglycans from cartilage tissue both basally and after stimulation with interleukin-1 ⁇ and at 24 and 72 hours after treatment, thereby indicating that these PRO polypeptides are useful for stimulating proteoglycan release from cartilage tissue. As such, these PRO polypeptides are useful for the treatment of sports-related joint problems, articular cartilage defects, osteoarthritis or rheumatoid arthritis.
  • the polypeptides testing positive in this assay are: PRO1565, PRO1693, PRO1801 and PRO10096.
  • This assay is designed to determine whether PRO polypeptides show the ability to affect glucose or FFA uptake by skeletal muscle cells.
  • PRO polypeptides testing positive in this assay would be expected to be useful for the therapeutic treatment of disorders where either the stimulation or inhibition of glucose uptake by skeletal muscle would be beneficial including, for example, diabetes or hyper- or hypo-insulinemia.
  • PRO polypeptides to be assayed are added to primary rat differentiated skeletal muscle, and allowed to incubate overnight. Then fresh media with the PRO polypeptide and +/ ⁇ insulin are added to the wells. The sample media is then monitored to determine glucose and FFA uptake by the skeletal muscle cells. The insulin will stimulate glucose and FFA uptake by the skeletal muscle, and insulin in media without the PRO polypeptide is used as a positive control, and a limit for scoring. As the PRO polypeptide being tested may either stimulate or inhibit glucose and FFA uptake, results are scored as positive in the assay if greater than 1.5 times or less than 0.5 times the insulin control.
  • This assay shows that certain PRO polypeptides of the present invention act to stimulate the release of TNF- ⁇ in human blood.
  • PRO polypeptides testing positive in this assay are useful for, among other things, research purposes where stimulation of the release of TNF- ⁇ would be desired and for the therapeutic treatment of conditions wherein enhanced TNF- ⁇ release would be beneficial.
  • 200 ⁇ l of human blood supplemented with 50 mM Hepes buffer (pH 7.2) is aliquotted per well in a 96 well test plate.
  • To each well is then added 300 ⁇ l of either the test PRO polypeptide in 50 mM Hepes buffer (at various concentrations) or 50 mM Hepes buffer alone (negative control) and the plates are incubated at 37° C.
  • PRO polypeptides tested positive in this assay PRO263, PRO295, PRO1282, PRO1063, PRO1356, PRO3543, and PRO5990.
  • Oligonucleotide probes were constructed from some of the PRO polypeptide-encoding nucleotide sequences shown in the accompanying figures for use in quantitative PCR amplification reactions.
  • the oligonucleotide probes were chosen so as to give an approximately 200-600 base pair amplified fragment from the 3′ end of its associated template in a standard PCR reaction.
  • the oligonucleotide probes were employed in standard quantitative PCR amplification reactions with cDNA libraries isolated from different human tumor and normal human tissue samples and analyzed by agarose gel electrophoresis so as to obtain a quantitative determination of the level of expression of the PRO polypeptide-encoding nucleic acid in the various tumor and normal tissues tested.
  • ⁇ -actin was used as a control to assure that equivalent amounts of nucleic acid was used in each reaction.
  • Identification of the differential expression of the PRO polypeptide-encoding nucleic acid in one or more tumor tissues as compared to one or more normal tissues of the same tissue type renders the molecule useful diagnostically for the determination of the presence or absence of tumor in a subject suspected of possessing a tumor as well as therapeutically as a target for the treatment of a tumor in a subject possessing such a tumor.
  • Molecule is more highly expressed in: as compared to: DNA26843-1389 normal lung lung tumor rectum tumor normal rectum DNA30867-1335 normal kidney kidney tumor DNA40621-1440 normal lung lung rumor DNA40625-1189 normal lung lung tumor DNA45409-2511 melanoma tumor normal akin DNA56406-1704 kidney tumor normal kidney normal skin melanoma rumor DNA56410-1414 normal stomach stomach tumor DNA56436-1448 normal skin melanoma tumor DNA56855-1447 normal esophagus esophageal tumor rectum tumor normal rectum DNA56860-1510 normal kidney kidney rumor rectum tumor normal rectum DNA56862-1343 kidney tumor normal kidney normal lung lung rumor DNA56868-1478 normal stomach stomach tumor normal lung lung rumor DNA56869-1545 normal esophagus esophageal tumor normal skin melanoma tumor DNA57704-1452 normal stomach stomach tumor rectum rumor normal rectum DNA5
  • various PRO polypeptides are tested for ability to bind to a panel of potential receptor or ligand molecules for the purpose of identifying receptor/ligand interactions.
  • the identification of a ligand for a known receptor, a receptor for a known ligand or a novel receptor/ligand pair is useful for a variety of indications including, for example, targeting bioactive molecules (linked to the ligand or receptor) to a cell known to express the receptor or ligand, use of the receptor or ligand as a reagent to detect the presence of the ligand or receptor in a composition suspected of containing the same, wherein the composition may comprise cells suspected of expressing the ligand or receptor, modulating the growth of or another biological or immunological activity of a cell known to express or respond to the receptor or ligand, modulating the immune response of cells or toward cells that express the receptor or ligand, allowing the preparation of agonists, antagonists and/or antibodies directed against the receptor or ligand which will modulate the growth of or ligand
  • a PRO polypeptide of the present invention suspected of being a ligand for a receptor is expressed as a fusion protein containing the Fc domain of human IgG (an immunoadhesin).
  • Receptor-ligand binding is detected by allowing interaction of the immunoadhesin polypeptide with cells (e.g. Cos cells) expressing candidate PRO polypeptide receptors and visualization of bound immunoadhesin with fluorescent reagents directed toward the Fc fusion domain and examination by microscope.
  • Cells expressing candidate receptors are produced by transient transfection, in parallel, of defined subsets of a library of cDNA expression vectors encoding PRO polypeptides that may function as receptor molecules.
  • Cells are the incubated for 1 hour in the presence of the PRO polypeptide immunoadhesin being tested for possible receptor binding. The cells are then washed and fixed with paraformaldehyde. The cells are then incubated with fluorescent conjugated antibody directed against the Fc portion of the PRO polypeptide immunoadhesin (e.g. FITC conjugated goat anti-human-Fc antibody). The cells are then washed again and examined by microscope.
  • fluorescent conjugated antibody directed against the Fc portion of the PRO polypeptide immunoadhesin e.g. FITC conjugated goat anti-human-Fc antibody
  • a positive interaction is judged by the presence of fluorescent labeling of cells transfected with cDNA encoding a particular PRO polypeptide receptor or pool of receptors and an absence of similar fluorescent labeling of similarly prepared cells that have been transfected with other cDNA or pools of cDNA, if a defined pool of cDNA expression vectors is judged to be positive for interaction with a PRO polypeptide immunoadhesin, the individual cDNA species that comprise the pool are tested individually (the pool is “broken down”) to determine the specific cDNA that encodes a receptor able to interact with the PRO polypeptide immunoadhesin.
  • an epitope-tagged potential ligand PRO polypeptide e.g. 8 histidine “His” tag
  • a panel of potential receptor PRO polypeptide molecules that have been expressed as fusions with the Fc domain of human IgG (immunoadhesins).
  • the candidate receptors are each immunoprecipitated with protein A beads and the beads are washed.
  • Potential ligand interaction is determined by western blot analysis of the immunoprecipitated complexes with antibody directed towards the epitope tag. An interaction is judged to occur if a band of the anticipated molecular weight of the epitope tagged protein is observed in the western blot analysis with a candidate receptor, but is not observed to occur with the other members of the panel of potential receptors.
  • PRO10272 binds to PRO5801.
  • PRO20110 binds to the human IL-17 receptor (Yao et al., Cytokine 9(11):794-800 (1997); also herein designated as PRO1) and to PRO20040.
  • PRO19670 binds to PRO1890.

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Abstract

The present invention is directed to novel polypeptides and to nucleic acid molecules encoding those polypeptides. Also provided herein are vectors and host cells comprising those nucleic acid sequences, chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, antibodies which bind to the polypeptides of the present invention and to methods for producing the polypeptides of the present invention.

Description

    BACKGROUND OF THE INVENTION
  • The present invention relates generally to the identification and isolation of novel DNA and to the recombinant production of novel polypeptides. [0001]
  • Extracellular proteins play important roles in, among other things, the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment. [0002]
  • Secreted proteins have various industrial applications, including as pharmaceuticals, diagnostics, biosensors and bioreactors. Most protein drugs available at present, such as thrombolytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents. Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci. 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)]. [0003]
  • Membrane-bound proteins and receptors can play important roles in, among other things, the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor. [0004]
  • Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents. Receptor immunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interactions. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction. [0005]
  • Efforts are being undertaken by both industry and academia to identify new, native receptor or membrane-bound proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor or membrane-bound proteins. [0006]
    • SUMMARY OF THE INVENTION
  • In one embodiment, the invention provides an isolated nucleic acid molecule comprising a nucleotide sequence that encodes a PRO polypeptide. [0007]
  • In one aspect, the isolated nucleic acid molecule comprises a nucleotide sequence having at least about 80% nucleic acid sequence identity, alternatively at least about 81% nucleic acid sequence identity, alternatively at least about 82% nucleic acid sequence identity, alternatively at least about 83% nucleic acid sequence identity, alternatively at least about 84% nucleic acid sequence identity, alternatively at least about 85% nucleic acid sequence identity, alternatively at least about 86% nucleic acid sequence identity, alternatively at least about 87% nucleic acid sequence identity, alternatively at least about 88% nucleic acid sequence identity, alternatively at least about 89% nucleic acid sequence identity, alternatively at least about 90% nucleic acid sequence identity, alternatively at least about 91% nucleic acid sequence identity, alternatively at least about 92% nucleic acid sequence identity, alternatively at least about 93% nucleic acid sequence identity, alternatively at least about 94% nucleic acid sequence identity, alternatively at least about 95% nucleic acid sequence identity, alternatively at least about 96% nucleic acid sequence identity, alternatively at least about 97% nucleic acid sequence identity, alternatively at least about 98% nucleic acid sequence identity and alternatively at least about 99% nucleic acid sequence identity to (a) a DNA molecule encoding a PRO polypeptide having a full-length amino acid sequence as disclosed herein, an amino acid sequence lacking the signal peptide as disclosed herein, an extracellular domain of a transmembrane protein, with or without the signal peptide, as disclosed herein or any other specifically defined fragment of the full-length amino acid sequence as disclosed herein, or (b) the complement of the DNA molecule of (a). [0008]
  • In other aspects, the isolated nucleic acid molecule comprises a nucleotide sequence having at least about 80% nucleic acid sequence identity, alternatively at least about 81% nucleic acid sequence identity, alternatively at least about 82% nucleic acid sequence identity, alternatively at least about 83% nucleic acid sequence identity, alternatively at least about 84% nucleic acid sequence identity, alternatively at least about 85% nucleic acid sequence identity, alternatively at least about 86% nucleic acid sequence identity, alternatively at least about 87% nucleic acid sequence identity, alternatively at least about 88% nucleic acid sequence identity, alternatively at least about 89% nucleic acid sequence identity, alternatively at least about 90% nucleic acid sequence identity, alternatively at least about 91% nucleic acid sequence identity, alternatively at least about 92% nucleic acid sequence identity, alternatively at least about 93% nucleic acid sequence identity, alternatively at least about 94% nucleic acid sequence identity, alternatively at least about 95% nucleic acid sequence identity, alternatively at least about 96% nucleic acid sequence identity, alternatively at least about 97% nucleic acid sequence identity, alternatively at least about 98% nucleic acid sequence identity and alternatively at least about 99% nucleic acid sequence identity to (a) a DNA molecule comprising the coding sequence of a full-length PRO polypeptide cDNA as disclosed herein, the coding sequence of a PRO polypeptide lacking the signal peptide as disclosed herein, the coding sequence of an extracellular domain of a transmembrane PRO polypeptide, with or without the signal peptide, as disclosed herein or the coding sequence of any other specifically defined fragment of the full-length amino acid sequence as disclosed herein, or (b) the complement of the DNA molecule of (a). [0009]
  • In a further aspect, the invention concerns an isolated nucleic acid molecule comprising a nucleotide sequence having at least about 80% nucleic acid sequence identity, alternatively at least about 81% nucleic acid sequence identity, alternatively at least about 82% nucleic acid sequence identity, alternatively at least about 83% nucleic acid sequence identity, alternatively at least about 84% nucleic acid sequence identity, alternatively at least about 85% nucleic acid sequence identity, alternatively at least about 86% nucleic acid sequence identity, alternatively at least about 87% nucleic acid sequence identity, alternatively at least about 88% nucleic acid sequence identity, alternatively at least about 89% nucleic acid sequence identity, alternatively at least about 90% nucleic acid sequence identity, alternatively at least about 91% nucleic acid sequence identity, alternatively at least about 92% nucleic acid sequence identity, alternatively at least about 93% nucleic acid sequence identity, alternatively at least about 94% nucleic acid sequence identity, alternatively at least about 95% nucleic acid sequence identity, alternatively at least about 96% nucleic acid sequence identity, alternatively at least about 97% nucleic acid sequence identity, alternatively at least about 98% nucleic acid sequence identity and alternatively at least about 99% nucleic acid sequence identity to (a) a DNA molecule that encodes the same mature polypeptide encoded by any of the human protein cDNAs deposited with the ATCC as disclosed herein, or (b) the complement of the DNA molecule of (a). [0010]
  • Another aspect the invention provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding a PRO polypeptide which is either transmembrane domain-deleted or transmembrane domain-inactivated, or is complementary to such encoding nucleotide sequence, wherein the transmembrane domain(s) of such polypeptide are disclosed herein. Therefore, soluble extracellular domains of the herein described PRO polypeptides are contemplated. [0011]
  • Another embodiment is directed to fragments of a PRO polypeptide coding sequence, or the complement thereof, that may find use as, for example, hybridization probes, for encoding fragments of a PRO polypeptide that may optionally encode a polypeptide comprising a binding site for an anti-PRO antibody or as antisense oligonucleotide probes. Such nucleic acid fragments are usually at least about 20 nucleotides in length, alternatively at least about 30 nucleotides in length, alternatively at least about 40 nucleotides in length, alternatively at least about 50 nucleotides in length, alternatively at least about 60 nucleotides in length, alternatively at least about 70 nucleotides in length, alternatively at least about 80 nucleotides in length, alternatively at least about 90 nucleotides in length, alternatively at least about 100 nucleotides in length, alternatively at least about 110 nucleotides in length, alternatively at least about 120 nucleotides in length, alternatively at least about 130 nucleotides in length, alternatively at least about 140 nucleotides in length, alternatively at least about 150 nucleotides in length, alternatively at least about 160 nucleotides in length, alternatively at least about 170 nucleotides in length, alternatively at least about 180 nucleotides in length, alternatively at least about 190 nucleotides in length, alternatively at least about 200 nucleotides in length, alternatively at least about 250 nucleotides in length, alternatively at least about 300 nucleotides in length, alternatively at least about 350 nucleotides in length, alternatively at least about 400 nucleotides in length, alternatively at least about 450 nucleotides in length, alternatively at least about 500 nucleotides in length, alternatively at least about 600 nucleotides in length, alternatively at least about 700 nucleotides in length, alternatively at least about 800 nucleotides in length, alternatively at least about 900 nucleotides in length and alternatively at least about 1000 nucleotides in length, wherein in this context the term “about” means the referenced nucleotide sequence length plus or minus 10% of that referenced length. It is noted that novel fragments of a PRO polypeptide-encoding nucleotide sequence may be determined in a routine manner by aligning the PRO polypeptide-encoding nucleotide sequence with other known nucleotide sequences using any of a number of well known sequence alignment programs and determining which PRO polypeptide-encoding nucleotide sequence fragment(s) are novel. All of such PRO polypeptide-encoding nucleotide sequences are contemplated herein. Also contemplated are the PRO polypeptide fragments encoded by these nucleotide molecule fragments, preferably those PRO polypeptide fragments that comprise a binding site for an anti-PRO antibody. [0012]
  • In another embodiment, the invention provides isolated PRO polypeptide encoded by any of the isolated nucleic acid sequences hereinabove identified. [0013]
  • In a certain aspect, the invention concerns an isolated PRO polypeptide, comprising an amino acid sequence having at least about 80% amino acid sequence identity, alternatively at least about 81% amino acid sequence identity, alternatively at least about 82% amino acid sequence identity, alternatively at least about 83% amino acid sequence identity, alternatively at least about 84% amino acid sequence identity, alternatively at least about 85% amino acid sequence identity, alternatively at least about 86% amino acid sequence identity, alternatively at least about 87% amino acid sequence identity, alternatively at least about 88% amino acid sequence identity, alternatively at least about 89% amino acid sequence identity, alternatively at least about 90% amino acid sequence identity, alternatively at least about 91% amino acid sequence identity, alternatively at least about 92% amino acid sequence identity, alternatively at least about 93% amino acid sequence identity, alternatively at least about 94% amino acid sequence identity, alternatively at least about 95% amino acid sequence identity, alternatively at least about 96% amino acid sequence identity, alternatively at least about 97% amino acid sequence identity, alternatively at least about 98% amino acid sequence identity and alternatively at least about 99% amino acid sequence identity to a PRO polypeptide having a full-length amino acid sequence as disclosed herein, an amino acid sequence lacking the signal peptide as disclosed herein, an extracellular domain of a transmembrane protein, with or without the signal peptide, as disclosed herein or any other specifically defined fragment of the full-length amino acid sequence as disclosed herein. [0014]
  • In a further aspect, the invention concerns an isolated PRO polypeptide comprising an amino acid sequence having at least about 80% amino acid sequence identity, alternatively at least about 81% amino acid sequence identity, alternatively at least about 82% amino acid sequence identity, alternatively at least about 83% amino acid sequence identity, alternatively at least about 84% amino acid sequence identity, alternatively at least about 85% amino acid sequence identity, alternatively at least about 86% amino acid sequence identity, alternatively at least about 87% amino acid sequence identity, alternatively at least about 88% amino acid sequence identity, alternatively at least about 89% amino acid sequence identity, alternatively at least about 90% amino acid sequence identity, alternatively at least about 91% amino acid sequence identity, alternatively at least about 92% amino acid sequence identity, alternatively at least about 93% amino acid sequence identity, alternatively at least about 94% amino acid sequence identity, alternatively at least about 95% amino acid sequence identity, alternatively at least about 96% amino acid sequence identity, alternatively at least about 97% amino acid sequence identity, alternatively at least about 98% amino acid sequence identity and alternatively at least about 99% amino acid sequence identity to an amino acid sequence encoded by any of the human protein cDNAs deposited with the ATCC as disclosed herein. [0015]
  • In a specific aspect, the invention provides an isolated PRO polypeptide without the N-terminal signal sequence and/or the initiating methionine and is encoded by a nucleotide sequence that encodes such an amino acid sequence as hereinbefore described. Processes for producing the same are also herein described, wherein those processes comprise culturing a host cell comprising a vector which comprises the appropriate encoding nucleic acid molecule under conditions suitable for expression of the PRO polypeptide and recovering the PRO polypeptide from the cell culture. [0016]
  • Another aspect the invention provides an isolated PRO polypeptide which is either transmembrane domain-deleted or transmembrane domain-inactivated. Processes for producing the same are also herein described, wherein those processes comprise culturing a host cell comprising a vector which comprises the appropriate encoding nucleic acid molecule under conditions suitable for expression of the PRO polypeptide and recovering the PRO polypeptide from the cell culture. [0017]
  • In yet another embodiment, the invention concerns agonists and antagonists of a native PRO polypeptide as defined herein. In a particular embodiment, the agonist or antagonist is an anti-PRO antibody or a small molecule. [0018]
  • In a further embodiment, the invention concerns a method of identifying agonists or antagonists to a PRO polypeptide which comprise contacting the PRO polypeptide with a candidate molecule and monitoring a biological activity mediated by said PRO polypeptide. Preferably, the PRO polypeptide is a native PRO polypeptide. [0019]
  • In a still further embodiment, the invention concerns a composition of matter comprising a PRO polypeptide, or an agonist or antagonist of a PRO polypeptide as herein described, or an anti-PRO antibody, in combination with a carrier. Optionally, the carrier is a pharmaceutically acceptable carrier. [0020]
  • Another embodiment of the present invention is directed to the use of a PRO polypeptide, or an agonist or antagonist thereof as hereinbefore described, or an anti-PRO antibody, for the preparation of a medicament useful in the treatment of a condition which is responsive to the PRO polypeptide, an agonist or antagonist thereof or an anti-PRO antibody. [0021]
  • In other embodiments of the present invention, the invention provides vectors comprising DNA encoding any of the herein described polypeptides. Host cell comprising any such vector are also provided. By way of example, the host cells may be CHO cells, [0022] E. coli, or yeast. A process for producing any of the herein described polypeptides is further provided and comprises culturing host cells under conditions suitable for expression of the desired polypeptide and recovering the desired polypeptide from the cell culture.
  • In other embodiments, the invention provides chimeric molecules comprising any of the herein described polypeptides fused to a heterologous polypeptide or amino acid sequence. Example of such chimeric molecules comprise any of the herein described polypeptides fused to an epitope tag sequence or a Fc region of an immunoglobulin. [0023]
  • In another embodiment, the invention provides an antibody which binds, preferably specifically, to any of the above or below described polypeptides. Optionally, the antibody is a monoclonal antibody, humanized antibody, antibody fragment or single-chain antibody. [0024]
  • In yet other embodiments, the invention provides oligonucleotide probes useful for isolating genomic and cDNA nucleotide sequences or as antisense probes, wherein those probes may be derived from any of the above or below described nucleotide sequences. [0025]
  • In yet other embodiments, the present invention is directed to methods of using the PRO polypeptides of the present invention for a variety of uses based upon the functional biological assay data presented in the Examples below.[0026]
    • BRIEF DESCRIPTION OF DRAWINGS
  • FIG. 1 shows a nucleotide sequence (SEQ ID NO:1) of a native sequence PRO180 cDNA, wherein SEQ ID NO:1 is a clone designated herein as “DNA26843-1389”. [0027]
  • FIG. 2 shows the amino acid sequence (SEQ ID NO:2) derived from the coding sequence of SEQ ID NO:1 shown in FIG. 1. [0028]
  • FIG. 3 shows a nucleotide sequence (SEQ ID NO:3) of a native sequence PRO218 cDNA, wherein SEQ ID NO:3 is a clone designated herein as “DNA30867-1335”. [0029]
  • FIG. 4 shows the amino acid sequence (SEQ ID NO:4) derived from the coding sequence of SEQ ID NO:3 shown in FIG. 3. [0030]
  • FIG. 5 shows a nucleotide sequence (SEQ ID NO:5) of a native sequence PRO263 cDNA, wherein SEQ ID NO:5 is a clone designated herein as “DNA34431-1177”. [0031]
  • FIG. 6 shows the amino acid sequence (SEQ ID NO:6) derived from the coding sequence of SEQ ID NO:5 shown in FIG. 5. [0032]
  • FIG. 7 shows a nucleotide sequence (SEQ ID NO:7) of a native sequence PRO295 cDNA, wherein SEQ ID NO:7 is a clone designated herein as “DNA38268-1188”. [0033]
  • FIG. 8 shows the amino acid sequence (SEQ ID NO:8) derived from the coding sequence of SEQ ID NO:7 shown in FIG. 7. [0034]
  • FIG. 9 shows a nucleotide sequence (SEQ ID NO:9) of a native sequence PRO874 cDNA, wherein SEQ ID NO:9 is a clone designated herein as “DNA40621-1440”. [0035]
  • FIG. 10 shows the amino acid sequence (SEQ ID NO:10) derived from the coding sequence of SEQ ID NO:9 shown in FIG. 9. [0036]
  • FIG. 11 shows a nucleotide sequence (SEQ ID NO:11) of a native sequence PRO300 cDNA, wherein SEQ ID NO:11 is a clone designated herein as “DNA40625-1189”. [0037]
  • FIG. 12 shows the amino acid sequence (SEQ ID NO:12) derived from the coding sequence of SEQ ID NO:11 shown in FIG. 11. [0038]
  • FIG. 13 shows a nucleotide sequence (SEQ ID NO:13) of a native sequence PRO1864 cDNA, wherein SEQ ID NO:13 is a clone designated herein as “DNA45409-2511”. [0039]
  • FIG. 14 shows the amino acid sequence (SEQ ID NO:14) derived from the coding sequence of SEQ ID NO:13 shown in FIG. 13. [0040]
  • FIG. 15 shows a nucleotide sequence (SEQ ID NO:15) of a native sequence PRO1282 cDNA, wherein SEQ ID NO:15 is a clone designated herein as “DNA45495-1550”. [0041]
  • FIG. 16 shows the amino acid sequence (SEQ ID NO:16) derived from the coding sequence of SEQ ID NO:15 shown in FIG. 15. [0042]
  • FIG. 17 shows a nucleotide sequence (SEQ ID NO:17) of a native sequence PRO1063 cDNA, wherein SEQ ID NO:17 is a clone designated herein as “DNA49820-1427”. [0043]
  • FIG. 18 shows the amino acid sequence (SEQ ID NO:18) derived from the coding sequence of SEQ ID NO:17 shown in FIG. 17. [0044]
  • FIG. 19 shows a nucleotide sequence (SEQ ID NO:19) of a native sequence PRO1773 cDNA, wherein SEQ ID NO:19 is a clone designated herein as “DNA56406-1704”. [0045]
  • FIG. 20 shows the amino acid sequence (SEQ ID NO:20) derived from the coding sequence of SEQ ID NO:19 shown in FIG. 19. [0046]
  • FIG. 21 shows a nucleotide sequence (SEQ ID NO:21) of a native sequence PRO1013 cDNA, wherein SEQ ID NO:21 is a clone designated herein as “DNA56410-1414”. [0047]
  • FIG. 22 shows the amino acid sequence (SEQ ID NO:22) derived from the coding sequence of SEQ ID NO:21 shown in FIG. 21. [0048]
  • FIG. 23 shows a nucleotide sequence (SEQ ID NO:23) of a native sequence PRO937 cDNA, wherein SEQ ID NO:23 is a clone designated herein as “DNA56436-1448”. [0049]
  • FIG. 24 shows the amino acid sequence (SEQ ID NO:24) derived from the coding sequence of SEQ ID NO:23 shown in FIG. 23. [0050]
  • FIG. 25 shows a nucleotide sequence (SEQ ID NO:25) of a native sequence PRO842 cDNA, wherein SEQ ID NO:25 is a clone designated herein as “DNA56855-1447”. [0051]
  • FIG. 26 shows the amino acid sequence (SEQ ID NO:26) derived from the coding sequence of SEQ ID NO:25 shown in FIG. 25. [0052]
  • FIG. 27 shows a nucleotide sequence (SEQ ID NO:27) of a native sequence PRO1180 cDNA, wherein SEQ ID NO:27 is a clone designated herein as “DNA56860-1510”. [0053]
  • FIG. 28 shows the amino acid sequence (SEQ ID NO:28) derived from the coding sequence of SEQ ID NO:27 shown in FIG. 27. [0054]
  • FIG. 29 shows a nucleotide sequence (SEQ ID NO:29) of a native sequence PRO831 cDNA, wherein SEQ ID NO:29 is a clone designated herein as “DNA56862-1343”. [0055]
  • FIG. 30 shows the amino acid sequence (SEQ ID NO:30) derived from the coding sequence of SEQ ID NO:29 shown in FIG. 29. [0056]
  • FIG. 31 shows a nucleotide sequence (SEQ ID NO:31) of a native sequence PRO1115 cDNA, wherein SEQ ID NO:31 is a clone designated herein as “DNA56868-1478”. [0057]
  • FIG. 32 shows the amino acid sequence (SEQ ID NO:32) derived from the coding sequence of SEQ ID NO:31 shown in FIG. 31. [0058]
  • FIG. 33 shows a nucleotide sequence (SEQ ID NO:33) of a native sequence PRO1277 cDNA, wherein SEQ ID NO:33 is a clone designated herein as “DNA56869-1545”. [0059]
  • FIG. 34 shows the amino acid sequence (SEQ ID NO:34) derived from the coding sequence of SEQ ID NO:33 shown in FIG. 33. [0060]
  • FIG. 35 shows a nucleotide sequence (SEQ ID NO:35) of a native sequence PRO1074 cDNA, wherein SEQ ID NO:35 is a clone designated herein as “DNA57704-1452”. [0061]
  • FIG. 36 shows the amino acid sequence (SEQ ID NO:36) derived from the coding sequence of SEQ ID NO:35 shown in FIG. 35. [0062]
  • FIG. 37 shows a nucleotide sequence (SEQ ID NO:37) of a native sequence PRO1344 cDNA, wherein SEQ ID NO:37 is a clone designated herein as “DNA58723-1588”. [0063]
  • FIG. 38 shows the amino acid sequence (SEQ ID NO:38) derived from the coding sequence of SEQ ID NO:37 shown in FIG. 37. [0064]
  • FIG. 39 shows a nucleotide sequence (SEQ ID NO:39) of a native sequence PRO1136 cDNA, wherein SEQ ID NO:39 is a clone designated herein as “DNA57827-1493”. [0065]
  • FIG. 40 shows the amino acid sequence (SEQ ID NO:40) derived from the coding sequence of SEQ ID NO:39 shown in FIG. 39. [0066]
  • FIG. 41 shows a nucleotide sequence (SEQ ID NO:41) of a native sequence PRO1109 cDNA, wherein SEQ ID NO:41 is a clone designated herein as “DNA58737-1473”. [0067]
  • FIG. 42 shows the amino acid sequence (SEQ ID NO:42) derived from the coding sequence of SEQ ID NO:41 shown in FIG. 41. [0068]
  • FIG. 43 shows a nucleotide sequence (SEQ ID NO:43) of a native sequence PRO1003 cDNA, wherein SEQ ID NO:43 is a clone designated herein as “DNA58846-1409”. [0069]
  • FIG. 44 shows the amino acid sequence (SEQ ID NO:44) derived from the coding sequence of SEQ ID NO:43 shown in FIG. 43. [0070]
  • FIG. 45 shows a nucleotide sequence (SEQ ID NO:45) of a native sequence PRO1138 cDNA, wherein SEQ ID NO:45 is a clone designated herein as “DNA58850-1495”. [0071]
  • FIG. 46 shows the amino acid sequence (SEQ ID NO:46) derived from the coding sequence of SEQ ID NO:45 shown in FIG. 45. [0072]
  • FIG. 47 shows a nucleotide sequence (SEQ ID NO:47) of a native sequence PRO994 cDNA, wherein SEQ ID NO:47 is a clone designated herein as “DNA58855-1422”. [0073]
  • FIG. 48 shows the amino acid sequence (SEQ ID NO:48) derived from the coding sequence of SEQ ID NO:47 shown in FIG. 47. [0074]
  • FIG. 49 shows a nucleotide sequence (SEQ ID NO:49) of a native sequence PRO1069 cDNA, wherein SEQ ID NO:49 is a clone designated herein as “DNA59211-1450”. [0075]
  • FIG. 50 shows the amino acid sequence (SEQ ID NO:50) derived from the coding sequence of SEQ ID NO:49 shown in FIG. 49. [0076]
  • FIG. 51 shows a nucleotide sequence (SEQ ID NO:51) of a native sequence PRO1411 cDNA, wherein SEQ ID NO:51 is a clone designated herein as “DNA59212-1627”. [0077]
  • FIG. 52 shows the amino acid sequence (SEQ ID NO:52) derived from the coding sequence of SEQ ID NO:51 shown in FIG. 51. [0078]
  • FIG. 53 shows a nucleotide sequence (SEQ ID NO:53) of a native sequence PRO1129 cDNA, wherein SEQ ID NO:53 is a clone designated herein as “DNA59213-1487”. [0079]
  • FIG. 54 shows the amino acid sequence (SEQ ID NO:54) derived from the coding sequence of SEQ ID NO:53 shown in FIG. 53. [0080]
  • FIG. 55 shows a nucleotide sequence (SEQ ID NO:55) of a native sequence PRO1027 cDNA, wherein SEQ ID NO:55 is a clone designated herein as “DNA59605-1418”. [0081]
  • FIG. 56 shows the amino acid sequence (SEQ ID NO:56) derived from the coding sequence of SEQ ID NO:55 shown in FIG. 55. [0082]
  • FIG. 57 shows a nucleotide sequence (SEQ ID NO:57) of a native sequence PRO1106 cDNA, wherein SEQ ID NO:57 is a clone designated herein as “DNA59609-1470”. [0083]
  • FIG. 58 shows the amino acid sequence (SEQ ID NO:58) derived from the coding sequence of SEQ ID NO:57 shown in FIG. 57. [0084]
  • FIG. 59 shows a nucleotide sequence (SEQ ID NO:59) of a native sequence PRO1291 cDNA, wherein SEQ ID NO:59 is a clone designated herein as “DNA59610-1556”. [0085]
  • FIG. 60 shows the amino acid sequence (SEQ ID NO:60) derived from the coding sequence of SEQ ID NO:59 shown in FIG. 59. [0086]
  • FIG. 61 shows a nucleotide sequence (SEQ ID NO:61) of a native sequence PRO3573 cDNA, wherein SEQ ID NO:61 is a clone designated herein as “DNA59837-2545”. [0087]
  • FIG. 62 shows the amino acid sequence (SEQ ID NO:62) derived from the coding sequence of SEQ ID NO:61 shown in FIG. 61. [0088]
  • FIG. 63 shows a nucleotide sequence (SEQ ID NO:63) of a native sequence PRO3566 cDNA, wherein SEQ ID NO:63 is a clone designated herein as “DNA59844-2542”. [0089]
  • FIG. 64 shows the amino acid sequence (SEQ ID NO:64) derived from the coding sequence of SEQ ID NO:63 shown in FIG. 63. [0090]
  • FIG. 65 shows a nucleotide sequence (SEQ ID NO:65) of a native sequence PRO1098 cDNA, wherein SEQ ID NO:65 is a clone designated herein as “DNA59854-1459”. [0091]
  • FIG. 66 shows the amino acid sequence (SEQ ID NO:66) derived from the coding sequence of SEQ ID NO:65 shown in FIG. 65. [0092]
  • FIG. 67 shows a nucleotide sequence (SEQ ID NO:67) of a native sequence PRO1158 cDNA, wherein SEQ ID NO:67 is a clone designated herein as “DNA60625-1507”. [0093]
  • FIG. 68 shows the amino acid sequence (SEQ ID NO:68) derived from the coding sequence of SEQ ID NO:67 shown in FIG. 67. [0094]
  • FIG. 69 shows a nucleotide sequence (SEQ ID NO:69) of a native sequence PRO1124 cDNA, wherein SEQ ID NO:69 is a clone designated herein as “DNA60629-1481”. [0095]
  • FIG. 70 shows the amino acid sequence (SEQ ID NO:70) derived from the coding sequence of SEQ ID NO:69 shown in FIG. 69. [0096]
  • FIG. 71 shows a nucleotide sequence (SEQ ID NO:71) of a native sequence PRO1287 cDNA, wherein SEQ ID NO:71 is a clone designated herein as “DNA61755-1554”. [0097]
  • FIG. 72 shows the amino acid sequence (SEQ ID NO:72) derived from the coding sequence of SEQ ID NO:71 shown in FIG. 71. [0098]
  • FIG. 73 shows a nucleotide sequence (SEQ ID NO:73) of a native sequence PRO1335 cDNA, wherein SEQ ID NO:73 is a clone designated herein as “DNA62812-1594”. [0099]
  • FIG. 74 shows the amino acid sequence (SEQ ID NO:74) derived from the coding sequence of SEQ ID NO:73 shown in FIG. 73. [0100]
  • FIG. 75 shows a nucleotide sequence (SEQ ID NO:75) of a native sequence PRO1315 cDNA, wherein SEQ ID NO:75 is a clone designated herein as “DNA62815-1576”. [0101]
  • FIG. 76 shows the amino acid sequence (SEQ ID NO:76) derived from the coding sequence of SEQ ID NO:75 shown in FIG. 75. [0102]
  • FIG. 77 shows a nucleotide sequence (SEQ ID NO:77) of a native sequence PRO1357 cDNA, wherein SEQ ID NO:77 is a clone designated herein as “DNA64881-1602”. [0103]
  • FIG. 78 shows the amino acid sequence (SEQ ID NO:78) derived from the coding sequence of SEQ ID NO:77 shown in FIG. 77. [0104]
  • FIG. 79 shows a nucleotide sequence (SEQ ID NO:79) of a native sequence PRO1356 cDNA, wherein SEQ ID NO:79 is a clone designated herein as “DNA64886-1601”. [0105]
  • FIG. 80 shows the amino acid sequence (SEQ ID NO:80) derived from the coding sequence of SEQ ID NO:79 shown in FIG. 79. [0106]
  • FIG. 81 shows a nucleotide sequence (SEQ ID NO:81) of a native sequence PRO1557 cDNA, wherein SEQ ID NO:81 is a clone designated herein as “DNA64902-1667”. [0107]
  • FIG. 82 shows the amino acid sequence (SEQ ID NO:82) derived from the coding sequence of SEQ ID NO:81 shown in FIG. 81. [0108]
  • FIG. 83 shows a nucleotide sequence (SEQ ID NO:83) of a native sequence PRO1347 cDNA, wherein SEQ ID NO:83 is a clone designated herein as “DNA64950-1590”. [0109]
  • FIG. 84 shows the amino acid sequence (SEQ ID NO:84) derived from the coding sequence of SEQ ID NO:83 shown in FIG. 83. [0110]
  • FIG. 85 shows a nucleotide sequence (SEQ ID NO:85) of a native sequence PRO1302 cDNA, wherein SEQ ID NO:85 is a clone designated herein as “DNA65403-1565”. [0111]
  • FIG. 86 shows the amino acid sequence (SEQ ID NO:86) derived from the coding sequence of SEQ ID NO:85 shown in FIG. 85. [0112]
  • FIG. 87 shows a nucleotide sequence (SEQ ID NO:87) of a native sequence PRO1270 cDNA, wherein SEQ ID NO:87 is a clone designated herein as “DNA66308-1537”. [0113]
  • FIG. 88 shows the amino acid sequence (SEQ ID NO:88) derived from the coding sequence of SEQ ID NO:87 shown in FIG. 87. [0114]
  • FIG. 89 shows a nucleotide sequence (SEQ ID NO:89) of a native sequence PRO1268 cDNA, wherein SEQ ID NO:89 is a clone designated herein as “DNA66519-1535”. [0115]
  • FIG. 90 shows the amino acid sequence (SEQ ID NO:90) derived from the coding sequence of SEQ ID NO:89 shown in FIG. 89. [0116]
  • FIG. 91 shows a nucleotide sequence (SEQ ID NO:91) of a native sequence PRO1327 cDNA, wherein SEQ ID NO:91 is a clone designated herein as “DNA66521-1583”. [0117]
  • FIG. 92 shows the amino acid sequence (SEQ ID NO:92) derived from the coding sequence of SEQ ID NO:91 shown in FIG. 91. [0118]
  • FIG. 93 shows a nucleotide sequence (SEQ ID NO:93) of a native sequence PRO1328 cDNA, wherein SEQ ID NO:93 is a clone designated herein as “DNA66658-1584”. [0119]
  • FIG. 94 shows the amino acid sequence (SEQ ID NO:94) derived from the coding sequence of SEQ ID NO:93 shown in FIG. 93. [0120]
  • FIG. 95 shows a nucleotide sequence (SEQ ID NO:95) of a native sequence PRO1329 cDNA, wherein SEQ ID NO:95 is a clone designated herein as “DNA66660-1585”. [0121]
  • FIG. 96 shows the amino acid sequence (SEQ ID NO:96) derived from the coding sequence of SEQ ID NO:95 shown in FIG. 95. [0122]
  • FIG. 97 shows a nucleotide sequence (SEQ ID NO:97) of a native sequence PRO1340 cDNA, wherein SEQ ID NO:97 is a clone designated herein as “DNA66663-1598”. [0123]
  • FIG. 98 shows the amino acid sequence (SEQ ID NO:98) derived from the coding sequence of SEQ ID NO:97 shown in FIG. 97. [0124]
  • FIG. 99 shows a nucleotide sequence (SEQ ID NO:99) of a native sequence PRO1342 cDNA, wherein SEQ ID NO:99 is a clone designated herein as “DNA66674-1599”. [0125]
  • FIG. 100 shows the amino acid sequence (SEQ ID NO:100) derived from the coding sequence of SEQ ID NO:99 shown in FIG. 99. [0126]
  • FIG. 101 shows a nucleotide sequence (SEQ ID NO:101) of a native sequence PRO3579 cDNA, wherein SEQ ID NO:101 is a clone designated herein as “DNA68862-2546”. [0127]
  • FIG. 102 shows the amino acid sequence (SEQ ID NO:102) derived from the coding sequence of SEQ ID NO:101 shown in FIG. 101. [0128]
  • FIG. 103 shows a nucleotide sequence (SEQ ID NO:103) of a native sequence PRO1472 cDNA, wherein SEQ ID NO:103 is a clone designated herein as “DNA68866-1644”. [0129]
  • FIG. 104 shows the amino acid sequence (SEQ ID NO:104) derived from the coding sequence of SEQ ID NO:103 shown in FIG. 103. [0130]
  • FIG. 105 shows a nucleotide sequence (SEQ ID NO:105) of a native sequence PRO1461 cDNA, wherein SEQ ID NO:105 is a clone designated herein as “DNA68871-1638”. [0131]
  • FIG. 106 shows the amino acid sequence (SEQ ID NO:106) derived from the coding sequence of SEQ ID NO:105 shown in FIG. 105. [0132]
  • FIG. 107 shows a nucleotide sequence (SEQ ID NO:107) of a native sequence PRO1568 cDNA, wherein SEQ ID NO:107 is a clone designated herein as “DNA68880-1676”. [0133]
  • FIG. 108 shows the amino acid sequence (SEQ ID NO:108) derived from the coding sequence of SEQ ID NO:107 shown in FIG. 107. [0134]
  • FIG. 109 shows a nucleotide sequence (SEQ ID NO:109) of a native sequence PRO1753 cDNA, wherein SEQ ID NO:109 is a clone designated herein as “DNA68883-1691”. [0135]
  • FIG. 110 shows the amino acid sequence (SEQ ID NO:110) derived from the coding sequence of SEQ ID NO:109 shown in FIG. 109. [0136]
  • FIG. 111 shows a nucleotide sequence (SEQ ID NO:111) of a native sequence PRO1570 cDNA, wherein SEQ ID NO:111 is a clone designated herein as “DNA68885-1678”. [0137]
  • FIG. 112 shows the amino acid sequence (SEQ ID NO:112) derived from the coding sequence of SEQ ID NO:111 shown in FIG. 111. [0138]
  • FIG. 113 shows a nucleotide sequence (SEQ ID NO:113) of a native sequence PRO1446 cDNA, wherein SEQ ID NO:113 is a clone designated herein as “DNA71277-1636”. [0139]
  • FIG. 114 shows the amino acid sequence (SEQ ID NO:114) derived from the coding sequence of SEQ ID NO:113 shown in FIG. 113. [0140]
  • FIG. 115 shows a nucleotide sequence (SEQ ID NO:115) of a native sequence PRO1565 cDNA, wherein SEQ ID NO:115 is a clone designated herein as “DNA73727-1673”. [0141]
  • FIG. 116 shows the amino acid sequence (SEQ ID NO:116) derived from the coding sequence of SEQ ID NO:115 shown in FIG. 115. [0142]
  • FIG. 117 shows a nucleotide sequence (SEQ ID NO:117) of a native sequence PRO1572 cDNA, wherein SEQ ID NO:117 is a clone designated herein as “DNA73734-1680”. [0143]
  • FIG. 118 shows the amino acid sequence (SEQ ID NO:118) derived from the coding sequence of SEQ ID NO:117 shown in FIG. 117. [0144]
  • FIG. 119 shows a nucleotide sequence (SEQ ID NO:119) of a native sequence PRO1573 cDNA, wherein SEQ ID NO:119 is a clone designated herein as “DNA73735-1681”. [0145]
  • FIG. 120 shows the amino acid sequence (SEQ ID NO:120) derived from the coding sequence of SEQ ID NO:119 shown in FIG. 119. [0146]
  • FIG. 121 shows a nucleotide sequence (SEQ ID NO:121) of a native sequence PRO1550 cDNA, wherein SEQ ID NO:121 is a clone designated herein as “DNA76393-1664”. [0147]
  • FIG. 122 shows the amino acid sequence (SEQ ID NO:122) derived from the coding sequence of SEQ ID NO:121 shown in FIG. 121. [0148]
  • FIG. 123 shows a nucleotide sequence (SEQ ID NO:123) of a native sequence PRO1693 cDNA, wherein SEQ ID NO:123 is a clone designated herein as “DNA77301-1708”. [0149]
  • FIG. 124 shows the amino acid sequence (SEQ ID NO:124) derived from the coding sequence of SEQ ID NO:123 shown in FIG. 123. [0150]
  • FIG. 125 shows a nucleotide sequence (SEQ ID NO:125) of a native sequence PRO1566 cDNA, wherein SEQ ID NO:125 is a clone designated herein as “DNA77568-1626”. [0151]
  • FIG. 126 shows the amino acid sequence (SEQ ID NO:126) derived from the coding sequence of SEQ ID NO:125 shown in FIG. 125. [0152]
  • FIG. 127 shows a nucleotide sequence (SEQ ID NO:127) of a native sequence PRO1774 cDNA, wherein SEQ ID NO:127 is a clone designated herein as “DNA77626-1705”. [0153]
  • FIG. 128 shows the amino acid sequence (SEQ ID NO:128) derived from the coding sequence of SEQ ID NO:127 shown in FIG. 127. [0154]
  • FIG. 129 shows a nucleotide sequence (SEQ ID NO:129) of a native sequence PRO1928 cDNA, wherein SEQ ID NO:129 is a clone designated herein as “DNA81754-2532”. [0155]
  • FIG. 130 shows the amino acid sequence (SEQ ID NO:130) derived from the coding sequence of SEQ ID NO:129 shown in FIG. 129. [0156]
  • FIG. 131 shows a nucleotide sequence (SEQ ID NO:131) of a native sequence PRO1865 cDNA, wherein SEQ ID NO:131 is a clone designated herein as “DNA81757-2512”. [0157]
  • FIG. 132 shows the amino acid sequence (SEQ ID NO:132) derived from the coding sequence of SEQ ID NO:131 shown in FIG. 131. [0158]
  • FIG. 133 shows a nucleotide sequence (SEQ ID NO:133) of a native sequence PRO1925 cDNA, wherein SEQ ID NO:133 is a clone designated herein as “DNA82302-2529”. [0159]
  • FIG. 134 shows the amino acid sequence (SEQ ID NO:134) derived from the coding sequence of SEQ ID NO:133 shown in FIG. 133. [0160]
  • FIG. 135 shows a nucleotide sequence (SEQ ID NO:135) of a native sequence PRO1926 cDNA, wherein SEQ ID NO:135 is a clone designated herein as “DNA82340-2530”. [0161]
  • FIG. 136 shows the amino acid sequence (SEQ ID NO:136) derived from the coding sequence of SEQ ID NO:135 shown in FIG. 135. [0162]
  • FIG. 137 shows a nucleotide sequence (SEQ ID NO:137) of a native sequence PRO1801 cDNA, wherein SEQ ID NO:137 is a clone designated herein as “DNA83500-2506”. [0163]
  • FIG. 138 shows the amino acid sequence (SEQ ID NO:138) derived from the coding sequence of SEQ ID NO:137 shown in FIG. 137. [0164]
  • FIG. 139 shows a nucleotide sequence (SEQ ID NO:139) of a native sequence PRO4405 cDNA, wherein SEQ ID NO:139 is a clone designated herein as “DNA84920-2614”. [0165]
  • FIG. 140 shows the amino acid sequence (SEQ ID NO:140) derived from the coding sequence of SEQ ID NO:139 shown in FIG. 139. [0166]
  • FIG. 141 shows a nucleotide sequence (SEQ ID NO:141) of a native sequence PRO3435 cDNA, wherein SEQ ID NO:141 is a clone designated herein as “DNA85066-2534”. [0167]
  • FIG. 142 shows the amino acid sequence (SEQ ID NO:142) derived from the coding sequence of SEQ ID NO:141 shown in FIG. 141. [0168]
  • FIG. 143 shows a nucleotide sequence (SEQ ID NO:143) of a native sequence PRO3543 cDNA, wherein SEQ ID NO:143 is a clone designated herein as “DNA86571-2551”. [0169]
  • FIG. 144 shows the amino acid sequence (SEQ ID NO:144) derived from the coding sequence of SEQ ID NO:143 shown in FIG. 143. [0170]
  • FIG. 145 shows a nucleotide sequence (SEQ ID NO:145) of a native sequence PRO3443 cDNA, wherein SEQ ID NO:145 is a clone designated herein as “DNA87991-2540”. [0171]
  • FIG. 146 shows the amino acid sequence (SEQ ID NO:146) derived from the coding sequence of SEQ ID NO:145 shown in FIG. 145. [0172]
  • FIG. 147 shows a nucleotide sequence (SEQ ID NO:147) of a native sequence PRO3442 cDNA, wherein SEQ ID NO:147 is a clone designated herein as “DNA92238-2539”. [0173]
  • FIG. 148 shows the amino acid sequence (SEQ ID NO:148) derived from the coding sequence of SEQ ID NO:147 shown in FIG. 147. [0174]
  • FIG. 149 shows a nucleotide sequence (SEQ ID NO:149) of a native sequence PRO5990 cDNA, wherein SEQ ID NO:149 is a clone designated herein as “DNA96042-2682”. [0175]
  • FIG. 150 shows the amino acid sequence (SEQ ID NO:150) derived from the coding sequence of SEQ ID NO:149 shown in FIG. 149. [0176]
  • FIG. 151 shows a nucleotide sequence (SEQ ID NO:151) of a native sequence PRO4342 cDNA, wherein SEQ ID NO:151 is a clone designated herein as “DNA96787-2534”. [0177]
  • FIG. 152 shows the amino acid sequence (SEQ ID NO:152) derived from the coding sequence of SEQ ID NO:151 shown in FIG. 151. [0178]
  • FIG. 153 shows a nucleotide sequence (SEQ ID NO:153) of a native sequence PRO10096 cDNA, wherein SEQ ID NO:153 is a clone designated herein as “DNA125185-2806”. [0179]
  • FIG. 154 shows the amino acid sequence (SEQ ID NO:154) derived from the coding sequence of SEQ ID NO:153 shown in FIG. 153. [0180]
  • FIG. 155 shows a nucleotide sequence (SEQ ID NO:155) of a native sequence PRO10272 cDNA, wherein SEQ ID NO:155 is a clone designated herein as “DNA147531-2821”. [0181]
  • FIG. 156 shows the amino acid sequence (SEQ ID NO:156) derived from the coding sequence of SEQ ID NO:155 shown in FIG. 155. [0182]
  • FIG. 157 shows a nucleotide sequence (SEQ ID NO:157) of a native sequence PRO5801 cDNA, wherein SEQ ID NO:157 is a clone designated herein as “DNA115291-2681”. [0183]
  • FIG. 158 shows the amino acid sequence (SEQ ID NO:158) derived from the coding sequence of SEQ ID NO:157 shown in FIG. 157. [0184]
  • FIG. 159 shows a nucleotide sequence (SEQ ID NO:159) of a native sequence PRO20110 cDNA, wherein SEQ ID NO:159 is a clone designated herein as “DNA166819”. [0185]
  • FIG. 160 shows the amino acid sequence (SEQ ID NO:160) derived from the coding sequence of SEQ ID NO:159 shown in FIG. 159. [0186]
  • FIG. 161 shows a nucleotide sequence (SEQ ID NO:161) of a native sequence PRO20040 cDNA, wherein SEQ ID NO:161 is a clone designated herein as “DNA164625-2890”. [0187]
  • FIG. 162 shows the amino acid sequence (SEQ ID NO:162) derived from the coding sequence of SEQ ID NO:161 shown in FIG. 161. [0188]
  • FIG. 163 shows a nucleotide sequence (SEQ ID NO:163) of a native sequence PRO20233 cDNA, wherein SEQ ID NO:163 is a clone designated herein as “DNA165608”. [0189]
  • FIG. 164 shows the amino acid sequence (SEQ ID NO:164) derived from the coding sequence of SEQ ID NO:163 shown in FIG. 163. [0190]
  • FIG. 165 shows a nucleotide sequence (SEQ ID NO:165) of a native sequence PRO19670 cDNA, wherein SEQ ID NO:165 is a clone designated herein as “DNA131639-2874”. [0191]
  • FIG. 166 shows the amino acid sequence (SEQ ID NO:166) derived from the coding sequence of SEQ ID NO:165 shown in FIG. 165. [0192]
  • FIG. 167 shows a nucleotide sequence (SEQ ID NO:167) of a native sequence PRO1890 cDNA, wherein SEQ ID NO:167 is a clone designated herein as “DNA79230-2525”. [0193]
  • FIG. 168 shows the amino acid sequence (SEQ ID NO:168) derived from the coding sequence of SEQ ID NO:167 shown in FIG. 167.[0194]
    • DETAILED DESCRIPTION
  • I. Definitions [0195]
  • The terms “PRO polypeptide” and “PRO” as used herein and when immediately followed by a numerical designation refer to various polypeptides, wherein the complete designation (i.e., PRO/number) refers to specific polypeptide sequences as described herein. The terms “PRO/number polypeptide” and “PRO/number” wherein the term “number” is provided as an actual numerical designation as used herein encompass native sequence polypeptides and polypeptide variants (which are further defined herein). The PRO polypeptides described herein may be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods. The term “PRO polypeptide” refers to each individual PRO/number polypeptide disclosed herein. All disclosures in this specification which refer to the “PRO polypeptide” refer to each of the polypeptides individually as well as jointly. For example, descriptions of the preparation of, purification of, derivation of, formation of antibodies to or against, administration of, compositions containing, treatment of a disease with, etc., pertain to each polypeptide of the invention individually. The term “PRO polypeptide” also includes variants of the PRO/number polypeptides disclosed herein. [0196]
  • A “native sequence PRO polypeptide” comprises a polypeptide having the same amino acid sequence as the corresponding PRO polypeptide derived from nature. Such native sequence PRO polypeptides can be isolated from nature or can be produced by recombinant or synthetic means. The term “native sequence PRO polypeptide” specifically encompasses naturally-occurring truncated or secreted forms of the specific PRO polypeptide (e.g., an extracellular domain sequence), naturally-occurring variant forms (e.g., alternatively spliced forms) and naturally-occurring allelic variants of the polypeptide. In various embodiments of the invention, the native sequence PRO polypeptides disclosed herein are mature or full-length native sequence polypeptides comprising the full-length amino acids sequences shown in the accompanying figures. Start and stop codons are shown in bold font and underlined in the figures. However, while the PRO polypeptide disclosed in the accompanying figures are shown to begin with methionine residues designated herein as [0197] amino acid position 1 in the figures, it is conceivable and possible that other methionine residues located either upstream or downstream from the amino acid position 1 in the figures may be employed as the starting amino acid residue for the PRO polypeptides.
  • The PRO polypeptide “extracellular domain” or “ECD” refers to a form of the PRO polypeptide which is essentially free of the transmembrane and cytoplasmic domains. Ordinarily, a PRO polypeptide ECD will have less than 1% of such transmembrane and/or cytoplasmic domains and preferably, will have less than 0.5% of such domains. It will be understood that any transmembrane domains identified for the PRO polypeptides of the present invention are identified pursuant to criteria routinely employed in the art for identifying that type of hydrophobic domain. The exact boundaries of a transmembrane domain may vary but most likely by no more than about 5 amino acids at either end of the domain as initially identified herein. Optionally, therefore, an extracellular domain of a PRO polypeptide may contain from about 5 or fewer amino acids on either side of the transmembrane domain/extracellular domain boundary as identified in the Examples or specification and such polypeptides, with or without the associated signal peptide, and nucleic acid encoding them, are comtemplated by the present invention. [0198]
  • The approximate location of the “signal peptides” of the various PRO polypeptides disclosed herein are shown in the present specification and/or the accompanying figures. It is noted, however, that the C-terminal boundary of a signal peptide may vary, but most likely by no more than about 5 amino acids on either side of the signal peptide C-terminal boundary as initially identified herein, wherein the C-terminal boundary of the signal peptide may be identified pursuant to criteria routinely employed in the art for identifying that type of amino acid sequence element (e.g., Nielsen et al., Prot. Eng. 10:1 -6 (1997) and von Heinje et al., Nucl. Acids. Res. 14:4683-4690 (1986)). Moreover, it is also recognized that, in some cases, cleavage of a signal sequence from a secreted polypeptide is not entirely uniform, resulting in more than one secreted species. These mature polypeptides, where the signal peptide is cleaved within no more than about 5 amino acids on either side of the C-terminal boundary of the signal peptide as identified herein, and the polynucleotides encoding them, are contemplated by the present invention. [0199]
  • “PRO polypeptide variant” means an active PRO polypeptide as defined above or below having at least about 80% amino acid sequence identity with a full-length native sequence PRO polypeptide sequence as disclosed herein, a PRO polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO polypeptide, with or without the signal peptide, as disclosed herein or any other fragment of a full-length PRO polypeptide sequence as disclosed herein. Such PRO polypeptide variants include, for instance, PRO polypeptides wherein one or more amino acid residues are added, or deleted, at the N- or C-terminus of the full-length native amino acid sequence. Ordinarily, a PRO polypeptide variant will have at least about 80% amino acid sequence identity, alternatively at least about 81% amino acid sequence identity, alternatively at least about 82% amino acid sequence identity, alternatively at least about 83% amino acid sequence identity, alternatively at least about 84% amino acid sequence identity, alternatively at least about 85% amino acid sequence identity, alternatively at least about 86% amino acid sequence identity, alternatively at least about 87% amino acid sequence identity, alternatively at least about 88% amino acid sequence identity, alternatively at least about 89% amino acid sequence identity, alternatively at least about 90% amino acid sequence identity, alternatively at least about 91% amino acid sequence identity, alternatively at least about 92% amino acid sequence identity, alternatively at least about 93% amino acid sequence identity, alternatively at least about 94% amino acid sequence identity, alternatively at least about 95% amino acid sequence identity, alternatively at least about 96% amino acid sequence identity, alternatively at least about 97% amino acid sequence identity, alternatively at least about 98% amino acid sequence identity and alternatively at least about 99% amino acid sequence identity to a full-length native sequence PRO polypeptide sequence as disclosed herein, a PRO polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO polypeptide, with or without the signal peptide, as disclosed herein or any other specifically defined fragment of a full-length PRO polypeptide sequence as disclosed herein. Ordinarily, PRO variant polypeptides are at least about 10 amino acids in length, alternatively at least about 20 amino acids in length, alternatively at least about 30 amino acids in length, alternatively at least about 40 amino acids in length, alternatively at least about 50 amino acids in length, alternatively at least about 60 amino acids in length, alternatively at least about 70 amino acids in length, alternatively at least about 80 amino acids in length, alternatively at least about 90 amino acids in length, alternatively at least about 100 amino acids in length, alternatively at least about 150 amino acids in length, alternatively at least about 200 amino acids in length, alternatively at least about 300 amino acids in length, or more. [0200]
  • “Percent (%) amino acid sequence identity” with respect to the PRO polypeptide sequences identified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific PRO polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2, wherein the complete source code for the ALIGN-2 program is provided in Table 1 below. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc. and the source code shown in Table 1 below has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available through Genentech, Inc., South San Francisco, Calif. or may be compiled from the source code provided in Table 1 below. The ALIGN-2 program should be compiled for use on a UNIX operating system, preferably digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary. [0201]
  • In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: [0202]
  • 100 times the fraction X/Y [0203]
  • where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. As examples of % amino acid sequence identity calculations using this method, Tables 2 and 3 demonstrate how to calculate the % amino acid sequence identity of the amino acid sequence designated “Comparison Protein” to the amino acid sequence designated “PRO”, wherein “PRO” represents the amino acid sequence of a hypothetical PRO polypeptide of interest, “Comparison Protein” represents the amino acid sequence of a polypeptide against which the “PRO” polypeptide of interest is being compared, and “X”, “Y” and “Z” each represent different hypothetical amino acid residues. [0204]
  • Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program. However, % amino acid sequence identity values may also be obtained as described below by using the WU-BLAST-2 computer program (Altschul et al., Methods in Enzymology 266:460-480 (1996)). Most of the WU-BLAST-2 search parameters are set to the default values. Those not set to default values, i.e., the adjustable parameters, are set with the following values: overlap span=1, overlap fraction=0.125, word threshold (T)=11, and scoring matrix=BLOSUM62. When WU-BLAST-2 is employed, a % amino acid sequence identity value is determined by dividing (a) the number of matching identical amino acid residues between the amino acid sequence of the PRO polypeptide of interest having a sequence derived from the native PRO polypeptide and the comparison amino acid sequence of interest (i.e., the sequence against which the PRO polypeptide of interest is being compared which may be a PRO variant polypeptide) as determined by WU-BLAST-2 by (b) the total number of amino acid residues of the PRO polypeptide of interest. For example, in the statement “a polypeptide comprising an the amino acid sequence A which has or having at least 80% amino acid sequence identity to the amino acid sequence B”, the amino acid sequence A is the comparison amino acid sequence of interest and the amino acid sequence B is the amino acid sequence of the PRO polypeptide of interest. [0205]
  • Percent amino acid sequence identity may also be determined using the sequence comparison program NCBI-BLAST2 (Altschul et al., Nucleic Acids Res. 25:3389-3402 (1997)). The NCBI-BLAST2 sequence comparison program may be downloaded from http://www.ncbi.nlm.nih.gov or otherwise obtained from the National Institute of Health, Bethesda, Md. NCBI-BLAST2 uses several search parameters, wherein all of those search parameters are set to default values including, for example, unmask=yes, strand=all, expected occurrences=10, minimum low complexity length=15/5, multi-pass e-value=0.01, constant for multi-pass=25, dropoff for final gapped alignment=25 and scoring matrix=BLOSUM62. [0206]
  • In situations where NCBI-BLAST2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: [0207]
  • 100 times the fraction X/Y [0208]
  • where X is the number of amino acid residues scored as identical matches by the sequence alignment program NCBI-BLAST2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. [0209]
  • “PRO variant polynucleotide” or “PRO variant nucleic acid sequence” means a nucleic acid molecule which encodes an active PRO polypeptide as defined below and which has at least about 80% nucleic acid sequence identity with a nucleotide acid sequence encoding a full-length native sequence PRO polypeptide sequence as disclosed herein, a full-length native sequence PRO polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO polypeptide, with or without the signal peptide, as disclosed herein or any other fragment of a full-length PRO polypeptide sequence as disclosed herein. Ordinarily, a PRO variant polynucleotide will have at least about 80% nucleic acid sequence identity, alternatively at least about 81% nucleic acid sequence identity, alternatively at least about 82% nucleic acid sequence identity, alternatively at least about 83% nucleic acid sequence identity, alternatively at least about 84% nucleic acid sequence identity, alternatively at least about 85% nucleic acid sequence identity, alternatively at least about 86% nucleic acid sequence identity, alternatively at least about 87% nucleic acid sequence identity, alternatively at least about 88% nucleic acid sequence identity, alternatively at least about 89% nucleic acid sequence identity, alternatively at least about 90% nucleic acid sequence identity, alternatively at least about 91% nucleic acid sequence identity, alternatively at least about 92% nucleic acid sequence identity, alternatively at least about 93% nucleic acid sequence identity, alternatively at least about 94% nucleic acid sequence identity, alternatively at least about 95% nucleic acid sequence identity, alternatively at least about 96% nucleic acid sequence identity, alternatively at least about 97% nucleic acid sequence identity, alternatively at least about 98% nucleic acid sequence identity and alternatively at least about 99% nucleic acid sequence identity with a nucleic acid sequence encoding a full-length native sequence PRO polypeptide sequence as disclosed herein, a full-length native sequence PRO polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO polypeptide, with or without the signal sequence, as disclosed herein or any other fragment of a full-length PRO polypeptide sequence as disclosed herein. Variants do not encompass the native nucleotide sequence. [0210]
  • Ordinarily, PRO variant polynucleotides are at least about 30 nucleotides in length, alternatively at least about 60 nucleotides in length, alternatively at least about 90 nucleotides in length, alternatively at least about 120 nucleotides in length, alternatively at least about 150 nucleotides in length, alternatively at least about 180 nucleotides in length, alternatively at least about 210 nucleotides in length, alternatively at least about 240 nucleotides in length, alternatively at least about 270 nucleotides in length, alternatively at least about 300 nucleotides in length, alternatively at least about 450 nucleotides in length, alternatively at least about 600 nucleotides in length, alternatively at least about 900 nucleotides in length, or more. [0211]
  • “Percent (%) nucleic acid sequence identity” with respect to PRO-encoding nucleic acid sequences identified herein is defined as the percentage of nucleotides in a candidate sequence that are identical with the nucleotides in the PRO nucleic acid sequence of interest, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. For purposes herein, however, % nucleic acid sequence identity values are generated using the sequence comparison computer program ALIGN-2, wherein the complete source code for the ALIGN-2 program is provided in Table 1 below. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc. and the source code shown in Table 1 below has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available through Genentech, Inc., South San Francisco, Calif. or may be compiled from the source code provided in Table 1 below. The ALIGN-2 program should be compiled for use on a UNIX operating system, preferably digital UNIX V4.OD. All sequence comparison parameters are set by the ALIGN-2 program and do not vary. [0212]
  • In situations where ALIGN-2 is employed for nucleic acid sequence comparisons, the % nucleic acid sequence identity of a given nucleic acid sequence C to, with, or against a given nucleic acid sequence D (which can alternatively be phrased as a given nucleic acid sequence C that has or comprises a certain % nucleic acid sequence identity to, with, or against a given nucleic acid sequence D) is calculated as follows: [0213]
  • 100 times the fraction W/Z [0214]
  • where W is the number of nucleotides scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of C and D, and where Z is the total number of nucleotides in D. It will be appreciated that where the length of nucleic acid sequence C is not equal to the length of nucleic acid sequence D, the % nucleic acid sequence identity of C to D will not equal the % nucleic acid sequence identity of D to C. As examples of % nucleic acid sequence identity calculations, Tables 4 and 5, demonstrate how to calculate the % nucleic acid sequence identity of the nucleic acid sequence designated “Comparison DNA” to the nucleic acid sequence designated “PRO-DNA”, wherein “PRO-DNA” represents a hypothetical PRO-encoding nucleic acid sequence of interest, “Comparison DNA” represents the nucleotide sequence of a nucleic acid molecule against which the “PRO-DNA” nucleic acid molecule of interest is being compared, and “N”, “L” and “V” each represent different hypothetical nucleotides. [0215]
  • Unless specifically stated otherwise, all % nucleic acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program. However, % nucleic acid sequence identity values may also be obtained as described below by using the WU-BLAST-2 computer program (Altschul et al., Methods in Enzymology 266:460-480 (1996)). Most of the WU-BLAST-2 search parameters are set to the default values. Those not set to default values, i.e., the adjustable parameters, are set with the following values: overlap span=1, overlap fraction=0.125, word threshold (T)=11, and scoring matrix=BLOSUM62. When WU-BLAST-2 is employed, a % nucleic acid sequence identity value is determined by dividing (a) the number of matching identical nucleotides between the nucleic acid sequence of the PRO polypeptide-encoding nucleic acid molecule of interest having a sequence derived from the native sequence PRO polypeptide-encoding nucleic acid and the comparison nucleic acid molecule of interest (i.e., the sequence against which the PRO polypeptide-encoding nucleic acid molecule of interest is being compared which may be a variant PRO polynucleotide) as determined by WU-BLAST-2 by (b) the total number of nucleotides of the PRO polypeptide-encoding nucleic acid molecule of interest. For example, in the statement “an isolated nucleic acid molecule comprising a nucleic acid sequence A which has or having at least 80% nucleic acid sequence identity to the nucleic acid sequence B”, the nucleic acid sequence A is the comparison nucleic acid molecule of interest and the nucleic acid sequence B is the nucleic acid sequence of the PRO polypeptide-encoding nucleic acid molecule of interest. [0216]
  • Percent nucleic acid sequence identity may also be determined using the sequence comparison program NCBI-BLAST2 (Altschul et al., Nucleic Acids Res. 25:3389-3402 (1997)). The NCBI-BLAST2 sequence comparison program may be downloaded from http://www.ncbi.nlm.nih.gov or otherwise obtained from the National Institute of Health, Bethesda, Md. NCBI-BLAST2 uses several search parameters, wherein all of those search parameters are set to default values including, for example, unmask=yes, strand=all, expected occurrences=10, minimum low complexity length=15/5, multi-pass e-value=0.01, constant for multi-pass=25, dropoff for final gapped alignment=25 and scoring matrix=BLOSUM62. [0217]
  • In situations where NCBI-BLAST2 is employed for sequence comparisons, the % nucleic acid sequence identity of a given nucleic acid sequence C to, with, or against a given nucleic acid sequence D (which can alternatively be phrased as a given nucleic acid sequence C that has or comprises a certain % nucleic acid sequence identity to, with, or against a given nucleic acid sequence D) is calculated as follows: [0218]
  • 100 times the fraction W/Z [0219]
  • where W is the number of nucleotides scored as identical matches by the sequence alignment program NCBI-BLAST2 in that program's alignment of C and D, and where Z is the total number of nucleotides in D. It will be appreciated that where the length of nucleic acid sequence C is not equal to the length of nucleic acid sequence D, the % nucleic acid sequence identity of C to D will not equal the % nucleic acid sequence identity of D to C. [0220]
  • In other embodiments, PRO variant polynucleotides are nucleic acid molecules that encode an active PRO polypeptide and which are capable of hybridizing, preferably under stringent hybridization and wash conditions, to nucleotide sequences encoding a full-length PRO polypeptide as disclosed herein. PRO variant polypeptides may be those that are encoded by a PRO variant polynucleotide. [0221]
  • “Isolated,” when used to describe the various polypeptides disclosed herein, means polypeptide that has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In preferred embodiments, the polypeptide will be purified (1) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain. Isolated polypeptide includes polypeptide in situ within recombinant cells, since at least one component of the PRO polypeptide natural environment will not be present. Ordinarily, however, isolated polypeptide will be prepared by at least one purification step. [0222]
  • An “isolated” PRO polypeptide-encoding nucleic acid or other polypeptide-encoding nucleic acid is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the natural source of the polypeptide-encoding nucleic acid. An isolated polypeptide-encoding nucleic acid molecule is other than in the form or setting in which it is found in nature. Isolated polypeptide-encoding nucleic acid molecules therefore are distinguished from the specific polypeptide-encoding nucleic acid molecule as it exists in natural cells. However, an isolated polypeptide-encoding nucleic acid molecule includes polypeptide-encoding nucleic acid molecules contained in cells that ordinarily express the polypeptide where, for example, the nucleic acid molecule is in a chromosomal location different from that of natural cells. [0223]
  • The term “control sequences” refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism. The control sequences that are suitable for prokaryotes, for example, include a promoter, optionally an operator sequence, and a ribosome binding site. Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers. [0224]
  • Nucleic acid is “operably linked” when it is placed into a functional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation. Generally, “operably linked” means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice. [0225]
  • The term “antibody” is used in the broadest sense and specifically covers, for example, single anti-PRO monoclonal antibodies (including agonist, antagonist, and neutralizing antibodies), anti-PRO antibody compositions with polyepitopic specificity, single chain anti-PRO antibodies, and fragments of anti-PRO antibodies (see below). The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts. [0226]
  • “Stringency” of hybridization reactions is readily determinable by one of ordinary skill in the art, and generally is an empirical calculation dependent upon probe length, washing temperature, and salt concentration. In general, longer probes require higher temperatures for proper annealing, while shorter probes need lower temperatures. Hybridization generally depends on the ability of denatured DNA to reanneal when complementary strands are present in an environment below their melting temperature. The higher the degree of desired homology between the probe and hybridizable sequence, the higher the relative temperature which can be used. As a result, it follows that higher relative temperatures would tend to make the reaction conditions more stringent, while lower temperatures less so. For additional details and explanation of stringency of hybridization reactions, see Ausubel et al., Current Protocols in Molecular Biology, Wiley lnterscience Publishers, (1995). [0227]
  • “Stringent conditions” or “high stringency condition”, as defined herein, may be identified by those that: (1) employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50° C.; (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42° C.; or (3) employ 50% formamide, 5× SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5× Denhardt's solution, sonicated salmon sperm DNA (50 μg/ml), 0.1% SDS, and 10% dextran sulfate at 42° C., with washes at 42° C. in 0.2× SSC (sodium chloride/sodium citrate) and 50% formamide at 55° C., followed by a high-stringency wash consisting of 0.1× SSC containing EDTA at 55° C. [0228]
  • “Moderately stringent conditions” may be identified as described by Sambrook et al., Molecular Cloning: A Laboratory Manual, New York: Cold Spring Harbor Press, 1989, and include the use of washing solution and hybridization conditions (e.g., temperature, ionic strength and % SDS) less stringent that those described above. An example of moderately stringent conditions is overnight incubation at 37° C. in a solution comprising: 20% formamide, 5× SSC (150 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5× Denhardt's solution, 10% dextran sulfate, and 20 mg/ml denatured sheared salmon sperm DNA, followed by washing the filters in 1× SSC at about 37-50° C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc. as necessary to accommodate factors such as probe length and the like. [0229]
  • The term “epitope tagged” when used herein refers to a chimeric polypeptide comprising a PRO polypeptide fused to a “tag polypeptide”. The tag polypeptide has enough residues to provide an epitope against which an antibody can be made, yet is short enough such that it does not interfere with activity of the polypeptide to which it is fused. The tag polypeptide preferably also is fairly unique so that the antibody does not substantially cross-react with other epitopes. Suitable tag polypeptides generally have at least six amino acid residues and usually between about 8 and 50 amino acid residues (preferably, between about 10 and 20 amino acid residues). [0230]
  • As used herein, the term “immunoadhesin” designates antibody-like molecules which combine the binding specificity of a heterologous protein (an “adhesin”) with the effector functions of immunoglobulin constant domains. Structurally, the immunoadhesins comprise a fusion of an amino acid sequence with the desired binding specificity which is other than the antigen recognition and binding site of an antibody (i.e., is “heterologous”), and an immunoglobulin constant domain sequence. The adhesin part of an immunoadhesin molecule typically is a contiguous amino acid sequence comprising at least the binding site of a receptor or a ligand. The immunoglobulin constant domain sequence in the immunoadhesin may be obtained from any immunoglobulin, such as IgG-1, IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE, IgD or IgM. [0231]
  • “Active” or “activity” for the purposes herein refers to form(s) of a PRO polypeptide which retain a biological and/or an immunological activity of native or naturally-occurring PRO, wherein “biological” activity refers to a biological function (either inhibitory or stimulatory) caused by a native or naturally-occurring PRO other than the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally-occurring PRO and an “immunological” activity refers to the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally-occurring PRO. [0232]
  • The term “antagonist” is used in the broadest sense, and includes any molecule that partially or fully blocks, inhibits, or neutralizes a biological activity of a native PRO polypeptide disclosed herein. In a similar manner, the term “agonist” is used in the broadest sense and includes any molecule that mimics a biological activity of a native PRO polypeptide disclosed herein. Suitable agonist or antagonist molecules specifically include agonist or antagonist antibodies or antibody fragments, fragments or amino acid sequence variants of native PRO polypeptides, peptides, antisense oligonucleotides, small organic molecules, etc. Methods for identifying agonists or antagonists of a PRO polypeptide may comprise contacting a PRO polypeptide with a candidate agonist or antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the PRO polypeptide. [0233]
  • “Treatment” refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder. Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented. [0234]
  • “Chronic” administration refers to administration of the agent(s) in a continuous mode as opposed to an acute mode, so as to maintain the initial therapeutic effect (activity) for an extended period of time. “Intermittent” administration is treatment that is not consecutively done without interruption, but rather is cyclic in nature. [0235]
  • “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats, rabbits, etc. Preferably, the mammal is human. [0236]
  • Administration “in combination with” one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order. [0237]
  • “Carriers” as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers which are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™. [0238]
  • “Antibody fragments” comprise a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab′, F(ab′)[0239] 2 and Fv fragments; diabodies; linear antibodies (Zapata et al., Protein Eng. 8(10): 1057-1062[1995]); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
  • Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual “Fc” fragment, a designation reflecting the ability to crystallize readily Pepsin treatment yields an F(ab′)[0240] 2 fragment that has two antigen-combining sites and is still capable of cross-linking antigen.
  • “Fv” is the minimum antibody fragment which contains a complete antigen-recognition and—binding site. This region consists of a dimer of one heavy—and one light-chain variable domain in tight, non-covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the V[0241] H-VL dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
  • The Fab fragment also contains the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. Fab fragments differ from Fab′ fragments by the addition of a few residues at the carboxy terminus of the heavy chain CH1 domain including one or more cysteines from the antibody hinge region. Fab′-SH is the designation herein for Fab′ in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab′)[0242] 2 antibody fragments originally were produced as pairs of Fab′ fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
  • The “light chains” of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains. [0243]
  • Depending on the amino acid sequence of the constant domain of their heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2. [0244]
  • “Single-chain Fv” or “sFv” antibody fragments comprise the V[0245] H and VL domains of antibody, wherein these domains are present in a single polypeptide chain. Preferably, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the sFv to form the desired structure for antigen binding. For a review of sFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).
  • The term “diabodies” refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (V[0246] H) connected to a light-chain variable domain (VL) in the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Diabodies are described more fully in, for example, EP 404,097; WO 93/11161; and Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).
  • An “isolated” antibody is one which has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In preferred embodiments, the antibody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step. [0247]
  • An antibody that “specifically binds to” or is “specific for” a particular polypeptide or an epitope on a particular polypeptide is one that binds to that particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope. [0248]
  • The word “label” when used herein refers to a detectable compound or composition which is conjugated directly or indirectly to the antibody so as to generate a “labeled” antibody. The label may be detectable by itself (e.g. radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition which is detectable. [0249]
  • By “solid phase” is meant a non-aqueous matrix to which the antibody of the present invention can adhere. Examples of solid phases encompassed herein include those formed partially or entirely of glass (e.g., controlled pore glass), polysaccharides (e.g., agarose), polyacrylamides, polystyrene, polyvinyl alcohol and silicones. In certain embodiments, depending on the context, the solid phase can comprise the well of an assay plate; in others it is a purification column (e.g., an affinity chromatography column). This term also includes a discontinuous solid phase of discrete particles, such as those described in U.S. Pat. No. 4,275,149. [0250]
  • A “liposome” is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as a PRO polypeptide or antibody thereto) to a mammal. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes. [0251]
  • A “small molecule” is defined herein to have a molecular weight below about 500 Daltons [0252]
    TABLE 1
    /*
     *
     * C—C increased from 12 to 15
     * Z is average of EQ
     * B is average of ND
     * match with stop is _M; stop—stop = 0; J (joker) match = 0
     */
    #define _M −8 /* value of a match with a stop */
    int _day[26][26] = {
    /*  A B C D E F G H I J K L M N O P Q R S T U V W X Y Z */
    /* A */ {2, 0, −2, 0, 0, −4, 1, −1, −1, 0, −1, −2, −1, 0, _M, 1, 0, −2, 1, 1, 0, 0, −6, 0, −3, 0},
    /* B */ {0, 3, −4, 3, 2, −5, 0, 1, −2, 0, 0, −3, −2, 2, _M, −1, 1, 0, 0, 0, 0, −2, −5, 0, −3, 1},
    /* C */ {−2, −4, 15, −5, −5, −4, −3, −3, −2, 0, −5, −6, −5, −4, _M, −3, −5, −4, 0, −2, 0, −2, −8, 0, 0, −5},
    /* D */ {0, 3, −5, 4, 3, −6, 1, 1, −2, 0, 0, −4, −3, 2, _M, −1, 2, −1, 0, 0, 0, −2, −7, 0, −4, 2},
    /* E */ {0, 2, −5, 3, 4, −5, 0, 1, −2, 0, 0, −3, −2, 1, _M, −1, 2, −1, 0, 0, 0, −2, −7, 0, −4, 3},
    /* F */ {−4, −5, −4, −6, −5, 9, −5, −2, 1, 0, −5, 2, 0, −4, _M, −5, −5, −4, −3, −3, 0, −1, 0, 0, 7, −5},
    /* G */ {1, 0, −3, 1, 0, −5, 5, −2, −3, 0, −2, −4, −3, 0, _M, −1, −1, −3, 1, 0, 0, −1, −7, 0, −5, 0},
    /* H */ {−1, 1, −3, 1, 1, −2, −2, 6, −2, 0, 0, −2, −2, 2, _M, 0, 3, 2, −1, −1, 0, −2, −3, 0, 0, 2},
    /* I */ {−1, −2, −2, −2, −2, 1, −3, −2, 5, 0, −2, 2, 2, −2, _M, −2, −2, −2, −1, 0, 0, 4, −5, 0, −1, −2},
    /* J */ {0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, _M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0},
    /* K */ {−1, 0, −5, 0, 0, −5, −2, 0, −2, 0, 5, −3, 0, 1, _M, −1, 1, 3, 0, 0, 0, −2, −3, 0, −4, 0},
    /* L */ {−2, −3, −6, −4, −3, 2, −4, −2, 2, 0, −3, 6, 4, −3, _M, −3, −2, −3, −3 , −1, 0, 2, −2, 0, −1, −2}
    /* M */ {−1, −2, −5, −3, −2, 0, −3, −2, 2, 0, 0, 4, 6, −2, _M, −2, −1, 0, −2, −1, 0, 2, −4, 0, −2, −1},
    /* N */ {0, 2, −4, 2, 1, −4, 0, 2, −2, 0, 1, −3, −2, 2, _M, −1, 1, 0, 1, 0, 0, −2, −4, 0, −2, 1},
    /* O */ {_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M, 0,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,},
    /* P */ {1, −1, −3, −1, −1, −5, −1, 0, −2, 0, −1, −3, −2, −1,_M, 6, 0, 0, 1, 0, 0, −1, −6, 0, −5, 0},
    /* Q */ {0, 1, −5, 2, 2, −5, −1, 3, −2, 0, 1, −2, −1, 1, _M, 0, 4, 1, −1, −1, 0, −2, −5, 0, −4, 3},
    /* R */ {−2, 0, −4, −1, −1, −4, −3, 2, −2, 0, 3, −3, 0, 0, _M, 0, 1, 6, 0, −1, 0, −2, 2, 0, −4, 0},
    /* S */ {1, 0, 0, 0, 0, −3, 1, −1, −1, 0, 0, −3, −2, 1, _M, 1, −1, 0, 2, 1, 0, −1, −2, 0, −3, 0},
    /* T */ {1, 0, −2, 0, 0, −3, 0, −1, 0, 0, 0, −1, −1, 0, _M, 0, −1, −1, 1, 3, 0, 0, −5, 0, −3, 0},
    /* U */ {0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0,_M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0},
    /* V */ {0, −2, −2, −2, −2, −1, −1, −2, 4, 0, −2, 2, 2, −2,_M, −1, −2, −2, −1, 0, 0, 4, −6, 0, −2, −2},
    /* W */ {−6, −5, −8, −7, −7, 0, −7, −3, −5, 0, −3, −2, −4, −4,_M, −6, −5, 2, −2, −5, 0, −6, 17, 0, 0, −6},
    /* X */ {0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, _M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0},
    /* Y */ {−3, −3, 0, −4, −4, 7, −5, 0, −1, 0, −4, −1, −2, −2, _M, −5, −4, −4, −3, −3, 0, −2, 0, 0, 10, −4},
    /* Z */ {0, 1, −5, 2, 3, −5, 0, 2, −2, 0, 0, −2, −1, 1,_M, 0, 3, 0, 0, 0, 0, −2, −6, 0, −4, 4},
    };
    /*
     */
    #include <stdio.h>
    #include <ctype.h>
    #define MAXJMP  16 /* max jumps in a diag */
    #define MAXGAP  24 /* don't continue to penalize gaps larger than this */
    #define JMPS 1024 /* max jmps in an path */
    #define MX   4 /* save if there's at least MX-1 bases since last jmp */
    #define DMAT   3 /* value of matching bases */
    #define DMIS   0 /* penalty for mismatched bases */
    #define DINS0   8 /* penalty for a gap */
    #define DINS1   1 /* penalty per base */
    #define PINS0   8 /* penalty for a gap */
    #define PINS1   4 /* penalty per residue */
    struct jmp {
    short n[MAXJMP]; /* size of jmp (neg for dely) */
    unsigned short x[MAXJMP]; /* base no. of jmp in seq x */
    /* limits seq to 2{circumflex over ( )}16 −1 */
    };
    struct diag {
    int score; /* score at last jmp */
    long offset; /* offset of prev block */
    short ijmp; /* current jmp index */
    struct jmp jp; /* list of jmps */
    };
    struct path {
    int spc; /* number of leading spaces */
    short n[JMPS]; /* size of jmp (gap) */
    int x[JMPS]; /* loc of jmp (last elem before gap) */
    };
    char *ofile; /* output file name */
    char *namex[2]; /* seq names: getseqs() */
    char *prog; /* prog name for err msgs */
    char *seqx[2]; /* seqs: getseqs() */
    int dmax; /* best diag: nw() */
    int dmax0; /* final diag */
    int dna; /* set if dna: main() */
    int endgaps; /* set if penalizing end gaps */
    int gapx, gapy; /* total gaps in seqs */
    int len0, len1; /* seq lens */
    int ngapx, ngapy; /* total size of gaps */
    int smax; /* max score: nw() */
    int *xbm; /* bitmap for matching */
    long offset; /* current offset in jmp file */
    struct diag *dx; /* holds diagonals */
    struct path pp[2]; /* holds path for seqs */
    char *calloc(), *malloc(), *index(), *strcpy();
    char *getseq(), *g_calloc();
    /* Needleman-Wunsch alignment program
     *
     * usage: progs file1 file2
     *  where file1 and file2 are two dna or two protein sequences.
     *  The sequences can be in upper- or lower-case an may contain ambiguity
     *  Any lines beginning with ‘;’, ‘>’ or ‘<’ are ignored
     *  Max file length is 65535 (limited by unsigned short x in the jmp struct)
     *  A sequence with ⅓ or more of its elements ACGTU is assumed to be DNA
     *  Output is in the file “align.out”
     *
     * The program may create a tmp file in /tmp to hold info about traceback.
     * Original version developed under BSD 4.3 on a vax 8650
     */
    #include “nw.h”
    #include “day.h”
    static _dbval[26] = {
    1,14,2,13,0,0,4,11,0,0,12,0,3,15,0,0,0,5,6,8,8,7,9,0,10,0
    };
    static _pbval[26] = {
    1, 2|(1<<(‘D’-‘A’))|(1<<(‘N’-‘A’)), 4, 8, 16, 32, 64,
    128, 256, 0×FFFFFFF, 1<<10, 1<<11, 1<<12, 1<<13, 1<<14,
    1<<15, 1<<16, 1< <17, 1<<18, 1<<19, 1<<20, 1<<21, 1<<22,
    1<<23, 1<<24, 1<<25|(1<<(‘E’-‘A’))|(1<<(‘Q’-‘A’))
    };
    main(ac, av) main
    int ac;
    char *av[];
    {
    prog = av[0];
    if(ac != 3) {
    fprintf(stderr, “usage: %s file1 file2\n”, prog);
    fprintf(stderr, “where file1 and file2 are two dna or two protein sequences.\n”);
    fprintf(stderr, “The sequences can be in upper- or lower-case\n”);
    fprintf(stderr, “Any lines beginning with ‘;’ or ‘<’ are ignored\n”);
    fprintf(stderr, “Output is in the file \“align.out\”\n”);
    exit(1);
    }
    namex[0] = av[1];
    namex[1] = av[2];
    seqx[0] = getseq(namex[0], &len0);
    seqx[1] = getseq(namex[1], &len1);
    xbm = (dna)? _dbval : _pbval;
    endgaps = 0; /* 1 to penalize endgaps */
    ofile = “align.out”; /* output file */
    nw(); /* fill in the matrix, get the possible jmps */
    readjmps(); /* get the actual jmps */
    print(); /* print stats, alignment */
    cleanup(0); /* unlink any tmp files */
    }
    /* do the alignment, return best score: main()
     * dna: values in Fitch and Smith, PNAS, 80, 1382-1386, 1983
     * pro: PAM 250 values
     * When scores are equal, we prefer mismatches to any gap, prefer
     * a new gap to extending an ongoing gap, and prefer a gap in seqx
     * to a gap in seq y.
     */
    nw() nw
    {
    char *px, *py; /* seqs and ptrs */
    int *ndely, *dely; /* keep track of dely */
    int ndelx, delx; /* keep track of delx */
    int *tmp; /* for swapping row0, row1 */
    int mis; /* score for each type */
    int ins0, ins1; /* insertion penalties */
    register id; /* diagonal index */
    register ij; /* jmp index */
    register *col0, *col1; /* score for curr, last row */
    register xx, yy; /* index into seqs */
    dx = (struct diag *)g_calloc(“to get diags”, len0+len1+1, sizeof(struct diag));
    ndely = (int *)g_calloc(“to get ndely”, len1+1, sizeof(int));
    dely = (int *)g_calloc(“to get dely”, len1+1, sizeof(int));
    col0 = (int *)g_calloc(“to get col0”, len1+1, sizeof(int));
    col1 = (int *)g_calloc(“to get col1”, len1+1, sizeof(int));
    ins0 = (dna)? DINS0 : PINS0;
    ins1 = (dna)? DINS1 : PlNS1;
    smax = −10000;
    if (endgaps) {
    for (col0[0] = dely[0] = −ins0, yy = 1; yy <= len1; yy++) {
    col0[yy] = dely[yy] = col0[yy−1] − ins1;
    ndely[yy] = yy;
    }
    col0[0] = 0; /* Waterman Bull Math Biol 84 */
    }
    else
    for (yy = 1; yy <= len1; yy++)
    dely[yy] = −ins0;
    /* fill in match matrix
     */
    for (px = seqx[0], xx = 1; xx <= len0; px++, xx++) {
    /* initialize first entry in col
     */
    if (endgaps) {
    if (xx == 1)
    col1[0] = delx = −(ins0+ins1);
    else
    col1[0] = delx = col0[0]−ins1;
    ndelx = xx;
    }
    else {
    col1[0] = 0;
    delx = −ins0;
    ndelx = 0;
    }
    ...nw
    for (py = seqx[1], yy = 1; yy <= len1; py++, yy++) {
    mis = col0[yy−1];
    if (dna)
    mis += (xbm[*px−‘A’]&xbm[*py−‘A’])? DMAT : DMIS;
    else
    mis += _day[*px−‘A’][*py−‘A’];
    /* update penalty for del in x seq;
     * favor new del over ongong del
     * ignore MAXGAP if weighting endgaps
     */
    if (endgaps || ndely[yy] < MAXGAP) {
    if (col0[yy] − ins0 >= dely[yy]) {
    dely[yy] = col0[yy] − (ins0+ins1);
    ndely[yy] = 1;
    } else {
    dely[yy] −= ins1;
    ndely[yy]++;
    }
    } else {
    if (col0[yy] − (ins0+ins1) >= dely[yy]) {
    dely[yy] = col0[yy] − (ins0+ins1);
    ndely[yy] = 1;
    } else
    ndely[yy]++;
    }
    /* update penalty for del in y seq;
     * favor new del over ongong del
     */
    if (endgaps || ndelx < MAXGAP) {
    if(col1[yy−1] − ins0 >= delx) {
    delx = col1[yy−1] − (ins0+ins1);
    ndelx = 1;
    } else {
    delx −= ins1;
    ndelx++;
    }
    } else {
    if (col1[yy−1] − (ins0+ins1) >= delx) {
    delx = col1[yy−1] − (ins0+ins1);
    ndelx = 1;
    } else
    ndelx++;
    }
    /* pick the maximum score; we're favoring
     * mis over any del and delx over dely
     */
    ...nw
    id = xx − yy + len1 − 1;
    if (mis >= delx && mis >= dely[yy])
    col1[yy] = mis;
    else if (delx >= dely[yy]) {
    col1[yy] = delx;
    ij = dx[id].ijmp;
    if (dx[id].jp.n[0] && (!dna || (ndelx >= MAXJMP
    && xx > dx[id].jp.x[ij]+MX) || mis > dx[id].score+DINS0)) {
    dx[id].ijmp++;
    if (++ij >= MAXJMP) {
    writejmps(id);
    ij = dx[id].ijmp = 0;
    dx[id].offset = offset;
    offset += sizeof(struct jmp) + sizeof(offset);
    }
    }
    dx[id].jp.n[ij] = ndelx;
    dx[id].jp.x[ij] = xx;
    dx[id].score = delx;
    }
    else {
    col1[yy] = dely[yy];
    ij = dx[id].ijmp;
    if (dx[id].jp.n[0] && (!dna || (ndely[yy] >= MAXJMP
    && xx > dx[id].jp.x[ij]+MX) || mis > dx[id].score+DINS0)) {
    dx[id].ijmp++;
    if (++ij >= MAXJMP) {
    writejmps(id);
    ij = dx[id].ijmp = 0;
    dx[id].offset = offset;
    offset += sizeof(struct jmp) + sizeof(offset);
    }
    }
    dx[id].jp.n[ij] =− ndely[yy];
    dx[id].jp.x[ij] = xx;
    dx[id].score = dely[yy];
    }
    if (xx == len0 && yy < len1) {
    /* last col
     */
    if (endgaps)
    col1[yy] −= ins0+ins1*(len1−yy);
    if(col1[yy] > smax) {
    smax = col1[yy];
    dmax = id;
    }
    }
    }
    if (endgaps && xx < len0)
    col1[yy−1] −= ins0+ins1*(len0−xx);
    if (col1[yy−1] > smax) {
    smax = col1[yy−1];
    dmax = id;
    }
    tmp = col0; col0 = col1; col1 = tmp;
    }
    (void) free((char *)ndely);
    (void) free((char *)dely);
    (void) free((char *)col0);
    (void) free((char *)col1);
    }
    /*
     *
     * print() -- only routine visible outside this module
     *
     * static:
     * getmat() -- trace back best path, count matches: print()
     * pr_align() -- print alignment of described in array p[]: print()
     * dumpblock() -- dump a block of lines with numbers, stars: pr_align()
     * nums() -- put out a number line: dumpblock()
     * putline() -- put out a line (name, [num], seq, [num]): dumpblock()
     * stars() - -put a line of stars: dumpblock()
     * stripname() -- strip any path and prefix from a seqname
     */
    #include “nw.h”
    #define SPC  3
    #define P_LINE 256 /* maximum output line */
    #define P_SPC  3 /* space between name or num and seq */
    extern _day[26][26];
    int olen; /* set output line length */
    FILE *fx; /* output file */
    print() print
    {
    int lx, ly, firstgap, lastgap;  /* overlap */
    if ((fx = fopen(ofile, “w”)) == 0) {
    fprintf(stderr, “%s: can't write %s\n”, prog, ofile);
    cleanup(1);
    }
    fprintf(fx, “<first sequence: %s (length = %d)\n”, namex[0], len0);
    fprintf(fx, “<second sequence: %s (length = %d)\n”, namex[1], len1);
    olen = 60;
    lx = len0;
    ly = len1;
    firstgap = lastgap = 0;
    if (dmax < len1 − 1) { /* leading gap in x */
    pp[0].spc = firstgap = len1 − dmax − 1;
    ly −= pp[0].spc;
    }
    else if (dmax > len1 − 1) { /* leading gap in y */
    pp[1].spc = firstgap = dmax − (len1 − 1);
    lx −= pp[1].spc;
    }
    if (dmax0 < len0 − 1) { /* trailing gap in x */
    lastgap = len0 − dmax0 −1;
    lx −= lastgap;
    }
    else if (dmax0 > len0 − 1) { /* trailing gap in y */
    lastgap = dmax0 − (len0 − 1);
    ly −= lastgap;
    }
    getmat(lx, ly, firstgap, lastgap);
    pr_align();
    }
    /*
     * trace back the best path, count matches
     */
    static
    getmat(lx, ly, firstgap, lastgap) getmat
    int lx, ly; /* “core” (minus endgaps) */
    int firstgap, lastgap; /* leading trailing overlap */
    {
    int nm, i0, i1, siz0, siz1;
    char outx[32];
    double pct;
    register n0, n1;
    register char *p0, *p1;
    /* get total matches, score
     */
    i0 = i1 = siz0 = siz1 = 0;
    p0 = seqx[0] + pp[1].spc;
    p1 = seqx[1] + pp[0].spc;
    n0 = pp[1].spc + 1;
    n1 = pp[0].spc + 1;
    nm = 0;
    while ( *p0 && *p1 ) {
    if (siz0) {
    p1++;
    n1++;
    siz0−−;
    }
    else if (siz1) {
    p0++;
    n0++;
    siz1−−;
    }
    else {
    if (xbm[*p0−‘A’]&xbm[*p1−‘A’])
    nm++;
    if (n0++ == pp[0].x[i0])
    siz0 = pp[0].n[i0++];
    if (nl++ == pp[1].x[i1])
    siz1 = pp[1].n[il++];
    p0++;
    p1++;
    }
    }
    /* pct homology:
     * if penalizing endgaps, base is the shorter seq
     * else, knock off overhangs and take shorter core
     */
    if (endgaps)
    lx = (len0 < len1)? len0 : len1;
    else
    lx = (lx < ly)? lx : ly;
    pct = 100.*(double)nm/(double)lx;
    fprintf(fx, “\n”);
    fprintf(fx, “<%d match%s in an overlap of %d: %.2f percent similarity\n”,
    nm, (nm == 1)? “” : “es”, lx, pct);
    fprintf(fx, “<gaps in first sequence: %d”, gapx); ...getmat
    if (gapx) {
    (void) sprintf(outx, “(%d %s%s)”,
    ngapx, (dna)? “base”: “residue”, (ngapx == 1)? “”:“s”);
    fprintf(fx, “%s”, outx);
    fprintf(fx, “, gaps in second sequence: %d”, gapy);
    if (gapy) {
    (void) sprintf(outx, “(%d %s%s)”,
    ngapy, (dna)? “base”:“residue”, (ngapy == 1)? “”:“s”);
    fprintf(fx, “%s”, outx);
    }
    if (dna)
    fprintf(fx,
    “\n<score: %d (match = %d, mismatch = %d, gap penalty = %d + %d per base)\n”,
    smax, DMAT, DMIS, DINS0, DINS1);
    else
    fprintf(fx,
    “\n<score: %d (Dayhoff PAM 250 matrix, gap penalty = %d + %d per residue)\n”,
    smax, PINS0, PINS1);
    if (endgaps)
    fprintf(fx,
    “<endgaps penalized. left endgap: %d %s%s, right endgap: %d %s%s\n”,
    firstgap, (dna)? “base” : “residue”, (firstgap == 1)? “” : “s”,
    lastgap, (dna)? “base” : “residue”, (lastgap == 1)? “” : “s”);
    else
    fprintf(fx, “<endgaps not penalized\n”);
    }
    static nm; /* matches in core -- for checking */
    static lmax; /* lengths of stripped file names */
    static ij[2]; /* jmp index for a path */
    static nc[2]; /* number at start of current line */
    static ni[2]; /* current elem number -- for gapping */
    static siz[2];
    static char *ps[2]; /* ptr to current element */
    static char *po[2]; /* ptr to next output char slot */
    static char out[2][P_LINE]; /* output line */
    static char star[P_LINE]; /* set by stars() */
    /*
     * print alignment of described in struct path pp[]
     */
    static
    pr_align() pr_align
    {
    int nn; /* char count */
    int more;
    register i;
    for (i = 0, lmax = 0; i < 2;i++) {
    nn = stripname(namex[i]);
    if (nn > lmax)
    lmax = nn;
    nc[i] = 1;
    ni[i] = 1;
    siz[i] = ij[i] = 0;
    ps[i] = seqx[i];
    po[i] = out[i];
    }
    for (nn = nm = 0, more = 1; more;) { ...pr_align
    for (i = more = 0; i < 2; i++) {
    /*
     * do we have more of this sequence?
     */
    if (!*ps[i])
    continue;
    more++;
    if (pp[i].spc) { /* leading space */
    *po[i]++ = ‘ ’;
    pp[i].spc−−;
    }
    else if (siz[i]) { /* in a gap */
    *po[i]++ = ‘−’;
    siz[i]−−;
    }
    else { /* we're putting a seq element
    */
    *po[i] = *ps[i];
    if (islower(*ps[i]))
       *ps[i] = toupper(*ps[i]);
    po[i]++;
    ps[i]++;
    /*
     * are we at next gap for this seq?
     */
    if (ni[i] == pp[i].x[ij[i]]) {
    /*
     * we need to merge all gaps
     * at this location
     */
    siz[i] == pp[i].n[ij[i]++];
    while (ni[i] == pp[i].x[ij[i]])
    siz[i] += pp[i].n[ij[i]++];
    }
    ni[i]++;
    }
    }
    if (++nn == olen || !more && nn) {
    dumpblock();
    for (i = 0; i < 2; i++)
    po[i] = out[i];
    nn = 0;
    }
    }
    }
    /*
     * dump a block of lines, including numbers, stars: pr_align()
     */
    static
    dumpblock() dumpblock
    {
    register i;
    for(i = 0; i < 2; i++)
    *po[i]−− = ‘\0’;
    ...dumpblock
    (void) putc(‘\n’, fx);
    for (i = 0; i < 2; i++) {
    if (*out[i] && (*out[i] != ‘ ’ || *(po[i]) != ‘ ’)) {
    if (i == 0)
    nums(i);
    if (i == 0 && *out[1])
    stars();
    putline(i);
    if (i == 0 && *out[1])
    fprintf(fx, star);
    if (i == 1)
    nums(i);
    }
    }
    }
    /*
    * put out a number line: dumpblock()
     */
    static
    nums(ix) nums
    int  ix; /* index in out[] holding seq line */
    {
    char nline[P_LINE];
    register i, j;
    register char *pn, *px, *py;
    for(pn = nline, i = 0; i < lmax+P_SPC; i++, pn++)
    *pn = ‘ ’;
    for (i = nc[ix], py = out[ix]; *py; py++, pn++) {
    if (*py == ‘ ’ || *py == ‘−’)
    *pn = ‘ ’;
    else {
    if (i%10 == 0 || (i == 1 && nc[ix] != 1)) {
    j = (i < 0)? −i : i;
    for (px = pn; j; j/= 10, px−−)
    *px = j%10 + ‘0’;
    if (i < 0)
    *px = ‘−’;
    }
    else
    *pn = ‘ ’;
    i++;
    }
    }
    *pn = ‘\0’;
    nc[ix] = i;
    for (pn = nline; *pn; pn++)
    (void) putc(*pn, fx);
    (void) putc(‘\n’, fx);
    }
    /*
     * put out a line (name, [num], seq. [num]): dumpblock()
     */
    static
    putline(ix) putline
    int   ix; {
    ...putline
    int i;
    register char *px;
    for (px = namex[ix], i = 0; *px && *px != ‘:’; px++, i++)
    (void) putc(*px, fx);
    for (;i < lmax+P_SPC; i++)
    (void) putc(‘ ’, fx);
    /* these count from 1:
     * ni[] is current element (from 1)
     * nc[] is number at start of current line
     */
    for (px = out[ix]; *px; px++)
    (void) putc(*px&0x7F, fx);
    (void) putc(‘\n’, fx);
    }
    /*
     * put a line of stars (seqs always in out[0], out[1]): dumpblock()
     */
    static
    stars() stars
    {
    int i;
    register char *p0, *p1, cx, *px;
    if (!*out[0] || (*out[0] == ‘ ’ && *(p0[0]) == ‘ ’) ||
    !*out[1] || (*out[1] == ‘ ’ && *(po[1]) == ‘ ’))
    return;
    px = star;
    for (i = lmax+P_SPC; i; i−−)
    *px++ = ‘ ’;
    for (p0 = out[0], p1 = out[1]; *p0 && *p1; p0++, p1++) {
    if (isalpha(*p0) && isalpha(*p1)) {
    if (xbm[*p0−‘A’]&xbm[*p1−‘A’]) {
    cx = ‘*’;
    nm++;
    }
    else if (!dna && _day[*p0− ‘A’][*p1−‘A’] > 0)
    cx = ‘.’;
    else
    cx = ‘ ’;
    }
    else
    cx = ‘ ’;
    *px++ = cx;
    }
    *px++ = ‘\n’;
    *px = ‘\0’;
    }
    /*
     * strip path or prefix from pn, return len: pr_align()
     */
    static
    stripname(pn) stripname
    char *pn; /* file name (may be path) */
    {
    register char *px, *py;
    py = 0;
    for (px = pn; *px; px++)
    if (*px == ‘/’)
    py = px + 1;
    if (py)
    (void) strcpy(pn, py);
    return(strlen(pn));
    }
    /*
     * cleanup() -- cleanup any tmp file
     * getseq() -- read in seq, set dna, len, maxlen
     * g_calloc() -- calloc() with error checkin
     * readjmps() -- get the good jmps, from tmp file if necessary
     * writejmps() -- write a filled array of jmps to a tmp file: nw()
     */
    #include “nw.h”
    #include <sys/file.h>
    char *jname = “/tmp/homgXXXXXX”; /* tmp file for jmps */
    FILE *fj;
    int cleanup(); /* cleanup tmp file */
    long lseek();
    /*
     * remove any tmp file if we blow
     */
    cleanup(i) cleanup
    int i;
    {
    if (fj)
    (void) unlink(jname);
    exit(i);
    }
    /*
     * read, return ptr to seq, set dna, len, maxlen
     * skip lines starting with ‘;’, ‘<’, or ‘>’
     * seq in upper or lower case
     */
    char *
    getseq(file, len) getseq
    char *file; /* file name */
    int *len; /* seq len */
    {
    char line[1024], *pseq;
    register char *px, *py;
    int natgc, tlen;
    FILE *fp;
    if ((fp = fopen(file, “r”)) == 0) {
    fprintf(stderr, “%s: can't read %s\n”, prog, file);
    exit(1);
    }
    tlen = natgc = 0;
    while (fgets(line, 1024, fp)) {
    if (*line == ‘;’ || *line == ‘<’ || *line == ‘>’)
    continue;
    for (px = line; *px != ‘\n’; px++)
    if (isupper(*px) || islower(*px))
    tlen++;
    }
    if ((pseq = malloc((unsigned)(tlen+6))) == 0) {
    fprintf(stderr, “%s: malloc() failed to get %d bytes for %s\n”, prog, tlen+6, file);
    exit(1);
    }
    pseq[0] = pseq[1] = pseq[2] = pseq[3] = ‘\0’;
    ...getseq
    py = pseq + 4;
    *len = tlen;
    rewind(fp);
    while (fgets(line, 1024, fp)) {
    if (*line == ‘;’ || *line == ‘<’ || *line == ‘>’)
    continue;
    for (px = line; *px != ‘\n’; px++) {
    if (isupper(*px))
    *py++ = *px;
    else if (islower(*px))
    *py++ = toupper(*px);
    if (index(“ATGCU”, *(py−1)))
    natgc++;
    }
    }
    *py++ = ‘\0’;
    *py = ‘\0’;
    (void) fclose(fp);
    dna = natgc > (tlen/3);
    return(pseq+4);
    }
    char *
    g_calloc(msg, nx, sz) g_calloc
    char *msg; /* program, calling routine */
    int nx, sz; /* number and size of elements */
    {
    char *px, *calloc();
    if ((px = calloc((unsigned)nx, (unsigned)sz)) == 0) {
    if (*msg) {
    fprintf(stderr, “%s: g_calloc() failed %s (n= %d, sz= %d)\n”, prog, msg, nx, sz);
    exit(1);
    }
    }
    return(px);
    }
    /*
     * get final jmps from dx[] or tmp file, set pp[], reset dmax: main()
     */
    readjmps() readjmps
    {
    int fd = −1;
    int siz, i0, i1;
    register i, j, xx;
    if (fj) {
    (void) fclose(fj);
    if ((fd = open(jname, O_RDONLY, 0)) < 0) {
    fprintf(stderr, “%s: can't open() %s\n”, prog, jname);
    cleanup(1);
    }
    }
    for (i = i0 = i1 = 0, dmax0 = dmax, xx = len0; ;i++) {
    while (1) {
    for (j = dx[dmax].ijmp; j >= 0 && dx[dmax].jp.x[j] >= xx; j−−)
    ;
    ...readjmps
    if (j < 0 && dx[dmax].offset && fj) {
    (void) lseek(fd, dx[dmax].offset, 0);
    (void) read(fd, (char *)&dx[dmax].jp, sizeof(struct jmp));
    (void) read(fd, (char *)&dx[dmax].offset, sizeof(dx[dmax].offset));
    dx[dmax].ijmp = MAXJMP−1;
    }
    else
    break;
    }
    if (i >= JMPS) {
    fprintf(stderr, “%s: too many gaps in alignment\n”, prog);
    cleanup(1);
    }
    if (j >= 0) {
    siz = dx[dmax].jp.n[j];
    xx = dx[dmax].jp.x[j];
    dmax += siz;
    if (siz < 0) { /* gap in second seq */
    pp[1].n[il] = −siz;
    xx += siz;
    /* id = xx − yy + len1 − 1
     */
    pp[1].x[il] = xx − dmax + len1 − 1;
    gapy++;
    ngapy −= siz;
    /* ignore MAXGAP when doing endgaps */
    siz = (−siz < MAXGAP || endgaps)? −siz : MAXGAP;
    il++;
    }
    else if (siz > 0) { /* gap in first seq */
    pp[0] .n[i0] = siz;
    pp[0] .x[i0] = xx;
    gapx++;
    ngapx += siz;
    /* ignore MAXGAP when doing endgaps */
    siz = (siz < MAXGAP || endgaps)? siz : MAXGAP;
    i0++;
    }
    }
    else
    break;
    }
    /* reverse the order of jmps
     */
    for (j = 0, i0−−; j < i0; j++, i0−−) {
    i = pp[0].n[j]; pp[0].n[j] = pp[0].n[i0]; pp[0].n[i0] = i;
    i = pp[0].x[j]; pp[0].x[j] = pp[0].x[i0]; pp[0].x[i0] = i;
    }
    for (j = 0, i1−−; j < i1; j++, i1−−) {
    i = pp[1].n[j]; pp[1].n[j] = pp[1].n[i1]; pp[1].n[i1] = i;
    i = pp[1].x[j]; pp[1].x[j] = pp[1].x[i1]; pp[1].x[i1] = i;
    }
    if (fd >= 0)
    (void) close(fd);
    if (fj) {
    (void) unlink(jname);
    fj = 0;
    offset = 0;
    } }
    /*
     * write a filled jmp struct offset of the prev one (if any): nw()
     */
    writejmps(ix) writejmps
    int ix;
    {
    char *mktemp();
    if (!fj) {
    if (mktemp(jname) < 0) {
    fprintf(stderr, “%s: can't mktemp() %s\n”, prog, jname);
    cleanup(1);
    }
    if ((fj = fopen(jname, “w”)) == 0) {
    fprintf(stderr, “%s: can't write %s\n”, prog, jname);
    exit(1);
    }
    }
    (void) fwrite((char *)&dx[ix].jp, sizeof(struct jmp), 1, fj);
    (void) fwrite((char *)&dx[ix].offset, sizeof(dx[ix].offset), 1, fj);
    }
  • [0253]
    TABLE 2
    PRO XXXXXXXXXXXXXXX (Length = 15 amino acids)
    Comparison XXXXXYYYYYYY (Length = 12 amino acids)
    Protein
  • [0254]
    TABLE 3
    PRO XXXXXXXXXX (Length = 10 amino acids)
    Comparison XXXXXYYYYYYZZYZ (Length = 15 amino acids)
    Protein
  • [0255]
    TABLE 4
    PRO-DNA NNNNNNNNNNNNNN (Length = 14 nucleotides)
    Comparison NNNNNNLLLLLLLLLL (Length = 16 nucleotides)
    DNA
  • [0256]
    TABLE 5
    PRO-DNA NNNNNNNNNNNN (Length = 12 nucleotides)
    Comparison DNA NNNNLLLVV (Length = 9 nucleotides)
    DNA
  • II. Compositions and Methods of the Invention [0257]
  • A. Full-Length PRO Polypeptides [0258]
  • The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO polypeptides. In particular, cDNAs encoding various PRO polypeptides have been identified and isolated, as disclosed in further detail in the Examples below. It is noted that proteins produced in separate expression rounds may be given different PRO numbers but the UNQ number is unique for any given DNA and the encoded protein, and will not be changed. However, for sake of simplicity, in the present specification the protein encoded by the full length native nucleic acid molecules disclosed herein as well as all further native homologues and variants included in the foregoing definition of PRO, will be referred to as “PRO/number”, regardless of their origin or mode of preparation. [0259]
  • As disclosed in the Examples below, various cDNA clones have been deposited with the ATCC. The actual nucleotide sequences of those clones can readily be determined by the skilled artisan by sequencing of the deposited clone using routine methods in the art. The predicted amino acid sequence can be determined from the nucleotide sequence using routine skill. For the PRO polypeptides and encoding nucleic acids described herein, Applicants have identified what is believed to be the reading frame best identifiable with the sequence information available at the time. [0260]
  • B. PRO Polypeptide Variants [0261]
  • In addition to the full-length native sequence PRO polypeptides described herein, it is contemplated that PRO variants can be prepared. PRO variants can be prepared by introducing appropriate nucleotide changes into the PRO DNA, and/or by synthesis of the desired PRO polypeptide. Those skilled in the art will appreciate that amino acid changes may alter post-translational processes of the PRO, such as changing the number or position of glycosylation sites or altering the membrane anchoring characteristics. [0262]
  • Variations in the native full-length sequence PRO or in various domains of the PRO described herein, can be made, for example, using any of the techniques and guidelines for conservative and non-conservative mutations set forth, for instance, in U.S. Pat. No. 5,364,934. Variations may be a substitution, deletion or insertion of one or more codons encoding the PRO that results in a change in the amino acid sequence of the PRO as compared with the native sequence PRO. Optionally the variation is by substitution of at least one amino acid with any other amino acid in one or more of the domains of the PRO. Guidance in determining which amino acid residue may be inserted, substituted or deleted without adversely affecting the desired activity may be found by comparing the sequence of the PRO with that of homologous known protein molecules and minimizing the number of amino acid sequence changes made in regions of high homology. Amino acid substitutions can be the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, such as the replacement of a leucine with a serine, i.e., conservative amino acid replacements. Insertions or deletions may optionally be in the range of about 1 to 5 amino acids. The variation allowed may be determined by systematically making insertions, deletions or substitutions of amino acids in the sequence and testing the resulting variants for activity exhibited by the full-length or mature native sequence. [0263]
  • PRO polypeptide fragments are provided herein. Such fragments may be truncated at the N-terminus or C-terminus, or may lack internal residues, for example, when compared with a full length native protein. Certain fragments lack amino acid residues that are not essential for a desired biological activity of the PRO polypeptide. [0264]
  • PRO fragments may be prepared by any of a number of conventional techniques. Desired peptide fragments may be chemically synthesized. An alternative approach involves generating PRO fragments by enzymatic digestion, e.g., by treating the protein with an enzyme known to cleave proteins at sites defined by particular amino acid residues, or by digesting the DNA with suitable restriction enzymes and isolating the desired fragment. Yet another suitable technique involves isolating and amplifying a DNA fragment encoding a desired polypeptide fragment, by polymerase chain reaction (PCR). Oligonucleotides that define the desired termini of the DNA fragment are employed at the 5′ and 3′ primers in the PCR. Preferably, PRO polypeptide fragments share at least one biological and/or immunological activity with the native PRO polypeptide disclosed herein. [0265]
  • In particular embodiments, conservative substitutions of interest are shown in Table 6 under the heading of preferred substitutions. If such substitutions result in a change in biological activity, then more substantial changes, denominated exemplary substitutions in Table 6, or as further described below in reference to amino acid classes, are introduced and the products screened. [0266]
    TABLE 6
    Original Exemplary Preferred
    Residue Substitutions Substitutions
    Ala (A) val; leu; ile val
    Arg (R) lys; gln; asn lys
    Asn (N) gln; his; lys; arg gln
    Asp (D) glu glu
    Cys (C) ser ser
    Gln (Q) asn asn
    Glu (E) asp asp
    Gly (G) pro; ala ala
    His (H) asn; gln; lys; arg arg
    Ile (I) leu; val; met; ala; phe; leu
    norleucine
    Leu (L) norleucine; ile; val; ile
    met; ala; phe
    Lys (K) arg; gln; asn arg
    Met (M) leu; phe; ile leu
    Phe (F) leu; val; ile; ala; tyr leu
    Pro (P) ala ala
    Ser (S) thr thr
    Thr (T) ser ser
    Trp (W) tyr; phe tyr
    Tyr (Y) trp; phe; thr; ser phe
    Val (V) ile; leu; met; phe; leu
    ala; norleucine
  • Substantial modifications in function or immunological identity of the PRO polypeptide are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. [0267]
  • Naturally occurring residues are divided into groups based on common side-chain properties: [0268]
  • (1) hydrophobic: norleucine, met, ala, val, leu, ile; [0269]
  • (2) neutral hydrophilic: cys, ser, thr; [0270]
  • (3) acidic: asp, glu; [0271]
  • (4) basic: asn, gin, his, lys, arg; [0272]
  • (5) residues that influence chain orientation: gly, pro; and [0273]
  • (6) aromatic: trp, tyr, phe. [0274]
  • Non-conservative substitutions will entail exchanging a member of one of these classes for another class. Such substituted residues also may be introduced into the conservative substitution sites or, more preferably, into the remaining (non-conserved) sites. [0275]
  • The variations can be made using methods known in the art such as oligonucleotide-mediated (site-directed) mutagenesis, alanine scanning, and PCR mutagenesis. Site-directed mutagenesis [Carter et al., Nucl. Acids Res., 13:4331 (1986); Zoller et al., Nucl. Acids Res., 10:6487 (1987)], cassette mutagenesis [Wells et al., Gene, 34:315 (1985)], restriction selection mutagenesis [Wells et al., Philos. Trans. R. Soc. London SerA, 317:415 (1986)] or other known techniques can be performed on the cloned DNA to produce the PRO variant DNA. [0276]
  • Scanning amino acid analysis can also be employed to identify one or more amino acids along a contiguous sequence. Among the preferred scanning amino acids are relatively small, neutral amino acids. Such amino acids include alanine, glycine, serine, and cysteine. Alanine is typically a preferred scanning amino acid among this group because it eliminates the side-chain beyond the beta-carbon and is less likely to alter the main-chain conformation of the variant [Cunningham and Wells, Science, 244:1081-1085 (1989)]. Alanine is also typically preferred because it is the most common amino acid. Further, it is frequently found in both buried and exposed positions [Creighton, The Proteins, (W. H. Freeman & Co., N.Y.); Chothia, J. Mol. Biol., 150:1 (1976)]. If alanine substitution does not yield adequate amounts of variant, an isoteric amino acid can be used. [0277]
  • C. Modifications of PRO [0278]
  • Covalent modifications of PRO are included within the scope of this invention. One type of covalent modification includes reacting targeted amino acid residues of a PRO -polypeptide with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C- terminal residues of the PRO. Derivatization with bifunctional agents is useful, for instance, for crosslinking PRO to a water-insoluble support matrix or surface for use in the method for purifying anti-PRO antibodies, and vice-versa. Commonly used crosslinking agents include, e.g., 1,1-bis (diazoacetyl)-2-phenylethane, glutaraldehyde, N-hydroxysuccinimide esters, for example, esters with 4-azidosalicylic acid, homobifunctional imidoesters, including disuccinimidyl esters such as 3,3′-dithiobis(succinimidylpropionate), bifunctional maleimides such as bis-N-maleimido-1,8-octane and agents such as methyl-3-[(p-azidophenyl)dithio]propioimidate. [0279]
  • Other modifications include deamidation of glutaminyl and asparaginyl residues to the corresponding glutamyl and aspartyl residues, respectively, hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the α-amino groups of lysine, arginine, and histidine side chains [T. E. Creighton, Proteins: Structure and Molecular Properties, W. H. Freeman & Co., San Francisco, pp. 79-86 (1983)], acetylation of the N-terminal amine, and amidation of any C-terminal carboxyl group. [0280]
  • Another type of covalent modification of the PRO polypeptide included within the scope of this invention comprises altering the native glycosylation pattern of the polypeptide. “Altering the native glycosylation pattern” is intended for purposes herein to mean deleting one or more carbohydrate moieties found in native sequence PRO (either by removing the underlying glycosylation site or by deleting the glycosylation by chemical and/or enzymatic means), and/or adding one or more glycosylation sites that are not present in the native sequence PRO. In addition, the phrase includes qualitative changes in the glycosylation of the native proteins, involving a change in the nature and proportions of the various carbohydrate moieties present. [0281]
  • Addition of glycosylation sites to the PRO polypeptide may be accomplished by altering the amino acid sequence. The alteration may be made, for example, by the addition of, or substitution by, one or more serine or threonine residues to the native sequence PRO (for O-linked glycosylation sites). The PRO amino acid sequence may optionally be altered through changes at the DNA level, particularly by mutating the DNA encoding the PRO polypeptide at preselected bases such that codons are generated that will translate into the desired amino acids. [0282]
  • Another means of increasing the number of carbohydrate moieties on the PRO polypeptide is by chemical or enzymatic coupling of glycosides to the polypeptide. Such methods are described in the art, e.g., in WO 87/05330 published Sep. 11, 1987, and in Aplin and Wriston, CRC Crit. Rev. Biochem., pp. 259-306 (1981). [0283]
  • Removal of carbohydrate moieties present on the PRO polypeptide may be accomplished chemically or enzymatically or by mutational substitution of codons encoding for amino acid residues that serve as targets for glycosylation. Chemical deglycosylation techniques are known in the art and described, for instance, by Hakimuddin, et al., Arch. Biochem. Biophys., 259:52 (1987) and by Edge et al., Anal. Biochem., 118:131 (1981). Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al., Meth. Enzymol., 138:350 (1987). [0284]
  • Another type of covalent modification of PRO comprises linking the PRO polypeptide to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol (PEG), polypropylene glycol, or polyoxyalkylenes, in the manner set forth in U.S. Pat. Nos. 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192 or 4,179,337. [0285]
  • The PRO of the present invention may also be modified in a way to form a chimeric molecule comprising PRO fused to another, heterologous polypeptide or amino acid sequence. [0286]
  • In one embodiment, such a chimeric molecule comprises a fusion of the PRO with a tag polypeptide which provides an epitope to which an anti-tag antibody can selectively bind. The epitope tag is generally placed at the amino- or carboxyl-terminus of the PRO. The presence of such epitope-tagged forms of the PRO can be detected using an antibody against the tag polypeptide. Also, provision of the epitope tag enables the PRO to be readily purified by affinity purification using an anti-tag antibody or another type of affinity matrix that binds to the epitope tag. Various tag polypeptides and their respective antibodies are well known in the art. Examples include poly-histidine (poly-his) or poly-histidine-glycine (poly-his-gly) tags; the flu HA tag polypeptide and its antibody 12CA5 [Field et al., Mol. Cell. Biol., 8:21 59-2165 (1988)]; the c-myc tag and the 8F9, 3C7, 6E10, G4, B7 and 9E10 antibodies thereto [Evan et al., Molecular and Cellular Biology, 5:3610-3616 (1985)]; and the Herpes Simplex virus glycoprotein D (gD) tag and its antibody [Paborsky et al., Protein Engineering, 3(6):547-553 (1990)]. Other tag polypeptides include the Flag-peptide [Hopp et al., BioTechnology, 6:1204-1210 (1988)]; the KT3 epitope peptide [Martin et al., Science, 255:192-194 (1992)]; an α-tubulin epitope peptide [Skinner et al., J. Biol. Chem., 266:15163-15166 (1991)]; and the T7 gene 10 protein peptide tag [Lutz-Freyermuth et al., Proc. Natl. Acad. Sci. USA, 87:6393-6397 (1990)]. [0287]
  • In an alternative embodiment, the chimeric molecule may comprise a fusion of the PRO with an immunoglobulin or a particular region of an immunoglobulin. For a bivalent form of the chimeric molecule (also referred to as an “immunoadhesin”), such a fusion could be to the Fc region of an IgG molecule. The Ig fusions preferably include the substitution of a soluble (transmembrane domain deleted or inactivated) form of a PRO polypeptide in place of at least one variable region within an Ig molecule. In a particularly preferred embodiment, the immunoglobulin fusion includes the hinge, CH2 and CH3, or the hinge, CH1, CH2 and CH3 regions of an IgG1 molecule. For the production of immunoglobulin fusions see also U.S. Pat. No. 5,428,130 issued Jun. 27, 1995. [0288]
  • D. Preparation of PRO [0289]
  • The description below relates primarily to production of PRO by culturing cells transformed or transfected with a vector containing PRO nucleic acid. It is, of course, contemplated that alternative methods, which are well known in the art, may be employed to prepare PRO. For instance, the PRO sequence; or portions thereof, may be produced by direct peptide synthesis using solid-phase techniques [see, e.g., Stewart et al., Solid-Phase Peptide Synthesis, W. H. Freeman Co., San Francisco, Calif. (1969); Merrifield, J. Am. Chem. Soc., 85:2149-2154 (1963)]. In vitro protein synthesis may be performed using manual techniques or by automation. Automated synthesis may be accomplished, for instance, using an Applied Biosystems Peptide Synthesizer (Foster City, Calif.) using manufacturer's instructions. Various portions of the PRO may be chemically synthesized separately and combined using chemical or enzymatic methods to produce the full-length PRO. [0290]
  • 1. Isolation of DNA Encoding PRO [0291]
  • DNA encoding PRO may be obtained from a cDNA library prepared from tissue believed to possess the PRO mRNA and to express it at a detectable level. Accordingly, human PRO DNA can be conveniently obtained from a cDNA library prepared from human tissue, such as described in the Examples. The PRO-encoding gene may also be obtained from a genomic library or by known synthetic procedures (e.g., automated nucleic acid synthesis). [0292]
  • Libraries can be screened with probes (such as antibodies to the PRO or oligonucleotides of at least about 20-80 bases) designed to identify the gene of interest or the protein encoded by it. Screening the cDNA or genomic library with the selected probe may be conducted using standard procedures, such as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989). An alternative means to isolate the gene encoding PRO is to use PCR methodology [Sambrook et al., supra; Dieffenbach et al., PCR Primer: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 1995)]. [0293]
  • The Examples below describe techniques for screening a cDNA library. The oligonucleotide sequences selected as probes should be of sufficient length and sufficiently unambiguous that false positives are minimized. The oligonucleotide is preferably labeled such that it can be detected upon hybridization to DNA in the library being screened. Methods of labeling are well known in the art, and include the use of radiolabels like [0294] 32P-labeled ATP, biotinylation or enzyme labeling. Hybridization conditions, including moderate stringency and high stringency, are provided in Sambrook et al., supra.
  • Sequences identified in such library screening methods can be compared and aligned to other known sequences deposited and available in public databases such as GenBank or other private sequence databases. Sequence identity (at either the amino acid or nucleotide level) within defined regions of the molecule or across the full-length sequence can be determined using methods known in the art and as described herein. [0295]
  • Nucleic acid having protein coding sequence may be obtained by screening selected cDNA or genomic libraries using the deduced amino acid sequence disclosed herein for the first time, and, if necessary, using conventional primer extension procedures as described in Sambrook et al., supra, to detect precursors and processing intermediates of mRNA that may not have been reverse-transcribed into cDNA. [0296]
  • 2. Selection and Transformation of Host Cells [0297]
  • Host cells are transfected or transformed with expression or cloning vectors described herein for PRO production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences. The culture conditions, such as media, temperature, pH and the like, can be selected by the skilled artisan without undue experimentation. In general, principles, protocols, and practical techniques for maximizing the productivity of cell cultures can be found in Mammalian Cell Biotechnology: a Practical Approach, M. Butler, ed. (IRL Press, 1991) and Sambrook et al., supra. [0298]
  • Methods of eukaryotic cell transfection and prokaryotic cell transformation are known to the ordinarily skilled artisan, for example, CaCl[0299] 2, CaPO4, liposome-mediated and electroporation. Depending on the host cell used, transformation is performed using standard techniques appropriate to such cells. The calcium treatment employing calcium chloride, as described in Sambrook et al., supra, or electroporation is generally used for prokaryotes. Infection with Agrobacterium tumefaciens is used for transformation of certain plant cells, as described by Shaw et al., Gene, 23:315 (1983) and WO 89/05859 published Jun. 29, 1989. For mammalian cells without such cell walls, the calcium phosphate precipitation method of Graham and van der Eb, Virology, 52:456-457 (1978) can be employed. General aspects of mammalian cell host system transfections have been described in U.S. Pat. No. 4,399,216. Transformations into yeast are typically carried out according to the method of Van Solingen et al., J. Bact., 130:946 (1977) and Hsiao et al., Proc. Natl. Acad. Sci. (USA), 76:3829 (1979). However, other methods for introducing DNA into cells, such as by nuclear microinjection, electroporation, bacterial protoplast fusion with intact cells, or polycations, e.g., polybrene, polyornithine, may also be used. For various techniques for transforming mammalian cells, see Keown et al., Methods in Enzymology, 185:527-537 (1990) and Mansour et al., Nature, 336:348-352 (1988).
  • Suitable host cells for cloning or expressing the DNA in the vectors herein include prokaryote, yeast, or higher eukaryote cells. Suitable prokaryotes include but are not limited to eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae such as [0300] E. coli. Various E. coli strains are publicly available, such as E coli K12 strain MM294 (ATCC 31,446); E coli X1776 (ATCC 31,537); E. coli strain W3110 (ATCC 27,325) and K5 772 (ATCC 53,635). Other suitable prokaryotic host cells include Enterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter, Erwlinla, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium, Serratia, e.g., Serratia marcescans, and Shigella, as well as Bacili such as B. subtilis and B. licheniformis (e.g., B. licheniformis 41 P disclosed in DD 266,710 published Apr. 12, 1989), Pseudomonas such as P. aeruginosa, and Streptomyces. These examples are illustrative rather than limiting. Strain W3110 is one particularly preferred host or parent host because it is a common host strain for recombinant DNA product fermentations. Preferably, the host cell secretes minimal amounts of proteolytic enzymes. For example, strain W3110 may be modified to effect a genetic mutation in the genes encoding proteins endogenous to the host, with examples of such hosts including E. coli W3110 strain 1A2, which has the complete genotype tonA; E coli W3110 strain 9E4, which has the complete genotype tonA ptr3; E. coli W3110 strain 27C7 (ATCC 55,244), which has the complete genotype tonA ptr3 phoA E15 (argF-lac)769 degP ompT kanr ; E. coli W3110 strain 37D6, which has the complete genotype tonA ptr3 phoA E15 (argF-lac)169 degP ompT rbs7 ilvG kanr ; E. coli W3110 strain 40B4, which is strain 37D6 with a non-kanamycin resistant degP deletion mutation; and an E. coli strain having mutant periplasmic protease disclosed in U.S. Pat. No. 4,946,783 issued Aug. 7, 1990. Alternatively, in vitro methods of cloning, e.g., PCR or other nucleic acid polymerase reactions, are suitable.
  • In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for PRO-encoding vectors. [0301] Saccharomyces cerevisiae is a commonly used lower eukaryotic host microorganism. Others include Schizosaccharomyces pombe (Beach and Nurse, Nature, 290: 140 [1981]; EP 139,383 published May 2, 1985); Kluyveromyces hosts (U.S. Pat. No. 4,943,529; Fleer et al., Bio/Technology, 9:968-975 (1991)) such as, e.g., K. lactis (MW98-8C, CBS683, CBS4574; Louvencourt et al., J. Bacteriol., 154(2):737-742 [1983]), K. fragilis (ATCC 12,424), K. bulgaricus (ATCC 16,045), K. wickeramii (ATCC 24,178), K. waltii (ATCC 56,500), K. drosophilarum (ATCC 36,906; Van den Berg et al., Bio/Technology, 8:135 (1990)), K. thermotolerans, and K. marxianus; yarrowia (EP 402,226); Pichia pastoris (EP 183,070; Sreekrishna et al., J. Basic Microbiol., 28:265-278 [1988]); Candida; Trichoderma reesia (EP 244,234); Neurospora crassa (Case et al., Proc. Natl. Acad. Sci. USA, 76:5259-5263 [1979]); Schwanniomyces such as Schwanniomyces occidentalis (EP 394,538 published Oct. 31, 1990); and filamentous fungi such as, e.g., Neurospora, Penicilium, Tolypocladium(WO 91/00357 published Jan. 10, 1991), and Aspergillus hosts such as A. nidulans (Ballance et al., Biochem. Biophys. Res. Commun., 112:284-289 [1983]; Tilburn et al., Gene, 26:205-221 [1983]; Yelton et al., Proc. Natl. Acad. Sci. USA, 81: 1470-1474 [1984]) and A. niger (Kelly and Hynes, EMBO J., 4:475-479 [1985]). Methylotropic yeasts are suitable herein and include, but are not limited to, yeast capable of growth on methanol selected from the genera consisting of Hansenula, Candida, Kloeckera, Pichia, Saccharomyces, Torulopsis, and Rhodotorula. A list of specific species that are exemplary of this class of yeasts may be found in C. Anthony, The Biochemistry of Methylotrophs, 269 (1982).
  • Suitable host cells for the expression of glycosylated PRO are derived from multicellular organisms. Examples of invertebrate cells include insect cells such as Drosophila S2 and Spodoptera Sf9, as well as plant cells. Examples of useful mammalian host cell lines include Chinese hamster ovary (CHO) and COS cells. More specific examples include monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture, Graham et al., J. Gen Virol., 36:59 (1977)); Chinese hamster ovary cells/-DHFR (CHO, Urlaub and Chasin, Proc. Natl. Acad. Sci. USA, 77:4216 (1980)); mouse sertoli cells (TM4, Mather, Biol. Reprod., 23:243-251 (1980)); human lung cells (W138, ATCC CCL 75); human liver cells (Hep G2, HB 8065); and mouse mammary tumor (MMT 060562, ATCC CCL51). The selection of the appropriate host cell is deemed to be within the skill in the art. [0302]
  • 3. Selection and Use of a Replicable Vector [0303]
  • The nucleic acid (e.g., cDNA or genomic DNA) encoding PRO may be inserted into a replicable vector for cloning (amplification of the DNA) or for expression. Various vectors are publicly available. The vector may, for example, be in the form of a plasmid, cosmid, viral particle, or phage. The appropriate nucleic acid sequence may be inserted into the vector by a variety of procedures. In general, DNA is inserted into an appropriate restriction endonuclease site(s) using techniques known in the art. Vector components generally include, but are not limited to, one or more of a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. Construction of suitable vectors containing one or more of these components employs standard ligation techniques which are known to the skilled artisan. [0304]
  • The PRO may be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, which may be a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide. In general, the signal sequence may be a component of the vector, or it may be a part of the PRO-encoding DNA that is inserted into the vector. The signal sequence may be a prokaryotic signal sequence selected, for example, from the group of the alkaline phosphatase, penicillinase, lpp, or heat-stable enterotoxin II leaders. For yeast secretion the signal sequence may be, e.g., the yeast invertase leader, alpha factor leader (including Saccharomyces and Kluyveromyces α-factor leaders, the latter described in U.S. Pat. No. 5,010,182), or acid phosphatase leader, the [0305] C. albicans glucoamylase leader (EP 362,179 published Apr. 4, 1990), or the signal described in WO 90/13646 published Nov. 15, 1990. In mammalian cell expression, mammalian signal sequences may be used to direct secretion of the protein, such as signal sequences from secreted polypeptides of the same or related species, as well as viral secretory leaders.
  • Both expression and cloning vectors contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells. Such sequences are well known for a variety of bacteria, yeast, and viruses. The origin of replication from the plasmid pBR322 is suitable for most Gram-negative bacteria, the 2μ plasmid origin is suitable for yeast, and various viral origins (SV40, polyoma, adenovirus, VSV or BPV) are useful for cloning vectors in mammalian cells. [0306]
  • Expression and cloning vectors will typically contain a selection gene, also termed a selectable marker. Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g., ampicillin, neomycin, methotrexate, or tetracycline, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media, e.g., the gene encoding D-alanine racemase for Bacilli. [0307]
  • An example of suitable selectable markers for mammalian cells are those that enable the identification of cells competent to take up the PRO-encoding nucleic acid, such as DHFR or thymidine kinase. An appropriate host cell when wild-type DHFR is employed is the CHO cell line deficient in DHFR activity, prepared and propagated as described by Urlaub et al., Proc. Natl. Acad. Sci. USA, 77:4216 (1980). A suitable selection gene for use in yeast is the [0308] trp 1 gene present in the yeast plasmid YRp7 [Stinchcomb et al., Nature, 282:39 (1979); Kingsman et al., Gene, 7:141 (1979); Tschemper et al., Gene, 10:157 (1980)]. The trp 1 gene provides a selection marker for a mutant strain of yeast lacking the ability to grow in tryptophan, for example, ATCC No. 44076 or PEP4-1 [Jones, Genetics, 85:12 (1977)].
  • Expression and cloning vectors usually contain a promoter operably linked to the PRO-encoding nucleic acid sequence to direct mRNA synthesis. Promoters recognized by a variety of potential host cells are well known. Promoters suitable for use with prokaryotic hosts include the β-lactamase and lactose promoter systems [Chang et al., Nature, 275:615 (1978); Goeddel et al., Nature, 281:544 (1979)], alkaline phosphatase, a tryptophan (trp) promoter system [Goeddel, Nucleic Acids Res., 8:4057 (1980); EP 36,776], and hybrid promoters such as the tac promoter [deBoer et al., Proc. Natl. Acad. Sci. USA, 80:21-25 (1983)]. Promoters for use in bacterial systems also will contain a Shine-Dalgarno (S.D.) sequence operably linked to the DNA encoding PRO. [0309]
  • Examples of suitable promoting sequences for use with yeast hosts include the promoters for 3-phosphoglycerate kinase [Hitzeman et al., J. Biol. Chem., 255:2073 (1980)] or other glycolytic enzymes [Hess et al., J. Adv. Enzyme Reg., 7:149 (1968); Holland, Biochemistry, 17:4900 (1978)], such as enolase, glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase, and glucokinase. [0310]
  • Other yeast promoters, which are inducible promoters having the additional advantage of transcription controlled by growth conditions, are the promoter regions for [0311] alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, degradative enzymes associated with nitrogen metabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase, and enzymes responsible for maltose and galactose utilization. Suitable vectors and promoters for use in yeast expression are further described in EP 73,657.
  • PRO transcription from vectors in mammalian host cells is controlled, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowipox virus (UK 2,211,504 published Jul. 5, 1989), adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus and Simian Virus 40 (SV40), from heterologous mammalian promoters, e.g., the actin promoter or an immunoglobulin promoter, and from heat-shock promoters, provided such promoters are compatible with the host cell systems. [0312]
  • Transcription of a DNA encoding the PRO by higher eukaryotes may be increased by inserting an enhancer sequence into the vector. Enhancers are cis-acting elements of DNA, usually about from 10 to 300 bp, that act on a promoter to increase its transcription. Many enhancer sequences are now known from mammalian genes (globin, elastase, albumin, α-fetoprotein, and insulin). Typically, however, one will use an enhancer from a eukaryotic cell virus. Examples include the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers. The enhancer may be spliced into the vector at a position 5′ or 3′ to the PRO coding sequence, but is preferably located at a site 5′ from the promoter. [0313]
  • Expression vectors used in eukaryotic host cells (yeast, fungi, insect, plant, animal, human, or nucleated cells from other multicellular organisms) will also contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are commonly available from the 5′ and, occasionally 3′, untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA encoding PRO. [0314]
  • Still other methods, vectors, and host cells suitable for adaptation to the synthesis of PRO in recombinant vertebrate cell culture are described in Gething et al., Nature, 293:620-625 (1981); Mantei et al., Nature, 281:40-46 (1979); EP 117,060; and EP 117,058. [0315]
  • 4. Detecting Gene Amplification/Expression [0316]
  • Gene amplification and/or expression may be measured in a sample directly, for example, by conventional Southern blotting, Northern blotting to quantitate the transcription of mRNA [Thomas, Proc. Natl. Acad. Sci. USA, 77:5201(1980)], dot blotting (DNA analysis), or in situ hybridization, using an appropriately labeled probe, based on the sequences provided herein. Alternatively, antibodies may be employed that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. The antibodies in turn may be labeled and the assay may be carried out where the duplex is bound to a surface, so that upon the formation of duplex on the surface, the presence of antibody bound to the duplex can be detected. [0317]
  • Gene expression, alternatively, may be measured by immunological methods, such as immunohistochemical staining of cells or tissue sections and assay of cell culture or body fluids, to quantitate directly the expression of gene product. Antibodies useful for immunohistochemical staining and/or assay of sample fluids may be either monoclonal or polyclonal, and may be prepared in any mammal. Conveniently, the antibodies may be prepared against a native sequence PRO polypeptide or against a synthetic peptide based on the DNA sequences provided herein or against exogenous sequence fused to PRO DNA and encoding a specific antibody epitope. [0318]
  • 5. Purification of Polypeptide [0319]
  • Forms of PRO may be recovered from culture medium or from host cell lysates. If membrane-bound, it can be released from the membrane using a suitable detergent solution (e.g. Triton-X 100) or by enzymatic cleavage. Cells employed in expression of PRO can be disrupted by various physical or chemical means, such as freeze-thaw cycling, sonication, mechanical disruption, or cell lysing agents. [0320]
  • It may be desired to purify PRO from recombinant cell proteins or polypeptides. The following procedures are exemplary of suitable purification procedures: by fractionation on an ion-exchange column; ethanol precipitation; reverse phase HPLC; chromatography on silica or on a cation-exchange resin such as DEAE; chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gel filtration using, for example, Sephadex G-75; protein A Sepharose columns to remove contaminants such as IgG; and metal chelating columns to bind epitope-tagged forms of the PRO. Various methods of protein purification may be employed and such methods are known in the art and described for example in Deutscher, Methods in Enzymology, 182 (1990); Scopes, Protein Purification: Principles and Practice, Springer-Verlag, New York (1982). The purification step(s) selected will depend, for example, on the nature of the production process used and the particular PRO produced. [0321]
  • E. Uses for PRO [0322]
  • Nucleotide sequences (or their complement) encoding PRO have various applications in the art of molecular biology, including uses as hybridization probes, in chromosome and gene mapping and in the generation of anti-sense RNA and DNA. PRO nucleic acid will also be useful for the preparation of PRO polypeptides by the recombinant techniques described herein. [0323]
  • The full-length native sequence PRO gene, or portions thereof, may be used as hybridization probes for a cDNA library to isolate the full-length PRO cDNA or to isolate still other cDNAs (for instance, those encoding naturally-occurring variants of PRO or PRO from other species) which have a desired sequence identity to the native PRO sequence disclosed herein. Optionally, the length of the probes will be about 20 to about 50 bases. The hybridization probes may be derived from at least partially novel regions of the full length native nucleotide sequence wherein those regions may be determined without undue experimentation or from genomic sequences including promoters, enhancer elements and introns of native sequence PRO. By way of example, a screening method will comprise isolating the coding region of the PRO gene using the known DNA sequence to synthesize a selected probe of about 40 bases. Hybridization probes may be labeled by a variety of labels, including radionucleotides such as [0324] 32P or 35S, or enzymatic labels such as alkaline phosphatase coupled to the probe via avidin/biotin coupling systems. Labeled probes having a sequence complementary to that of the PRO gene of the present invention can be used to screen libraries of human cDNA, genomic DNA or mRNA to determine which members of such libraries the probe hybridizes to. Hybridization techniques are described in further detail in the Examples below.
  • Any EST sequences disclosed in the present application may similarly be employed as probes, using the methods disclosed herein. [0325]
  • Other useful fragments of the PRO nucleic acids include antisense or sense oligonucleotides comprising a singe-stranded nucleic acid sequence (either RNA or DNA) capable of binding to target PRO mRNA (sense) or PRO DNA (antisense) sequences. Antisense or sense oligonucleotides, according to the present invention, comprise a fragment of the coding region of PRO DNA. Such a fragment generally comprises at least about 14 nucleotides, preferably from about 14 to 30 nucleotides. The ability to derive an antisense or a sense oligonucleotide, based upon a cDNA sequence encoding a given protein is described in, for example, Stein and Cohen (Cancer Res. 48:2659, 1988) and van der Krol et al. (BioTechniques 6:958, 1988). [0326]
  • Binding of antisense or sense oligonucleotides to target nucleic acid sequences results in the formation of duplexes that block transcription or translation of the target sequence by one of several means, including enhanced degradation of the duplexes, premature termination of transcription or translation, or by other means. The antisense oligonucleotides thus may be used to block expression of PRO proteins. Antisense or sense oligonucleotides further comprise oligonucleotides having modified sugar-phosphodiester backbones (or other sugar linkages, such as those described in WO 91/06629) and wherein such sugar linkages are resistant to endogenous nucleases. Such oligonucleotides with resistant sugar linkages are stable in vivo (i.e., capable of resisting enzymatic degradation) but retain sequence specificity to be able to bind to target nucleotide sequences. [0327]
  • Other examples of sense or antisense oligonucleotides include those oligonucleotides which are covalently linked to organic moieties, such as those described in WO 90/10048, and other moieties that increases affinity of the oligonucleotide for a target nucleic acid sequence, such as poly-(L-lysine). Further still, intercalating agents, such as ellipticine, and alkylating agents or metal complexes may be attached to sense or antisense oligonucleotides to modify binding specificities of the antisense or sense oligonucleotide for the target nucleotide sequence. [0328]
  • Antisense or sense oligonucleotides may be introduced into a cell containing the target nucleic acid sequence by any gene transfer method, including, for example, CaPO[0329] 4- mediated DNA transfection, electroporation, or by using gene transfer vectors such as Epstein-Barr virus. In a preferred procedure, an antisense or sense oligonucleotide is inserted into a suitable retroviral vector. A cell containing the target nucleic acid sequence is contacted with the recombinant retroviral vector, either in vivo or ex vivo. Suitable retroviral vectors include, but are not limited to, those derived from the murine retrovirus M-MuLV, N2 (a retrovirus derived from M-MuLV), or the double copy vectors designated DCT5A, DCT5B and DCT5C (see WO 90/13641).
  • Sense or antisense oligonucleotides also may be introduced into a cell containing the target nucleotide sequence by formation of a conjugate with a ligand binding molecule, as described in WO 91/04753. Suitable ligand binding molecules include, but are not limited to, cell surface receptors, growth factors, other cytokines, or other ligands that bind to cell surface receptors. Preferably, conjugation of the ligand binding molecule does not substantially interfere with the ability of the ligand binding molecule to bind to its corresponding molecule or receptor, or block entry of the sense or antisense oligonucleotide or its conjugated version into the cell. [0330]
  • Alternatively, a sense or an antisense oligonucleotide may be introduced into a cell containing the target nucleic acid sequence by formation of an oligonucleotide-lipid complex, as described in WO 90/10448. The sense or antisense oligonucleotide-lipid complex is preferably dissociated within the cell by an endogenous lipase. [0331]
  • Antisense or sense RNA or DNA molecules are generally at least about 5 bases in length, about 10 bases in length, about 15 bases in length, about 20 bases in length, about 25 bases in length, about 30 bases in length, about 35 bases in length, about 40 bases in length, about 45 bases in length, about 50 bases in length, about 55 bases in length, about 60 bases in length, about 65 bases in length, about 70 bases in length, about 75 bases in length, about 80 bases in length, about 85 bases in length, about 90 bases in length, about 95 bases in length, about 100 bases in length, or more. [0332]
  • The probes may also be employed in PCR techniques to generate a pool of sequences for identification of closely related PRO coding sequences. [0333]
  • Nucleotide sequences encoding a PRO can also be used to construct hybridization probes for mapping the gene which encodes that PRO and for the genetic analysis of individuals with genetic disorders. The nucleotide sequences provided herein may be mapped to a chromosome and specific regions of a chromosome using known techniques, such as in situ hybridization, linkage analysis against known chromosomal markers, and hybridization screening with libraries. [0334]
  • When the coding sequences for PRO encode a protein which binds to another protein (example, where the PRO is a receptor), the PRO can be used in assays to identify the other proteins or molecules involved in the binding interaction. By such methods, inhibitors of the receptor/ligand binding interaction can be identified. Proteins involved in such binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction. Also, the receptor PRO can be used to isolate correlative ligand(s). Screening assays can be designed to find lead compounds that mimic the biological activity of a native PRO or a receptor for PRO. Such screening assays will include assays amenable to high-throughput screening of chemical libraries, making them particularly suitable for identifying small molecule drug candidates. Small molecules contemplated include synthetic organic or inorganic compounds. The assays can be performed in a variety of formats, including protein-protein binding assays, biochemical screening assays, immunoassays and cell based assays, which are well characterized in the art. [0335]
  • Nucleic acids which encode PRO or its modified forms can also be used to generate either transgenic animals or “knock out” animals which, in turn, are useful in the development and screening of therapeutically useful reagents. A transgenic animal (e.g., a mouse or rat) is an animal having cells that contain a transgene, which transgene was introduced into the animal or an ancestor of the animal at a prenatal, e.g., an embryonic stage. A transgene is a DNA which is integrated into the genome of a cell from which a transgenic animal develops. In one embodiment, cDNA encoding PRO can be used to clone genomic DNA encoding PRO in accordance with established techniques and the genomic sequences used to generate transgenic animals that contain cells which express DNA encoding PRO. Methods for generating transgenic animals, particularly animals such as mice or rats, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009. Typically, particular cells would be targeted for PRO transgene incorporation with tissue-specific enhancers. Transgenic animals that include a copy of a transgene encoding PRO introduced into the germ line of the animal at an embryonic stage can be used to examine the effect of increased expression of DNA encoding PRO. Such animals can be used as tester animals for reagents thought to confer protection from, for example, pathological conditions associated with its overexpression. In accordance with this facet of the invention, an animal is treated with the reagent and a reduced incidence of the pathological condition, compared to untreated animals bearing the transgene, would indicate a potential therapeutic intervention for the pathological condition. [0336]
  • Alternatively, non-human homologues of PRO can be used to construct a PRO “knock out” animal which has a defective or altered gene encoding PRO as a result of homologous recombination between the endogenous gene encoding PRO and altered genomic DNA encoding PRO introduced into an embryonic stem cell of the animal. For example, cDNA encoding PRO can be used to clone genomic DNA encoding PRO in accordance with established techniques. A portion of the genomic DNA encoding PRO can be deleted or replaced with another gene, such as a gene encoding a selectable marker which can be used to monitor integration. Typically, several kilobases of unaltered flanking DNA (both at the 5′ and 3′ ends) are included in the vector [see e.g., Thomas and Capecchi, Cell, 51:503 (1987) for a description of homologous recombination vectors]. The vector is introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced DNA has homologously recombined with the endogenous DNA are selected [see e.g., Li et al., Cell, 69:915 (1992)]. The selected cells are then injected into a blastocyst of an animal (e.g., a mouse or rat) to form aggregation chimeras [see e.g., Bradley, in [0337] Teratocarcinomas and Embryonic Stem Cells: A Practical Approach, E. J. Robertson, ed. (IRL, Oxford, 1987), pp. 113-152]. A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term to create a “knock out” animal. Progeny harboring the homologously recombined DNA in their germ cells can be identified by standard techniques and used to breed animals in which all cells of the animal contain the homologously recombined DNA. Knockout animals can be characterized for instance, for their ability to defend against certain pathological conditions and for their development of pathological conditions due to absence of the PRO polypeptide.
  • Nucleic acid encoding the PRO polypeptides may also be used in gene therapy. In gene therapy applications, genes are introduced into cells in order to achieve in vivo synthesis of a therapeutically effective genetic product, for example for replacement of a defective gene. “Gene therapy” includes both conventional gene therapy where a lasting effect is achieved by a single treatment, and the administration of gene therapeutic agents, which involves the one time or repeated administration of a therapeutically effective DNA or mRNA. Antisense RNAs and DNAs can be used as therapeutic agents for blocking the expression of certain genes in vivo. It has already been shown that short antisense oligonucleotides can be imported into cells where they act as inhibitors, despite their low intracellular concentrations caused by their restricted uptake by the cell membrane. (Zamecnik et al., Proc. Natl. Acad. Sci. USA 83:4143-4146 [1986]). The oligonucleotides can be modified to enhance their uptake, e.g. by substituting their negatively charged phosphodiester groups by uncharged groups. [0338]
  • There are a variety of techniques available for introducing nucleic acids into viable cells. The techniques vary depending upon whether the nucleic acid is transferred into cultured cells in vitro, or in vivo in the cells of the intended host. Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, microinjection, cell fusion, DEAE-dextran, the calcium phosphate precipitation method, etc. The currently preferred in vivo gene transfer techniques include transfection with viral (typically retroviral) vectors and viral coat protein-liposome mediated transfection (Dzau et al., Trends in Biotechnology 11, 205-210 [1993]). In some situations it is desirable to provide the nucleic acid source with an agent that targets the target cells, such as an antibody specific for a cell surface membrane protein or the target cell, a ligand for a receptor on the target cell, etc. Where liposomes are employed, proteins which bind to a cell surface membrane protein associated with endocytosis may be used for targeting and/or to facilitate uptake, e.g. capsid proteins or fragments thereof tropic for a particular cell type, antibodies for proteins which undergo internalization in cycling, proteins that target intracellular localization and enhance intracellular half-life. The technique of receptor-mediated endocytosis is described, for example, by Wu et al., J. Biol. Chem. 262, 4429-4432 (1987); and Wagner et al., Proc. Natl. Acad. Sci. USA 87, 3410-3414 (1990). For review of gene marking and gene therapy protocols see Anderson et al., Science 256, 808-813 (1992). [0339]
  • The PRO polypeptides described herein may also be employed as molecular weight markers for protein electrophoresis purposes and the isolated nucleic acid sequences may be used for recombinantly expressing those markers. [0340]
  • The nucleic acid molecules encoding the PRO polypeptides or fragments thereof described herein are useful for chromosome identification. In this regard, there exists an ongoing need to identify new chromosome markers, since relatively few chromosome marking reagents, based upon actual sequence data are presently available. Each PRO nucleic acid molecule of the present invention can be used as a chromosome marker. [0341]
  • The PRO polypeptides and nucleic acid molecules of the present invention may also be used diagnostically for tissue typing, wherein the PRO polypeptides of the present invention may be differentially expressed in one tissue as compared to another, preferably in a diseased tissue as compared to a normal tissue of the same tissue type. PRO nucleic acid molecules will find use for generating probes for PCR, Northern analysis, Southern analysis and Western analysis. [0342]
  • The PRO polypeptides described herein may also be employed as therapeutic agents. The PRO polypeptides of the present invention can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby the PRO product hereof is combined in admixture with a pharmaceutically acceptable carrier vehicle. Therapeutic formulations are prepared for storage by mixing the active ingredient having the desired degree of purity with optional physiologically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN™, PLURONICS™ or PEG. [0343]
  • The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes, prior to or following lyophilization and reconstitution. [0344]
  • Therapeutic compositions herein generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle. [0345]
  • The route of administration is in accord with known methods, e.g. injection or infusion by intravenous, intraperitoneal, intracerebral, intramuscular, intraocular, intraarterial or intralesional routes, topical administration, or by sustained release systems. [0346]
  • Dosages and desired drug concentrations of pharmaceutical compositions of the present invention may vary depending on the particular use envisioned. The determination of the appropriate dosage or route of administration is well within the skill of an ordinary physician. Animal experiments provide reliable guidance for the determination of effective doses for human therapy. Interspecies scaling of effective doses can be performed following the principles laid down by Mordenti, J. and Chappell, W. “The use of interspecies scaling in toxicokinetics” In Toxicokinetics and New Drug Development, Yacobi et al., Eds., Pergamon Press, New York 1989, pp. 42-96. [0347]
  • When in vivo administration of a PRO polypeptide or agonist or antagonist thereof is employed, normal dosage amounts may vary from about 10 ng/kg to up to 100 mg/kg of mammal body weight or more per day, preferably about 1 μg/kg/day to 10 mg/kg/day, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature; see, for example, U.S. Pat. Nos. 4,657,760; 5,206,344; or 5,225,212. It is anticipated that different formulations will be effective for different treatment compounds and different disorders, that administration targeting one organ or tissue, for example, may necessitate delivery in a manner different from that to another organ or tissue. [0348]
  • Where sustained-release administration of a PRO polypeptide is desired in a formulation with release characteristics suitable for the treatment of any disease or disorder requiring administration of the PRO polypeptide, microencapsulation of the PRO polypeptide is contemplated. Microencapsulation of recombinant proteins for sustained release has been successfully performed with human growth hormone (rhGH), interferon- (rhlFN-), interleukin-2, and MN rgp120. Johnson et al., Nat. Med., 2:795-799 (1996); Yasuda, Biomed. Ther., 27:1221-1223 (1993); Hora et al., Bio/Technology, 8:755-758 (1990); Cleland, “Design and Production of Single Immunization Vaccines Using Polylactide Polyglycolide Microsphere Systems,” in Vaccine Design: The Subunit and Adjuvant Approach, Powell and Newman, eds, (Plenum Press: New York, 1995), pp. 439-462; WO 97/03692, WO 96/40072, WO 96/07399; and U.S. Pat. No. 5,654,010. [0349]
  • The sustained-release formulations of these proteins were developed using poly-lactic-coglycolic acid (PLGA) polymer due to its biocompatibility and wide range of biodegradable properties. The degradation products of PLGA, lactic and glycolic acids, can be cleared quickly within the human body. Moreover, the degradability of this polymer can be adjusted from months to years depending on its molecular weight and composition. Lewis, “Controlled release of bioactive agents from lactide/glycolide polymer,” in: M. Chasin and R. Langer (Eds.), Biodegradable Polymers as Drug Delivery Systems (Marcel Dekker: New York, 1990), pp.1-41. [0350]
  • This invention encompasses methods of screening compounds to identify those that mimic the PRO polypeptide (agonists) or prevent the effect of the PRO polypeptide (antagonists). Screening assays for antagonist drug candidates are designed to identify compounds that bind or complex with the PRO polypeptides encoded by the genes identified herein, or otherwise interfere with the interaction of the encoded polypeptides with other cellular proteins. Such screening assays will include assays amenable to high-throughput screening of chemical libraries, making them particularly suitable for identifying small molecule drug candidates. [0351]
  • The assays can be performed in a variety of formats, including protein-protein binding assays, biochemical screening assays, immunoassays, and cell-based assays, which are well characterized in the art. [0352]
  • All assays for antagonists are common in that they call for contacting the drug candidate with a PRO polypeptide encoded by a nucleic acid identified herein under conditions and for a time sufficient to allow these two components to interact. [0353]
  • In binding assays, the interaction is binding and the complex formed can be isolated or detected in the reaction mixture. In a particular embodiment, the PRO polypeptide encoded by the gene identified herein or the drug candidate is immobilized on a solid phase, e.g., on a microtiter plate, by covalent or non-covalent attachments. Non-covalent attachment generally is accomplished by coating the solid surface with a solution of the PRO polypeptide and drying. Alternatively, an immobilized antibody, e.g., a monoclonal antibody, specific for the PRO polypeptide to be immobilized can be used to anchor it to a solid surface. The assay is performed by adding the non-immobilized component, which may be labeled by a detectable label, to the immobilized component, e.g., the coated surface containing the anchored component. When the reaction is complete, the non-reacted components are removed, e.g., by washing, and complexes anchored on the solid surface are detected. When the originally non-immobilized component carries a detectable label, the detection of label immobilized on the surface indicates that complexing occurred. Where the originally non-immobilized component does not carry a label, complexing can be detected, for example, by using a labeled antibody specifically binding the immobilized complex. [0354]
  • If the candidate compound interacts with but does not bind to a particular PRO polypeptide encoded by a gene identified herein, its interaction with that polypeptide can be assayed by methods well known for detecting protein-protein interactions. Such assays include traditional approaches, such as, e.g., cross-linking, co-immunoprecipitation, and co-purification through gradients or chromatographic columns. In addition, protein-protein interactions can be monitored by using a yeast-based genetic system described by Fields and co-workers (Fields and Song, Nature (London), 340:245-246 (1989); Chien et al., Proc. Natl. Acad. Sci. USA, 88:9578-9582 (1991)) as disclosed by Chevray and Nathans, Proc. Natl. Acad. Sci. USA, 89: 5789-5793 (1991). Many transcriptional activators, such as yeast GAL4, consist of two physically discrete modular domains, one acting as the DNA-binding domain, the other one functioning as the transcription-activation domain. The yeast expression system described in the foregoing publications (generally referred to as the “two-hybrid system”) takes advantage of this property, and employs two hybrid proteins, one in which the target protein is fused to the DNA-binding domain of GAL4, and another, in which candidate activating proteins are fused to the activation domain. The expression of a GAL1- lacZ reporter gene under control of a GAL4-activated promoter depends on reconstitution of GAL4 activity via protein-protein interaction. Colonies containing interacting polypeptides are detected with a chromogenic substrate for β-galactosidase. A complete kit (MATCHMAKER™) for identifying protein-protein interactions between two specific proteins using the two-hybrid technique is commercially available from Clontech. This system can also be extended to map protein domains involved in specific protein interactions as well as to pinpoint amino acid residues that are crucial for these interactions. [0355]
  • Compounds that interfere with the interaction of a gene encoding a PRO polypeptide identified herein and other intra- or extracellular components can be tested as follows: usually a reaction mixture is prepared containing the product of the gene and the intra- or extracellular component under conditions and for a time allowing for the interaction and binding of the two products. To test the ability of a candidate compound to inhibit binding, the reaction is run in the absence and in the presence of the test compound. In addition, a placebo may be added to a third reaction mixture, to serve as positive control. The binding (complex formation) between the test compound and the intra- or extracellular component present in the mixture is monitored as described hereinabove. The formation of a complex in the control reaction(s) but not in the reaction mixture containing the test compound indicates that the test compound interferes with the interaction of the test compound and its reaction partner. [0356]
  • To assay for antagonists, the PRO polypeptide may be added to a cell along with the compound to be screened for a particular activity and the ability of the compound to inhibit the activity of interest in the presence of the PRO polypeptide indicates that the compound is an antagonist to the PRO polypeptide. Alternatively, antagonists may be detected by combining the PRO polypeptide and a potential antagonist with membrane-bound PRO polypeptide receptors or recombinant receptors under appropriate conditions for a competitive inhibition assay. The PRO polypeptide can be labeled, such as by radioactivity, such that the number of PRO polypeptide molecules bound to the receptor can be used to determine the effectiveness of the potential antagonist. The gene encoding the receptor can be identified by numerous methods known to those of skill in the art, for example, ligand panning and FACS sorting. Coligan et al., Current Protocols in Immun., 1(2): Chapter 5 (1991). Preferably, expression cloning is employed wherein polyadenylated RNA is prepared from a cell responsive to the PRO polypeptide and a cDNA library created from this RNA is divided into pools and used to transfect COS cells or other cells that are not responsive to the PRO polypeptide. Transfected cells that are grown on glass slides are exposed to labeled PRO polypeptide. The PRO polypeptide can be labeled by a variety of means including iodination or inclusion of a recognition site for a site-specific protein kinase. Following fixation and incubation, the slides are subjected to autoradiographic analysis. Positive pools are identified and sub-pools are prepared and re-transfected using an interactive sub-pooling and re-screening process, eventually yielding a single clone that encodes the putative receptor. [0357]
  • As an alternative approach for receptor identification, labeled PRO polypeptide can be photoaffinity-linked with cell membrane or extract preparations that express the receptor molecule. Cross-linked material is resolved by PAGE and exposed to X-ray film. The labeled complex containing the receptor can be excised, resolved into peptide fragments, and subjected to protein micro-sequencing. The amino acid sequence obtained from micro- sequencing would be used to design a set of degenerate oligonucleotide probes to screen a cDNA library to identify the gene encoding the putative receptor. [0358]
  • In another assay for antagonists, mammalian cells or a membrane preparation expressing the receptor would be incubated with labeled PRO polypeptide in the presence of the candidate compound. The ability of the compound to enhance or block this interaction could then be measured. [0359]
  • More specific examples of potential antagonists include an oligonucleotide that binds to the fusions of immunoglobulin with PRO polypeptide, and, in particular, antibodies including, without limitation, poly- and monoclonal antibodies and antibody fragments, single-chain antibodies, anti-idiotypic antibodies, and chimeric or humanized versions of such antibodies or fragments, as well as human antibodies and antibody fragments. Alternatively, a potential antagonist may be a closely related protein, for example, a mutated form of the PRO polypeptide that recognizes the receptor but imparts no effect, thereby competitively inhibiting the action of the PRO polypeptide. [0360]
  • Another potential PRO polypeptide antagonist is an antisense RNA or DNA construct prepared using antisense technology, where, e.g., an antisense RNA or DNA molecule acts to block directly the translation of mRNA by hybridizing to targeted mRNA and preventing protein translation. Antisense technology can be used to control gene expression through triple-helix formation or antisense DNA or RNA, both of which methods are based on binding of a polynucleotide to DNA or RNA. For example, the 5′ coding portion of the polynucleotide sequence, which encodes the mature PRO polypeptides herein, is used to design an antisense RNA oligonucleotide of from about 10 to 40 base pairs in length. A DNA oligonucleotide is designed to be complementary to a region of the gene involved in transcription (triple helix—see Lee et al., Nucl. Acids Res., 6:3073 (1979); Cooney et al., Science, 241: 456 (1988); Dervan et al., Science, 251:1360 (1991)), thereby preventing transcription and the production of the PRO polypeptide. The antisense RNA oligonucleotide hybridizes to the mRNA in vivo and blocks translation of the mRNA molecule into the PRO polypeptide (antisense—Okano, Neurochem., 56:560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression (CRC Press: Boca Raton, Fla., 1988). The oligonucleotides described above can also be delivered to cells such that the antisense RNA or DNA may be expressed in vivo to inhibit production of the PRO polypeptide. When antisense DNA is used, oligodeoxyribonucleotides derived from the translation-initiation site, e.g., between about −10 and +10 positions of the target gene nucleotide sequence, are preferred. [0361]
  • Potential antagonists include small molecules that bind to the active site, the receptor binding site, or growth factor or other relevant binding site of the PRO polypeptide, thereby blocking the normal biological activity of the PRO polypeptide. Examples of small molecules include, but are not limited to, small peptides or peptide-like molecules, preferably soluble peptides, and synthetic non-peptidyl organic or inorganic compounds. [0362]
  • Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA. Ribozymes act by sequence-specific hybridization to the complementary target RNA, followed by endonucleolytic cleavage. Specific ribozyme cleavage sites within a potential RNA target can be identified by known techniques. For further details see, e.g., Rossi, Current Biology, 4:469-471 (1994), and PCT publication No. WO 97/33551 (published Sep. 18, 1997). [0363]
  • Nucleic acid molecules in triple-helix formation used to inhibit transcription should be single-stranded and composed of deoxynucleotides. The base composition of these oligonucleotides is designed such that it promotes triple-helix formation via Hoogsteen base-pairing rules, which generally require sizeable stretches of purines or pyrimidines on one strand of a duplex. For further details see, e.g., PCT publication No. WO 97/33551, supra. [0364]
  • These small molecules can be identified by any one or more of the screening assays discussed hereinabove and/or by any other screening techniques well known for those skilled in the art. [0365]
  • Diagnostic and therapeutic uses of the herein disclosed molecules may also be based upon the positive functional assay hits disclosed and described below. [0366]
  • F. Anti-PRO Antibodies [0367]
  • The present invention further provides anti-PRO antibodies. Exemplary antibodies include polyclonal, monoclonal, humanized, bispecific, and heteroconjugate antibodies. [0368]
  • 1. Polyclonal Antibodies [0369]
  • The anti-PRO antibodies may comprise polyclonal antibodies. Methods of preparing polyclonal antibodies are known to the skilled artisan. Polyclonal antibodies can be raised in a mammal, for example, by one or more injections of an immunizing agent and, if desired, an adjuvant. Typically, the immunizing agent and/or adjuvant will be injected in the mammal by multiple subcutaneous or intraperitoneal injections. The immunizing agent may include the PRO polypeptide or a fusion protein thereof. It may be useful to conjugate the immunizing agent to a protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. Examples of adjuvants which may be employed include Freund's complete adjuvant and MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate). The immunization protocol may be selected by one skilled in the art without undue experimentation. [0370]
  • 2. Monoclonal Antibodies [0371]
  • The anti-PRO antibodies may, alternatively, be monoclonal antibodies. Monoclonal antibodies may be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975). In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes may be immunized in vitro. [0372]
  • The immunizing agent will typically include the PRO polypeptide or a fusion protein thereof. Generally, either peripheral blood lymphocytes (“PBLs”) are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell [Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-103]. Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells may be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (“HAT medium”), which substances prevent the growth of HGPRT-deficient cells. [0373]
  • Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, California and the American Type Culture Collection, Manassas, Va. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies [Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51-63]. [0374]
  • The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against PRO. Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107:220 (1980). [0375]
  • After the desired hybridoma cells are identified, the clones may be subcloned by limiting dilution procedures and grown by standard methods [Goding, supra]. Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI -1640 medium. Alternatively, the hybridoma cells may be grown in vivo as ascites in a mammal. [0376]
  • The monoclonal antibodies secreted by the subclones may be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography. [0377]
  • The monoclonal antibodies may also be made by recombinant DNA methods, such as those described in U.S. Pat. No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells of the invention serve as a preferred source of such DNA. Once isolated, the DNA may be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also may be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences [U.S. Pat. No. 4,816,567; Morrison et al., supra] or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody. [0378]
  • The antibodies may be monovalent antibodies. Methods for preparing monovalent antibodies are well known in the art. For example, one method involves recombinant expression of immunoglobulin light chain and modified heavy chain. The heavy chain is truncated generally at any point in the Fc region so as to prevent heavy chain crosslinking. Alternatively, the relevant cysteine residues are substituted with another amino acid residue or are deleted so as to prevent crosslinking. [0379]
  • In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce fragments thereof, particularly, Fab fragments, can be accomplished using routine techniques known in the art. [0380]
  • 3. Human and Humanized Antibodies [0381]
  • The anti-PRO antibodies of the invention may further comprise humanized antibodies or human antibodies. Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab′, F(ab′)[0382] 2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin [ones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992)].
  • Methods for humanizing non-human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain. Humanization can be essentially performed following the method of Winter and co-workers [ones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1 534-1536 (1988)], by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such “humanized” antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies. [0383]
  • Human antibodies can also be produced using various techniques known in the art, including phage display libraries [Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)]. The techniques of Cole et al. and Boerner et al. are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boerner et al., J. Immunol., 147(1):86-95 (1991)]. Similarly, human antibodies can be made by introducing of human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in the following scientific publications: Marks et al., Bio/Technology 10, 779-783 (1992); Lonberg et al., Nature 368 856-859 (1994); Morrison, Nature 368, 812-13 (1994); Fishwild et al., Nature Biotechnology 14, 845-51 (1996); Neuberger, Nature Biotechnology 14, 826 (1996); Lonberg and Huszar, Intern. Rev. Immunol. 1365-93 (1995). [0384]
  • The antibodies may also be affinity matured using known selection and/or mutagenesis methods as described above. Preferred affinity matured antibodies have an affinity which is five times, more preferably 10 times, even more preferably 20 or 30 times greater than the starting antibody (generally murine, humanized or human) from which the matured antibody is prepared. [0385]
  • 4. Bispecific Antibodies [0386]
  • Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for the PRO, the other one is for any other antigen, and preferably for a cell-surface protein or receptor or receptor subunit. [0387]
  • Methods for making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities [Milstein and Cuello, Nature, 305:537-539 (1983)]. Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO 93/08829, published May 13, 1993, and in Traunecker et al., EMBO J., 10:3655-3659 (1991). [0388]
  • Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region (CH1) containing the site necessary for light-chain binding present in at least one of the fusions. DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology, 121:210 (1986). [0389]
  • According to another approach described in WO 96/27011, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH3 region of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g. tyrosine or tryptophan). Compensatory “cavities” of identical or similar size to the large side chain (s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers. [0390]
  • Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g. F(ab′)[0391] 2 bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al., Science 229:81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab′)2 fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab′ fragments generated are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab′-TNB derivatives is then reconverted to the Fab′-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab′-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.
  • Fab′ fragments may be directly recovered from [0392] E. coli and chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175:217(1992) describe the production of a fully humanized bispecific antibody F(ab′)2 molecule. Each Fab′ fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger-the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.
  • Various technique for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al., J. Immunol. 148 (5):1547-1553(1992). The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab′ portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers. The “diabody” technology described by Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448(1993) has provided an alternative mechanism for making bispecific antibody fragments. The fragments comprise a heavy-chain variable domain (V[0393] H) connected to a light-chain variable domain (VL) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See, Gruber et al., J. Immunol. 152:5368 (1994). Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991).
  • Exemplary bispecific antibodies may bind to two different epitopes on a given PRO polypeptide herein. Alternatively, an anti-PRO polypeptide arm may be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2, CD3, CD28, or B7), or Fc receptors for IgG (Fc y R), such as Fc y RI (CD64), Fc y RII (CD32) and Fc y RIII (CD16) so as to focus cellular defense mechanisms to the cell expressing the particular PRO polypeptide. Bispecific antibodies may also be used to localize cytotoxic agents to cells which express a particular PRO polypeptide. These antibodies possess a PRO-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. Another bispecific antibody of interest binds the PRO polypeptide and further binds tissue factor (TF). [0394]
  • 5. Heteroconjugate Antibodies [0395]
  • Heteroconjugate antibodies are also within the scope of the present invention. Heteroconjugate antibodies are composed of two covalentlyjoined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells [U.S. Pat. No. 4,676,980], and for treatment of HIV infection [WO 91/00360; WO 92/200373; EP 03089]. it is contemplated that the antibodies may be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins may be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S. Pat. No. 4,676,980. [0396]
  • 6. Effector Function Engineering [0397]
  • It may be desirable to modify the antibody of the invention with respect to effector function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer. For example, cysteine residue(s) may be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated may have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et al., J. Exp Med., 176: 1191-1195 (1992) and Shopes, J. Immunol., 148: 2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity may also be prepared using heterobifunctional cross-linkers as described in Wolff et al. Cancer Research, 53: 2560-2565 (1993). Alternatively, an antibody can be engineered that has dual Fc regions and may thereby have enhanced complement lysis and ADCC capabilities. See Stevenson et al., Anti-Cancer Drug Design, 3: 219-230 (1989). [0398]
  • 7. Immunoconjugates [0399]
  • The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate). [0400]
  • Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above. Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from [0401] Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include 212Bi, 131I, 131In, 90Y, and 186Re. Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyidithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyidiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO 94/11026.
  • In another embodiment, the antibody may be conjugated to a “receptor” (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a “ligand” (e.g., avidin) that is conjugated to a cytotoxic agent (e.g., a radionucleotide). [0402]
  • 8. Immunoliposomes [0403]
  • The antibodies disclosed herein may also be formulated as immunoliposomes. Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., Proc. Natl Acad. Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Pat. No. 5,013,556. [0404]
  • Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter. Fab′ fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin et al., J. Biol. Chem., 257: 286-288 (1982) via a disulfide-interchange reaction. A chemotherapeutic agent (such as Doxorubicin) is optionally contained within the liposome. See Gabizon et al., J. National Cancer Inst., 81(19): 1484 (1989). [0405]
  • 9. Pharmaceutical Compositions of Antibodies [0406]
  • Antibodies specifically binding a PRO polypeptide identified herein, as well as other molecules identified by the screening assays disclosed hereinbefore, can be administered for the treatment of various disorders in the form of pharmaceutical compositions. [0407]
  • If the PRO polypeptide is intracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred. However, lipofections or liposomes can also be used to deliver the antibody, or an antibody fragment, into cells. Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred. For example, based upon the variable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target protein sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA technology. See, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA, 90: 7889-7893 (1993). The formulation herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the composition may comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended. [0408]
  • The active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methyl methacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's [0409] Pharmaceutical Sciences, supra.
  • The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes. [0410]
  • Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and y ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated antibodies remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37° C., resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies can be devised for stabilization depending on the mechanism involved. For example, if the aggregation mechanism is discovered to be intermolecular S-S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions. [0411]
  • G. Uses for anti-PRO Antibodies [0412]
  • The anti-PRO antibodies of the invention have various utilities. For example, anti-PRO antibodies may be used in diagnostic assays for PRO, e.g., detecting its expression (and in some cases, differential expression) in specific cells, tissues, or serum. Various diagnostic assay techniques known in the art may be used, such as competitive binding assays, direct or indirect sandwich assays and immunoprecipitation assays conducted in either heterogeneous or homogeneous phases [Zola, Monoclonal Antibodies: A Manual of Techniques, CRC Press, Inc. (1987) pp.147-158]. The antibodies used in the diagnostic assays can be labeled with a detectable moiety. The detectable moiety should be capable of producing, either directly or indirectly, a detectable signal. For example, the detectable moiety may be a radioisotope, such as [0413] 3H, 14C, 32P, 35S, or 125I, a fluorescent or chemiluminescent compound, such as fluorescein isothiocyanate, rhodamine, or luciferin, or an enzyme, such as alkaline phosphatase, beta-galactosidase or horseradish peroxidase. Any method known in the art for conjugating the antibody to the detectable moiety may be employed, including those methods described by Hunter et al., Nature, 144:945 (1962); David et al., Biochemistry, 13:1014 (1974); Pain et al., J. Immunol. Meth., 40:219 (1981); and Nygren, J. Histochem. and Cytochem., 30:407 (1982).
  • Anti-PRO antibodies also are useful for the affinity purification of PRO from recombinant cell culture or natural sources. In this process, the antibodies against PRO are immobilized on a suitable support, such as Sephadex resin or filter paper, using methods well known in the art. The immobilized antibody then is contacted with a sample containing the PRO to be purified, and thereafter the support is washed with a suitable solvent that will remove substantially all the material in the sample except the PRO, which is bound to the immobilized antibody. Finally, the support is washed with another suitable solvent that will release the PRO from the antibody. [0414]
  • The following examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. [0415]
  • All patent and literature references cited in the present specification are hereby incorporated by reference in their entirety. [0416]
    • EXAMPLES
  • Commercially available reagents referred to in the examples were used according to manufacturer's instructions unless otherwise indicated. The source of those cells identified in the following examples, and throughout the specification, by ATCC accession numbers is the American Type Culture Collection, Manassas, Va. [0417]
    • EXAMPLE 1 Extracellular Domain Homology Screening to Identify Novel Polypeptides and cDNA Encoding Therefor
  • The extracellular domain (ECD) sequences (including the secretion signal sequence, if any) from about 950 known secreted proteins from the Swiss-Prot public database were used to search EST databases. The EST databases included public databases (e.g., Dayhoff, GenBank), and proprietary databases (e.g. LIFESEQ™, Incyte Pharmaceuticals, Palo Alto, Calif.). The search was performed using the computer program BLAST or BLAST-2 (Altschul et al., Methods in Enzymology 266:460-480 (1996)) as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequences. Those comparisons with a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program “phrap” (Phil Green, University of Washington, Seattle, Wash.). [0418]
  • Using this extracellular domain homology screen, consensus DNA sequences were assembled relative to the other identified EST sequences using phrap. In addition, the consensus DNA sequences obtained were often (but not always) extended using repeated cycles of BLAST or BLAST-2 and phrap to extend the consensus sequence as far as possible using the sources of EST sequences discussed above. [0419]
  • Based upon the consensus sequences obtained as described above, oligonucleotides were then synthesized and used to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for a PRO polypeptide. Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length. The probe sequences are typically 40-55 bp in length. In some cases, additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-1.5 kbp. In order to screen several libraries for a full-length clone, DNA from the libraries was screened by PCR amplification, as per Ausubel et al., Current Protocols in Molecular Biology, with the PCR primer pair. A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pairs. [0420]
  • The cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif. The cDNA was primed with oligo dT containing a NotI site, linked with blunt to SalI hemikinased adaptors, cleaved with NotI, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and NotI sites. [0421]
    • EXAMPLE 2 Isolation of cDNA clones by Amylase Screening
  • 1. Preparation of oligo dT primed cDNA library [0422]
  • mRNA was isolated from a human tissue of interest using reagents and protocols from Invitrogen, San Diego, Calif. (Fast Track 2). This RNA was used to generate an oligo dT primed cDNA library in the vector pRK5D using reagents and protocols from Life Technologies, Gaithersburg, Md. (Super Script Plasmid System). In this procedure, the double stranded cDNA was sized to greater than 1000 bp and the SalI/NotI linkered cDNA was cloned into XhoI/NotI cleaved vector. pRK5D is a cloning vector that has an sp6 transcription initiation site followed by an SfiI restriction enzyme site preceding the XhoI/NotI cDNA cloning sites. [0423]
  • 2. Preparation of random primed cDNA library [0424]
  • A secondary cDNA library was generated in order to preferentially represent the 5′ ends of the primary cDNA clones. Sp6 RNA was generated from the primary library (described above), and this RNA was used to generate a random primed cDNA library in the vector pSST-AMY.0 using reagents and protocols from Life Technologies (Super Script Plasmid System, referenced above). In this procedure the double stranded cDNA was sized to 500-1000 bp, Tinkered with blunt to NotI adaptors, cleaved with SfiI, and cloned into SfiI/NotI cleaved vector. pSST-AMY.0 is a cloning vector that has a yeast alcohol dehydrogenase promoter preceding the cDNA cloning sites and the mouse amylase sequence (the mature sequence without the secretion signal) followed by the yeast alcohol dehydrogenase terminator, after the cloning sites. Thus, cDNAs cloned into this vector that are fused in frame with amylase sequence will lead to the secretion of amylase from appropriately transfected yeast colonies. [0425]
  • 3. Transformation and Detection [0426]
  • DNA from the library described in [0427] paragraph 2 above was chilled on ice to which was added electrocompetent DH10B bacteria (Life Technologies, 20 ml). The bacteria and vector mixture was then electroporated as recommended by the manufacturer. Subsequently, SOC media (Life Technologies, 1 ml) was added and the mixture was incubated at 37° C. for 30 minutes. The transformants were then plated onto 20 standard 150 mm LB plates containing ampicillin and incubated for 16 hours (37° C.). Positive colonies were scraped off the plates and the DNA was isolated from the bacterial pellet using standard protocols, e.g. CsCl-gradient. The purified DNA was then carried on to the yeast protocols below.
  • The yeast methods were divided into three categories: (1) Transformation of yeast with the plasmid/cDNA combined vector; (2) Detection and isolation of yeast clones secreting amylase; and (3) PCR amplification of the insert directly from the yeast colony and purification of the DNA for sequencing and further analysis. [0428]
  • The yeast strain used was HD56-5A (ATCC-90785). This strain has the following genotype: MAT alpha, ura3-52, leu2-3, leu2-112, his3-11, his3-15, MAL[0429] +, SUC+, GAL+. Preferably, yeast mutants can be employed that have deficient post-translational pathways. Such mutants may have translocation deficient alleles in sec 71, sec72, sec62, with truncated sec71 being most preferred. Alternatively, antagonists (including antisense nucleotides and/or ligands) which interfere with the normal operation of these genes, other proteins implicated in this post translation pathway (e.g., SEC61 p, SEC72p, SEC62p, SEC63p, TDJ1 p or SSA1p-4p) or the complex formation of these proteins may also be preferably employed in combination with the amylase-expressing yeast.
  • Transformation was performed based on the protocol outlined by Gietz et al., Nucl. Acid. Res., 20:1425 (1992). Transformed cells were then inoculated from agar into YEPD complex media broth (100 ml) and grown overnight at 30° C. The YEPD broth was prepared as described in Kaiser et al., Methods in Yeast Genetics, Cold Spring Harbor Press, Cold Spring Harbor, N.Y., p. 207 (1994). The overnight culture was then diluted to about 2×10[0430] 6 cells/ml (approx. OD600=0.1) into fresh YEPD broth (500 ml) and regrown to 1×107 cells/ml (approx. OD=0.4-0.5).
  • The cells were then harvested and prepared for transformation by transfer into GS3 rotor bottles in a Sorval GS3 rotor at 5,000 rpm for 5 minutes, the supernatant discarded, and then resuspended into sterile water, and centrifuged again in 50 ml falcon tubes at 3,500 rpm in a Beckman GS-6KR centrifuge. The supernatant was discarded and the cells were subsequently washed with LiAc/TE (10 ml, 10 mM Tris-HCl, 1 mM EDTA pH 7.5, 100 mM Li[0431] 2OOCCH3), and resuspended into LiAc/TE (2.5 ml).
  • Transformation took place by mixing the prepared cells (100 μl) with freshly denatured single stranded salmon testes DNA (Lofstrand Labs, Gaithersburg, Md.) and transforming DNA (1 μg, vol. <10 μl) in microfuge tubes. The mixture was mixed briefly by vortexing, then 40% PEG/TE (600 μl, 40% polyethylene glycol-4000, 10 mM Tris-HCl, 1 mM EDTA, 100 mM Li[0432] 2OOCCH3, pH 7.5) was added. This mixture was gently mixed and incubated at 30° C. while agitating for 30 minutes. The cells were then heat shocked at 42° C. for 15 minutes, and the reaction vessel centrifuged in a microfuge at 12,000 rpm for 5-10 seconds, decanted and resuspended into TE (500 μl, 10 mM Tris-HCl, 1 mM EDTA pH 7.5) followed by recentrifugation. The cells were then diluted into TE (1 ml) and aliquots (200 μl) were spread onto the selective media previously prepared in 150 mm growth plates (VWR).
  • Alternatively, instead of multiple small reactions, the transformation was performed using a single, large scale reaction, wherein reagent amounts were scaled up accordingly. [0433]
  • The selective media used was a synthetic complete dextrose agar lacking uracil (SCD-Ura) prepared as described in Kaiser et al., Methods in Yeast Genetics, Cold Spring Harbor Press, Cold Spring Harbor, N.Y., p. 208-210 (1994). Transformants were grown at 30° C. for 2-3 days. [0434]
  • The detection of colonies secreting amylase was performed by including red starch in the selective growth media. Starch was coupled to the red dye (Reactive Red-120, Sigma) as per the procedure described by Biely et al., Anal. Biochem., 172:1 76-179 (1988). The coupled starch was incorporated into the SCD-Ura agar plates at a final concentration of 0.15% (w/v), and was buffered with potassium phosphate to a pH of 7.0 (50-100 mM final concentration). [0435]
  • The positive colonies were picked and streaked across fresh selective media (onto 150 mm plates) in order to obtain well isolated and identifiable single colonies. Well isolated single colonies positive for amylase secretion were detected by direct incorporation of red starch into buffered SCD-Ura agar. Positive colonies were determined by their ability to break down starch resulting in a clear halo around the positive colony visualized directly. [0436]
  • 4. Isolation of DNA by PCR Amplification [0437]
  • When a positive colony was isolated, a portion of it was picked by a toothpick and diluted into sterile water (30 μl) in a 96 well plate. At this time, the positive colonies were either frozen and stored for subsequent analysis or immediately amplified. An aliquot of cells (5 μl) was used as a template for the PCR reaction in a 25 μl volume containing: 0.5 μl Klentaq (Clontech, Palo Alto, Calif.); 4.0 μl 10 mM dNTP's (Perkin Elmer-Cetus); 2.5 μl Kentaq buffer (Clontech); 0.25 μl [0438] forward oligo 1; 0.25 μl reverse oligo 2; 1 2.5 μl distilled water.
    (SEQ ID NO:169)
    The sequence of the forward oligonucleotide 1 was:
    5′-TGTAAAACGACGGCCAGTTAAATAGACCTGCAATTATTAATCT-3′
    (SEQ ID NO:170)
    The sequence of reverse oligonucleotide 2 was:
    5′-CAGGAAACAGCTATGACCACCTGCACACCTGCAAATCCATT-3′
  • PCR was then performed as follows: [0439]
    a. Denature 92° C.,  5 minutes
    b.  3 cycles of: Denature 92° C., 30 seconds
    Anneal 59° C., 30 seconds
    Extend 72° C., 60 seconds
    c.  3 cycles of: Denature 92° C., 30 seconds
    Anneal 57° C., 30 seconds
    Extend 72° C., 60 seconds
    d. 25 cycles of: Denature 92° C., 30 seconds
    Anneal 55° C., 30 seconds
    Extend 72° C., 60 seconds
    e. Hold  4° C.
  • The underlined regions of the oligonucleotides annealed to the ADH promoter region and the amylase region, respectively, and amplified a 307 bp region from vector pSST-AMY.0 when no insert was present. Typically, the first 18 nucleotides of the 5′ end of these oligonucleotides contained annealing sites for the sequencing primers. Thus, the total product of the PCR reaction from an empty vector was 343 bp. However, signal sequence-fused cDNA resulted in considerably longer nucleotide sequences. [0440]
  • Following the PCR, an aliquot of the reaction (5 μl) was examined by agarose gel electrophoresis in a 1% agarose gel using a Tris-Borate-EDTA (TBE) buffering system as described by Sambrook et al., supra. Clones resulting in a single strong PCR product larger than 400 bp were further analyzed by DNA sequencing after purification with a 96 Qiaquick PCR clean-up column (Qiagen Inc., Chatsworth, Calif.). [0441]
    • EXAMPLE 3 Isolation of cDNA Clones Using Signal Algorithm Analysis
  • Various polypeptide-encoding nucleic acid sequences were identified by applying a proprietary signal sequence finding algorithm developed by Genentech, Inc. (South San Francisco, Calif.) upon ESTs as well as clustered and assembled EST fragments from public (e.g., GenBank) and/or private (LIFESEQ®, Incyte Pharmaceuticals, Inc., Palo Alto, Calif.) databases. The signal sequence algorithm computes a secretion signal score based on the character of the DNA nucleotides surrounding the first and optionally the second methionine codon(s) (ATG) at the 5′-end of the sequence or sequence fragment under consideration. The nucleotides following the first ATG must code for at least 35 unambiguous amino acids without any stop codons. If the first ATG has the required amino acids, the second is not examined. If neither meets the requirement, the candidate sequence is not scored. In order to determine whether the EST sequence contains an authentic signal sequence, the DNA and corresponding amino acid sequences surrounding the ATG codon are scored using a set of seven sensors (evaluation parameters) known to be associated with secretion signals. Use of this algorithm resulted in the identification of numerous polypeptide-encoding nucleic acid sequences. [0442]
    • EXAMPLE 4 Isolation of cDNA Clones Encoding Human PRO Polypeptides
  • Using the techniques described in Examples 1 to 3 above, numerous full-length cDNA clones were identified as encoding PRO polypeptides as disclosed herein. These cDNAs were then deposited under the terms of the Budapest Treaty with the American Type Culture Collection, 10801 University Blvd., Manassas, Va. 20110-2209, USA (ATCC) as shown in Tabl 7 below. [0443]
    TABLE 7
    Material ATCC Dep. No. Deposit Date
    DNA26843-1389 203099 Aug. 4,1998
    DNA30867-1335 209807 Apr. 28, 1998
    DNA34431-1177 209399 Oct. 17, 1997
    DNA38268-1188 209421 Oct. 28, 1997
    DNA40621-1440 209922 Jun. 2, 1998
    DNA40625-1189 209788 Apr. 21, 1998
    DNA45409-2511 203579 Jan. 12,1999
    DNA45495-1550 203156 Aug. 25, 1998
    DNA49820-1427 209932 Jun. 2, 1998
    DNA56406-1704 203478 Nov. 17, 1998
    DNA56410-1414 209923 Jun. 2, 1998
    DNA56436-1448 209902 May 27, 1998
    DNA56855-1447 203004 Jun. 23, 1998
    DNA56860-1510 209952 Jun. 9, 1998
    DNA56862-1343 203174 Sep. 1, 1998
    DNA56868-1478 203024 Jun. 23, 1998
    DNA56869-1545 203161 Aug. 25, 1998
    DNA57704-1452 209953 Jun. 9, 1998
    DNA58723-1588 203133 Aug. 18, 1998
    DNA57827-1493 203045 Jul. 1, 1998
    DNA58737-1473 203136 Aug. 18, 1998
    DNA58846-1409 209957 Jun. 9, 1998
    DNA58850-1495 209956 Jun. 9, 1998
    DNA58855-1422 203018 Jun. 23, 1998
    DNA59211-1450 209960 Jun. 9, 1998
    DNA59212-1627 203245 Sep. 9, 1998
    DNA59213-1487 209959 Jun. 9, 1998
    DNA59605-1418 203005 Jun. 23, 1998
    DNA59609-1470 209963 Jun. 9, 1998
    DNA59610-1556 209990 Jun. 16, 1998
    DNA59837-2545 203658 Feb. 9, 1999
    DNA59844-2542 203650 Feb. 9, 1999
    DNA59854-1459 209974 Jun. 16, 1998
    DNA60625-1507 209975 Jun. 16, 1998
    DNA60629-1481 209979 Jun. 16, 1998
    DNA61755-1554 203112 Aug. 11, 1998
    DNA62812-1594 203248 Sep. 9, 1998
    DNA62815-1576 203247 Sep. 9, 1998
    DNA64881-1602 203240 Sep. 9, 1998
    DNA64886-1601 203241 Sep. 9, 1998
    DNA64902-1667 203317 Oct. 6, 1998
    DNA64950-1590 203224 Sep. 15, 1998
    DNA65403-1565 203230 Sep. 15, 1998
    DNA66308-1537 203159 Aug. 25, 1998
    DNA66519-1535 203236 Sep. 15, 1998
    DNA66521-1583 203225 Sep. 15, 1998
    DNA66658-1584 203229 Sep. 15, 1998
    DNA66660-1585 203279 Sep. 22, 1998
    DNA66663-1598 203268 Sep. 22, 1998
    DNA66674-1599 203281 Sep. 22, 1998
    DNA68862-2546 203652 Feb. 9, 1999
    DNA68866-1644 203283 Sep. 22, 1998
    DNA68871-1638 203280 Sep. 22, 1998
    DNA68880-1676 203319 Oct. 6, 1998
    DNA68883-1691 203535 Dec. 15, 1998
    DNA68885-1678 203311 Oct. 6,1998
    DNA71277-1636 203285 Sep. 22, 1998
    DNA73727-1673 203459 Nov. 3,1998
    DNA73734-1680 203363 Oct. 20, 1998
    DNA73735-1681 203356 Oct. 20, 1998
    DNA76393-1664 203323 Oct. 6, 1998
    DNA77301-1708 203407 Oct. 27, 1998
    DNA77568-1626 203134 Aug. 18, 1998
    DNA77626-1705 203536 Dec. 15, 1998
    DNA81754-2532 203542 Dec. 15, 1998
    DNA81757-2512 203543 Dec. 15, 1998
    DNA82302-2529 203534 Dec. 15, 1998
    DNA82340-2530 203547 Dec. 22, 1998
    DNA83500-2506 203391 Oct. 29, 1998
    DNA84920-2614 203966 Apr. 27, 1999
    DNA85066-2534 203588 Jan. 12, 1999
    DNA86571-2551 203660 Feb. 9, 1999
    DNA87991-2540 203656 Feb. 9, 1999
    DNA92238-2539 203602 Jan. 20, 1999
    DNA96042-2682 PTA-382 Jul. 20, 1999
    DNA96787-2534 203589 Jan. 12, 1999
    DNA125185-2806 PTA-1031 Dec. 7, 1999
    DNA147531-2821 PTA-1185 Jan. 11, 2000
    DNA115291-2681 PTA-202 Jun. 8, 1999
    DNA164625-28890 PTA-1535 Mar. 21, 2000
    DNA131639-2874 PTA-1784 Apr. 25, 2000
    DNA79230-2525 203549 Dec. 22, 1998
  • These deposits were made under the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure and the Regulations thereunder (Budapest Treaty). This assures maintenance of a viable culture of the deposit for 30 years from the date of deposit. [0444]
  • The deposits will be made available by ATCC under the terms of the Budapest Treaty, and subject to an agreement between Genentech, Inc. and ATCC, which assures permanent and unrestricted availability of the progeny of the culture of the deposit to the public upon issuance of the pertinent U.S. patent or upon laying open to the public of any U.S. or foreign patent application, whichever comes first, and assures availability of the progeny to one determined by the U.S. Commissioner of Patents and Trademarks to be entitled thereto according to 35 USC § 122 and the Commissioner's rules pursuant thereto (including 37 CFR § 1.14 with particular reference to 886 OG 638). [0445]
  • The assignee of the present application has agreed that if a culture of the materials on deposit should die or be lost or destroyed when cultivated under suitable conditions, the materials will be promptly replaced on notification with another of the same. Availability of the deposited material is not to be construed as a license to practice the invention in contravention of the rights granted under the authority of any government in accordance with its patent laws. [0446]
    • EXAMPLE 5 Use of PRO as a Hybridization Probe
  • The following method describes use of a nucleotide sequence encoding PRO as a hybridization probe. [0447]
  • DNA comprising the coding sequence of full-length or mature PRO as disclosed herein is employed as a probe to screen for homologous DNAs (such as those encoding naturally-occurring variants of PRO) in human tissue cDNA libraries or human tissue genomic libraries. [0448]
  • Hybridization and washing of filters containing either library DNAs is performed under the following high stringency conditions. Hybridization of radiolabeled PRO-derived probe to the filters is performed in a solution of 50% formamide, 5× SSC, 0.1% SDS, 0.1% sodium pyrophosphate, 50 mM sodium phosphate, pH 6.8, 2× Denhardt's solution, and 10% dextran sulfate at 42° C. for 20 hours. Washing of the filters is performed in an aqueous solution of 0.1× SSC and 0.1% SDS at 42° C. [0449]
  • DNAs having a desired sequence identity with the DNA encoding full-length native sequence PRO can then be identified using standard techniques known in the art. [0450]
    • EXAMPLE 6 Expression of PRO in E. coli
  • This example illustrates preparation of an unglycosylated form of PRO by recombinant expression in [0451] E. coli.
  • The DNA sequence encoding PRO is initially amplified using selected PCR primers. [0452]
  • The primers should contain restriction enzyme sites which correspond to the restriction enzyme sites on the selected expression vector. A variety of expression vectors may be employed. An example of a suitable vector is pBR322 (derived from [0453] E. coli; see Bolivar et al., Gene, 2:95 (1977)) which contains genes for ampicillin and tetracycline resistance. The vector is digested with restriction enzyme and dephosphorylated. The PCR amplified sequences are then ligated into the vector. The vector will preferably include sequences which encode for an antibiotic resistance gene, a trp promoter, a polyhis leader (including the first six STII codons, polyhis sequence, and enterokinase cleavage site), the PRO coding region, lambda transcriptional terminator, and an argU gene.
  • The ligation mixture is then used to transform a selected [0454] E. coli strain using the methods described in Sambrook et al., supra. Transformants are identified by their ability to grow on LB plates and antibiotic resistant colonies are then selected. Plasmid DNA can be isolated and confirmed by restriction analysis and DNA sequencing.
  • Selected clones can be grown overnight in liquid culture medium such as LB broth supplemented with antibiotics. The overnight culture may subsequently be used to inoculate a larger scale culture. The cells are then grown to a desired optical density, during which the expression promoter is turned on. [0455]
  • After culturing the cells for several more hours, the cells can be harvested by centrifugation. The cell pellet obtained by the centrifugation can be solubilized using various agents known in the art, and the solubilized PRO protein can then be purified using a metal chelating column under conditions that allow tight binding of the protein. [0456]
  • PRO may be expressed in [0457] E. coli in a poly-His tagged form, using the following procedure. The DNA encoding PRO is initially amplified using selected PCR primers. The primers will contain restriction enzyme sites which correspond to the restriction enzyme sites on the selected expression vector, and other useful sequences providing for efficient and reliable translation initiation, rapid purification on a metal chelation column, and proteolytic removal with enterokinase. The PCR-amplified, poly-His tagged sequences are then ligated into an expression vector, which is used to transform an E. coli host based on strain 52 (W3110 fuhA(tonA) Ion galE rpoHts (htpRts) cIpP(laclq). Transformants are first grown in LB containing 50 mg/ml carbenicillin at 30° C. with shaking until an O.D.600 of 3-5 is reached. Cultures are then diluted 50-100 fold into CRAP media (prepared by mixing 3.57 g (NH4)2SO4, 0.71 g sodium citrate-2H2O, 1.07 g KCl, 5.36 g Difco yeast extract, 5.36 g Sheffield hycase SF in 500 mL water, as well as 110 mM MPOS, pH 7.3, 0.55% (w/v) glucose and 7 mM MgSO4) and grown for approximately 20-30 hours at 30° C. with shaking. Samples are removed to verify expression by SDS-page analysis, and the bulk culture is centrifuged to pellet the cells. Cell pellets are frozen until purification and refolding.
  • [0458] E. coli paste from 0.5 to 1 L fermentations (6-10 g pellets) is resuspended in 10 volumes (w/v) in 7 M guanidine, 20 mM Tris, pH 8 buffer. Solid sodium sulfite and sodium tetrathionate is added to make final concentrations of 0.1 M and 0.02 M, respectively, and the solution is stirred overnight at 4° C. This step results in a denatured protein with all cysteine residues blocked by sulfitolization. The solution is centrifuged at 40,000 rpm in a Beckman Ultracentifuge for 30 min. The supernatant is diluted with 3-5 volumes of metal chelate column buffer (6 M guanidine, 20 mM Tris, pH 7.4) and filtered through 0.22 micron filters to clarify. The clarified extract is loaded onto a 5 ml Qiagen Ni-NTA metal chelate column equilibrated in the metal chelate column buffer. The column is washed with additional buffer containing 50 mM imidazole (Calbiochem, Utrol grade), pH 7.4. The protein is eluted with buffer containing 250 mM imidazole. Fractions containing the desired protein are pooled and stored at 4° C. Protein concentration is estimated by its absorbance at 280 nm using the calculated extinction coefficient based on its amino acid sequence.
  • The proteins are refolded by diluting the sample slowly into freshly prepared refolding buffer consisting of: 20 mM Tris, pH 8.6, 0.3 M NaCl, 2.5 M urea, 5 mM cysteine, 20 mM glycine and 1 mM EDTA. Refolding volumes are chosen so that the final protein concentration is between 50 to 100 micrograms/ml. The refolding solution is stirred gently at 4° C. for 12-36 hours. The refolding reaction is quenched by the addition of TFA to a final concentration of 0.4% (pH of approximately 3). Before further purification of the protein, the solution is filtered through a 0.22 micron filter and acetonitrile is added to 2-10% final concentration. The refolded protein is chromatographed on a Poros R1/H reversed phase column using a mobile buffer of 0.1% TFA with elution with a gradient of acetonitrile from 10 to 80%. Aliquots of fractions with A280 absorbance are analyzed on SDS polyacrylamide gels and fractions containing homogeneous refolded protein are pooled. Generally, the properly refolded species of most proteins are eluted at the lowest concentrations of acetonitrile since those species are the most compact with their hydrophobic interiors shielded from interaction with the reversed phase resin. Aggregated species are usually eluted at higher acetonitrile concentrations. In addition to resolving misfolded forms of proteins from the desired form, the reversed phase step also removes endotoxin from the samples. [0459]
  • Fractions containing the desired folded PRO polypeptide are pooled and the acetonitrile removed using a gentle stream of nitrogen directed at the solution. Proteins are formulated into 20 mM Hepes, pH 6.8 with 0.14 M sodium chloride and 4% mannitol by dialysis or by gel filtration using G25 Superfine (Pharmacia) resins equilibrated in the formulation buffer and sterile filtered. [0460]
  • Many of the PRO polypeptides disclosed herein were successfully expressed as described above. [0461]
    • EXAMPLE 7 Expression of PRO in Mammalian Cells
  • This example illustrates preparation of a potentially glycosylated form of PRO by recombinant expression in mammalian cells. [0462]
  • The vector, pRK5 (see EP 307,247, published Mar. 15, 1989), is employed as the expression vector. Optionally, the PRO DNA is ligated into pRK5 with selected restriction enzymes to allow insertion of the PRO DNA using ligation methods such as described in Sambrook et al., supra. The resulting vector is called pRK5-PRO. [0463]
  • In one embodiment, the selected host cells may be 293 cells. Human 293 cells (ATCC CCL 1573) are grown to confluence in tissue culture plates in medium such as DMEM supplemented with fetal calf serum and optionally, nutrient components and/or antibiotics. About 10 μg pRK5-PRO DNA is mixed with about 1 μg DNA encoding the VA RNA gene [Thimmappaya et al., Cell, 31:543 (1982)] and dissolved in 500 μl of 1 mM Tris-HCl, 0.1 mM EDTA, 0.227 M CaCl[0464] 2. To this mixture is added, dropwise, 500 μl of 50 mM HEPES (pH 7.35), 280 mM NaCl, 1.5 mM NaPO4, and a precipitate is allowed to form for 10 minutes at 25° C. The precipitate is suspended and added to the 293 cells and allowed to settle for about four hours at 37° C. The culture medium is aspirated off and 2 ml of 20% glycerol in PBS is added for 30 seconds. The 293 cells are then washed with serum free medium, fresh medium is added and the cells are incubated for about 5 days.
  • Approximately 24 hours after the transfections, the culture medium is removed and replaced with culture medium (alone) or culture medium containing 200 μCi/ml [0465] 35S-cysteine and 200 μCi/ml 35S-methionine. After a 12 hour incubation, the conditioned medium is collected, concentrated on a spin filter, and loaded onto a 1 5% SDS gel. The processed gel may be dried and exposed to film for a selected period of time to reveal the presence of PRO polypeptide. The cultures containing transfected cells may undergo further incubation (in serum free medium) and the medium is tested in selected bioassays.
  • In an alternative technique, PRO may be introduced into 293 cells transiently using the dextran sulfate method described by Somparyrac et al., Proc. Natl. Acad. Sci., 12:7575 (1981). 293 cells are grown to maximal density in a spinner flask and 700 μg pRK5-PRO DNA is added. The cells are first concentrated from the spinner flask by centrifugation and washed with PBS. The DNA-dextran precipitate is incubated on the cell pellet for four hours. The cells are treated with 20% glycerol for 90 seconds, washed with tissue culture medium, and re-introduced into the spinner flask containing tissue culture medium, 5 μg/ml bovine insulin and 0.1 μg/ml bovine transferrin. After about four days, the conditioned media is centrifuged and filtered to remove cells and debris. The sample containing expressed PRO can then be concentrated and purified by any selected method, such as dialysis and/or column chromatography. [0466]
  • In another embodiment, PRO can be expressed in CHO cells. The pRKS-PRO can be transfected into CHO cells using known reagents such as CaPO[0467] 4 or DEAE-dextran. As described above, the cell cultures can be incubated, and the medium replaced with culture medium (alone) or medium containing a radiolabel such as 35S-methionine. After determining the presence of PRO polypeptide, the culture medium may be replaced with serum free medium. Preferably, the cultures are incubated for about 6 days, and then the conditioned medium is harvested. The medium containing the expressed PRO can then be concentrated and purified by any selected method.
  • Epitope-tagged PRO may also be expressed in host CHO cells. The PRO may be subcloned out of the pRK5 vector. The subclone insert can undergo PCR to fuse in frame with a selected epitope tag such as a poly-his tag into a Baculovirus expression vector. The poly-his tagged PRO insert can then be subcloned into a SV40 driven vector containing a selection marker such as DHFR for selection of stable clones. Finally, the CHO cells can be transfected (as described above) with the SV40 driven vector. Labeling may be performed, as described above, to verify expression. The culture medium containing the expressed poly-His tagged PRO can then be concentrated and purified by any selected method, such as by Ni[0468] 2+-chelate affinity chromatography.
  • PRO may also be expressed in CHO and/or COS cells by a transient expression procedure or in CHO cells by another stable expression procedure. [0469]
  • Stable expression in CHO cells is performed using the following procedure. The proteins are expressed as an IgG construct (immunoadhesin), in which the coding sequences for the soluble forms (e.g. extracellular domains) of the respective proteins are fused to an IgG1 constant region sequence containing the hinge, CH2 and CH2 domains and/or is a poly-His tagged form. [0470]
  • Following PCR amplification, the respective DNAs are subcloned in a CHO expression vector using standard techniques as described in Ausubel et al., Current Protocols of Molecular Biology, Unit 3.16, John Wiley and Sons (1997). CHO expression vectors are constructed to have compatible restriction sites 5′ and 3′ of the DNA of interest to allow the convenient shuttling of cDNA's. The vector used expression in CHO cells is as described in Lucas et al., Nucl. Acids Res. 24:9 (1774-1779 (1996), and uses the SV40 early promoter/enhancer to drive expression of the cDNA of interest and dihydrofolate reductase (DHFR). DHFR expression permits selection for stable maintenance of the plasmid following transfection. [0471]
  • Twelve micrograms of the desired plasmid DNA is introduced into approximately 10 million CHO cells using commercially available transfection reagents Superfect® (Quiagen), Dosper® or Fugene® (Boehringer Mannheim). The cells are grown as described in Lucas et al., supra. Approximately 3×10[0472] −7 cells are frozen in an ampule for further growth and production as described below.
  • The ampules containing the plasmid DNA are thawed by placement into water bath and mixed by vortexing. The contents are pipetted into a centrifuge tube containing 10 mLs of media and centrifuged at 1000 rpm for 5 minutes. The supernatant is aspirated and the cells are resuspended in 10 mL of selective media (0.2 μm filtered PS20 with 5% 0.2 μm diafiltered fetal bovine serum). The cells are then aliquoted into a 100 mL spinner containing 90 mL of selective media. After 1-2 days, the cells are transferred into a 250 mL spinner filled with 150 mL selective growth medium and incubated at 37° C. After another 2-3 days, 250 mL, 500 mL and 2000 mL spinners are seeded with 3×10[0473] 5 cells/mL. The cell media is exchanged with fresh media by centrifugation and resuspension in production medium. Although any suitable CHO media may be employed, a production medium described in U.S. Pat. No. 5,122,469, issued Jun. 16, 1992 may actually be used. A 3L production spinner is seeded at 1.2×106 cells/mL. On day 0, the cell number pH is determined. On day 1, the spinner is sampled and sparging with filtered air is commenced. On day 2, the spinner is sampled, the temperature shifted to 33° C., and 30 mL of 500 g/L glucose and 0.6 mL of 10% antifoam (e.g., 35% polydimethylsiloxane emulsion, Dow Corning 365 Medical Grade Emulsion) taken. Throughout the production, the pH is adjusted as necessary to keep it at around 7.2. After 10 days, or until the viability dropped below 70%, the cell culture is harvested by centrifugation and filtering through a 0.22 μm filter. The filtrate was either stored at 4° C. or immediately loaded onto columns for purification.
  • For the poly-His tagged constructs, the proteins are purified using a Ni-NTA column (Qiagen). Before purification, imidazole is added to the conditioned media to a concentration of 5 mM. The conditioned media is pumped onto a 6 ml Ni-NTA column equilibrated in 20 mM Hepes, pH 7.4, buffer containing 0.3 M NaCl and 5 mM imidazole at a flow rate of 4-5 ml/min. at 4° C. After loading, the column is washed with additional equilibration buffer and the protein eluted with equilibration buffer containing 0.25 M imidazole. The highly purified protein is subsequently desalted into a storage buffer containing 10 mM Hepes, 0.14 M NaCl and 4% mannitol, pH 6.8, with a 25 ml G25 Superfine (Pharmacia) column and stored at −80° C. [0474]
  • Immunoadhesin (Fc-containing) constructs are purified from the conditioned media as follows. The conditioned medium is pumped onto a 5 ml Protein A column (Pharmacia) which had been equilibrated in 20 mM Na phosphate buffer, pH 6.8. After loading, the column is washed extensively with equilibration buffer before elution with 100 mM citric acid, pH 3.5. The eluted protein is immediately neutralized by collecting 1 ml fractions into tubes containing 275 μL of 1 M Tris buffer, pH 9. The highly purified protein is subsequently desalted into storage buffer as described above for the poly-His tagged proteins. The homogeneity is assessed by SDS polyacrylamide gels and by N-terminal amino acid sequencing by Edman degradation. [0475]
  • Many of the PRO polypeptides disclosed herein were successfully expressed as described above. [0476]
    • EXAMPLE 8 Expression of PRO in Yeast
  • The following method describes recombinant expression of PRO in yeast. [0477]
  • First, yeast expression vectors are constructed for intracellular production or secretion of PRO from the ADH2/GAPDH promoter. DNA encoding PRO and the promoter is inserted into suitable restriction enzyme sites in the selected plasmid to direct intracellular expression of PRO. For secretion, DNA encoding PRO can be cloned into the selected plasmid, together with DNA encoding the ADH2/GAPDH promoter, a native PRO signal peptide or other mammalian signal peptide, or, for example, a yeast alpha-factor or invertase secretory signal/leader sequence, and linker sequences (if needed) for expression of PRO. [0478]
  • Yeast cells, such as yeast strain AB110, can then be transformed with the expression plasmids described above and cultured in selected fermentation media. The transformed yeast supernatants can be analyzed by precipitation with 10% trichloroacetic acid and separation by SDS-PAGE, followed by staining of the gels with Coomassie Blue stain. [0479]
  • Recombinant PRO can subsequently be isolated and purified by removing the yeast cells from the fermentation medium by centrifugation and then concentrating the medium using selected cartridge filters. The concentrate containing PRO may further be purified using selected column chromatography resins. [0480]
  • Many of the PRO polypeptides disclosed herein were successfully expressed as described above. [0481]
    • EXAMPLE 9 Expression of PRO in Baculovirus-Infected Insect Cells
  • The following method describes recombinant expression of PRO in Baculovirus- infected insect cells. [0482]
  • The sequence coding for PRO is fused upstream of an epitope tag contained within a baculovirus expression vector. Such epitope tags include poly-his tags and immunoglobulin tags (like Fc regions of IgG). A variety of plasmids may be employed, including plasmids derived from commercially available plasmids such as pVL1393 (Novagen). Briefly, the sequence encoding PRO or the desired portion of the coding sequence of PRO such as the sequence encoding the extracellular domain of a transmembrane protein or the sequence encoding the mature protein if the protein is extracellular is amplified by PCR with primers complementary to the 5′ and 3′ regions. The 5′ primer may incorporate flanking (selected) restriction enzyme sites. The product is then digested with those selected restriction enzymes and subcloned into the expression vector. [0483]
  • Recombinant baculovirus is generated by co-transfecting the above plasmid and BaculoGold™ virus DNA (Pharmingen) into [0484] Spodoptera frugiperda (“Sf9”) cells (ATCC CRL 1711) using lipofectin (commercially available from GIBCO-BRL). After 4-5 days of incubation at 28° C., the released viruses are harvested and used for further amplifications. Viral infection and protein expression are performed as described by O'Reilley et al., Baculovirus expression vectors: A Laboratory Manual, Oxford: Oxford University Press (1994).
  • Expressed poly-his tagged PRO can then be purified, for example, by Ni[0485] 2+-chelate affinity chromatography as follows. Extracts are prepared from recombinant virus-infected Sf9 cells as described by Rupert et al., Nature, 362:175-179 (1993). Briefly, Sf9 cells are washed, resuspended in sonication buffer (25 mL Hepes, pH 7.9; 12.5 mM MgCl2; 0.1 mM EDTA; 10% glycerol; 0.1% NP-40; 0.4 M KCl), and sonicated twice for 20 seconds on ice. The sonicates are cleared by centrifugation, and the supernatant is diluted 50-fold in loading buffer (50 mM phosphate, 300 mM NaCl, 10% glycerol, pH 7.8) and filtered through a 0.45 μm filter. A Ni2+-NTA agarose column (commercially available from Qiagen) is prepared with a bed volume of 5 mL, washed with 25 mL of water and equilibrated with 25 mL of loading buffer. The filtered cell extract is loaded onto the column at 0.5 mL per minute. The column is washed to baseline A280 with loading buffer, at which point fraction collection is started. Next, the column is washed with a secondary wash buffer (50 mM phosphate; 300 mM NaCl, 10% glycerol, pH 6.0), which elutes nonspecifically bound protein. After reaching A280 baseline again, the column is developed with a 0 to 500 mM Imidazole gradient in the secondary wash buffer. One mL fractions are collected and analyzed by SDS-PAGE and silver staining or Western blot with Ni2+-NTA-conjugated to alkaline phosphatase (Qiagen). Fractions containing the eluted His10-tagged PRO are pooled and dialyzed against loading buffer.
  • Alternatively, purification of the IgG tagged (or Fc tagged) PRO can be performed using known chromatography techniques, including for instance, Protein A or protein G column chromatography. [0486]
  • Many of the PRO polypeptides disclosed herein were successfully expressed as described above. [0487]
    • EXAMPLE 10 Preparation of Antibodies that Bind PRO
  • This example illustrates preparation of monoclonal antibodies which can specifically bind PRO. [0488]
  • Techniques for producing the monoclonal antibodies are known in the art and are described, for instance, in Goding, supra. Immunogens that may be employed include purified PRO, fusion proteins containing PRO, and cells expressing recombinant PRO on the cell surface. Selection of the immunogen can be made by the skilled artisan without undue experimentation. [0489]
  • Mice, such as Balb/c, are immunized with the PRO immunogen emulsified in complete Freund's adjuvant and injected subcutaneously or intraperitoneally in an amount from 1-100 micrograms. Alternatively, the immunogen is emulsified in MPL-TDM adjuvant (Ribi Immunochemical Research, Hamilton, Mont.) and injected into the animal's hind foot pads. The immunized mice are then boosted 10 to 12 days later with additional immunogen emulsified in the selected adjuvant. Thereafter, for several weeks, the mice may also be boosted with additional immunization injections. Serum samples may be periodically obtained from the mice by retro-orbital bleeding for testing in ELISA assays to detect anti-PRO antibodies. [0490]
  • After a suitable antibody titer has been detected, the animals “positive” for antibodies can be injected with a final intravenous injection of PRO. Three to four days later, the mice are sacrificed and the spleen cells are harvested. The spleen cells are then fused (using 35% polyethylene glycol) to a selected murine myeloma cell line such as P3X63AgU.1, available from ATCC, No. CRL 1597. The fusions generate hybridoma cells which can then be plated in 96 well tissue culture plates containing HAT (hypoxanthine, aminopterin, and thymidine) medium to inhibit proliferation of non-fused cells, myeloma hybrids, and spleen cell hybrids. [0491]
  • The hybridoma cells will be screened in an ELISA for reactivity against PRO. Determination of “positive” hybridoma cells secreting the desired monoclonal antibodies against PRO is within the skill in the art. [0492]
  • The positive hybridoma cells can be injected intraperitoneally into syngeneic Balb/c mice to produce ascites containing the anti-PRO monoclonal antibodies. Alternatively, the hybridoma cells can be grown in tissue culture flasks or roller bottles. Purification of the monoclonal antibodies produced in the ascites can be accomplished using ammonium sulfate precipitation, followed by gel exclusion chromatography. Alternatively, affinity chromatography based upon binding of antibody to protein A or protein G can be employed. [0493]
    • EXAMPLE 11 Purification of PRO Polypeptides Using Specific Antibodies
  • Native or recombinant PRO polypeptides may be purified by a variety of standard techniques in the art of protein purification. For example, pro-PRO polypeptide, mature PRO polypeptide, or pre-PRO polypeptide is purified by immunoaffinity chromatography using antibodies specific for the PRO polypeptide of interest. In general, an immunoaffinity column is constructed by covalently coupling the anti-PRO polypeptide antibody to an activated chromatographic resin. [0494]
  • Polyclonal immunoglobulins are prepared from immune sera either by precipitation with ammonium sulfate or by purification on immobilized Protein A (Pharmacia LKB Biotechnology, Piscataway, N.J.). Likewise, monoclonal antibodies are prepared from mouse ascites fluid by ammonium sulfate precipitation or chromatography on immobilized Protein A. Partially purified immunoglobulin is covalently attached to a chromatographic resin such as CnBr-activated SEPHAROSE™ (Pharmacia LKB Biotechnology). The antibody is coupled to the resin, the resin is blocked, and the derivative resin is washed according to the manufacturer's instructions. [0495]
  • Such an immunoaffinity column is utilized in the purification of PRO polypeptide by preparing a fraction from cells containing PRO polypeptide in a soluble form. This preparation is derived by solubilization of the whole cell or of a subcellular fraction obtained via differential centrifugation by the addition of detergent or by other methods well known in the art. Alternatively, soluble PRO polypeptide containing a signal sequence may be secreted in useful quantity into the medium in which the cells are grown. [0496]
  • A soluble PRO polypeptide-containing preparation is passed over the immunoaffinity column, and the column is washed under conditions that allow the preferential absorbance of PRO polypeptide ( e.g. , high ionic strength buffers in the presence of detergent). Then, the column is eluted under conditions that disrupt antibody/PRO polypeptide binding (e.g., a low pH buffer such as approximately pH 2-3, or a high concentration of a chaotrope such as urea or thiocyanate ion), and PRO polypeptide is collected. [0497]
    • EXAMPLE 12 Drug Screening
  • This invention is particularly useful for screening compounds by using PRO polypeptides or binding fragment thereof in any of a variety of drug screening techniques. The PRO polypeptide or fragment employed in such a test may either be free in solution, affixed to a solid support, borne on a cell surface, or located intracellularly. One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the PRO polypeptide or fragment. Drugs are screened against such transformed cells in competitive binding assays. Such cells, either in viable or fixed form, can be used for standard binding assays. One may measure, for example, the formation of complexes between PRO polypeptide or a fragment and the agent being tested. Alternatively, one can examine the diminution in complex formation between the PRO polypeptide and its target cell or target receptors caused by the agent being tested. [0498]
  • Thus, the present invention provides methods of screening for drugs or any other agents which can affect a PRO polypeptide-associated disease or disorder. These methods comprise contacting such an agent with a PRO polypeptide or fragment thereof and assaying (i) for the presence of a complex between the agent and the PRO polypeptide or fragment, or (ii) for the presence of a complex between the PRO polypeptide or fragment and the cell, by methods well known in the art. In such competitive binding assays, the PRO polypeptide or fragment is typically labeled. After suitable incubation, free PRO polypeptide or fragment is separated from that present in bound form, and the amount of free or uncomplexed label is a measure of the ability of the particular agent to bind to PRO polypeptide or to interfere with the PRO polypeptide/cell complex. [0499]
  • Another technique for drug screening provides high throughput screening for compounds having suitable binding affinity to a polypeptide and is described in detail in WO 84/03564, published on Sep. 13, 1984. Briefly stated, large numbers of different small peptide test compounds are synthesized on a solid substrate, such as plastic pins or some other surface. As applied to a PRO polypeptide, the peptide test compounds are reacted with PRO polypeptide and washed. Bound PRO polypeptide is detected by methods well known in the art. Purified PRO polypeptide can also be coated directly onto plates for use in the aforementioned drug screening techniques. In addition, non-neutralizing antibodies can be used to capture the peptide and immobilize it on the solid support. [0500]
  • This invention also contemplates the use of competitive drug screening assays in which neutralizing antibodies capable of binding PRO polypeptide specifically compete with a test compound for binding to PRO polypeptide or fragments thereof. In this manner, the antibodies can be used to detect the presence of any peptide which shares one or more antigenic determinants with PRO polypeptide. [0501]
    • EXAMPLE 13 Rational Drug Design
  • The goal of rational drug design is to produce structural analogs of biologically active polypeptide of interest (i.e., a PRO polypeptide) or of small molecules with which they interact, e.g., agonists, antagonists, or inhibitors. Any of these examples can be used to fashion drugs which are more active or stable forms of the PRO polypeptide or which enhance or interfere with the function of the PRO polypeptide in vivo (c.f., Hodgson, Bio/Technology, 9: 19-21(1991)). [0502]
  • In one approach, the three-dimensional structure of the PRO polypeptide, or of a PRO polypeptide-inhibitor complex, is determined by X-ray crystallography, by computer modeling or, most typically, by a combination of the two approaches. Both the shape and charges of the PRO polypeptide must be ascertained to elucidate the structure and to determine active site(s) of the molecule. Less often, useful information regarding the structure of the PRO polypeptide may be gained by modeling based on the structure of homologous proteins. In both cases, relevant structural information is used to design analogous PRO polypeptide-like molecules or to identify efficient inhibitors. Useful examples of rational drug design may include molecules which have improved activity or stability as shown by Braxton and Wells, Biochemistry, 31:7796-7801(1992) or which act as inhibitors, agonists, or antagonists of native peptides as shown by Athauda et al., J. Biochem., 113:742-746(1993). [0503]
  • It is also possible to isolate a target-specific antibody, selected by functional assay, as described above, and then to solve its crystal structure. This approach, in principle, yields a pharmacore upon which subsequent drug design can be based. It is possible to bypass protein crystallography altogether by generating anti-idiotypic antibodies (anti-ids) to a functional, pharmacologically active antibody. As a mirror image of a mirror image, the binding site of the anti-ids would be expected to be an analog of the original receptor. The anti-id could then be used to identify and isolate peptides from banks of chemically or biologically produced peptides. The isolated peptides would then act as the pharmacore. [0504]
  • By virtue of the present invention, sufficient amounts of the PRO polypeptide may be made available to perform such analytical studies as X-ray crystallography. In addition, knowledge of the PRO polypeptide amino acid sequence provided herein will provide guidance to those employing computer modeling techniques in place of or in addition to X-ray crystallography. [0505]
    • EXAMPLE 14 Pericyte c-Fos Induction (Assay 93)
  • This assay shows that certain polypeptides of the invention act to induce the expression of c-fos in pericyte cells and, therefore, are useful not only as diagnostic markers for particular types of pericyte-associated tumors but also for giving rise to antagonists which would be expected to be useful for the therapeutic treatment of pericyte-associated tumors. Induction of c-fos expression in pericytes is also indicative of the induction of angiogenesis and, as such, PRO polypeptides capable of inducing the expression of c-fos would be expected to be useful for the treatment of conditions where induced angiogenesis would be beneficial including, for example, wound healing, and the like. Specifically, on [0506] day 1, pericytes are received from VEC Technologies and all but 5 ml of media is removed from flask. On day 2, the pericytes are trypsinized, washed, spun and then plated onto 96 well plates. On day 7, the media is removed and the pericytes are treated with 100 μl of PRO polypeptide test samples and controls (positive control=DME+5% serum +/−PDGF at 500 ng/ml; negative control=protein 32). Replicates are averaged and SD/CV are determined. Fold increase over Protein 32 (buffer control) value indicated by chemiluminescence units (RLU) luminometer reading verses frequency is plotted on a histogram. Two-fold above Protein 32 value is considered positive for the assay. ASY Matrix: Growth media =low glucose DMEM=20% FBS+1× pen strep+1× fungizone. Assay Media=low glucose DMEM +5% FBS.
  • The following polypeptides tested positive in this assay: PRO1347 and PRO1340. [0507]
    • EXAMPLE 15 Ability of PRO Polypeptides to Stimulate the Release of Proteoglycans from Cartilage (Assay 97)
  • The ability of various PRO polypeptides to stimulate the release of proteoglycans from cartilage tissue was tested as follows. [0508]
  • The metacarphophalangeal joint of 4-6 month old pigs was aseptically dissected, and articular cartilage was removed by free hand slicing being careful to avoid the underlying bone. The cartilage was minced and cultured in bulk for 24 hours in a humidified atmosphere of 95% air, 5% CO[0509] 2 in serum free (SF) media (DME/F12 1:1) with 0.1% BSA and 100 U/ml penicillin and 100 μg/ml streptomycin. After washing three times, approximately 100 mg of articular cartilage was aliquoted into micronics tubes and incubated for an additional 24 hours in the above SF media. PRO polypeptides were then added at 1% either alone or in combination with 18 ng/ml interleukin-1 α, a known stimulator of proteoglycan release from cartilage tissue. The supernatant was then harvested and assayed for the amount of proteoglycans using the 1,9-dimethyl-methylene blue (DMB) colorimetric assay (Farndale and Buttle, Biochem. Biophys. Acta 883:173-177 (1985)). A positive result in this assay indicates that the test polypeptide will find use, for example, in the treatment of sports-related joint problems, articular cartilage defects, osteoarthritis or rheumatoid arthritis.
  • When various PRO polypeptides were tested in the above assay, the polypeptides demonstrated a marked ability to stimulate release of proteoglycans from cartilage tissue both basally and after stimulation with interleukin-1 α and at 24 and 72 hours after treatment, thereby indicating that these PRO polypeptides are useful for stimulating proteoglycan release from cartilage tissue. As such, these PRO polypeptides are useful for the treatment of sports-related joint problems, articular cartilage defects, osteoarthritis or rheumatoid arthritis. The polypeptides testing positive in this assay are: PRO1565, PRO1693, PRO1801 and PRO10096. [0510]
    • EXAMPLE 16 Detection of Polypeptides That Affect Glucose or FFA Uptake in Skeletal Muscle (Assay 706)
  • This assay is designed to determine whether PRO polypeptides show the ability to affect glucose or FFA uptake by skeletal muscle cells. PRO polypeptides testing positive in this assay would be expected to be useful for the therapeutic treatment of disorders where either the stimulation or inhibition of glucose uptake by skeletal muscle would be beneficial including, for example, diabetes or hyper- or hypo-insulinemia. [0511]
  • In a 96 well format, PRO polypeptides to be assayed are added to primary rat differentiated skeletal muscle, and allowed to incubate overnight. Then fresh media with the PRO polypeptide and +/−insulin are added to the wells. The sample media is then monitored to determine glucose and FFA uptake by the skeletal muscle cells. The insulin will stimulate glucose and FFA uptake by the skeletal muscle, and insulin in media without the PRO polypeptide is used as a positive control, and a limit for scoring. As the PRO polypeptide being tested may either stimulate or inhibit glucose and FFA uptake, results are scored as positive in the assay if greater than 1.5 times or less than 0.5 times the insulin control. [0512]
  • The following PRO polypeptides tested positive as either stimulators or inhibitors of glucose and/or FFA uptake in this assay: PRO4405. [0513]
    • EXAMPLE 17 Identification of PRO Polypeptides That Stimulate TNF-α Release In Human Blood (Assay 128)
  • This assay shows that certain PRO polypeptides of the present invention act to stimulate the release of TNF-α in human blood. PRO polypeptides testing positive in this assay are useful for, among other things, research purposes where stimulation of the release of TNF-α would be desired and for the therapeutic treatment of conditions wherein enhanced TNF-α release would be beneficial. Specifically, 200 μl of human blood supplemented with 50 mM Hepes buffer (pH 7.2) is aliquotted per well in a 96 well test plate. To each well is then added 300 μl of either the test PRO polypeptide in 50 mM Hepes buffer (at various concentrations) or 50 mM Hepes buffer alone (negative control) and the plates are incubated at 37° C. for 6 hours. The samples are then centrifuged and 50 μl of plasma is collected from each well and tested for the presence of TNF-α by ELISA assay. A positive in the assay is a higher amount of TNF-α in the PRO polypeptide treated samples as compared to the negative control samples. [0514]
  • The following PRO polypeptides tested positive in this assay: PRO263, PRO295, PRO1282, PRO1063, PRO1356, PRO3543, and PRO5990. [0515]
    • EXAMPLE 18 Tumor Versus Normal Differential Tissue Expression Distribution
  • Oligonucleotide probes were constructed from some of the PRO polypeptide-encoding nucleotide sequences shown in the accompanying figures for use in quantitative PCR amplification reactions. The oligonucleotide probes were chosen so as to give an approximately 200-600 base pair amplified fragment from the 3′ end of its associated template in a standard PCR reaction. The oligonucleotide probes were employed in standard quantitative PCR amplification reactions with cDNA libraries isolated from different human tumor and normal human tissue samples and analyzed by agarose gel electrophoresis so as to obtain a quantitative determination of the level of expression of the PRO polypeptide-encoding nucleic acid in the various tumor and normal tissues tested. β-actin was used as a control to assure that equivalent amounts of nucleic acid was used in each reaction. Identification of the differential expression of the PRO polypeptide-encoding nucleic acid in one or more tumor tissues as compared to one or more normal tissues of the same tissue type renders the molecule useful diagnostically for the determination of the presence or absence of tumor in a subject suspected of possessing a tumor as well as therapeutically as a target for the treatment of a tumor in a subject possessing such a tumor. These assays provided the following results. [0516]
    Molecule is more highly expressed in: as compared to:
    DNA26843-1389 normal lung lung tumor
    rectum tumor normal rectum
    DNA30867-1335 normal kidney kidney tumor
    DNA40621-1440 normal lung lung rumor
    DNA40625-1189 normal lung lung tumor
    DNA45409-2511 melanoma tumor normal akin
    DNA56406-1704 kidney tumor normal kidney
    normal skin melanoma rumor
    DNA56410-1414 normal stomach stomach tumor
    DNA56436-1448 normal skin melanoma tumor
    DNA56855-1447 normal esophagus esophageal tumor
    rectum tumor normal rectum
    DNA56860-1510 normal kidney kidney rumor
    rectum tumor normal rectum
    DNA56862-1343 kidney tumor normal kidney
    normal lung lung rumor
    DNA56868-1478 normal stomach stomach tumor
    normal lung lung rumor
    DNA56869-1545 normal esophagus esophageal tumor
    normal skin melanoma tumor
    DNA57704-1452 normal stomach stomach tumor
    rectum rumor normal rectum
    DNA58723-1588 normal stomach stomach tumor
    kidney rumor normal kidney
    normal akin melanoma tumor
    DNA57827-1493 normal stomach stomach tumor
    normal skin melanoma tumor
    DNA58737-1473 esophageal tumor normal esophagus
    normal stomach stomach tumor
    DNA58846-1409 lung tumor normal lung
    DNA58850-1495 esophageal tumor normal esophagus
    kidney tumor normal kidney
    DNA58855-1422 normal stomach stomach tumor
    rectum tumor normal rectum
    DNA59211-1450 normal kidney kidney tumor
    DNA59212-1627 normal skin melanoma tumor
    DNA59213-1487 normal stomach stomach tumor
    normal skin melanoma tumor
    DNA59605-1418 melanoma rumor normal skin
    DNA59609-1470 esophageal tumor normal esophagus
    DNA59610-1556 esophageal rumor normal esophagus
    lung tumor normal lung
    normal skin melanoma tumor
    DNA59837-2545 normal skin melanoma tumor
    DNA59844-2542 normal skin melanoma tumor
    esophageal tumor normal esophagus
    DNA59854-1459 normal esophagus esophageal tumor
    stomach tumor normal stomach
    normal lung lung tumor
    DNA60625-1507 normal lung lung rumor
    DNA60629-1481 normal esophagus esophageal tumor
    normal rectum rectum tumor
    DNA61755-1554 normal stomach stomach tumor
    kidney tumor normal kidney
    DNA62812-1594 normal stomach stomach tumor
    normal lung lung tumor
    normal rectum rectum tumor
    normal skin melanoma tumor
    DNA62815-1576 esophageal tumor normal esophagus
    DNA64881-1602 normal stomach stomach tumor
    normal lung lung tumor
    DNA64902-1667 esophageal tumor normal esophagus
    kidney tumor normal kidney
    DNA65403-1565 normal esophagus esophageal tumor
    DNA66308-1537 normal lung lung tumor
    DNA66519-1535 kidney tumor normal kidney
    DNA66521-1583 normal esophagus esophageal tumor
    normal stomach stomach tumor
    normal lung lung tumor
    normal rectum rectum tumor
    normal skin melanoma tumor
    DNA66658-1584 normal lung lung rumor
    melanoma tumor normal skin
    DNA66660-1585 lung rumor normal lung
    DNA66674-1599 kidney tumor normal kidney
    normal lung lung tumor
    DNA68862-2546 melanoma tumor normal skin
    DNA68866-1644 normal stomach stomach tumor
    DNA68871-1638 lung tumor normal lung
    normal skin melanoma tumor
    DNA68880-1676 normal lung lung tumor
    normal skin melanoma tumor
    DNA68883-1691 esophageal rumor normal esophagus
    DNA68885-1678 lung tumor normal lung
    DNA71277-1636 normal stomach stomach tumor
    DNA73734-1680 normal lung lung tumor
    DNA73735-1681 esophageal tumor normal esophagus
    normal kidney kidney tumor
    lung tumor normal lung
    normal skin melanoma tumor
    DNA76393-1664 esophageal rumor normal esophagus
    stomach rumor normal stomach
    lung tumor normal lung
    rectum rumor normal rectum
    DNA77568-1626 normal stomach stomach rumor
    lung rumor normal lung
    DNA77626-1705 normal rectum rectum rumor
    DNA81754-2532 normal skin melanoma rumor
    DNA81757-2512 esophageal tumor normal esophagus
    normal stomach stomach rumor
    melanoma tumor normal skin
    DNA82302-2529 normal stomach stomach rumor
    normal lung lung rumor
    DNA82340-2530 normal esophagus esophageal rumor
    DNA85066-2534 lung tumor normal lung
    normal skin melanoma rumor
    DNA87991-2540 esophageal rumor normal esophagus
    DNA92238-2539 normal skin melanoma rumor
    DNA96787-2534 normal kidney kidney rumor
    • EXAMPLE 19 Identification of Receptor/Ligand Interactions
  • In this assay, various PRO polypeptides are tested for ability to bind to a panel of potential receptor or ligand molecules for the purpose of identifying receptor/ligand interactions. The identification of a ligand for a known receptor, a receptor for a known ligand or a novel receptor/ligand pair is useful for a variety of indications including, for example, targeting bioactive molecules (linked to the ligand or receptor) to a cell known to express the receptor or ligand, use of the receptor or ligand as a reagent to detect the presence of the ligand or receptor in a composition suspected of containing the same, wherein the composition may comprise cells suspected of expressing the ligand or receptor, modulating the growth of or another biological or immunological activity of a cell known to express or respond to the receptor or ligand, modulating the immune response of cells or toward cells that express the receptor or ligand, allowing the preparation of agonists, antagonists and/or antibodies directed against the receptor or ligand which will modulate the growth of or a biological or immunological activity of a cell expressing the receptor or ligand, and various other indications which will be readily apparent to the ordinarily skilled artisan. [0517]
  • The assay is performed as follows. A PRO polypeptide of the present invention suspected of being a ligand for a receptor is expressed as a fusion protein containing the Fc domain of human IgG (an immunoadhesin). Receptor-ligand binding is detected by allowing interaction of the immunoadhesin polypeptide with cells (e.g. Cos cells) expressing candidate PRO polypeptide receptors and visualization of bound immunoadhesin with fluorescent reagents directed toward the Fc fusion domain and examination by microscope. Cells expressing candidate receptors are produced by transient transfection, in parallel, of defined subsets of a library of cDNA expression vectors encoding PRO polypeptides that may function as receptor molecules. Cells are the incubated for 1 hour in the presence of the PRO polypeptide immunoadhesin being tested for possible receptor binding. The cells are then washed and fixed with paraformaldehyde. The cells are then incubated with fluorescent conjugated antibody directed against the Fc portion of the PRO polypeptide immunoadhesin (e.g. FITC conjugated goat anti-human-Fc antibody). The cells are then washed again and examined by microscope. A positive interaction is judged by the presence of fluorescent labeling of cells transfected with cDNA encoding a particular PRO polypeptide receptor or pool of receptors and an absence of similar fluorescent labeling of similarly prepared cells that have been transfected with other cDNA or pools of cDNA, if a defined pool of cDNA expression vectors is judged to be positive for interaction with a PRO polypeptide immunoadhesin, the individual cDNA species that comprise the pool are tested individually (the pool is “broken down”) to determine the specific cDNA that encodes a receptor able to interact with the PRO polypeptide immunoadhesin. [0518]
  • In another embodiment of this assay, an epitope-tagged potential ligand PRO polypeptide (e.g. 8 histidine “His” tag) is allowed to interact with a panel of potential receptor PRO polypeptide molecules that have been expressed as fusions with the Fc domain of human IgG (immunoadhesins). Following a 1 hour co-incubation with the epitope tagged PRO polypeptide, the candidate receptors are each immunoprecipitated with protein A beads and the beads are washed. Potential ligand interaction is determined by western blot analysis of the immunoprecipitated complexes with antibody directed towards the epitope tag. An interaction is judged to occur if a band of the anticipated molecular weight of the epitope tagged protein is observed in the western blot analysis with a candidate receptor, but is not observed to occur with the other members of the panel of potential receptors. [0519]
  • Using these assays, the following receptor/ligand interactions have been herein identified: [0520]
  • (1) PRO10272 binds to PRO5801. [0521]
  • (2) PRO20110 binds to the human IL-17 receptor (Yao et al., Cytokine 9(11):794-800 (1997); also herein designated as PRO1) and to PRO20040. [0522]
  • (3) PRO10096 binds to PRO20233. [0523]
  • (4) PRO19670 binds to PRO1890. [0524]
  • The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the invention. The present invention is not to be limited in scope by the construct deposited, since the deposited embodiment is intended as a single illustration of certain aspects of the invention and any constructs that are functionally equivalent are within the scope of this invention. The deposit of material herein does not constitute an admission that the written description herein contained is inadequate to enable the practice of any aspect of the invention, including the best mode thereof, nor is it to be construed as limiting the scope of the claims to the specific illustrations that it represents. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. [0525]
  • 1 170 1 1173 DNA Homo Sapien 1 ggggcttcgg cgccagcggc cagcgctagt cggtctggta aggatttaca 50 aaaggtgcag gtatgagcag gtctgaagac taacattttg tgaagttgta 100 aaacagaaaa cctgttagaa atgtggtggt ttcagcaagg cctcagtttc 150 cttccttcag cccttgtaat ttggacatct gctgctttca tattttcata 200 cattactgca gtaacactcc accatataga cccggcttta ccttatatca 250 gtgacactgg tacagtagct ccagaaaaat gcttatttgg ggcaatgcta 300 aatattgcgg cagttttatg cattgctacc atttatgttc gttataagca 350 agttcatgct ctgagtcctg aagagaacgt tatcatcaaa ttaaacaagg 400 ctggccttgt acttggaata ctgagttgtt taggactttc tattgtggca 450 aacttccaga aaacaaccct ttttgctgca catgtaagtg gagctgtgct 500 tacctttggt atgggctcat tatatatgtt tgttcagacc atcctttcct 550 accaaatgca gcccaaaatc catggcaaac aagtcttctg gatcagactg 600 ttgttggtta tctggtgtgg agtaagtgca cttagcatgc tgacttgctc 650 atcagttttg cacagtggca attttgggac tgatttagaa cagaaactcc 700 attggaaccc cgaggacaaa ggttatgtgc ttcacatgat cactactgca 750 gcagaatggt ctatgtcatt ttccttcttt ggttttttcc tgacttacat 800 tcgtgatttt cagaaaattt ctttacgggt ggaagccaat ttacatggat 850 taaccctcta tgacactgca ccttgcccta ttaacaatga acgaacacgg 900 ctactttcca gagatatttg atgaaaggat aaaatatttc tgtaatgatt 950 atgattctca gggattgggg aaaggttcac agaagttgct tattcttctc 1000 tgaaattttc aaccacttaa tcaaggctga cagtaacact gatgaatgct 1050 gataatcagg aaacatgaaa gaagccattt gatagattat tctaaaggat 1100 atcatcaaga agactattaa aaacacctat gcctatactt ttttatctca 1150 gaaaataaag tcaaaagact atg 1173 2 266 PRT Homo Sapien 2 Met Trp Trp Phe Gln Gln Gly Leu Ser Phe Leu Pro Ser Ala Leu 1 5 10 15 Val Ile Trp Thr Ser Ala Ala Phe Ile Phe Ser Tyr Ile Thr Ala 20 25 30 Val Thr Leu His His Ile Asp Pro Ala Leu Pro Tyr Ile Ser Asp 35 40 45 Thr Gly Thr Val Ala Pro Glu Lys Cys Leu Phe Gly Ala Met Leu 50 55 60 Asn Ile Ala Ala Val Leu Cys Ile Ala Thr Ile Tyr Val Arg Tyr 65 70 75 Lys Gln Val His Ala Leu Ser Pro Glu Glu Asn Val Ile Ile Lys 80 85 90 Leu Asn Lys Ala Gly Leu Val Leu Gly Ile Leu Ser Cys Leu Gly 95 100 105 Leu Ser Ile Val Ala Asn Phe Gln Lys Thr Thr Leu Phe Ala Ala 110 115 120 His Val Ser Gly Ala Val Leu Thr Phe Gly Met Gly Ser Leu Tyr 125 130 135 Met Phe Val Gln Thr Ile Leu Ser Tyr Gln Met Gln Pro Lys Ile 140 145 150 His Gly Lys Gln Val Phe Trp Ile Arg Leu Leu Leu Val Ile Trp 155 160 165 Cys Gly Val Ser Ala Leu Ser Met Leu Thr Cys Ser Ser Val Leu 170 175 180 His Ser Gly Asn Phe Gly Thr Asp Leu Glu Gln Lys Leu His Trp 185 190 195 Asn Pro Glu Asp Lys Gly Tyr Val Leu His Met Ile Thr Thr Ala 200 205 210 Ala Glu Trp Ser Met Ser Phe Ser Phe Phe Gly Phe Phe Leu Thr 215 220 225 Tyr Ile Arg Asp Phe Gln Lys Ile Ser Leu Arg Val Glu Ala Asn 230 235 240 Leu His Gly Leu Thr Leu Tyr Asp Thr Ala Pro Cys Pro Ile Asn 245 250 255 Asn Glu Arg Thr Arg Leu Leu Ser Arg Asp Ile 260 265 3 2037 DNA Homo Sapien 3 cggacgcgtg ggcggacgcg tgggggagag ccgcagtccc ggctgcagca 50 cctgggagaa ggcagaccgt gtgagggggc ctgtggcccc agcgtgctgt 100 ggcctcgggg agtgggaagt ggaggcagga gccttcctta cacttcgcca 150 tgagtttcct catcgactcc agcatcatga ttacctccca gatactattt 200 tttggatttg ggtggctttt cttcatgcgc caattgttta aagactatga 250 gatacgtcag tatgttgtac aggtgatctt ctccgtgacg tttgcatttt 300 cttgcaccat gtttgagctc atcatctttg aaatcttagg agtattgaat 350 agcagctccc gttattttca ctggaaaatg aacctgtgtg taattctgct 400 gatcctggtt ttcatggtgc ctttttacat tggctatttt attgtgagca 450 atatccgact actgcataaa caacgactgc ttttttcctg tctcttatgg 500 ctgaccttta tgtatttctt ctggaaacta ggagatccct ttcccattct 550 cagcccaaaa catgggatct tatccataga acagctcatc agccgggttg 600 gtgtgattgg agtgactctc atggctcttc tttctggatt tggtgctgtc 650 aactgcccat acacttacat gtcttacttc ctcaggaatg tgactgacac 700 ggatattcta gccctggaac ggcgactgct gcaaaccatg gatatgatca 750 taagcaaaaa gaaaaggatg gcaatggcac ggagaacaat gttccagaag 800 ggggaagtgc ataacaaacc atcaggtttc tggggaatga taaaaagtgt 850 taccacttca gcatcaggaa gtgaaaatct tactcttatt caacaggaag 900 tggatgcttt ggaagaatta agcaggcagc tttttctgga aacagctgat 950 ctatatgcta ccaaggagag aatagaatac tccaaaacct tcaaggggaa 1000 atattttaat tttcttggtt actttttctc tatttactgt gtttggaaaa 1050 ttttcatggc taccatcaat attgtttttg atcgagttgg gaaaacggat 1100 cctgtcacaa gaggcattga gatcactgtg aattatctgg gaatccaatt 1150 tgatgtgaag ttttggtccc aacacatttc cttcattctt gttggaataa 1200 tcatcgtcac atccatcaga ggattgctga tcactcttac caagttcttt 1250 tatgccatct ctagcagtaa gtcctccaat gtcattgtcc tgctattagc 1300 acagataatg ggcatgtact ttgtctcctc tgtgctgctg atccgaatga 1350 gtatgccttt agaataccgc accataatca ctgaagtcct tggagaactg 1400 cagttcaact tctatcaccg ttggtttgat gtgatcttcc tggtcagcgc 1450 tctctctagc atactcttcc tctatttggc tcacaaacag gcaccagaga 1500 agcaaatggc accttgaact taagcctact acagactgtt agaggccagt 1550 ggtttcaaaa tttagatata agagggggga aaaatggaac cagggcctga 1600 cattttataa acaaacaaaa tgctatggta gcatttttca ccttcatagc 1650 atactccttc cccgtcaggt gatactatga ccatgagtag catcagccag 1700 aacatgagag ggagaactaa ctcaagacaa tactcagcag agagcatccc 1750 gtgtggatat gaggctggtg tagaggcgga gaggagccaa gaaactaaag 1800 gtgaaaaata cactggaact ctggggcaag acatgtctat ggtagctgag 1850 ccaaacacgt aggatttccg ttttaaggtt cacatggaaa aggttatagc 1900 tttgccttga gattgactca ttaaaatcag agactgtaac aaaaaaaaaa 1950 aaaaaaaaaa agggcggccg cgactctaga gtcgacctgc agaagcttgg 2000 ccgccatggc ccaacttgtt tattgcagct tataatg 2037 4 455 PRT Homo Sapien 4 Met Ser Phe Leu Ile Asp Ser Ser Ile Met Ile Thr Ser Gln Ile 1 5 10 15 Leu Phe Phe Gly Phe Gly Trp Leu Phe Phe Met Arg Gln Leu Phe 20 25 30 Lys Asp Tyr Glu Ile Arg Gln Tyr Val Val Gln Val Ile Phe Ser 35 40 45 Val Thr Phe Ala Phe Ser Cys Thr Met Phe Glu Leu Ile Ile Phe 50 55 60 Glu Ile Leu Gly Val Leu Asn Ser Ser Ser Arg Tyr Phe His Trp 65 70 75 Lys Met Asn Leu Cys Val Ile Leu Leu Ile Leu Val Phe Met Val 80 85 90 Pro Phe Tyr Ile Gly Tyr Phe Ile Val Ser Asn Ile Arg Leu Leu 95 100 105 His Lys Gln Arg Leu Leu Phe Ser Cys Leu Leu Trp Leu Thr Phe 110 115 120 Met Tyr Phe Phe Trp Lys Leu Gly Asp Pro Phe Pro Ile Leu Ser 125 130 135 Pro Lys His Gly Ile Leu Ser Ile Glu Gln Leu Ile Ser Arg Val 140 145 150 Gly Val Ile Gly Val Thr Leu Met Ala Leu Leu Ser Gly Phe Gly 155 160 165 Ala Val Asn Cys Pro Tyr Thr Tyr Met Ser Tyr Phe Leu Arg Asn 170 175 180 Val Thr Asp Thr Asp Ile Leu Ala Leu Glu Arg Arg Leu Leu Gln 185 190 195 Thr Met Asp Met Ile Ile Ser Lys Lys Lys Arg Met Ala Met Ala 200 205 210 Arg Arg Thr Met Phe Gln Lys Gly Glu Val His Asn Lys Pro Ser 215 220 225 Gly Phe Trp Gly Met Ile Lys Ser Val Thr Thr Ser Ala Ser Gly 230 235 240 Ser Glu Asn Leu Thr Leu Ile Gln Gln Glu Val Asp Ala Leu Glu 245 250 255 Glu Leu Ser Arg Gln Leu Phe Leu Glu Thr Ala Asp Leu Tyr Ala 260 265 270 Thr Lys Glu Arg Ile Glu Tyr Ser Lys Thr Phe Lys Gly Lys Tyr 275 280 285 Phe Asn Phe Leu Gly Tyr Phe Phe Ser Ile Tyr Cys Val Trp Lys 290 295 300 Ile Phe Met Ala Thr Ile Asn Ile Val Phe Asp Arg Val Gly Lys 305 310 315 Thr Asp Pro Val Thr Arg Gly Ile Glu Ile Thr Val Asn Tyr Leu 320 325 330 Gly Ile Gln Phe Asp Val Lys Phe Trp Ser Gln His Ile Ser Phe 335 340 345 Ile Leu Val Gly Ile Ile Ile Val Thr Ser Ile Arg Gly Leu Leu 350 355 360 Ile Thr Leu Thr Lys Phe Phe Tyr Ala Ile Ser Ser Ser Lys Ser 365 370 375 Ser Asn Val Ile Val Leu Leu Leu Ala Gln Ile Met Gly Met Tyr 380 385 390 Phe Val Ser Ser Val Leu Leu Ile Arg Met Ser Met Pro Leu Glu 395 400 405 Tyr Arg Thr Ile Ile Thr Glu Val Leu Gly Glu Leu Gln Phe Asn 410 415 420 Phe Tyr His Arg Trp Phe Asp Val Ile Phe Leu Val Ser Ala Leu 425 430 435 Ser Ser Ile Leu Phe Leu Tyr Leu Ala His Lys Gln Ala Pro Glu 440 445 450 Lys Gln Met Ala Pro 455 5 2372 DNA Homo Sapien 5 agcagggaaa tccggatgtc tcggttatga agtggagcag tgagtgtgag 50 cctcaacata gttccagaac tctccatccg gactagttat tgagcatctg 100 cctctcatat caccagtggc catctgaggt gtttccctgg ctctgaaggg 150 gtaggcacga tggccaggtg cttcagcctg gtgttgcttc tcacttccat 200 ctggaccacg aggctcctgg tccaaggctc tttgcgtgca gaagagcttt 250 ccatccaggt gtcatgcaga attatgggga tcacccttgt gagcaaaaag 300 gcgaaccagc agctgaattt cacagaagct aaggaggcct gtaggctgct 350 gggactaagt ttggccggca aggaccaagt tgaaacagcc ttgaaagcta 400 gctttgaaac ttgcagctat ggctgggttg gagatggatt cgtggtcatc 450 tctaggatta gcccaaaccc caagtgtggg aaaaatgggg tgggtgtcct 500 gatttggaag gttccagtga gccgacagtt tgcagcctat tgttacaact 550 catctgatac ttggactaac tcgtgcattc cagaaattat caccaccaaa 600 gatcccatat tcaacactca aactgcaaca caaacaacag aatttattgt 650 cagtgacagt acctactcgg tggcatcccc ttactctaca atacctgccc 700 ctactactac tcctcctgct ccagcttcca cttctattcc acggagaaaa 750 aaattgattt gtgtcacaga agtttttatg gaaactagca ccatgtctac 800 agaaactgaa ccatttgttg aaaataaagc agcattcaag aatgaagctg 850 ctgggtttgg aggtgtcccc acggctctgc tagtgcttgc tctcctcttc 900 tttggtgctg cagctggtct tggattttgc tatgtcaaaa ggtatgtgaa 950 ggccttccct tttacaaaca agaatcagca gaaggaaatg atcgaaacca 1000 aagtagtaaa ggaggagaag gccaatgata gcaaccctaa tgaggaatca 1050 aagaaaactg ataaaaaccc agaagagtcc aagagtccaa gcaaaactac 1100 cgtgcgatgc ctggaagctg aagtttagat gagacagaaa tgaggagaca 1150 cacctgaggc tggtttcttt catgctcctt accctgcccc agctggggaa 1200 atcaaaaggg ccaaagaacc aaagaagaaa gtccaccctt ggttcctaac 1250 tggaatcagc tcaggactgc cattggacta tggagtgcac caaagagaat 1300 gcccttctcc ttattgtaac cctgtctgga tcctatcctc ctacctccaa 1350 agcttcccac ggcctttcta gcctggctat gtcctaataa tatcccactg 1400 ggagaaagga gttttgcaaa gtgcaaggac ctaaaacatc tcatcagtat 1450 ccagtggtaa aaaggcctcc tggctgtctg aggctaggtg ggttgaaagc 1500 caaggagtca ctgagaccaa ggctttctct actgattccg cagctcagac 1550 cctttcttca gctctgaaag agaaacacgt atcccacctg acatgtcctt 1600 ctgagcccgg taagagcaaa agaatggcag aaaagtttag cccctgaaag 1650 ccatggagat tctcataact tgagacctaa tctctgtaaa gctaaaataa 1700 agaaatagaa caaggctgag gatacgacag tacactgtca gcagggactg 1750 taaacacaga cagggtcaaa gtgttttctc tgaacacatt gagttggaat 1800 cactgtttag aacacacaca cttacttttt ctggtctcta ccactgctga 1850 tattttctct aggaaatata cttttacaag taacaaaaat aaaaactctt 1900 ataaatttct atttttatct gagttacaga aatgattact aaggaagatt 1950 actcagtaat ttgtttaaaa agtaataaaa ttcaacaaac atttgctgaa 2000 tagctactat atgtcaagtg ctgtgcaagg tattacactc tgtaattgaa 2050 tattattcct caaaaaattg cacatagtag aacgctatct gggaagctat 2100 ttttttcagt tttgatattt ctagcttatc tacttccaaa ctaattttta 2150 tttttgctga gactaatctt attcattttc tctaatatgg caaccattat 2200 aaccttaatt tattattaac atacctaaga agtacattgt tacctctata 2250 taccaaagca cattttaaaa gtgccattaa caaatgtatc actagccctc 2300 ctttttccaa caagaaggga ctgagagatg cagaaatatt tgtgacaaaa 2350 aattaaagca tttagaaaac tt 2372 6 322 PRT Homo Sapien 6 Met Ala Arg Cys Phe Ser Leu Val Leu Leu Leu Thr Ser Ile Trp 1 5 10 15 Thr Thr Arg Leu Leu Val Gln Gly Ser Leu Arg Ala Glu Glu Leu 20 25 30 Ser Ile Gln Val Ser Cys Arg Ile Met Gly Ile Thr Leu Val Ser 35 40 45 Lys Lys Ala Asn Gln Gln Leu Asn Phe Thr Glu Ala Lys Glu Ala 50 55 60 Cys Arg Leu Leu Gly Leu Ser Leu Ala Gly Lys Asp Gln Val Glu 65 70 75 Thr Ala Leu Lys Ala Ser Phe Glu Thr Cys Ser Tyr Gly Trp Val 80 85 90 Gly Asp Gly Phe Val Val Ile Ser Arg Ile Ser Pro Asn Pro Lys 95 100 105 Cys Gly Lys Asn Gly Val Gly Val Leu Ile Trp Lys Val Pro Val 110 115 120 Ser Arg Gln Phe Ala Ala Tyr Cys Tyr Asn Ser Ser Asp Thr Trp 125 130 135 Thr Asn Ser Cys Ile Pro Glu Ile Ile Thr Thr Lys Asp Pro Ile 140 145 150 Phe Asn Thr Gln Thr Ala Thr Gln Thr Thr Glu Phe Ile Val Ser 155 160 165 Asp Ser Thr Tyr Ser Val Ala Ser Pro Tyr Ser Thr Ile Pro Ala 170 175 180 Pro Thr Thr Thr Pro Pro Ala Pro Ala Ser Thr Ser Ile Pro Arg 185 190 195 Arg Lys Lys Leu Ile Cys Val Thr Glu Val Phe Met Glu Thr Ser 200 205 210 Thr Met Ser Thr Glu Thr Glu Pro Phe Val Glu Asn Lys Ala Ala 215 220 225 Phe Lys Asn Glu Ala Ala Gly Phe Gly Gly Val Pro Thr Ala Leu 230 235 240 Leu Val Leu Ala Leu Leu Phe Phe Gly Ala Ala Ala Gly Leu Gly 245 250 255 Phe Cys Tyr Val Lys Arg Tyr Val Lys Ala Phe Pro Phe Thr Asn 260 265 270 Lys Asn Gln Gln Lys Glu Met Ile Glu Thr Lys Val Val Lys Glu 275 280 285 Glu Lys Ala Asn Asp Ser Asn Pro Asn Glu Glu Ser Lys Lys Thr 290 295 300 Asp Lys Asn Pro Glu Glu Ser Lys Ser Pro Ser Lys Thr Thr Val 305 310 315 Arg Cys Leu Glu Ala Glu Val 320 7 2586 DNA Homo Sapien 7 cgccgcgctc ccgcacccgc ggcccgccca ccgcgccgct cccgcatctg 50 cacccgcagc ccggcggcct cccggcggga gcgagcagat ccagtccggc 100 ccgcagcgca actcggtcca gtcggggcgg cggctgcggg cgcagagcgg 150 agatgcagcg gcttggggcc accctgctgt gcctgctgct ggcggcggcg 200 gtccccacgg cccccgcgcc cgctccgacg gcgacctcgg ctccagtcaa 250 gcccggcccg gctctcagct acccgcagga ggaggccacc ctcaatgaga 300 tgttccgcga ggttgaggaa ctgatggagg acacgcagca caaattgcgc 350 agcgcggtgg aagagatgga ggcagaagaa gctgctgcta aagcatcatc 400 agaagtgaac ctggcaaact tacctcccag ctatcacaat gagaccaaca 450 cagacacgaa ggttggaaat aataccatcc atgtgcaccg agaaattcac 500 aagataacca acaaccagac tggacaaatg gtcttttcag agacagttat 550 cacatctgtg ggagacgaag aaggcagaag gagccacgag tgcatcatcg 600 acgaggactg tgggcccagc atgtactgcc agtttgccag cttccagtac 650 acctgccagc catgccgggg ccagaggatg ctctgcaccc gggacagtga 700 gtgctgtgga gaccagctgt gtgtctgggg tcactgcacc aaaatggcca 750 ccaggggcag caatgggacc atctgtgaca accagaggga ctgccagccg 800 gggctgtgct gtgccttcca gagaggcctg ctgttccctg tgtgcacacc 850 cctgcccgtg gagggcgagc tttgccatga ccccgccagc cggcttctgg 900 acctcatcac ctgggagcta gagcctgatg gagccttgga ccgatgccct 950 tgtgccagtg gcctcctctg ccagccccac agccacagcc tggtgtatgt 1000 gtgcaagccg accttcgtgg ggagccgtga ccaagatggg gagatcctgc 1050 tgcccagaga ggtccccgat gagtatgaag ttggcagctt catggaggag 1100 gtgcgccagg agctggagga cctggagagg agcctgactg aagagatggc 1150 gctgggggag cctgcggctg ccgccgctgc actgctggga ggggaagaga 1200 tttagatctg gaccaggctg tgggtagatg tgcaatagaa atagctaatt 1250 tatttcccca ggtgtgtgct ttaggcgtgg gctgaccagg cttcttccta 1300 catcttcttc ccagtaagtt tcccctctgg cttgacagca tgaggtgttg 1350 tgcatttgtt cagctccccc aggctgttct ccaggcttca cagtctggtg 1400 cttgggagag tcaggcaggg ttaaactgca ggagcagttt gccacccctg 1450 tccagattat tggctgcttt gcctctacca gttggcagac agccgtttgt 1500 tctacatggc tttgataatt gtttgagggg aggagatgga aacaatgtgg 1550 agtctccctc tgattggttt tggggaaatg tggagaagag tgccctgctt 1600 tgcaaacatc aacctggcaa aaatgcaaca aatgaatttt ccacgcagtt 1650 ctttccatgg gcataggtaa gctgtgcctt cagctgttgc agatgaaatg 1700 ttctgttcac cctgcattac atgtgtttat tcatccagca gtgttgctca 1750 gctcctacct ctgtgccagg gcagcatttt catatccaag atcaattccc 1800 tctctcagca cagcctgggg agggggtcat tgttctcctc gtccatcagg 1850 gatctcagag gctcagagac tgcaagctgc ttgcccaagt cacacagcta 1900 gtgaagacca gagcagtttc atctggttgt gactctaagc tcagtgctct 1950 ctccactacc ccacaccagc cttggtgcca ccaaaagtgc tccccaaaag 2000 gaaggagaat gggatttttc ttgaggcatg cacatctgga attaaggtca 2050 aactaattct cacatccctc taaaagtaaa ctactgttag gaacagcagt 2100 gttctcacag tgtggggcag ccgtccttct aatgaagaca atgatattga 2150 cactgtccct ctttggcagt tgcattagta actttgaaag gtatatgact 2200 gagcgtagca tacaggttaa cctgcagaaa cagtacttag gtaattgtag 2250 ggcgaggatt ataaatgaaa tttgcaaaat cacttagcag caactgaaga 2300 caattatcaa ccacgtggag aaaatcaaac cgagcagggc tgtgtgaaac 2350 atggttgtaa tatgcgactg cgaacactga actctacgcc actccacaaa 2400 tgatgttttc aggtgtcatg gactgttgcc accatgtatt catccagagt 2450 tcttaaagtt taaagttgca catgattgta taagcatgct ttctttgagt 2500 tttaaattat gtataaacat aagttgcatt tagaaatcaa gcataaatca 2550 cttcaactgc aaaaaaaaaa aaaaaaaaaa aaaaaa 2586 8 350 PRT Homo Sapien 8 Met Gln Arg Leu Gly Ala Thr Leu Leu Cys Leu Leu Leu Ala Ala 1 5 10 15 Ala Val Pro Thr Ala Pro Ala Pro Ala Pro Thr Ala Thr Ser Ala 20 25 30 Pro Val Lys Pro Gly Pro Ala Leu Ser Tyr Pro Gln Glu Glu Ala 35 40 45 Thr Leu Asn Glu Met Phe Arg Glu Val Glu Glu Leu Met Glu Asp 50 55 60 Thr Gln His Lys Leu Arg Ser Ala Val Glu Glu Met Glu Ala Glu 65 70 75 Glu Ala Ala Ala Lys Ala Ser Ser Glu Val Asn Leu Ala Asn Leu 80 85 90 Pro Pro Ser Tyr His Asn Glu Thr Asn Thr Asp Thr Lys Val Gly 95 100 105 Asn Asn Thr Ile His Val His Arg Glu Ile His Lys Ile Thr Asn 110 115 120 Asn Gln Thr Gly Gln Met Val Phe Ser Glu Thr Val Ile Thr Ser 125 130 135 Val Gly Asp Glu Glu Gly Arg Arg Ser His Glu Cys Ile Ile Asp 140 145 150 Glu Asp Cys Gly Pro Ser Met Tyr Cys Gln Phe Ala Ser Phe Gln 155 160 165 Tyr Thr Cys Gln Pro Cys Arg Gly Gln Arg Met Leu Cys Thr Arg 170 175 180 Asp Ser Glu Cys Cys Gly Asp Gln Leu Cys Val Trp Gly His Cys 185 190 195 Thr Lys Met Ala Thr Arg Gly Ser Asn Gly Thr Ile Cys Asp Asn 200 205 210 Gln Arg Asp Cys Gln Pro Gly Leu Cys Cys Ala Phe Gln Arg Gly 215 220 225 Leu Leu Phe Pro Val Cys Thr Pro Leu Pro Val Glu Gly Glu Leu 230 235 240 Cys His Asp Pro Ala Ser Arg Leu Leu Asp Leu Ile Thr Trp Glu 245 250 255 Leu Glu Pro Asp Gly Ala Leu Asp Arg Cys Pro Cys Ala Ser Gly 260 265 270 Leu Leu Cys Gln Pro His Ser His Ser Leu Val Tyr Val Cys Lys 275 280 285 Pro Thr Phe Val Gly Ser Arg Asp Gln Asp Gly Glu Ile Leu Leu 290 295 300 Pro Arg Glu Val Pro Asp Glu Tyr Glu Val Gly Ser Phe Met Glu 305 310 315 Glu Val Arg Gln Glu Leu Glu Asp Leu Glu Arg Ser Leu Thr Glu 320 325 330 Glu Met Ala Leu Gly Glu Pro Ala Ala Ala Ala Ala Ala Leu Leu 335 340 345 Gly Gly Glu Glu Ile 350 9 1395 DNA Homo Sapien 9 cggacgcgtg ggcggacgcg tgggggctgt gagaaagtgc caataaatac 50 atcatgcaac cccacggccc accttgtgaa ctcctcgtgc ccagggctga 100 tgtgcgtctt ccagggctac tcatccaaag gcctaatcca acgttctgtc 150 ttcaatctgc aaatctatgg ggtcctgggg ctcttctgga cccttaactg 200 ggtactggcc ctgggccaat gcgtcctcgc tggagccttt gcctccttct 250 actgggcctt ccacaagccc caggacatcc ctaccttccc cttaatctct 300 gccttcatcc gcacactccg ttaccacact gggtcattgg catttggagc 350 cctcatcctg acccttgtgc agatagcccg ggtcatcttg gagtatattg 400 accacaagct cagaggagtg cagaaccctg tagcccgctg catcatgtgc 450 tgtttcaagt gctgcctctg gtgtctggaa aaatttatca agttcctaaa 500 ccgcaatgca tacatcatga tcgccatcta cgggaagaat ttctgtgtct 550 cagccaaaaa tgcgttcatg ctactcatgc gaaacattgt cagggtggtc 600 gtcctggaca aagtcacaga cctgctgctg ttctttggga agctgctggt 650 ggtcggaggc gtgggggtcc tgtccttctt ttttttctcc ggtcgcatcc 700 cggggctggg taaagacttt aagagccccc acctcaacta ttactggctg 750 cccatcatga cctccatcct gggggcctat gtcatcgcca gcggcttctt 800 cagcgttttc ggcatgtgtg tggacacgct cttcctctgc ttcctggaag 850 acctggagcg gaacaacggc tccctggacc ggccctacta catgtccaag 900 agccttctaa agattctggg caagaagaac gaggcgcccc cggacaacaa 950 gaagaggaag aagtgacagc tccggccctg atccaggact gcaccccacc 1000 cccaccgtcc agccatccaa cctcacttcg ccttacaggt ctccattttg 1050 tggtaaaaaa aggttttagg ccaggcgccg tggctcacgc ctgtaatcca 1100 acactttgag aggctgaggc gggcggatca cctgagtcag gagttcgaga 1150 ccagcctggc caacatggtg aaacctccgt ctctattaaa aatacaaaaa 1200 ttagccgaga gtggtggcat gcacctgtca tcccagctac tcgggaggct 1250 gaggcaggag aatcgcttga acccgggagg cagaggttgc agtgagccga 1300 gatcgcgcca ctgcactcca acctgggtga cagactctgt ctccaaaaca 1350 aaacaaacaa acaaaaagat tttattaaag atattttgtt aactc 1395 10 321 PRT Homo Sapien 10 Arg Thr Arg Gly Arg Thr Arg Gly Gly Cys Glu Lys Val Pro Ile 1 5 10 15 Asn Thr Ser Cys Asn Pro Thr Ala His Leu Val Asn Ser Ser Cys 20 25 30 Pro Gly Leu Met Cys Val Phe Gln Gly Tyr Ser Ser Lys Gly Leu 35 40 45 Ile Gln Arg Ser Val Phe Asn Leu Gln Ile Tyr Gly Val Leu Gly 50 55 60 Leu Phe Trp Thr Leu Asn Trp Val Leu Ala Leu Gly Gln Cys Val 65 70 75 Leu Ala Gly Ala Phe Ala Ser Phe Tyr Trp Ala Phe His Lys Pro 80 85 90 Gln Asp Ile Pro Thr Phe Pro Leu Ile Ser Ala Phe Ile Arg Thr 95 100 105 Leu Arg Tyr His Thr Gly Ser Leu Ala Phe Gly Ala Leu Ile Leu 110 115 120 Thr Leu Val Gln Ile Ala Arg Val Ile Leu Glu Tyr Ile Asp His 125 130 135 Lys Leu Arg Gly Val Gln Asn Pro Val Ala Arg Cys Ile Met Cys 140 145 150 Cys Phe Lys Cys Cys Leu Trp Cys Leu Glu Lys Phe Ile Lys Phe 155 160 165 Leu Asn Arg Asn Ala Tyr Ile Met Ile Ala Ile Tyr Gly Lys Asn 170 175 180 Phe Cys Val Ser Ala Lys Asn Ala Phe Met Leu Leu Met Arg Asn 185 190 195 Ile Val Arg Val Val Val Leu Asp Lys Val Thr Asp Leu Leu Leu 200 205 210 Phe Phe Gly Lys Leu Leu Val Val Gly Gly Val Gly Val Leu Ser 215 220 225 Phe Phe Phe Phe Ser Gly Arg Ile Pro Gly Leu Gly Lys Asp Phe 230 235 240 Lys Ser Pro His Leu Asn Tyr Tyr Trp Leu Pro Ile Met Thr Ser 245 250 255 Ile Leu Gly Ala Tyr Val Ile Ala Ser Gly Phe Phe Ser Val Phe 260 265 270 Gly Met Cys Val Asp Thr Leu Phe Leu Cys Phe Leu Glu Asp Leu 275 280 285 Glu Arg Asn Asn Gly Ser Leu Asp Arg Pro Tyr Tyr Met Ser Lys 290 295 300 Ser Leu Leu Lys Ile Leu Gly Lys Lys Asn Glu Ala Pro Pro Asp 305 310 315 Asn Lys Lys Arg Lys Lys 320 11 1901 DNA Homo Sapien 11 gccccgcgcc cggcgccggg cgcccgaagc cgggagccac cgccatgggg 50 gcctgcctgg gagcctgctc cctgctcagc tgcgcgtcct gcctctgcgg 100 ctctgccccc tgcatcctgt gcagctgctg ccccgccagc cgcaactcca 150 ccgtgagccg cctcatcttc acgttcttcc tcttcctggg ggtgctggtg 200 tccatcatta tgctgagccc gggcgtggag agtcagctct acaagctgcc 250 ctgggtgtgt gaggaggggg ccgggatccc caccgtcctg cagggccaca 300 tcgactgtgg ctccctgctt ggctaccgcg ctgtctaccg catgtgcttc 350 gccacggcgg ccttcttctt cttctttttc accctgctca tgctctgcgt 400 gagcagcagc cgggaccccc gggctgccat ccagaatggg ttttggttct 450 ttaagttcct gatcctggtg ggcctcaccg tgggtgcctt ctacatccct 500 gacggctcct tcaccaacat ctggttctac ttcggcgtcg tgggctcctt 550 cctcttcatc ctcatccagc tggtgctgct catcgacttt gcgcactcct 600 ggaaccagcg gtggctgggc aaggccgagg agtgcgattc ccgtgcctgg 650 tacgcaggcc tcttcttctt cactctcctc ttctacttgc tgtcgatcgc 700 ggccgtggcg ctgatgttca tgtactacac tgagcccagc ggctgccacg 750 agggcaaggt cttcatcagc ctcaacctca ccttctgtgt ctgcgtgtcc 800 atcgctgctg tcctgcccaa ggtccaggac gcccagccca actcgggtct 850 gctgcaggcc tcggtcatca ccctctacac catgtttgtc acctggtcag 900 ccctatccag tatccctgaa cagaaatgca acccccattt gccaacccag 950 ctgggcaacg agacagttgt ggcaggcccc gagggctatg agacccagtg 1000 gtgggatgcc ccgagcattg tgggcctcat catcttcctc ctgtgcaccc 1050 tcttcatcag tctgcgctcc tcagaccacc ggcaggtgaa cagcctgatg 1100 cagaccgagg agtgcccacc tatgctagac gccacacagc agcagcagca 1150 gcaggtggca gcctgtgagg gccgggcctt tgacaacgag caggacggcg 1200 tcacctacag ctactccttc ttccacttct gcctggtgct ggcctcactg 1250 cacgtcatga tgacgctcac caactggtac aagcccggtg agacccggaa 1300 gatgatcagc acgtggaccg ccgtgtgggt gaagatctgt gccagctggg 1350 cagggctgct cctctacctg tggaccctgg tagccccact cctcctgcgc 1400 aaccgcgact tcagctgagg cagcctcaca gcctgccatc tggtgcctcc 1450 tgccacctgg tgcctctcgg ctcggtgaca gccaacctgc cccctcccca 1500 caccaatcag ccaggctgag cccccacccc tgccccagct ccaggacctg 1550 cccctgagcc gggccttcta gtcgtagtgc cttcagggtc cgaggagcat 1600 caggctcctg cagagcccca tccccccgcc acacccacac ggtggagctg 1650 cctcttcctt cccctcctcc ctgttgccca tactcagcat ctcggatgaa 1700 agggctccct tgtcctcagg ctccacggga gcggggctgc tggagagagc 1750 ggggaactcc caccacagtg gggcatccgg cactgaagcc ctggtgttcc 1800 tggtcacgtc ccccagggga ccctgccccc ttcctggact tcgtgcctta 1850 ctgagtctct aagacttttt ctaataaaca agccagtgcg tgtaaaaaaa 1900 a 1901 12 457 PRT Homo Sapien 12 Met Gly Ala Cys Leu Gly Ala Cys Ser Leu Leu Ser Cys Ala Ser 1 5 10 15 Cys Leu Cys Gly Ser Ala Pro Cys Ile Leu Cys Ser Cys Cys Pro 20 25 30 Ala Ser Arg Asn Ser Thr Val Ser Arg Leu Ile Phe Thr Phe Phe 35 40 45 Leu Phe Leu Gly Val Leu Val Ser Ile Ile Met Leu Ser Pro Gly 50 55 60 Val Glu Ser Gln Leu Tyr Lys Leu Pro Trp Val Cys Glu Glu Gly 65 70 75 Ala Gly Ile Pro Thr Val Leu Gln Gly His Ile Asp Cys Gly Ser 80 85 90 Leu Leu Gly Tyr Arg Ala Val Tyr Arg Met Cys Phe Ala Thr Ala 95 100 105 Ala Phe Phe Phe Phe Phe Phe Thr Leu Leu Met Leu Cys Val Ser 110 115 120 Ser Ser Arg Asp Pro Arg Ala Ala Ile Gln Asn Gly Phe Trp Phe 125 130 135 Phe Lys Phe Leu Ile Leu Val Gly Leu Thr Val Gly Ala Phe Tyr 140 145 150 Ile Pro Asp Gly Ser Phe Thr Asn Ile Trp Phe Tyr Phe Gly Val 155 160 165 Val Gly Ser Phe Leu Phe Ile Leu Ile Gln Leu Val Leu Leu Ile 170 175 180 Asp Phe Ala His Ser Trp Asn Gln Arg Trp Leu Gly Lys Ala Glu 185 190 195 Glu Cys Asp Ser Arg Ala Trp Tyr Ala Gly Leu Phe Phe Phe Thr 200 205 210 Leu Leu Phe Tyr Leu Leu Ser Ile Ala Ala Val Ala Leu Met Phe 215 220 225 Met Tyr Tyr Thr Glu Pro Ser Gly Cys His Glu Gly Lys Val Phe 230 235 240 Ile Ser Leu Asn Leu Thr Phe Cys Val Cys Val Ser Ile Ala Ala 245 250 255 Val Leu Pro Lys Val Gln Asp Ala Gln Pro Asn Ser Gly Leu Leu 260 265 270 Gln Ala Ser Val Ile Thr Leu Tyr Thr Met Phe Val Thr Trp Ser 275 280 285 Ala Leu Ser Ser Ile Pro Glu Gln Lys Cys Asn Pro His Leu Pro 290 295 300 Thr Gln Leu Gly Asn Glu Thr Val Val Ala Gly Pro Glu Gly Tyr 305 310 315 Glu Thr Gln Trp Trp Asp Ala Pro Ser Ile Val Gly Leu Ile Ile 320 325 330 Phe Leu Leu Cys Thr Leu Phe Ile Ser Leu Arg Ser Ser Asp His 335 340 345 Arg Gln Val Asn Ser Leu Met Gln Thr Glu Glu Cys Pro Pro Met 350 355 360 Leu Asp Ala Thr Gln Gln Gln Gln Gln Gln Val Ala Ala Cys Glu 365 370 375 Gly Arg Ala Phe Asp Asn Glu Gln Asp Gly Val Thr Tyr Ser Tyr 380 385 390 Ser Phe Phe His Phe Cys Leu Val Leu Ala Ser Leu His Val Met 395 400 405 Met Thr Leu Thr Asn Trp Tyr Lys Pro Gly Glu Thr Arg Lys Met 410 415 420 Ile Ser Thr Trp Thr Ala Val Trp Val Lys Ile Cys Ala Ser Trp 425 430 435 Ala Gly Leu Leu Leu Tyr Leu Trp Thr Leu Val Ala Pro Leu Leu 440 445 450 Leu Arg Asn Arg Asp Phe Ser 455 13 1572 DNA Homo Sapien 13 cgggccagcc tggggcggcc ggccaggaac cacccgttaa ggtgtcttct 50 ctttagggat ggtgaggttg gaaaaagact cctgtaaccc tcctccagga 100 tgaaccacct gccagaagac atggagaacg ctctcaccgg gagccagagc 150 tcccatgctt ctctgcgcaa tatccattcc atcaacccca cacaactcat 200 ggccaggatt gagtcctatg aaggaaggga aaagaaaggc atatctgatg 250 tcaggaggac tttctgtttg tttgtcacct ttgacctctt attcgtaaca 300 ttactgtgga taatagagtt aaatgtgaat ggaggcattg agaacacatt 350 agagaaggag gtgatgcagt atgactacta ttcttcatat tttgatatat 400 ttcttctggc agtttttcga tttaaagtgt taatacttgc atatgctgtg 450 tgcagactgc gccattggtg ggcaatagcg ttgacaacgg cagtgaccag 500 tgccttttta ctagcaaaag tgatcctttc gaagcttttc tctcaagggg 550 cttttggcta tgtgctgccc atcatttcat tcatccttgc ctggattgag 600 acgtggttcc tggatttcaa agtgttacct caagaagcag aagaagaaaa 650 cagactcctg atagttcagg atgcttcaga gagggcagca cttatacctg 700 gtggtctttc tgatggtcag ttttattccc ctcctgaatc cgaagcagga 750 tctgaagaag ctgaagaaaa acaggacagt gagaaaccac ttttagaact 800 atgagtacta cttttgttaa atgtgaaaaa ccctcacaga aagtcatcga 850 ggcaaaaaga ggcaggcagt ggagtctccc tgtcgacagt aaagttgaaa 900 tggtgacgtc cactgctggc tttattgaac agctaataaa gatttattta 950 ttgtaatacc tcacaaacgt tgtaccatat ccatgcacat ttagttgcct 1000 gcctgtggct ggtaaggtaa tgtcatgatt catcctctct tcagtgagac 1050 tgagcctgat gtgttaacaa ataggtgaag aaagtcttgt gctgtattcc 1100 taatcaaaag acttaatata ttgaagtaac acttttttag taagcaagat 1150 acctttttat ttcaattcac agaatggaat ttttttgttt catgtctcag 1200 atttattttg tatttctttt ttaacactct acatttccct tgttttttaa 1250 ctcatgcaca tgtgctcttt gtacagtttt aaaaagtgta ataaaatctg 1300 acatgtcaat gtggctagtt ttatttttct tgttttgcat tatgtgtatg 1350 gcctgaagtg ttggacttgc aaaaggggaa gaaaggaatt gcgaatacat 1400 gtaaaatgtc accagacatt tgtattattt ttatcatgaa atcatgtttt 1450 tctctgattg ttctgaaatg ttctaaatac tcttattttg aatgcacaaa 1500 atgacttaaa ccattcatat catgtttcct ttgcgttcag ccaatttcaa 1550 ttaaaatgaa ctaaattaaa aa 1572 14 234 PRT Homo Sapien 14 Met Asn His Leu Pro Glu Asp Met Glu Asn Ala Leu Thr Gly Ser 1 5 10 15 Gln Ser Ser His Ala Ser Leu Arg Asn Ile His Ser Ile Asn Pro 20 25 30 Thr Gln Leu Met Ala Arg Ile Glu Ser Tyr Glu Gly Arg Glu Lys 35 40 45 Lys Gly Ile Ser Asp Val Arg Arg Thr Phe Cys Leu Phe Val Thr 50 55 60 Phe Asp Leu Leu Phe Val Thr Leu Leu Trp Ile Ile Glu Leu Asn 65 70 75 Val Asn Gly Gly Ile Glu Asn Thr Leu Glu Lys Glu Val Met Gln 80 85 90 Tyr Asp Tyr Tyr Ser Ser Tyr Phe Asp Ile Phe Leu Leu Ala Val 95 100 105 Phe Arg Phe Lys Val Leu Ile Leu Ala Tyr Ala Val Cys Arg Leu 110 115 120 Arg His Trp Trp Ala Ile Ala Leu Thr Thr Ala Val Thr Ser Ala 125 130 135 Phe Leu Leu Ala Lys Val Ile Leu Ser Lys Leu Phe Ser Gln Gly 140 145 150 Ala Phe Gly Tyr Val Leu Pro Ile Ile Ser Phe Ile Leu Ala Trp 155 160 165 Ile Glu Thr Trp Phe Leu Asp Phe Lys Val Leu Pro Gln Glu Ala 170 175 180 Glu Glu Glu Asn Arg Leu Leu Ile Val Gln Asp Ala Ser Glu Arg 185 190 195 Ala Ala Leu Ile Pro Gly Gly Leu Ser Asp Gly Gln Phe Tyr Ser 200 205 210 Pro Pro Glu Ser Glu Ala Gly Ser Glu Glu Ala Glu Glu Lys Gln 215 220 225 Asp Ser Glu Lys Pro Leu Leu Glu Leu 230 15 2768 DNA Homo Sapien 15 actcgaacgc agttgcttcg ggacccagga ccccctcggg cccgacccgc 50 caggaaagac tgaggccgcg gcctgccccg cccggctccc tgcgccgccg 100 ccgcctcccg ggacagaaga tgtgctccag ggtccctctg ctgctgccgc 150 tgctcctgct actggccctg gggcctgggg tgcagggctg cccatccggc 200 tgccagtgca gccagccaca gacagtcttc tgcactgccc gccaggggac 250 cacggtgccc cgagacgtgc cacccgacac ggtggggctg tacgtctttg 300 agaacggcat caccatgctc gacgcaggca gctttgccgg cctgccgggc 350 ctgcagctcc tggacctgtc acagaaccag atcgccagcc tgcccagcgg 400 ggtcttccag ccactcgcca acctcagcaa cctggacctg acggccaaca 450 ggctgcatga aatcaccaat gagaccttcc gtggcctgcg gcgcctcgag 500 cgcctctacc tgggcaagaa ccgcatccgc cacatccagc ctggtgcctt 550 cgacacgctc gaccgcctcc tggagctcaa gctgcaggac aacgagctgc 600 gggcactgcc cccgctgcgc ctgccccgcc tgctgctgct ggacctcagc 650 cacaacagcc tcctggccct ggagcccggc atcctggaca ctgccaacgt 700 ggaggcgctg cggctggctg gtctggggct gcagcagctg gacgaggggc 750 tcttcagccg cttgcgcaac ctccacgacc tggatgtgtc cgacaaccag 800 ctggagcgag tgccacctgt gatccgaggc ctccggggcc tgacgcgcct 850 gcggctggcc ggcaacaccc gcattgccca gctgcggccc gaggacctgg 900 ccggcctggc tgccctgcag gagctggatg tgagcaacct aagcctgcag 950 gccctgcctg gcgacctctc gggcctcttc ccccgcctgc ggctgctggc 1000 agctgcccgc aaccccttca actgcgtgtg ccccctgagc tggtttggcc 1050 cctgggtgcg cgagagccac gtcacactgg ccagccctga ggagacgcgc 1100 tgccacttcc cgcccaagaa cgctggccgg ctgctcctgg agcttgacta 1150 cgccgacttt ggctgcccag ccaccaccac cacagccaca gtgcccacca 1200 cgaggcccgt ggtgcgggag cccacagcct tgtcttctag cttggctcct 1250 acctggctta gccccacagc gccggccact gaggccccca gcccgccctc 1300 cactgcccca ccgactgtag ggcctgtccc ccagccccag gactgcccac 1350 cgtccacctg cctcaatggg ggcacatgcc acctggggac acggcaccac 1400 ctggcgtgct tgtgccccga aggcttcacg ggcctgtact gtgagagcca 1450 gatggggcag gggacacggc ccagccctac accagtcacg ccgaggccac 1500 cacggtccct gaccctgggc atcgagccgg tgagccccac ctccctgcgc 1550 gtggggctgc agcgctacct ccaggggagc tccgtgcagc tcaggagcct 1600 ccgtctcacc tatcgcaacc tatcgggccc tgataagcgg ctggtgacgc 1650 tgcgactgcc tgcctcgctc gctgagtaca cggtcaccca gctgcggccc 1700 aacgccactt actccgtctg tgtcatgcct ttggggcccg ggcgggtgcc 1750 ggagggcgag gaggcctgcg gggaggccca tacaccccca gccgtccact 1800 ccaaccacgc cccagtcacc caggcccgcg agggcaacct gccgctcctc 1850 attgcgcccg ccctggccgc ggtgctcctg gccgcgctgg ctgcggtggg 1900 ggcagcctac tgtgtgcggc gggggcgggc catggcagca gcggctcagg 1950 acaaagggca ggtggggcca ggggctgggc ccctggaact ggagggagtg 2000 aaggtcccct tggagccagg cccgaaggca acagagggcg gtggagaggc 2050 cctgcccagc gggtctgagt gtgaggtgcc actcatgggc ttcccagggc 2100 ctggcctcca gtcacccctc cacgcaaagc cctacatcta agccagagag 2150 agacagggca gctggggccg ggctctcagc cagtgagatg gccagccccc 2200 tcctgctgcc acaccacgta agttctcagt cccaacctcg gggatgtgtg 2250 cagacagggc tgtgtgacca cagctgggcc ctgttccctc tggacctcgg 2300 tctcctcatc tgtgagatgc tgtggcccag ctgacgagcc ctaacgtccc 2350 cagaaccgag tgcctatgag gacagtgtcc gccctgccct ccgcaacgtg 2400 cagtccctgg gcacggcggg ccctgccatg tgctggtaac gcatgcctgg 2450 gtcctgctgg gctctcccac tccaggcgga ccctgggggc cagtgaagga 2500 agctcccgga aagagcagag ggagagcggg taggcggctg tgtgactcta 2550 gtcttggccc caggaagcga aggaacaaaa gaaactggaa aggaagatgc 2600 tttaggaaca tgttttgctt ttttaaaata tatatattta taagagatcc 2650 tttcccattt attctgggaa gatgtttttc aaactcagag acaaggactt 2700 tggtttttgt aagacaaacg atgatatgaa ggccttttgt aagaaaaaat 2750 aaaagatgaa gtgtgaaa 2768 16 673 PRT Homo Sapien 16 Met Cys Ser Arg Val Pro Leu Leu Leu Pro Leu Leu Leu Leu Leu 1 5 10 15 Ala Leu Gly Pro Gly Val Gln Gly Cys Pro Ser Gly Cys Gln Cys 20 25 30 Ser Gln Pro Gln Thr Val Phe Cys Thr Ala Arg Gln Gly Thr Thr 35 40 45 Val Pro Arg Asp Val Pro Pro Asp Thr Val Gly Leu Tyr Val Phe 50 55 60 Glu Asn Gly Ile Thr Met Leu Asp Ala Gly Ser Phe Ala Gly Leu 65 70 75 Pro Gly Leu Gln Leu Leu Asp Leu Ser Gln Asn Gln Ile Ala Ser 80 85 90 Leu Pro Ser Gly Val Phe Gln Pro Leu Ala Asn Leu Ser Asn Leu 95 100 105 Asp Leu Thr Ala Asn Arg Leu His Glu Ile Thr Asn Glu Thr Phe 110 115 120 Arg Gly Leu Arg Arg Leu Glu Arg Leu Tyr Leu Gly Lys Asn Arg 125 130 135 Ile Arg His Ile Gln Pro Gly Ala Phe Asp Thr Leu Asp Arg Leu 140 145 150 Leu Glu Leu Lys Leu Gln Asp Asn Glu Leu Arg Ala Leu Pro Pro 155 160 165 Leu Arg Leu Pro Arg Leu Leu Leu Leu Asp Leu Ser His Asn Ser 170 175 180 Leu Leu Ala Leu Glu Pro Gly Ile Leu Asp Thr Ala Asn Val Glu 185 190 195 Ala Leu Arg Leu Ala Gly Leu Gly Leu Gln Gln Leu Asp Glu Gly 200 205 210 Leu Phe Ser Arg Leu Arg Asn Leu His Asp Leu Asp Val Ser Asp 215 220 225 Asn Gln Leu Glu Arg Val Pro Pro Val Ile Arg Gly Leu Arg Gly 230 235 240 Leu Thr Arg Leu Arg Leu Ala Gly Asn Thr Arg Ile Ala Gln Leu 245 250 255 Arg Pro Glu Asp Leu Ala Gly Leu Ala Ala Leu Gln Glu Leu Asp 260 265 270 Val Ser Asn Leu Ser Leu Gln Ala Leu Pro Gly Asp Leu Ser Gly 275 280 285 Leu Phe Pro Arg Leu Arg Leu Leu Ala Ala Ala Arg Asn Pro Phe 290 295 300 Asn Cys Val Cys Pro Leu Ser Trp Phe Gly Pro Trp Val Arg Glu 305 310 315 Ser His Val Thr Leu Ala Ser Pro Glu Glu Thr Arg Cys His Phe 320 325 330 Pro Pro Lys Asn Ala Gly Arg Leu Leu Leu Glu Leu Asp Tyr Ala 335 340 345 Asp Phe Gly Cys Pro Ala Thr Thr Thr Thr Ala Thr Val Pro Thr 350 355 360 Thr Arg Pro Val Val Arg Glu Pro Thr Ala Leu Ser Ser Ser Leu 365 370 375 Ala Pro Thr Trp Leu Ser Pro Thr Ala Pro Ala Thr Glu Ala Pro 380 385 390 Ser Pro Pro Ser Thr Ala Pro Pro Thr Val Gly Pro Val Pro Gln 395 400 405 Pro Gln Asp Cys Pro Pro Ser Thr Cys Leu Asn Gly Gly Thr Cys 410 415 420 His Leu Gly Thr Arg His His Leu Ala Cys Leu Cys Pro Glu Gly 425 430 435 Phe Thr Gly Leu Tyr Cys Glu Ser Gln Met Gly Gln Gly Thr Arg 440 445 450 Pro Ser Pro Thr Pro Val Thr Pro Arg Pro Pro Arg Ser Leu Thr 455 460 465 Leu Gly Ile Glu Pro Val Ser Pro Thr Ser Leu Arg Val Gly Leu 470 475 480 Gln Arg Tyr Leu Gln Gly Ser Ser Val Gln Leu Arg Ser Leu Arg 485 490 495 Leu Thr Tyr Arg Asn Leu Ser Gly Pro Asp Lys Arg Leu Val Thr 500 505 510 Leu Arg Leu Pro Ala Ser Leu Ala Glu Tyr Thr Val Thr Gln Leu 515 520 525 Arg Pro Asn Ala Thr Tyr Ser Val Cys Val Met Pro Leu Gly Pro 530 535 540 Gly Arg Val Pro Glu Gly Glu Glu Ala Cys Gly Glu Ala His Thr 545 550 555 Pro Pro Ala Val His Ser Asn His Ala Pro Val Thr Gln Ala Arg 560 565 570 Glu Gly Asn Leu Pro Leu Leu Ile Ala Pro Ala Leu Ala Ala Val 575 580 585 Leu Leu Ala Ala Leu Ala Ala Val Gly Ala Ala Tyr Cys Val Arg 590 595 600 Arg Gly Arg Ala Met Ala Ala Ala Ala Gln Asp Lys Gly Gln Val 605 610 615 Gly Pro Gly Ala Gly Pro Leu Glu Leu Glu Gly Val Lys Val Pro 620 625 630 Leu Glu Pro Gly Pro Lys Ala Thr Glu Gly Gly Gly Glu Ala Leu 635 640 645 Pro Ser Gly Ser Glu Cys Glu Val Pro Leu Met Gly Phe Pro Gly 650 655 660 Pro Gly Leu Gln Ser Pro Leu His Ala Lys Pro Tyr Ile 665 670 17 1672 DNA Homo Sapien 17 gcagcggcga ggcggcggtg gtggctgagt ccgtggtggc agaggcgaag 50 gcgacagctc atgcgggtcc ggatagggct gacgctgctg ctgtgtgcgg 100 tgctgctgag cttggcctcg gcgtcctcgg atgaagaagg cagccaggat 150 gaatccttag attccaagac tactttgaca tcagatgagt cagtaaagga 200 ccatactact gcaggcagag tagttgctgg tcaaatattt cttgattcag 250 aagaatctga attagaatcc tctattcaag aagaggaaga cagcctcaag 300 agccaagagg gggaaagtgt cacagaagat atcagctttc tagagtctcc 350 aaatccagaa aacaaggact atgaagagcc aaagaaagta cggaaaccag 400 ctttgaccgc cattgaaggc acagcacatg gggagccctg ccacttccct 450 tttcttttcc tagataagga gtatgatgaa tgtacatcag atgggaggga 500 agatggcaga ctgtggtgtg ctacaaccta tgactacaaa gcagatgaaa 550 agtggggctt ttgtgaaact gaagaagagg ctgctaagag acggcagatg 600 caggaagcag aaatgatgta tcaaactgga atgaaaatcc ttaatggaag 650 caataagaaa agccaaaaaa gagaagcata tcggtatctc caaaaggcag 700 caagcatgaa ccataccaaa gccctggaga gagtgtcata tgctctttta 750 tttggtgatt acttgccaca gaatatccag gcagcgagag agatgtttga 800 gaagctgact gaggaaggct ctcccaaggg acagactgct cttggctttc 850 tgtatgcctc tggacttggt gttaattcaa gtcaggcaaa ggctcttgta 900 tattatacat ttggagctct tgggggcaat ctaatagccc acatggtttt 950 ggtaagtaga ctttagtgga aggctaataa tattaacatc agaagaattt 1000 gtggtttata gcggccacaa ctttttcagc tttcatgatc cagatttgct 1050 tgtattaaga ccaaatattc agttgaactt ccttcaaatt cttgttaatg 1100 gatataacac atggaatcta catgtaaatg aaagttggtg gagtccacaa 1150 tttttcttta aaatgattag tttggctgat tgcccctaaa aagagagatc 1200 tgataaatgg ctctttttaa attttctctg agttggaatt gtcagaatca 1250 ttttttacat tagattatca taattttaaa aatttttctt tagtttttca 1300 aaattttgta aatggtggct atagaaaaac aacatgaaat attatacaat 1350 attttgcaac aatgccctaa gaattgttaa aattcatgga gttatttgtg 1400 cagaatgact ccagagagct ctactttctg ttttttactt ttcatgattg 1450 gctgtcttcc catttattct ggtcatttat tgctagtgac actgtgcctg 1500 cttccagtag tctcattttc cctattttgc taatttgtta ctttttcttt 1550 gctaatttgg aagattaact catttttaat aaaattatgt ctaagattaa 1600 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1650 aaaaaaaaaa aaaaaaaaaa aa 1672 18 301 PRT Homo Sapien 18 Met Arg Val Arg Ile Gly Leu Thr Leu Leu Leu Cys Ala Val Leu 1 5 10 15 Leu Ser Leu Ala Ser Ala Ser Ser Asp Glu Glu Gly Ser Gln Asp 20 25 30 Glu Ser Leu Asp Ser Lys Thr Thr Leu Thr Ser Asp Glu Ser Val 35 40 45 Lys Asp His Thr Thr Ala Gly Arg Val Val Ala Gly Gln Ile Phe 50 55 60 Leu Asp Ser Glu Glu Ser Glu Leu Glu Ser Ser Ile Gln Glu Glu 65 70 75 Glu Asp Ser Leu Lys Ser Gln Glu Gly Glu Ser Val Thr Glu Asp 80 85 90 Ile Ser Phe Leu Glu Ser Pro Asn Pro Glu Asn Lys Asp Tyr Glu 95 100 105 Glu Pro Lys Lys Val Arg Lys Pro Ala Leu Thr Ala Ile Glu Gly 110 115 120 Thr Ala His Gly Glu Pro Cys His Phe Pro Phe Leu Phe Leu Asp 125 130 135 Lys Glu Tyr Asp Glu Cys Thr Ser Asp Gly Arg Glu Asp Gly Arg 140 145 150 Leu Trp Cys Ala Thr Thr Tyr Asp Tyr Lys Ala Asp Glu Lys Trp 155 160 165 Gly Phe Cys Glu Thr Glu Glu Glu Ala Ala Lys Arg Arg Gln Met 170 175 180 Gln Glu Ala Glu Met Met Tyr Gln Thr Gly Met Lys Ile Leu Asn 185 190 195 Gly Ser Asn Lys Lys Ser Gln Lys Arg Glu Ala Tyr Arg Tyr Leu 200 205 210 Gln Lys Ala Ala Ser Met Asn His Thr Lys Ala Leu Glu Arg Val 215 220 225 Ser Tyr Ala Leu Leu Phe Gly Asp Tyr Leu Pro Gln Asn Ile Gln 230 235 240 Ala Ala Arg Glu Met Phe Glu Lys Leu Thr Glu Glu Gly Ser Pro 245 250 255 Lys Gly Gln Thr Ala Leu Gly Phe Leu Tyr Ala Ser Gly Leu Gly 260 265 270 Val Asn Ser Ser Gln Ala Lys Ala Leu Val Tyr Tyr Thr Phe Gly 275 280 285 Ala Leu Gly Gly Asn Leu Ile Ala His Met Val Leu Val Ser Arg 290 295 300 Leu 19 1508 DNA Homo Sapien 19 aattcagatt ttaagcccat tctgcagtgg aatttcatga actagcaaga 50 ggacaccatc ttcttgtatt atacaagaaa ggagtgtacc tatcacacac 100 agggggaaaa atgctctttt gggtgctagg cctcctaatc ctctgtggtt 150 ttctgtggac tcgtaaagga aaactaaaga ttgaagacat cactgataag 200 tacattttta tcactggatg tgactcgggc tttggaaact tggcagccag 250 aacttttgat aaaaagggat ttcatgtaat cgctgcctgt ctgactgaat 300 caggatcaac agctttaaag gcagaaacct cagagagact tcgtactgtg 350 cttctggatg tgaccgaccc agagaatgtc aagaggactg cccagtgggt 400 gaagaaccaa gttggggaga aaggtctctg gggtctgatc aataatgctg 450 gtgttcccgg cgtgctggct cccactgact ggctgacact agaggactac 500 agagaaccta ttgaagtgaa cctgtttgga ctcatcagtg tgacactaaa 550 tatgcttcct ttggtcaaga aagctcaagg gagagttatt aatgtctcca 600 gtgttggagg tcgccttgca atcgttggag ggggctatac tccatccaaa 650 tatgcagtgg aaggtttcaa tgacagctta agacgggaca tgaaagcttt 700 tggtgtgcac gtctcatgca ttgaaccagg attgttcaaa acaaacttgg 750 cagatccagt aaaggtaatt gaaaaaaaac tcgccatttg ggagcagctg 800 tctccagaca tcaaacaaca atatggagaa ggttacattg aaaaaagtct 850 agacaaactg aaaggcaata aatcctatgt gaacatggac ctctctccgg 900 tggtagagtg catggaccac gctctaacaa gtctcttccc taagactcat 950 tatgccgctg gaaaagatgc caaaattttc tggatacctc tgtctcacat 1000 gccagcagct ttgcaagact ttttattgtt gaaacagaaa gcagagctgg 1050 ctaatcccaa ggcagtgtga ctcagctaac cacaaatgtc tcctccaggc 1100 tatgaaattg gccgatttca agaacacatc tccttttcaa ccccattcct 1150 tatctgctcc aacctggact catttagatc gtgcttattt ggattgcaaa 1200 agggagtccc accatcgctg gtggtatccc agggtccctg ctcaagtttt 1250 ctttgaaaag gagggctgga atggtacatc acataggcaa gtcctgccct 1300 gtatttaggc tttgcctgct tggtgtgatg taagggaaat tgaaagactt 1350 gcccattcaa aatgatcttt accgtggcct gccccatgct tatggtcccc 1400 agcatttaca gtaacttgtg aatgttaagt atcatctctt atctaaatat 1450 taaaagataa gtcaacccaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1500 aaaaaaaa 1508 20 319 PRT Homo Sapien 20 Met Leu Phe Trp Val Leu Gly Leu Leu Ile Leu Cys Gly Phe Leu 1 5 10 15 Trp Thr Arg Lys Gly Lys Leu Lys Ile Glu Asp Ile Thr Asp Lys 20 25 30 Tyr Ile Phe Ile Thr Gly Cys Asp Ser Gly Phe Gly Asn Leu Ala 35 40 45 Ala Arg Thr Phe Asp Lys Lys Gly Phe His Val Ile Ala Ala Cys 50 55 60 Leu Thr Glu Ser Gly Ser Thr Ala Leu Lys Ala Glu Thr Ser Glu 65 70 75 Arg Leu Arg Thr Val Leu Leu Asp Val Thr Asp Pro Glu Asn Val 80 85 90 Lys Arg Thr Ala Gln Trp Val Lys Asn Gln Val Gly Glu Lys Gly 95 100 105 Leu Trp Gly Leu Ile Asn Asn Ala Gly Val Pro Gly Val Leu Ala 110 115 120 Pro Thr Asp Trp Leu Thr Leu Glu Asp Tyr Arg Glu Pro Ile Glu 125 130 135 Val Asn Leu Phe Gly Leu Ile Ser Val Thr Leu Asn Met Leu Pro 140 145 150 Leu Val Lys Lys Ala Gln Gly Arg Val Ile Asn Val Ser Ser Val 155 160 165 Gly Gly Arg Leu Ala Ile Val Gly Gly Gly Tyr Thr Pro Ser Lys 170 175 180 Tyr Ala Val Glu Gly Phe Asn Asp Ser Leu Arg Arg Asp Met Lys 185 190 195 Ala Phe Gly Val His Val Ser Cys Ile Glu Pro Gly Leu Phe Lys 200 205 210 Thr Asn Leu Ala Asp Pro Val Lys Val Ile Glu Lys Lys Leu Ala 215 220 225 Ile Trp Glu Gln Leu Ser Pro Asp Ile Lys Gln Gln Tyr Gly Glu 230 235 240 Gly Tyr Ile Glu Lys Ser Leu Asp Lys Leu Lys Gly Asn Lys Ser 245 250 255 Tyr Val Asn Met Asp Leu Ser Pro Val Val Glu Cys Met Asp His 260 265 270 Ala Leu Thr Ser Leu Phe Pro Lys Thr His Tyr Ala Ala Gly Lys 275 280 285 Asp Ala Lys Ile Phe Trp Ile Pro Leu Ser His Met Pro Ala Ala 290 295 300 Leu Gln Asp Phe Leu Leu Leu Lys Gln Lys Ala Glu Leu Ala Asn 305 310 315 Pro Lys Ala Val 21 1849 DNA Homo Sapien 21 ctgaggcggc ggtagcatgg agggggagag tacgtcggcg gtgctctcgg 50 gctttgtgct cggcgcactc gctttccagc acctcaacac ggactcggac 100 acggaaggtt ttcttcttgg ggaagtaaaa ggtgaagcca agaacagcat 150 tactgattcc caaatggatg atgttgaagt tgtttataca attgacattc 200 agaaatatat tccatgctat cagcttttta gcttttataa ttcttcaggc 250 gaagtaaatg agcaagcact gaagaaaata ttatcaaatg tcaaaaagaa 300 tgtggtaggt tggtacaaat tccgtcgtca ttcagatcag atcatgacgt 350 ttagagagag gctgcttcac aaaaacttgc aggagcattt ttcaaaccaa 400 gaccttgttt ttctgctatt aacaccaagt ataataacag aaagctgctc 450 tactcatcga ctggaacatt ccttatataa acctcaaaaa ggactttttc 500 acagggtacc tttagtggtt gccaatctgg gcatgtctga acaactgggt 550 tataaaactg tatcaggttc ctgtatgtcc actggtttta gccgagcagt 600 acaaacacac agctctaaat tttttgaaga agatggatcc ttaaaggagg 650 tacataagat aaatgaaatg tatgcttcat tacaagagga attaaagagt 700 atatgcaaaa aagtggaaga cagtgaacaa gcagtagata aactagtaaa 750 ggatgtaaac agattaaaac gagaaattga gaaaaggaga ggagcacaga 800 ttcaggcagc aagagagaag aacatccaaa aagaccctca ggagaacatt 850 tttctttgtc aggcattacg gacctttttt ccaaattctg aatttcttca 900 ttcatgtgtt atgtctttaa aaaatagaca tgtttctaaa agtagctgta 950 actacaacca ccatctcgat gtagtagaca atctgacctt aatggtagaa 1000 cacactgaca ttcctgaagc tagtccagct agtacaccac aaatcattaa 1050 gcataaagcc ttagacttag atgacagatg gcaattcaag agatctcggt 1100 tgttagatac acaagacaaa cgatctaaag caaatactgg tagtagtaac 1150 caagataaag catccaaaat gagcagccca gaaacagatg aagaaattga 1200 aaagatgaag ggttttggtg aatattcacg gtctcctaca ttttgatcct 1250 tttaacctta caaggagatt tttttatttg gctgatgggt aaagccaaac 1300 atttctattg tttttactat gttgagctac ttgcagtaag ttcatttgtt 1350 tttactatgt tcacctgttt gcagtaatac acagataact cttagtgcat 1400 ttacttcaca aagtactttt tcaaacatca gatgctttta tttccaaacc 1450 tttttttcac ctttcactaa gttgttgagg ggaaggctta cacagacaca 1500 ttctttagaa ttggaaaagt gagaccaggc acagtggctc acacctgtaa 1550 tcccagcact tagggaagac aagtcaggag gattgattga agctaggagt 1600 tagagaccag cctgggcaac gtattgagac catgtctatt aaaaaataaa 1650 atggaaaagc aagaatagcc ttattttcaa aatatggaaa gaaatttata 1700 tgaaaattta tctgagtcat taaaattctc cttaagtgat acttttttag 1750 aagtacatta tggctagagt tgccagataa aatgctggat atcatgcaat 1800 aaatttgcaa aacatcatct aaaatttaaa aaaaaaaaaa aaaaaaaaa 1849 22 409 PRT Homo Sapien 22 Met Glu Gly Glu Ser Thr Ser Ala Val Leu Ser Gly Phe Val Leu 1 5 10 15 Gly Ala Leu Ala Phe Gln His Leu Asn Thr Asp Ser Asp Thr Glu 20 25 30 Gly Phe Leu Leu Gly Glu Val Lys Gly Glu Ala Lys Asn Ser Ile 35 40 45 Thr Asp Ser Gln Met Asp Asp Val Glu Val Val Tyr Thr Ile Asp 50 55 60 Ile Gln Lys Tyr Ile Pro Cys Tyr Gln Leu Phe Ser Phe Tyr Asn 65 70 75 Ser Ser Gly Glu Val Asn Glu Gln Ala Leu Lys Lys Ile Leu Ser 80 85 90 Asn Val Lys Lys Asn Val Val Gly Trp Tyr Lys Phe Arg Arg His 95 100 105 Ser Asp Gln Ile Met Thr Phe Arg Glu Arg Leu Leu His Lys Asn 110 115 120 Leu Gln Glu His Phe Ser Asn Gln Asp Leu Val Phe Leu Leu Leu 125 130 135 Thr Pro Ser Ile Ile Thr Glu Ser Cys Ser Thr His Arg Leu Glu 140 145 150 His Ser Leu Tyr Lys Pro Gln Lys Gly Leu Phe His Arg Val Pro 155 160 165 Leu Val Val Ala Asn Leu Gly Met Ser Glu Gln Leu Gly Tyr Lys 170 175 180 Thr Val Ser Gly Ser Cys Met Ser Thr Gly Phe Ser Arg Ala Val 185 190 195 Gln Thr His Ser Ser Lys Phe Phe Glu Glu Asp Gly Ser Leu Lys 200 205 210 Glu Val His Lys Ile Asn Glu Met Tyr Ala Ser Leu Gln Glu Glu 215 220 225 Leu Lys Ser Ile Cys Lys Lys Val Glu Asp Ser Glu Gln Ala Val 230 235 240 Asp Lys Leu Val Lys Asp Val Asn Arg Leu Lys Arg Glu Ile Glu 245 250 255 Lys Arg Arg Gly Ala Gln Ile Gln Ala Ala Arg Glu Lys Asn Ile 260 265 270 Gln Lys Asp Pro Gln Glu Asn Ile Phe Leu Cys Gln Ala Leu Arg 275 280 285 Thr Phe Phe Pro Asn Ser Glu Phe Leu His Ser Cys Val Met Ser 290 295 300 Leu Lys Asn Arg His Val Ser Lys Ser Ser Cys Asn Tyr Asn His 305 310 315 His Leu Asp Val Val Asp Asn Leu Thr Leu Met Val Glu His Thr 320 325 330 Asp Ile Pro Glu Ala Ser Pro Ala Ser Thr Pro Gln Ile Ile Lys 335 340 345 His Lys Ala Leu Asp Leu Asp Asp Arg Trp Gln Phe Lys Arg Ser 350 355 360 Arg Leu Leu Asp Thr Gln Asp Lys Arg Ser Lys Ala Asn Thr Gly 365 370 375 Ser Ser Asn Gln Asp Lys Ala Ser Lys Met Ser Ser Pro Glu Thr 380 385 390 Asp Glu Glu Ile Glu Lys Met Lys Gly Phe Gly Glu Tyr Ser Arg 395 400 405 Ser Pro Thr Phe 23 2651 DNA Homo Sapien 23 ggcacagccg cgcggcggag ggcagagtca gccgagccga gtccagccgg 50 acgagcggac cagcgcaggg cagcccaagc agcgcgcagc gaacgcccgc 100 cgccgcccac accctctgcg gtccccgcgg cgcctgccac ccttccctcc 150 ttccccgcgt ccccgcctcg ccggccagtc agcttgccgg gttcgctgcc 200 ccgcgaaacc ccgaggtcac cagcccgcgc ctctgcttcc ctgggccgcg 250 cgccgcctcc acgccctcct tctcccctgg cccggcgcct ggcaccgggg 300 accgttgcct gacgcgaggc ccagctctac ttttcgcccc gcgtctcctc 350 cgcctgctcg cctcttccac caactccaac tccttctccc tccagctcca 400 ctcgctagtc cccgactccg ccagccctcg gcccgctgcc gtagcgccgc 450 ttcccgtccg gtcccaaagg tgggaacgcg tccgccccgg cccgcaccat 500 ggcacggttc ggcttgcccg cgcttctctg caccctggca gtgctcagcg 550 ccgcgctgct ggctgccgag ctcaagtcga aaagttgctc ggaagtgcga 600 cgtctttacg tgtccaaagg cttcaacaag aacgatgccc ccctccacga 650 gatcaacggt gatcatttga agatctgtcc ccagggttct acctgctgct 700 ctcaagagat ggaggagaag tacagcctgc aaagtaaaga tgatttcaaa 750 agtgtggtca gcgaacagtg caatcatttg caagctgtct ttgcttcacg 800 ttacaagaag tttgatgaat tcttcaaaga actacttgaa aatgcagaga 850 aatccctgaa tgatatgttt gtgaagacat atggccattt atacatgcaa 900 aattctgagc tatttaaaga tctcttcgta gagttgaaac gttactacgt 950 ggtgggaaat gtgaacctgg aagaaatgct aaatgacttc tgggctcgcc 1000 tcctggagcg gatgttccgc ctggtgaact cccagtacca ctttacagat 1050 gagtatctgg aatgtgtgag caagtatacg gagcagctga agcccttcgg 1100 agatgtccct cgcaaattga agctccaggt tactcgtgct tttgtagcag 1150 cccgtacttt cgctcaaggc ttagcggttg cgggagatgt cgtgagcaag 1200 gtctccgtgg taaaccccac agcccagtgt acccatgccc tgttgaagat 1250 gatctactgc tcccactgcc ggggtctcgt gactgtgaag ccatgttaca 1300 actactgctc aaacatcatg agaggctgtt tggccaacca aggggatctc 1350 gattttgaat ggaacaattt catagatgct atgctgatgg tggcagagag 1400 gctagagggt cctttcaaca ttgaatcggt catggatccc atcgatgtga 1450 agatttctga tgctattatg aacatgcagg ataatagtgt tcaagtgtct 1500 cagaaggttt tccagggatg tggacccccc aagcccctcc cagctggacg 1550 aatttctcgt tccatctctg aaagtgcctt cagtgctcgc ttcagaccac 1600 atcaccccga ggaacgccca accacagcag ctggcactag tttggaccga 1650 ctggttactg atgtcaagga gaaactgaaa caggccaaga aattctggtc 1700 ctcccttccg agcaacgttt gcaacgatga gaggatggct gcaggaaacg 1750 gcaatgagga tgactgttgg aatgggaaag gcaaaagcag gtacctgttt 1800 gcagtgacag gaaatggatt agccaaccag ggcaacaacc cagaggtcca 1850 ggttgacacc agcaaaccag acatactgat ccttcgtcaa atcatggctc 1900 ttcgagtgat gaccagcaag atgaagaatg catacaatgg gaacgacgtg 1950 gacttctttg atatcagtga tgaaagtagt ggagaaggaa gtggaagtgg 2000 ctgtgagtat cagcagtgcc cttcagagtt tgactacaat gccactgacc 2050 atgctgggaa gagtgccaat gagaaagccg acagtgctgg tgtccgtcct 2100 ggggcacagg cctacctcct cactgtcttc tgcatcttgt tcctggttat 2150 gcagagagag tggagataat tctcaaactc tgagaaaaag tgttcatcaa 2200 aaagttaaaa ggcaccagtt atcacttttc taccatccta gtgactttgc 2250 tttttaaatg aatggacaac aatgtacagt ttttactatg tggccactgg 2300 tttaagaagt gctgactttg ttttctcatt cagttttggg aggaaaaggg 2350 actgtgcatt gagttggttc ctgctccccc aaaccatgtt aaacgtggct 2400 aacagtgtag gtacagaact atagttagtt gtgcatttgt gattttatca 2450 ctctattatt tgtttgtatg tttttttctc atttcgtttg tgggtttttt 2500 tttccaactg tgatctcgcc ttgtttctta caagcaaacc agggtccctt 2550 cttggcacgt aacatgtacg tatttctgaa atattaaata gctgtacaga 2600 agcaggtttt atttatcatg ttatcttatt aaaagaaaaa gcccaaaaag 2650 c 2651 24 556 PRT Homo Sapien 24 Met Ala Arg Phe Gly Leu Pro Ala Leu Leu Cys Thr Leu Ala Val 1 5 10 15 Leu Ser Ala Ala Leu Leu Ala Ala Glu Leu Lys Ser Lys Ser Cys 20 25 30 Ser Glu Val Arg Arg Leu Tyr Val Ser Lys Gly Phe Asn Lys Asn 35 40 45 Asp Ala Pro Leu His Glu Ile Asn Gly Asp His Leu Lys Ile Cys 50 55 60 Pro Gln Gly Ser Thr Cys Cys Ser Gln Glu Met Glu Glu Lys Tyr 65 70 75 Ser Leu Gln Ser Lys Asp Asp Phe Lys Ser Val Val Ser Glu Gln 80 85 90 Cys Asn His Leu Gln Ala Val Phe Ala Ser Arg Tyr Lys Lys Phe 95 100 105 Asp Glu Phe Phe Lys Glu Leu Leu Glu Asn Ala Glu Lys Ser Leu 110 115 120 Asn Asp Met Phe Val Lys Thr Tyr Gly His Leu Tyr Met Gln Asn 125 130 135 Ser Glu Leu Phe Lys Asp Leu Phe Val Glu Leu Lys Arg Tyr Tyr 140 145 150 Val Val Gly Asn Val Asn Leu Glu Glu Met Leu Asn Asp Phe Trp 155 160 165 Ala Arg Leu Leu Glu Arg Met Phe Arg Leu Val Asn Ser Gln Tyr 170 175 180 His Phe Thr Asp Glu Tyr Leu Glu Cys Val Ser Lys Tyr Thr Glu 185 190 195 Gln Leu Lys Pro Phe Gly Asp Val Pro Arg Lys Leu Lys Leu Gln 200 205 210 Val Thr Arg Ala Phe Val Ala Ala Arg Thr Phe Ala Gln Gly Leu 215 220 225 Ala Val Ala Gly Asp Val Val Ser Lys Val Ser Val Val Asn Pro 230 235 240 Thr Ala Gln Cys Thr His Ala Leu Leu Lys Met Ile Tyr Cys Ser 245 250 255 His Cys Arg Gly Leu Val Thr Val Lys Pro Cys Tyr Asn Tyr Cys 260 265 270 Ser Asn Ile Met Arg Gly Cys Leu Ala Asn Gln Gly Asp Leu Asp 275 280 285 Phe Glu Trp Asn Asn Phe Ile Asp Ala Met Leu Met Val Ala Glu 290 295 300 Arg Leu Glu Gly Pro Phe Asn Ile Glu Ser Val Met Asp Pro Ile 305 310 315 Asp Val Lys Ile Ser Asp Ala Ile Met Asn Met Gln Asp Asn Ser 320 325 330 Val Gln Val Ser Gln Lys Val Phe Gln Gly Cys Gly Pro Pro Lys 335 340 345 Pro Leu Pro Ala Gly Arg Ile Ser Arg Ser Ile Ser Glu Ser Ala 350 355 360 Phe Ser Ala Arg Phe Arg Pro His His Pro Glu Glu Arg Pro Thr 365 370 375 Thr Ala Ala Gly Thr Ser Leu Asp Arg Leu Val Thr Asp Val Lys 380 385 390 Glu Lys Leu Lys Gln Ala Lys Lys Phe Trp Ser Ser Leu Pro Ser 395 400 405 Asn Val Cys Asn Asp Glu Arg Met Ala Ala Gly Asn Gly Asn Glu 410 415 420 Asp Asp Cys Trp Asn Gly Lys Gly Lys Ser Arg Tyr Leu Phe Ala 425 430 435 Val Thr Gly Asn Gly Leu Ala Asn Gln Gly Asn Asn Pro Glu Val 440 445 450 Gln Val Asp Thr Ser Lys Pro Asp Ile Leu Ile Leu Arg Gln Ile 455 460 465 Met Ala Leu Arg Val Met Thr Ser Lys Met Lys Asn Ala Tyr Asn 470 475 480 Gly Asn Asp Val Asp Phe Phe Asp Ile Ser Asp Glu Ser Ser Gly 485 490 495 Glu Gly Ser Gly Ser Gly Cys Glu Tyr Gln Gln Cys Pro Ser Glu 500 505 510 Phe Asp Tyr Asn Ala Thr Asp His Ala Gly Lys Ser Ala Asn Glu 515 520 525 Lys Ala Asp Ser Ala Gly Val Arg Pro Gly Ala Gln Ala Tyr Leu 530 535 540 Leu Thr Val Phe Cys Ile Leu Phe Leu Val Met Gln Arg Glu Trp 545 550 555 Arg 25 870 DNA Homo Sapien 25 ctcgccctca aatgggaacg ctggcctggg actaaagcat agaccaccag 50 gctgagtatc ctgacctgag tcatccccag ggatcaggag cctccagcag 100 ggaaccttcc attatattct tcaagcaact tacagctgca ccgacagttg 150 cgatgaaagt tctaatctct tccctcctcc tgttgctgcc actaatgctg 200 atgtccatgg tctctagcag cctgaatcca ggggtcgcca gaggccacag 250 ggaccgaggc caggcttcta ggagatggct ccaggaaggc ggccaagaat 300 gtgagtgcaa agattggttc ctgagagccc cgagaagaaa attcatgaca 350 gtgtctgggc tgccaaagaa gcagtgcccc tgtgatcatt tcaagggcaa 400 tgtgaagaaa acaagacacc aaaggcacca cagaaagcca aacaagcatt 450 ccagagcctg ccagcaattt ctcaaacaat gtcagctaag aagctttgct 500 ctgcctttgt aggagctctg agcgcccact cttccaatta aacattctca 550 gccaagaaga cagtgagcac acctaccaga cactcttctt ctcccacctc 600 actctcccac tgtacccacc cctaaatcat tccagtgctc tcaaaaagca 650 tgtttttcaa gatcattttg tttgttgctc tctctagtgt cttcttctct 700 cgtcagtctt agcctgtgcc ctccccttac ccaggcttag gcttaattac 750 ctgaaagatt ccaggaaact gtagcttcct agctagtgtc atttaacctt 800 aaatgcaatc aggaaagtag caaacagaag tcaataaata tttttaaatg 850 tcaaaaaaaa aaaaaaaaaa 870 26 119 PRT Homo Sapien 26 Met Lys Val Leu Ile Ser Ser Leu Leu Leu Leu Leu Pro Leu Met 1 5 10 15 Leu Met Ser Met Val Ser Ser Ser Leu Asn Pro Gly Val Ala Arg 20 25 30 Gly His Arg Asp Arg Gly Gln Ala Ser Arg Arg Trp Leu Gln Glu 35 40 45 Gly Gly Gln Glu Cys Glu Cys Lys Asp Trp Phe Leu Arg Ala Pro 50 55 60 Arg Arg Lys Phe Met Thr Val Ser Gly Leu Pro Lys Lys Gln Cys 65 70 75 Pro Cys Asp His Phe Lys Gly Asn Val Lys Lys Thr Arg His Gln 80 85 90 Arg His His Arg Lys Pro Asn Lys His Ser Arg Ala Cys Gln Gln 95 100 105 Phe Leu Lys Gln Cys Gln Leu Arg Ser Phe Ala Leu Pro Leu 110 115 27 1371 DNA Homo Sapien 27 ggacgccagc gcctgcagag gctgagcagg gaaaaagcca gtgccccagc 50 ggaagcacag ctcagagctg gtctgccatg gacatcctgg tcccactcct 100 gcagctgctg gtgctgcttc ttaccctgcc cctgcacctc atggctctgc 150 tgggctgctg gcagcccctg tgcaaaagct acttccccta cctgatggcc 200 gtgctgactc ccaagagcaa ccgcaagatg gagagcaaga aacgggagct 250 cttcagccag ataaaggggc ttacaggagc ctccgggaaa gtggccctac 300 tggagctggg ctgcggaacc ggagccaact ttcagttcta cccaccgggc 350 tgcagggtca cctgcctaga cccaaatccc cactttgaga agttcctgac 400 aaagagcatg gctgagaaca ggcacctcca atatgagcgg tttgtggtgg 450 ctcctggaga ggacatgaga cagctggctg atggctccat ggatgtggtg 500 gtctgcactc tggtgctgtg ctctgtgcag agcccaagga aggtcctgca 550 ggaggtccgg agagtactga gaccgggagg tgtgctcttt ttctgggagc 600 atgtggcaga accatatgga agctgggcct tcatgtggca gcaagttttc 650 gagcccacct ggaaacacat tggggatggc tgctgcctca ccagagagac 700 ctggaaggat cttgagaacg cccagttctc cgaaatccaa atggaacgac 750 agccccctcc cttgaagtgg ctacctgttg ggccccacat catgggaaag 800 gctgtcaaac aatctttccc aagctccaag gcactcattt gctccttccc 850 cagcctccaa ttagaacaag ccacccacca gcctatctat cttccactga 900 gagggaccta gcagaatgag agaagacatt catgtaccac ctactagtcc 950 ctctctcccc aacctctgcc agggcaatct ctaacttcaa tcccgccttc 1000 gacagtgaaa aagctctact tctacgctga cccagggagg aaacactagg 1050 accctgttgt atcctcaact gcaagtttct ggactagtct cccaacgttt 1100 gcctcccaat gttgtccctt tccttcgttc ccatggtaaa gctcctctcg 1150 ctttcctcct gaggctacac ccatgcgtct ctaggaactg gtcacaaaag 1200 tcatggtgcc tgcatccctg ccaagccccc ctgaccctct ctccccacta 1250 ccaccttctt cctgagctgg gggcaccagg gagaatcaga gatgctgggg 1300 atgccagagc aagactcaaa gaggcagagg ttttgttctc aaatattttt 1350 taataaatag acgaaaccac g 1371 28 277 PRT Homo Sapien 28 Met Asp Ile Leu Val Pro Leu Leu Gln Leu Leu Val Leu Leu Leu 1 5 10 15 Thr Leu Pro Leu His Leu Met Ala Leu Leu Gly Cys Trp Gln Pro 20 25 30 Leu Cys Lys Ser Tyr Phe Pro Tyr Leu Met Ala Val Leu Thr Pro 35 40 45 Lys Ser Asn Arg Lys Met Glu Ser Lys Lys Arg Glu Leu Phe Ser 50 55 60 Gln Ile Lys Gly Leu Thr Gly Ala Ser Gly Lys Val Ala Leu Leu 65 70 75 Glu Leu Gly Cys Gly Thr Gly Ala Asn Phe Gln Phe Tyr Pro Pro 80 85 90 Gly Cys Arg Val Thr Cys Leu Asp Pro Asn Pro His Phe Glu Lys 95 100 105 Phe Leu Thr Lys Ser Met Ala Glu Asn Arg His Leu Gln Tyr Glu 110 115 120 Arg Phe Val Val Ala Pro Gly Glu Asp Met Arg Gln Leu Ala Asp 125 130 135 Gly Ser Met Asp Val Val Val Cys Thr Leu Val Leu Cys Ser Val 140 145 150 Gln Ser Pro Arg Lys Val Leu Gln Glu Val Arg Arg Val Leu Arg 155 160 165 Pro Gly Gly Val Leu Phe Phe Trp Glu His Val Ala Glu Pro Tyr 170 175 180 Gly Ser Trp Ala Phe Met Trp Gln Gln Val Phe Glu Pro Thr Trp 185 190 195 Lys His Ile Gly Asp Gly Cys Cys Leu Thr Arg Glu Thr Trp Lys 200 205 210 Asp Leu Glu Asn Ala Gln Phe Ser Glu Ile Gln Met Glu Arg Gln 215 220 225 Pro Pro Pro Leu Lys Trp Leu Pro Val Gly Pro His Ile Met Gly 230 235 240 Lys Ala Val Lys Gln Ser Phe Pro Ser Ser Lys Ala Leu Ile Cys 245 250 255 Ser Phe Pro Ser Leu Gln Leu Glu Gln Ala Thr His Gln Pro Ile 260 265 270 Tyr Leu Pro Leu Arg Gly Thr 275 29 494 DNA Homo Sapien 29 caatgtttgc ctatccacct cccccaagcc cctttaccta tgctgctgct 50 aacgctgctg ctgctgctgc tgctgcttaa aggctcatgc ttggagtggg 100 gactggtcgg tgcccagaaa gtctcttctg ccactgacgc ccccatcagg 150 gattgggcct tctttccccc ttcctttctg tgtctcctgc ctcatcggcc 200 tgccatgacc tgcagccaag cccagccccg tggggaaggg gagaaagtgg 250 gggatggcta agaaagctgg gagataggga acagaagagg gtagtgggtg 300 ggctaggggg gctgccttat ttaaagtggt tgtttatgat tcttatacta 350 atttatacaa agatattaag gccctgttca ttaagaaatt gttcccttcc 400 cctgtgttca atgtttgtaa agattgttct gtgtaaatat gtctttataa 450 taaacagtta aaagctgaaa aaaaaaaaaa aaaaaaaaaa aaaa 494 30 73 PRT Homo Sapien 30 Met Leu Leu Leu Thr Leu Leu Leu Leu Leu Leu Leu Leu Lys Gly 1 5 10 15 Ser Cys Leu Glu Trp Gly Leu Val Gly Ala Gln Lys Val Ser Ser 20 25 30 Ala Thr Asp Ala Pro Ile Arg Asp Trp Ala Phe Phe Pro Pro Ser 35 40 45 Phe Leu Cys Leu Leu Pro His Arg Pro Ala Met Thr Cys Ser Gln 50 55 60 Ala Gln Pro Arg Gly Glu Gly Glu Lys Val Gly Asp Gly 65 70 31 1660 DNA Homo Sapien 31 gtttgaattc cttcaactat acccacagtc caaaagcaga ctcactgtgt 50 cccaggctac cagttcctcc aagcaagtca tttcccttat ttaaccgatg 100 tgtccctcaa acacctgagt gctactccct atttgcatct gttttgataa 150 atgatgttga caccctccac cgaattctaa gtggaatcat gtcgggaaga 200 gatacaatcc ttggcctgtg tatcctcgca ttagccttgt ctttggccat 250 gatgtttacc ttcagattca tcaccaccct tctggttcac attttcattt 300 cattggttat tttgggattg ttgtttgtct gcggtgtttt atggtggctg 350 tattatgact ataccaacga cctcagcata gaattggaca cagaaaggga 400 aaatatgaag tgcgtgctgg ggtttgctat cgtatccaca ggcatcacgg 450 cagtgctgct cgtcttgatt tttgttctca gaaagagaat aaaattgaca 500 gttgagcttt tccaaatcac aaataaagcc atcagcagtg ctcccttcct 550 gctgttccag ccactgtgga catttgccat cctcattttc ttctgggtcc 600 tctgggtggc tgtgctgctg agcctgggaa ctgcaggagc tgcccaggtt 650 atggaaggcg gccaagtgga atataagccc ctttcgggca ttcggtacat 700 gtggtcgtac catttaattg gcctcatctg gactagtgaa ttcatccttg 750 cgtgccagca aatgactata gctggggcag tggttacttg ttatttcaac 800 agaagtaaaa atgatcctcc tgatcatccc atcctttcgt ctctctccat 850 tctcttcttc taccatcaag gaaccgttgt gaaagggtca tttttaatct 900 ctgtggtgag gattccgaga atcattgtca tgtacatgca aaacgcactg 950 aaagaacagc agcatggtgc attgtccagg tacctgttcc gatgctgcta 1000 ctgctgtttc tggtgtcttg acaaatacct gctccatctc aaccagaatg 1050 catatactac aactgctatt aatgggacag atttctgtac atcagcaaaa 1100 gatgcattca aaatcttgtc caagaactca agtcacttta catctattaa 1150 ctgctttgga gacttcataa tttttctagg aaaggtgtta gtggtgtgtt 1200 tcactgtttt tggaggactc atggctttta actacaatcg ggcattccag 1250 gtgtgggcag tccctctgtt attggtagct ttttttgcct acttagtagc 1300 ccatagtttt ttatctgtgt ttgaaactgt gctggatgca cttttcctgt 1350 gttttgctgt tgatctggaa acaaatgatg gatcgtcaga aaagccctac 1400 tttatggatc aagaatttct gagtttcgta aaaaggagca acaaattaaa 1450 caatgcaagg gcacagcagg acaagcactc attaaggaat gaggagggaa 1500 cagaactcca ggccattgtg agatagatac ccatttaggt atctgtacct 1550 ggaaaacatt tccttctaag agccatttac agaatagaag atgagaccac 1600 tagagaaaag ttagtgaatt tttttttaaa agacctaata aaccctattc 1650 ttcctcaaaa 1660 32 445 PRT Homo Sapien 32 Met Ser Gly Arg Asp Thr Ile Leu Gly Leu Cys Ile Leu Ala Leu 1 5 10 15 Ala Leu Ser Leu Ala Met Met Phe Thr Phe Arg Phe Ile Thr Thr 20 25 30 Leu Leu Val His Ile Phe Ile Ser Leu Val Ile Leu Gly Leu Leu 35 40 45 Phe Val Cys Gly Val Leu Trp Trp Leu Tyr Tyr Asp Tyr Thr Asn 50 55 60 Asp Leu Ser Ile Glu Leu Asp Thr Glu Arg Glu Asn Met Lys Cys 65 70 75 Val Leu Gly Phe Ala Ile Val Ser Thr Gly Ile Thr Ala Val Leu 80 85 90 Leu Val Leu Ile Phe Val Leu Arg Lys Arg Ile Lys Leu Thr Val 95 100 105 Glu Leu Phe Gln Ile Thr Asn Lys Ala Ile Ser Ser Ala Pro Phe 110 115 120 Leu Leu Phe Gln Pro Leu Trp Thr Phe Ala Ile Leu Ile Phe Phe 125 130 135 Trp Val Leu Trp Val Ala Val Leu Leu Ser Leu Gly Thr Ala Gly 140 145 150 Ala Ala Gln Val Met Glu Gly Gly Gln Val Glu Tyr Lys Pro Leu 155 160 165 Ser Gly Ile Arg Tyr Met Trp Ser Tyr His Leu Ile Gly Leu Ile 170 175 180 Trp Thr Ser Glu Phe Ile Leu Ala Cys Gln Gln Met Thr Ile Ala 185 190 195 Gly Ala Val Val Thr Cys Tyr Phe Asn Arg Ser Lys Asn Asp Pro 200 205 210 Pro Asp His Pro Ile Leu Ser Ser Leu Ser Ile Leu Phe Phe Tyr 215 220 225 His Gln Gly Thr Val Val Lys Gly Ser Phe Leu Ile Ser Val Val 230 235 240 Arg Ile Pro Arg Ile Ile Val Met Tyr Met Gln Asn Ala Leu Lys 245 250 255 Glu Gln Gln His Gly Ala Leu Ser Arg Tyr Leu Phe Arg Cys Cys 260 265 270 Tyr Cys Cys Phe Trp Cys Leu Asp Lys Tyr Leu Leu His Leu Asn 275 280 285 Gln Asn Ala Tyr Thr Thr Thr Ala Ile Asn Gly Thr Asp Phe Cys 290 295 300 Thr Ser Ala Lys Asp Ala Phe Lys Ile Leu Ser Lys Asn Ser Ser 305 310 315 His Phe Thr Ser Ile Asn Cys Phe Gly Asp Phe Ile Ile Phe Leu 320 325 330 Gly Lys Val Leu Val Val Cys Phe Thr Val Phe Gly Gly Leu Met 335 340 345 Ala Phe Asn Tyr Asn Arg Ala Phe Gln Val Trp Ala Val Pro Leu 350 355 360 Leu Leu Val Ala Phe Phe Ala Tyr Leu Val Ala His Ser Phe Leu 365 370 375 Ser Val Phe Glu Thr Val Leu Asp Ala Leu Phe Leu Cys Phe Ala 380 385 390 Val Asp Leu Glu Thr Asn Asp Gly Ser Ser Glu Lys Pro Tyr Phe 395 400 405 Met Asp Gln Glu Phe Leu Ser Phe Val Lys Arg Ser Asn Lys Leu 410 415 420 Asn Asn Ala Arg Ala Gln Gln Asp Lys His Ser Leu Arg Asn Glu 425 430 435 Glu Gly Thr Glu Leu Gln Ala Ile Val Arg 440 445 33 2773 DNA Homo Sapien 33 gttcgattag ctcctctgag aagaagagaa aaggttcttg gacctctccc 50 tgtttcttcc ttagaataat ttgtatggga tttgtgatgc aggaaagcct 100 aagggaaaaa gaatattcat tctgtgtggt gaaaattttt tgaaaaaaaa 150 attgccttct tcaaacaagg gtgtcattct gatatttatg aggactgttg 200 ttctcactat gaaggcatct gttattgaaa tgttccttgt tttgctggtg 250 actggagtac attcaaacaa agaaacggca aagaagatta aaaggcccaa 300 gttcactgtg cctcagatca actgcgatgt caaagccgga aagatcatcg 350 atcctgagtt cattgtgaaa tgtccagcag gatgccaaga ccccaaatac 400 catgtttatg gcactgacgt gtatgcatcc tactccagtg tgtgtggcgc 450 tgccgtacac agtggtgtgc ttgataattc aggagggaaa atacttgttc 500 ggaaggttgc tggacagtct ggttacaaag ggagttattc caacggtgtc 550 caatcgttat ccctaccacg atggagagaa tcctttatcg tcttagaaag 600 taaacccaaa aagggtgtaa cctacccatc agctcttaca tactcatcat 650 cgaaaagtcc agctgcccaa gcaggtgaga ccacaaaagc ctatcagagg 700 ccacctattc cagggacaac tgcacagccg gtcactctga tgcagcttct 750 ggctgtcact gtagctgtgg ccacccccac caccttgcca aggccatccc 800 cttctgctgc ttctaccacc agcatcccca gaccacaatc agtgggccac 850 aggagccagg agatggatct ctggtccact gccacctaca caagcagcca 900 aaacaggccc agagctgatc caggtatcca aaggcaagat ccttcaggag 950 ctgccttcca gaaacctgtt ggagcggatg tcagcctggg acttgttcca 1000 aaagaagaat tgagcacaca gtctttggag ccagtatccc tgggagatcc 1050 aaactgcaaa attgacttgt cgtttttaat tgatgggagc accagcattg 1100 gcaaacggcg attccgaatc cagaagcagc tcctggctga tgttgcccaa 1150 gctcttgaca ttggccctgc cggtccactg atgggtgttg tccagtatgg 1200 agacaaccct gctactcact ttaacctcaa gacacacacg aattctcgag 1250 atctgaagac agccatagag aaaattactc agagaggagg actttctaat 1300 gtaggtcggg ccatctcctt tgtgaccaag aacttctttt ccaaagccaa 1350 tggaaacaga agcggggctc ccaatgtggt ggtggtgatg gtggatggct 1400 ggcccacgga caaagtggag gaggcttcaa gacttgcgag agagtcagga 1450 atcaacattt tcttcatcac cattgaaggt gctgctgaaa atgagaagca 1500 gtatgtggtg gagcccaact ttgcaaacaa ggccgtgtgc agaacaaacg 1550 gcttctactc gctccacgtg cagagctggt ttggcctcca caagaccctg 1600 cagcctctgg tgaagcgggt ctgcgacact gaccgcctgg cctgcagcaa 1650 gacctgcttg aactcggctg acattggctt cgtcatcgac ggctccagca 1700 gtgtggggac gggcaacttc cgcaccgtcc tccagtttgt gaccaacctc 1750 accaaagagt ttgagatttc cgacacggac acgcgcatcg gggccgtgca 1800 gtacacctac gaacagcggc tggagtttgg gttcgacaag tacagcagca 1850 agcctgacat cctcaacgcc atcaagaggg tgggctactg gagtggtggc 1900 accagcacgg gggctgccat caacttcgcc ctggagcagc tcttcaagaa 1950 gtccaagccc aacaagagga agttaatgat cctcatcacc gacgggaggt 2000 cctacgacga cgtccggatc ccagccatgg ctgcccatct gaagggagtg 2050 atcacctatg cgataggcgt tgcctgggct gcccaagagg agctagaagt 2100 cattgccact caccccgcca gagaccactc cttctttgtg gacgagtttg 2150 acaacctcca tcagtatgtc cccaggatca tccagaacat ttgtacagag 2200 ttcaactcac agcctcggaa ctgaattcag agcaggcaga gcaccagcaa 2250 gtgctgcttt actaactgac gtgttggacc accccaccgc ttaatggggc 2300 acgcacggtg catcaagtct tgggcagggc atggagaaac aaatgtcttg 2350 ttattattct ttgccatcat gctttttcat attccaaaac ttggagttac 2400 aaagatgatc acaaacgtat agaatgagcc aaaaggctac atcatgttga 2450 gggtgctgga gattttacat tttgacaatt gttttcaaaa taaatgttcg 2500 gaatacagtg cagcccttac gacaggctta cgtagagctt ttgtgagatt 2550 tttaagttgt tatttctgat ttgaactctg taaccctcag caagtttcat 2600 ttttgtcatg acaatgtagg aattgctgaa ttaaatgttt agaaggatga 2650 aaaataaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2700 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2750 aaaaaaaaaa aaaaaaaaaa aag 2773 34 678 PRT Homo Sapien 34 Met Arg Thr Val Val Leu Thr Met Lys Ala Ser Val Ile Glu Met 1 5 10 15 Phe Leu Val Leu Leu Val Thr Gly Val His Ser Asn Lys Glu Thr 20 25 30 Ala Lys Lys Ile Lys Arg Pro Lys Phe Thr Val Pro Gln Ile Asn 35 40 45 Cys Asp Val Lys Ala Gly Lys Ile Ile Asp Pro Glu Phe Ile Val 50 55 60 Lys Cys Pro Ala Gly Cys Gln Asp Pro Lys Tyr His Val Tyr Gly 65 70 75 Thr Asp Val Tyr Ala Ser Tyr Ser Ser Val Cys Gly Ala Ala Val 80 85 90 His Ser Gly Val Leu Asp Asn Ser Gly Gly Lys Ile Leu Val Arg 95 100 105 Lys Val Ala Gly Gln Ser Gly Tyr Lys Gly Ser Tyr Ser Asn Gly 110 115 120 Val Gln Ser Leu Ser Leu Pro Arg Trp Arg Glu Ser Phe Ile Val 125 130 135 Leu Glu Ser Lys Pro Lys Lys Gly Val Thr Tyr Pro Ser Ala Leu 140 145 150 Thr Tyr Ser Ser Ser Lys Ser Pro Ala Ala Gln Ala Gly Glu Thr 155 160 165 Thr Lys Ala Tyr Gln Arg Pro Pro Ile Pro Gly Thr Thr Ala Gln 170 175 180 Pro Val Thr Leu Met Gln Leu Leu Ala Val Thr Val Ala Val Ala 185 190 195 Thr Pro Thr Thr Leu Pro Arg Pro Ser Pro Ser Ala Ala Ser Thr 200 205 210 Thr Ser Ile Pro Arg Pro Gln Ser Val Gly His Arg Ser Gln Glu 215 220 225 Met Asp Leu Trp Ser Thr Ala Thr Tyr Thr Ser Ser Gln Asn Arg 230 235 240 Pro Arg Ala Asp Pro Gly Ile Gln Arg Gln Asp Pro Ser Gly Ala 245 250 255 Ala Phe Gln Lys Pro Val Gly Ala Asp Val Ser Leu Gly Leu Val 260 265 270 Pro Lys Glu Glu Leu Ser Thr Gln Ser Leu Glu Pro Val Ser Leu 275 280 285 Gly Asp Pro Asn Cys Lys Ile Asp Leu Ser Phe Leu Ile Asp Gly 290 295 300 Ser Thr Ser Ile Gly Lys Arg Arg Phe Arg Ile Gln Lys Gln Leu 305 310 315 Leu Ala Asp Val Ala Gln Ala Leu Asp Ile Gly Pro Ala Gly Pro 320 325 330 Leu Met Gly Val Val Gln Tyr Gly Asp Asn Pro Ala Thr His Phe 335 340 345 Asn Leu Lys Thr His Thr Asn Ser Arg Asp Leu Lys Thr Ala Ile 350 355 360 Glu Lys Ile Thr Gln Arg Gly Gly Leu Ser Asn Val Gly Arg Ala 365 370 375 Ile Ser Phe Val Thr Lys Asn Phe Phe Ser Lys Ala Asn Gly Asn 380 385 390 Arg Ser Gly Ala Pro Asn Val Val Val Val Met Val Asp Gly Trp 395 400 405 Pro Thr Asp Lys Val Glu Glu Ala Ser Arg Leu Ala Arg Glu Ser 410 415 420 Gly Ile Asn Ile Phe Phe Ile Thr Ile Glu Gly Ala Ala Glu Asn 425 430 435 Glu Lys Gln Tyr Val Val Glu Pro Asn Phe Ala Asn Lys Ala Val 440 445 450 Cys Arg Thr Asn Gly Phe Tyr Ser Leu His Val Gln Ser Trp Phe 455 460 465 Gly Leu His Lys Thr Leu Gln Pro Leu Val Lys Arg Val Cys Asp 470 475 480 Thr Asp Arg Leu Ala Cys Ser Lys Thr Cys Leu Asn Ser Ala Asp 485 490 495 Ile Gly Phe Val Ile Asp Gly Ser Ser Ser Val Gly Thr Gly Asn 500 505 510 Phe Arg Thr Val Leu Gln Phe Val Thr Asn Leu Thr Lys Glu Phe 515 520 525 Glu Ile Ser Asp Thr Asp Thr Arg Ile Gly Ala Val Gln Tyr Thr 530 535 540 Tyr Glu Gln Arg Leu Glu Phe Gly Phe Asp Lys Tyr Ser Ser Lys 545 550 555 Pro Asp Ile Leu Asn Ala Ile Lys Arg Val Gly Tyr Trp Ser Gly 560 565 570 Gly Thr Ser Thr Gly Ala Ala Ile Asn Phe Ala Leu Glu Gln Leu 575 580 585 Phe Lys Lys Ser Lys Pro Asn Lys Arg Lys Leu Met Ile Leu Ile 590 595 600 Thr Asp Gly Arg Ser Tyr Asp Asp Val Arg Ile Pro Ala Met Ala 605 610 615 Ala His Leu Lys Gly Val Ile Thr Tyr Ala Ile Gly Val Ala Trp 620 625 630 Ala Ala Gln Glu Glu Leu Glu Val Ile Ala Thr His Pro Ala Arg 635 640 645 Asp His Ser Phe Phe Val Asp Glu Phe Asp Asn Leu His Gln Tyr 650 655 660 Val Pro Arg Ile Ile Gln Asn Ile Cys Thr Glu Phe Asn Ser Gln 665 670 675 Pro Arg Asn 35 2095 DNA Homo Sapien 35 ccgagcacag gagattgcct gcgtttagga ggtggctgcg ttgtgggaaa 50 agctatcaag gaagaaattg ccaaaccatg tctttttttc tgttttcaga 100 gtagttcaca acagatctga gtgttttaat taagcatgga atacagaaaa 150 caacaaaaaa cttaagcttt aatttcatct ggaattccac agttttctta 200 gctccctgga cccggttgac ctgttggctc ttcccgctgg ctgctctatc 250 acgtggtgct ctccgactac tcaccccgag tgtaaagaac cttcggctcg 300 cgtgcttctg agctgctgtg gatggcctcg gctctctgga ctgtccttcc 350 gagtaggatg tcactgagat ccctcaaatg gagcctcctg ctgctgtcac 400 tcctgagttt ctttgtgatg tggtacctca gccttcccca ctacaatgtg 450 atagaacgcg tgaactggat gtacttctat gagtatgagc cgatttacag 500 acaagacttt cacttcacac ttcgagagca ttcaaactgc tctcatcaaa 550 atccatttct ggtcattctg gtgacctccc acccttcaga tgtgaaagcc 600 aggcaggcca ttagagttac ttggggtgaa aaaaagtctt ggtggggata 650 tgaggttctt acatttttct tattaggcca agaggctgaa aaggaagaca 700 aaatgttggc attgtcctta gaggatgaac accttcttta tggtgacata 750 atccgacaag attttttaga cacatataat aacctgacct tgaaaaccat 800 tatggcattc aggtgggtaa ctgagttttg ccccaatgcc aagtacgtaa 850 tgaagacaga cactgatgtt ttcatcaata ctggcaattt agtgaagtat 900 cttttaaacc taaaccactc agagaagttt ttcacaggtt atcctctaat 950 tgataattat tcctatagag gattttacca aaaaacccat atttcttacc 1000 aggagtatcc tttcaaggtg ttccctccat actgcagtgg gttgggttat 1050 ataatgtcca gagatttggt gccaaggatc tatgaaatga tgggtcacgt 1100 aaaacccatc aagtttgaag atgtttatgt cgggatctgt ttgaatttat 1150 taaaagtgaa cattcatatt ccagaagaca caaatctttt ctttctatat 1200 agaatccatt tggatgtctg tcaactgaga cgtgtgattg cagcccatgg 1250 cttttcttcc aaggagatca tcactttttg gcaggtcatg ctaaggaaca 1300 ccacatgcca ttattaactt cacattctac aaaaagccta gaaggacagg 1350 ataccttgtg gaaagtgtta aataaagtag gtactgtgga aaattcatgg 1400 ggaggtcagt gtgctggctt acactgaact gaaactcatg aaaaacccag 1450 actggagact ggagggttac acttgtgatt tattagtcag gcccttcaaa 1500 gatgatatgt ggaggaatta aatataaagg aattggaggt ttttgctaaa 1550 gaaattaata ggaccaaaca atttggacat gtcattctgt agactagaat 1600 ttcttaaaag ggtgttactg agttataagc tcactaggct gtaaaaacaa 1650 aacaatgtag agttttattt attgaacaat gtagtcactt gaaggttttg 1700 tgtatatctt atgtggatta ccaatttaaa aatatatgta gttctgtgtc 1750 aaaaaacttc ttcactgaag ttatactgaa caaaatttta cctgtttttg 1800 gtcatttata aagtacttca agatgttgca gtatttcaca gttattatta 1850 tttaaaatta cttcaacttt gtgtttttaa atgttttgac gatttcaata 1900 caagataaaa aggatagtga atcattcttt acatgcaaac attttccagt 1950 tacttaactg atcagtttat tattgataca tcactccatt aatgtaaagt 2000 cataggtcat tattgcatat cagtaatctc ttggactttg ttaaatattt 2050 tactgtggta atatagagaa gaattaaagc aagaaaatct gaaaa 2095 36 331 PRT Homo Sapien 36 Met Ala Ser Ala Leu Trp Thr Val Leu Pro Ser Arg Met Ser Leu 1 5 10 15 Arg Ser Leu Lys Trp Ser Leu Leu Leu Leu Ser Leu Leu Ser Phe 20 25 30 Phe Val Met Trp Tyr Leu Ser Leu Pro His Tyr Asn Val Ile Glu 35 40 45 Arg Val Asn Trp Met Tyr Phe Tyr Glu Tyr Glu Pro Ile Tyr Arg 50 55 60 Gln Asp Phe His Phe Thr Leu Arg Glu His Ser Asn Cys Ser His 65 70 75 Gln Asn Pro Phe Leu Val Ile Leu Val Thr Ser His Pro Ser Asp 80 85 90 Val Lys Ala Arg Gln Ala Ile Arg Val Thr Trp Gly Glu Lys Lys 95 100 105 Ser Trp Trp Gly Tyr Glu Val Leu Thr Phe Phe Leu Leu Gly Gln 110 115 120 Glu Ala Glu Lys Glu Asp Lys Met Leu Ala Leu Ser Leu Glu Asp 125 130 135 Glu His Leu Leu Tyr Gly Asp Ile Ile Arg Gln Asp Phe Leu Asp 140 145 150 Thr Tyr Asn Asn Leu Thr Leu Lys Thr Ile Met Ala Phe Arg Trp 155 160 165 Val Thr Glu Phe Cys Pro Asn Ala Lys Tyr Val Met Lys Thr Asp 170 175 180 Thr Asp Val Phe Ile Asn Thr Gly Asn Leu Val Lys Tyr Leu Leu 185 190 195 Asn Leu Asn His Ser Glu Lys Phe Phe Thr Gly Tyr Pro Leu Ile 200 205 210 Asp Asn Tyr Ser Tyr Arg Gly Phe Tyr Gln Lys Thr His Ile Ser 215 220 225 Tyr Gln Glu Tyr Pro Phe Lys Val Phe Pro Pro Tyr Cys Ser Gly 230 235 240 Leu Gly Tyr Ile Met Ser Arg Asp Leu Val Pro Arg Ile Tyr Glu 245 250 255 Met Met Gly His Val Lys Pro Ile Lys Phe Glu Asp Val Tyr Val 260 265 270 Gly Ile Cys Leu Asn Leu Leu Lys Val Asn Ile His Ile Pro Glu 275 280 285 Asp Thr Asn Leu Phe Phe Leu Tyr Arg Ile His Leu Asp Val Cys 290 295 300 Gln Leu Arg Arg Val Ile Ala Ala His Gly Phe Ser Ser Lys Glu 305 310 315 Ile Ile Thr Phe Trp Gln Val Met Leu Arg Asn Thr Thr Cys His 320 325 330 Tyr 37 2846 DNA Homo Sapien 37 cgctcgggca ccagccgcgg caaggatgga gctgggttgc tggacgcagt 50 tggggctcac ttttcttcag ctccttctca tctcgtcctt gccaagagag 100 tacacagtca ttaatgaagc ctgccctgga gcagagtgga atatcatgtg 150 tcgggagtgc tgtgaatatg atcagattga gtgcgtctgc cccggaaaga 200 gggaagtcgt gggttatacc atcccttgct gcaggaatga ggagaatgag 250 tgtgactcct gcctgatcca cccaggttgt accatctttg aaaactgcaa 300 gagctgccga aatggctcat gggggggtac cttggatgac ttctatgtga 350 aggggttcta ctgtgcagag tgccgagcag gctggtacgg aggagactgc 400 atgcgatgtg gccaggttct gcgagcccca aagggtcaga ttttgttgga 450 aagctatccc ctaaatgctc actgtgaatg gaccattcat gctaaacctg 500 ggtttgtcat ccaactaaga tttgtcatgt tgagtctgga gtttgactac 550 atgtgccagt atgactatgt tgaggttcgt gatggagaca accgcgatgg 600 ccagatcatc aagcgtgtct gtggcaacga gcggccagct cctatccaga 650 gcataggatc ctcactccac gtcctcttcc actccgatgg ctccaagaat 700 tttgacggtt tccatgccat ttatgaggag atcacagcat gctcctcatc 750 cccttgtttc catgacggca cgtgcgtcct tgacaaggct ggatcttaca 800 agtgtgcctg cttggcaggc tatactgggc agcgctgtga aaatctcctt 850 gaagaaagaa actgctcaga ccctgggggc ccagtcaatg ggtaccagaa 900 aataacaggg ggccctgggc ttatcaacgg acgccatgct aaaattggca 950 ccgtggtgtc tttcttttgt aacaactcct atgttcttag tggcaatgag 1000 aaaagaactt gccagcagaa tggagagtgg tcagggaaac agcccatctg 1050 cataaaagcc tgccgagaac caaagatttc agacctggtg agaaggagag 1100 ttcttccgat gcaggttcag tcaagggaga caccattaca ccagctatac 1150 tcagcggcct tcagcaagca gaaactgcag agtgccccta ccaagaagcc 1200 agcccttccc tttggagatc tgcccatggg ataccaacat ctgcataccc 1250 agctccagta tgagtgcatc tcacccttct accgccgcct gggcagcagc 1300 aggaggacat gtctgaggac tgggaagtgg agtgggcggg caccatcctg 1350 catccctatc tgcgggaaaa ttgagaacat cactgctcca aagacccaag 1400 ggttgcgctg gccgtggcag gcagccatct acaggaggac cagcggggtg 1450 catgacggca gcctacacaa gggagcgtgg ttcctagtct gcagcggtgc 1500 cctggtgaat gagcgcactg tggtggtggc tgcccactgt gttactgacc 1550 tggggaaggt caccatgatc aagacagcag acctgaaagt tgttttgggg 1600 aaattctacc gggatgatga ccgggatgag aagaccatcc agagcctaca 1650 gatttctgct atcattctgc atcccaacta tgaccccatc ctgcttgatg 1700 ctgacatcgc catcctgaag ctcctagaca aggcccgtat cagcacccga 1750 gtccagccca tctgcctcgc tgccagtcgg gatctcagca cttccttcca 1800 ggagtcccac atcactgtgg ctggctggaa tgtcctggca gacgtgagga 1850 gccctggctt caagaacgac acactgcgct ctggggtggt cagtgtggtg 1900 gactcgctgc tgtgtgagga gcagcatgag gaccatggca tcccagtgag 1950 tgtcactgat aacatgttct gtgccagctg ggaacccact gccccttctg 2000 atatctgcac tgcagagaca ggaggcatcg cggctgtgtc cttcccggga 2050 cgagcatctc ctgagccacg ctggcatctg atgggactgg tcagctggag 2100 ctatgataaa acatgcagcc acaggctctc cactgccttc accaaggtgc 2150 tgccttttaa agactggatt gaaagaaata tgaaatgaac catgctcatg 2200 cactccttga gaagtgtttc tgtatatccg tctgtacgtg tgtcattgcg 2250 tgaagcagtg tgggcctgaa gtgtgatttg gcctgtgaac ttggctgtgc 2300 cagggcttct gacttcaggg acaaaactca gtgaagggtg agtagacctc 2350 cattgctggt aggctgatgc cgcgtccact actaggacag ccaattggaa 2400 gatgccaggg cttgcaagaa gtaagtttct tcaaagaaga ccatatacaa 2450 aacctctcca ctccactgac ctggtggtct tccccaactt tcagttatac 2500 gaatgccatc agcttgacca gggaagatct gggcttcatg aggccccttt 2550 tgaggctctc aagttctaga gagctgcctg tgggacagcc cagggcagca 2600 gagctgggat gtggtgcatg cctttgtgta catggccaca gtacagtctg 2650 gtccttttcc ttccccatct cttgtacaca ttttaataaa ataagggttg 2700 gcttctgaac tacaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2750 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2800 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaa 2846 38 720 PRT Homo Sapien 38 Met Glu Leu Gly Cys Trp Thr Gln Leu Gly Leu Thr Phe Leu Gln 1 5 10 15 Leu Leu Leu Ile Ser Ser Leu Pro Arg Glu Tyr Thr Val Ile Asn 20 25 30 Glu Ala Cys Pro Gly Ala Glu Trp Asn Ile Met Cys Arg Glu Cys 35 40 45 Cys Glu Tyr Asp Gln Ile Glu Cys Val Cys Pro Gly Lys Arg Glu 50 55 60 Val Val Gly Tyr Thr Ile Pro Cys Cys Arg Asn Glu Glu Asn Glu 65 70 75 Cys Asp Ser Cys Leu Ile His Pro Gly Cys Thr Ile Phe Glu Asn 80 85 90 Cys Lys Ser Cys Arg Asn Gly Ser Trp Gly Gly Thr Leu Asp Asp 95 100 105 Phe Tyr Val Lys Gly Phe Tyr Cys Ala Glu Cys Arg Ala Gly Trp 110 115 120 Tyr Gly Gly Asp Cys Met Arg Cys Gly Gln Val Leu Arg Ala Pro 125 130 135 Lys Gly Gln Ile Leu Leu Glu Ser Tyr Pro Leu Asn Ala His Cys 140 145 150 Glu Trp Thr Ile His Ala Lys Pro Gly Phe Val Ile Gln Leu Arg 155 160 165 Phe Val Met Leu Ser Leu Glu Phe Asp Tyr Met Cys Gln Tyr Asp 170 175 180 Tyr Val Glu Val Arg Asp Gly Asp Asn Arg Asp Gly Gln Ile Ile 185 190 195 Lys Arg Val Cys Gly Asn Glu Arg Pro Ala Pro Ile Gln Ser Ile 200 205 210 Gly Ser Ser Leu His Val Leu Phe His Ser Asp Gly Ser Lys Asn 215 220 225 Phe Asp Gly Phe His Ala Ile Tyr Glu Glu Ile Thr Ala Cys Ser 230 235 240 Ser Ser Pro Cys Phe His Asp Gly Thr Cys Val Leu Asp Lys Ala 245 250 255 Gly Ser Tyr Lys Cys Ala Cys Leu Ala Gly Tyr Thr Gly Gln Arg 260 265 270 Cys Glu Asn Leu Leu Glu Glu Arg Asn Cys Ser Asp Pro Gly Gly 275 280 285 Pro Val Asn Gly Tyr Gln Lys Ile Thr Gly Gly Pro Gly Leu Ile 290 295 300 Asn Gly Arg His Ala Lys Ile Gly Thr Val Val Ser Phe Phe Cys 305 310 315 Asn Asn Ser Tyr Val Leu Ser Gly Asn Glu Lys Arg Thr Cys Gln 320 325 330 Gln Asn Gly Glu Trp Ser Gly Lys Gln Pro Ile Cys Ile Lys Ala 335 340 345 Cys Arg Glu Pro Lys Ile Ser Asp Leu Val Arg Arg Arg Val Leu 350 355 360 Pro Met Gln Val Gln Ser Arg Glu Thr Pro Leu His Gln Leu Tyr 365 370 375 Ser Ala Ala Phe Ser Lys Gln Lys Leu Gln Ser Ala Pro Thr Lys 380 385 390 Lys Pro Ala Leu Pro Phe Gly Asp Leu Pro Met Gly Tyr Gln His 395 400 405 Leu His Thr Gln Leu Gln Tyr Glu Cys Ile Ser Pro Phe Tyr Arg 410 415 420 Arg Leu Gly Ser Ser Arg Arg Thr Cys Leu Arg Thr Gly Lys Trp 425 430 435 Ser Gly Arg Ala Pro Ser Cys Ile Pro Ile Cys Gly Lys Ile Glu 440 445 450 Asn Ile Thr Ala Pro Lys Thr Gln Gly Leu Arg Trp Pro Trp Gln 455 460 465 Ala Ala Ile Tyr Arg Arg Thr Ser Gly Val His Asp Gly Ser Leu 470 475 480 His Lys Gly Ala Trp Phe Leu Val Cys Ser Gly Ala Leu Val Asn 485 490 495 Glu Arg Thr Val Val Val Ala Ala His Cys Val Thr Asp Leu Gly 500 505 510 Lys Val Thr Met Ile Lys Thr Ala Asp Leu Lys Val Val Leu Gly 515 520 525 Lys Phe Tyr Arg Asp Asp Asp Arg Asp Glu Lys Thr Ile Gln Ser 530 535 540 Leu Gln Ile Ser Ala Ile Ile Leu His Pro Asn Tyr Asp Pro Ile 545 550 555 Leu Leu Asp Ala Asp Ile Ala Ile Leu Lys Leu Leu Asp Lys Ala 560 565 570 Arg Ile Ser Thr Arg Val Gln Pro Ile Cys Leu Ala Ala Ser Arg 575 580 585 Asp Leu Ser Thr Ser Phe Gln Glu Ser His Ile Thr Val Ala Gly 590 595 600 Trp Asn Val Leu Ala Asp Val Arg Ser Pro Gly Phe Lys Asn Asp 605 610 615 Thr Leu Arg Ser Gly Val Val Ser Val Val Asp Ser Leu Leu Cys 620 625 630 Glu Glu Gln His Glu Asp His Gly Ile Pro Val Ser Val Thr Asp 635 640 645 Asn Met Phe Cys Ala Ser Trp Glu Pro Thr Ala Pro Ser Asp Ile 650 655 660 Cys Thr Ala Glu Thr Gly Gly Ile Ala Ala Val Ser Phe Pro Gly 665 670 675 Arg Ala Ser Pro Glu Pro Arg Trp His Leu Met Gly Leu Val Ser 680 685 690 Trp Ser Tyr Asp Lys Thr Cys Ser His Arg Leu Ser Thr Ala Phe 695 700 705 Thr Lys Val Leu Pro Phe Lys Asp Trp Ile Glu Arg Asn Met Lys 710 715 720 39 2571 DNA Homo Sapien 39 ggttcctaca tcctctcatc tgagaatcag agagcataat cttcttacgg 50 gcccgtgatt tattaacgtg gcttaatctg aaggttctca gtcaaattct 100 ttgtgatcta ctgattgtgg gggcatggca aggtttgctt aaaggagctt 150 ggctggtttg ggcccttgta gctgacagaa ggtggccagg gagaatgcag 200 cacactgctc ggagaatgaa ggcgcttctg ttgctggtct tgccttggct 250 cagtcctgct aactacattg acaatgtggg caacctgcac ttcctgtatt 300 cagaactctg taaaggtgcc tcccactacg gcctgaccaa agataggaag 350 aggcgctcac aagatggctg tccagacggc tgtgcgagcc tcacagccac 400 ggctccctcc ccagaggttt ctgcagctgc caccatctcc ttaatgacag 450 acgagcctgg cctagacaac cctgcctacg tgtcctcggc agaggacggg 500 cagccagcaa tcagcccagt ggactctggc cggagcaacc gaactagggc 550 acggcccttt gagagatcca ctattagaag cagatcattt aaaaaaataa 600 atcgagcttt gagtgttctt cgaaggacaa agagcgggag tgcagttgcc 650 aaccatgccg accagggcag ggaaaattct gaaaacacca ctgcccctga 700 agtctttcca aggttgtacc acctgattcc agatggtgaa attaccagca 750 tcaagatcaa tcgagtagat cccagtgaaa gcctctctat taggctggtg 800 ggaggtagcg aaaccccact ggtccatatc attatccaac acatttatcg 850 tgatggggtg atcgccagag acggccggct actgccagga gacatcattc 900 taaaggtcaa cgggatggac atcagcaatg tccctcacaa ctacgctgtg 950 cgtctcctgc ggcagccctg ccaggtgctg tggctgactg tgatgcgtga 1000 acagaagttc cgcagcagga acaatggaca ggccccggat gcctacagac 1050 cccgagatga cagctttcat gtgattctca acaaaagtag ccccgaggag 1100 cagcttggaa taaaactggt gcgcaaggtg gatgagcctg gggttttcat 1150 cttcaatgtg ctggatggcg gtgtggcata tcgacatggt cagcttgagg 1200 agaatgaccg tgtgttagcc atcaatggac atgatcttcg atatggcagc 1250 ccagaaagtg cggctcatct gattcaggcc agtgaaagac gtgttcacct 1300 cgtcgtgtcc cgccaggttc ggcagcggag ccctgacatc tttcaggaag 1350 ccggctggaa cagcaatggc agctggtccc cagggccagg ggagaggagc 1400 aacactccca agcccctcca tcctacaatt acttgtcatg agaaggtggt 1450 aaatatccaa aaagaccccg gtgaatctct cggcatgacc gtcgcagggg 1500 gagcatcaca tagagaatgg gatttgccta tctatgtcat cagtgttgag 1550 cccggaggag tcataagcag agatggaaga ataaaaacag gtgacatttt 1600 gttgaatgtg gatggggtcg aactgacaga ggtcagccgg agtgaggcag 1650 tggcattatt gaaaagaaca tcatcctcga tagtactcaa agctttggaa 1700 gtcaaagagt atgagcccca ggaagactgc agcagcccag cagccctgga 1750 ctccaaccac aacatggccc cacccagtga ctggtcccca tcctgggtca 1800 tgtggctgga attaccacgg tgcttgtata actgtaaaga tattgtatta 1850 cgaagaaaca cagctggaag tctgggcttc tgcattgtag gaggttatga 1900 agaatacaat ggaaacaaac cttttttcat caaatccatt gttgaaggaa 1950 caccagcata caatgatgga agaattagat gtggtgatat tcttcttgct 2000 gtcaatggta gaagtacatc aggaatgata catgcttgct tggcaagact 2050 gctgaaagaa cttaaaggaa gaattactct aactattgtt tcttggcctg 2100 gcactttttt atagaatcaa tgatgggtca gaggaaaaca gaaaaatcac 2150 aaataggcta agaagttgaa acactatatt tatcttgtca gtttttatat 2200 ttaaagaaag aatacattgt aaaaatgtca ggaaaagtat gatcatctaa 2250 tgaaagccag ttacacctca gaaaatatga ttccaaaaaa attaaaacta 2300 ctagtttttt ttcagtgtgg aggatttctc attactctac aacattgttt 2350 atattttttc tattcaataa aaagccctaa aacaactaaa atgattgatt 2400 tgtatacccc actgaattca agctgattta aatttaaaat ttggtatatg 2450 ctgaagtctg ccaagggtac attatggcca tttttaattt acagctaaaa 2500 tattttttaa aatgcattgc tgagaaacgt tgctttcatc aaacaagaat 2550 aaatattttt cagaagttaa a 2571 40 632 PRT Homo Sapien 40 Met Lys Ala Leu Leu Leu Leu Val Leu Pro Trp Leu Ser Pro Ala 1 5 10 15 Asn Tyr Ile Asp Asn Val Gly Asn Leu His Phe Leu Tyr Ser Glu 20 25 30 Leu Cys Lys Gly Ala Ser His Tyr Gly Leu Thr Lys Asp Arg Lys 35 40 45 Arg Arg Ser Gln Asp Gly Cys Pro Asp Gly Cys Ala Ser Leu Thr 50 55 60 Ala Thr Ala Pro Ser Pro Glu Val Ser Ala Ala Ala Thr Ile Ser 65 70 75 Leu Met Thr Asp Glu Pro Gly Leu Asp Asn Pro Ala Tyr Val Ser 80 85 90 Ser Ala Glu Asp Gly Gln Pro Ala Ile Ser Pro Val Asp Ser Gly 95 100 105 Arg Ser Asn Arg Thr Arg Ala Arg Pro Phe Glu Arg Ser Thr Ile 110 115 120 Arg Ser Arg Ser Phe Lys Lys Ile Asn Arg Ala Leu Ser Val Leu 125 130 135 Arg Arg Thr Lys Ser Gly Ser Ala Val Ala Asn His Ala Asp Gln 140 145 150 Gly Arg Glu Asn Ser Glu Asn Thr Thr Ala Pro Glu Val Phe Pro 155 160 165 Arg Leu Tyr His Leu Ile Pro Asp Gly Glu Ile Thr Ser Ile Lys 170 175 180 Ile Asn Arg Val Asp Pro Ser Glu Ser Leu Ser Ile Arg Leu Val 185 190 195 Gly Gly Ser Glu Thr Pro Leu Val His Ile Ile Ile Gln His Ile 200 205 210 Tyr Arg Asp Gly Val Ile Ala Arg Asp Gly Arg Leu Leu Pro Gly 215 220 225 Asp Ile Ile Leu Lys Val Asn Gly Met Asp Ile Ser Asn Val Pro 230 235 240 His Asn Tyr Ala Val Arg Leu Leu Arg Gln Pro Cys Gln Val Leu 245 250 255 Trp Leu Thr Val Met Arg Glu Gln Lys Phe Arg Ser Arg Asn Asn 260 265 270 Gly Gln Ala Pro Asp Ala Tyr Arg Pro Arg Asp Asp Ser Phe His 275 280 285 Val Ile Leu Asn Lys Ser Ser Pro Glu Glu Gln Leu Gly Ile Lys 290 295 300 Leu Val Arg Lys Val Asp Glu Pro Gly Val Phe Ile Phe Asn Val 305 310 315 Leu Asp Gly Gly Val Ala Tyr Arg His Gly Gln Leu Glu Glu Asn 320 325 330 Asp Arg Val Leu Ala Ile Asn Gly His Asp Leu Arg Tyr Gly Ser 335 340 345 Pro Glu Ser Ala Ala His Leu Ile Gln Ala Ser Glu Arg Arg Val 350 355 360 His Leu Val Val Ser Arg Gln Val Arg Gln Arg Ser Pro Asp Ile 365 370 375 Phe Gln Glu Ala Gly Trp Asn Ser Asn Gly Ser Trp Ser Pro Gly 380 385 390 Pro Gly Glu Arg Ser Asn Thr Pro Lys Pro Leu His Pro Thr Ile 395 400 405 Thr Cys His Glu Lys Val Val Asn Ile Gln Lys Asp Pro Gly Glu 410 415 420 Ser Leu Gly Met Thr Val Ala Gly Gly Ala Ser His Arg Glu Trp 425 430 435 Asp Leu Pro Ile Tyr Val Ile Ser Val Glu Pro Gly Gly Val Ile 440 445 450 Ser Arg Asp Gly Arg Ile Lys Thr Gly Asp Ile Leu Leu Asn Val 455 460 465 Asp Gly Val Glu Leu Thr Glu Val Ser Arg Ser Glu Ala Val Ala 470 475 480 Leu Leu Lys Arg Thr Ser Ser Ser Ile Val Leu Lys Ala Leu Glu 485 490 495 Val Lys Glu Tyr Glu Pro Gln Glu Asp Cys Ser Ser Pro Ala Ala 500 505 510 Leu Asp Ser Asn His Asn Met Ala Pro Pro Ser Asp Trp Ser Pro 515 520 525 Ser Trp Val Met Trp Leu Glu Leu Pro Arg Cys Leu Tyr Asn Cys 530 535 540 Lys Asp Ile Val Leu Arg Arg Asn Thr Ala Gly Ser Leu Gly Phe 545 550 555 Cys Ile Val Gly Gly Tyr Glu Glu Tyr Asn Gly Asn Lys Pro Phe 560 565 570 Phe Ile Lys Ser Ile Val Glu Gly Thr Pro Ala Tyr Asn Asp Gly 575 580 585 Arg Ile Arg Cys Gly Asp Ile Leu Leu Ala Val Asn Gly Arg Ser 590 595 600 Thr Ser Gly Met Ile His Ala Cys Leu Ala Arg Leu Leu Lys Glu 605 610 615 Leu Lys Gly Arg Ile Thr Leu Thr Ile Val Ser Trp Pro Gly Thr 620 625 630 Phe Leu 41 1964 DNA Homo Sapien 41 accaggcatt gtatcttcag ttgtcatcaa gttcgcaatc agattggaaa 50 agctcaactt gaagctttct tgcctgcagt gaagcagaga gatagatatt 100 attcacgtaa taaaaaacat gggcttcaac ctgactttcc acctttccta 150 caaattccga ttactgttgc tgttgacttt gtgcctgaca gtggttgggt 200 gggccaccag taactacttc gtgggtgcca ttcaagagat tcctaaagca 250 aaggagttca tggctaattt ccataagacc ctcattttgg ggaagggaaa 300 aactctgact aatgaagcat ccacgaagaa ggtagaactt gacaactgtc 350 cttctgtgtc tccttacctc agaggccaga gcaagctcat tttcaaacca 400 gatctcactt tggaagaggt acaggcagaa aatcccaaag tgtccagagg 450 ccggtatcgc cctcaggaat gtaaagcttt acagagggtc gccatcctcg 500 ttccccaccg gaacagagag aaacacctga tgtacctgct ggaacatctg 550 catcccttcc tgcagaggca gcagctggat tatggcatct acgtcatcca 600 ccaggctgaa ggtaaaaagt ttaatcgagc caaactcttg aatgtgggct 650 atctagaagc cctcaaggaa gaaaattggg actgctttat attccacgat 700 gtggacctgg tacccgagaa tgactttaac ctttacaagt gtgaggagca 750 tcccaagcat ctggtggttg gcaggaacag cactgggtac aggttacgtt 800 acagtggata ttttgggggt gttactgccc taagcagaga gcagtttttc 850 aaggtgaatg gattctctaa caactactgg ggatggggag gcgaagacga 900 tgacctcaga ctcagggttg agctccaaag aatgaaaatt tcccggcccc 950 tgcctgaagt gggtaaatat acaatggtct tccacactag agacaaaggc 1000 aatgaggtga acgcagaacg gatgaagctc ttacaccaag tgtcacgagt 1050 ctggagaaca gatgggttga gtagttgttc ttataaatta gtatctgtgg 1100 aacacaatcc tttatatatc aacatcacag tggatttctg gtttggtgca 1150 tgaccctgga tcttttggtg atgtttggaa gaactgattc tttgtttgca 1200 ataattttgg cctagagact tcaaatagta gcacacatta agaacctgtt 1250 acagctcatt gttgagctga atttttcctt tttgtatttt cttagcagag 1300 ctcctggtga tgtagagtat aaaacagttg taacaagaca gctttcttag 1350 tcattttgat catgagggtt aaatattgta atatggatac ttgaaggact 1400 ttatataaaa ggatgactca aaggataaaa tgaacgctat ttgaggactc 1450 tggttgaagg agatttattt aaatttgaag taatatatta tgggataaaa 1500 ggccacagga aataagactg ctgaatgtct gagagaacca gagttgttct 1550 cgtccaaggt agaaaggtac gaagatacaa tactgttatt catttatcct 1600 gtacaatcat ctgtgaagtg gtggtgtcag gtgagaaggc gtccacaaaa 1650 gaggggagaa aaggcgacga atcaggacac agtgaacttg ggaatgaaga 1700 ggtagcagga gggtggagtg tcggctgcaa aggcagcagt agctgagctg 1750 gttgcaggtg ctgatagcct tcaggggagg acctgcccag gtatgccttc 1800 cagtgatgcc caccagagaa tacattctct attagttttt aaagagtttt 1850 tgtaaaatga ttttgtacaa gtaggatatg aattagcagt ttacaagttt 1900 acatattaac taataataaa tatgtctatc aaatacctct gtagtaaaat 1950 gtgaaaaagc aaaa 1964 42 344 PRT Homo Sapien 42 Met Gly Phe Asn Leu Thr Phe His Leu Ser Tyr Lys Phe Arg Leu 1 5 10 15 Leu Leu Leu Leu Thr Leu Cys Leu Thr Val Val Gly Trp Ala Thr 20 25 30 Ser Asn Tyr Phe Val Gly Ala Ile Gln Glu Ile Pro Lys Ala Lys 35 40 45 Glu Phe Met Ala Asn Phe His Lys Thr Leu Ile Leu Gly Lys Gly 50 55 60 Lys Thr Leu Thr Asn Glu Ala Ser Thr Lys Lys Val Glu Leu Asp 65 70 75 Asn Cys Pro Ser Val Ser Pro Tyr Leu Arg Gly Gln Ser Lys Leu 80 85 90 Ile Phe Lys Pro Asp Leu Thr Leu Glu Glu Val Gln Ala Glu Asn 95 100 105 Pro Lys Val Ser Arg Gly Arg Tyr Arg Pro Gln Glu Cys Lys Ala 110 115 120 Leu Gln Arg Val Ala Ile Leu Val Pro His Arg Asn Arg Glu Lys 125 130 135 His Leu Met Tyr Leu Leu Glu His Leu His Pro Phe Leu Gln Arg 140 145 150 Gln Gln Leu Asp Tyr Gly Ile Tyr Val Ile His Gln Ala Glu Gly 155 160 165 Lys Lys Phe Asn Arg Ala Lys Leu Leu Asn Val Gly Tyr Leu Glu 170 175 180 Ala Leu Lys Glu Glu Asn Trp Asp Cys Phe Ile Phe His Asp Val 185 190 195 Asp Leu Val Pro Glu Asn Asp Phe Asn Leu Tyr Lys Cys Glu Glu 200 205 210 His Pro Lys His Leu Val Val Gly Arg Asn Ser Thr Gly Tyr Arg 215 220 225 Leu Arg Tyr Ser Gly Tyr Phe Gly Gly Val Thr Ala Leu Ser Arg 230 235 240 Glu Gln Phe Phe Lys Val Asn Gly Phe Ser Asn Asn Tyr Trp Gly 245 250 255 Trp Gly Gly Glu Asp Asp Asp Leu Arg Leu Arg Val Glu Leu Gln 260 265 270 Arg Met Lys Ile Ser Arg Pro Leu Pro Glu Val Gly Lys Tyr Thr 275 280 285 Met Val Phe His Thr Arg Asp Lys Gly Asn Glu Val Asn Ala Glu 290 295 300 Arg Met Lys Leu Leu His Gln Val Ser Arg Val Trp Arg Thr Asp 305 310 315 Gly Leu Ser Ser Cys Ser Tyr Lys Leu Val Ser Val Glu His Asn 320 325 330 Pro Leu Tyr Ile Asn Ile Thr Val Asp Phe Trp Phe Gly Ala 335 340 43 485 DNA Homo Sapien 43 gctcaagacc cagcagtggg acagccagac agacggcacg atggcactga 50 gctcccagat ctgggccgct tgcctcctgc tcctcctcct cctcgccagc 100 ctgaccagtg gctctgtttt cccacaacag acgggacaac ttgcagagct 150 gcaaccccag gacagagctg gagccagggc cagctggatg cccatgttcc 200 agaggcgaag gaggcgagac acccacttcc ccatctgcat tttctgctgc 250 ggctgctgtc atcgatcaaa gtgtgggatg tgctgcaaga cgtagaacct 300 acctgccctg cccccgtccc ctcccttcct tatttattcc tgctgcccca 350 gaacataggt cttggaataa aatggctggt tcttttgttt tccaaaaaaa 400 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 450 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaa 485 44 84 PRT Homo Sapien 44 Met Ala Leu Ser Ser Gln Ile Trp Ala Ala Cys Leu Leu Leu Leu 1 5 10 15 Leu Leu Leu Ala Ser Leu Thr Ser Gly Ser Val Phe Pro Gln Gln 20 25 30 Thr Gly Gln Leu Ala Glu Leu Gln Pro Gln Asp Arg Ala Gly Ala 35 40 45 Arg Ala Ser Trp Met Pro Met Phe Gln Arg Arg Arg Arg Arg Asp 50 55 60 Thr His Phe Pro Ile Cys Ile Phe Cys Cys Gly Cys Cys His Arg 65 70 75 Ser Lys Cys Gly Met Cys Cys Lys Thr 80 45 1076 DNA Homo Sapien 45 gtggcttcat ttcagtggct gacttccaga gagcaatatg gctggttccc 50 caacatgcct caccctcatc tatatccttt ggcagctcac agggtcagca 100 gcctctggac ccgtgaaaga gctggtcggt tccgttggtg gggccgtgac 150 tttccccctg aagtccaaag taaagcaagt tgactctatt gtctggacct 200 tcaacacaac ccctcttgtc accatacagc cagaaggggg cactatcata 250 gtgacccaaa atcgtaatag ggagagagta gacttcccag atggaggcta 300 ctccctgaag ctcagcaaac tgaagaagaa tgactcaggg atctactatg 350 tggggatata cagctcatca ctccagcagc cctccaccca ggagtacgtg 400 ctgcatgtct acgagcacct gtcaaagcct aaagtcacca tgggtctgca 450 gagcaataag aatggcacct gtgtgaccaa tctgacatgc tgcatggaac 500 atggggaaga ggatgtgatt tatacctgga aggccctggg gcaagcagcc 550 aatgagtccc ataatgggtc catcctcccc atctcctgga gatggggaga 600 aagtgatatg accttcatct gcgttgccag gaaccctgtc agcagaaact 650 tctcaagccc catccttgcc aggaagctct gtgaaggtgc tgctgatgac 700 ccagattcct ccatggtcct cctgtgtctc ctgttggtgc ccctcctgct 750 cagtctcttt gtactggggc tatttctttg gtttctgaag agagagagac 800 aagaagagta cattgaagag aagaagagag tggacatttg tcgggaaact 850 cctaacatat gcccccattc tggagagaac acagagtacg acacaatccc 900 tcacactaat agaacaatcc taaaggaaga tccagcaaat acggtttact 950 ccactgtgga aataccgaaa aagatggaaa atccccactc actgctcacg 1000 atgccagaca caccaaggct atttgcctat gagaatgtta tctagacagc 1050 agtgcactcc cctaagtctc tgctca 1076 46 335 PRT Homo Sapien 46 Met Ala Gly Ser Pro Thr Cys Leu Thr Leu Ile Tyr Ile Leu Trp 1 5 10 15 Gln Leu Thr Gly Ser Ala Ala Ser Gly Pro Val Lys Glu Leu Val 20 25 30 Gly Ser Val Gly Gly Ala Val Thr Phe Pro Leu Lys Ser Lys Val 35 40 45 Lys Gln Val Asp Ser Ile Val Trp Thr Phe Asn Thr Thr Pro Leu 50 55 60 Val Thr Ile Gln Pro Glu Gly Gly Thr Ile Ile Val Thr Gln Asn 65 70 75 Arg Asn Arg Glu Arg Val Asp Phe Pro Asp Gly Gly Tyr Ser Leu 80 85 90 Lys Leu Ser Lys Leu Lys Lys Asn Asp Ser Gly Ile Tyr Tyr Val 95 100 105 Gly Ile Tyr Ser Ser Ser Leu Gln Gln Pro Ser Thr Gln Glu Tyr 110 115 120 Val Leu His Val Tyr Glu His Leu Ser Lys Pro Lys Val Thr Met 125 130 135 Gly Leu Gln Ser Asn Lys Asn Gly Thr Cys Val Thr Asn Leu Thr 140 145 150 Cys Cys Met Glu His Gly Glu Glu Asp Val Ile Tyr Thr Trp Lys 155 160 165 Ala Leu Gly Gln Ala Ala Asn Glu Ser His Asn Gly Ser Ile Leu 170 175 180 Pro Ile Ser Trp Arg Trp Gly Glu Ser Asp Met Thr Phe Ile Cys 185 190 195 Val Ala Arg Asn Pro Val Ser Arg Asn Phe Ser Ser Pro Ile Leu 200 205 210 Ala Arg Lys Leu Cys Glu Gly Ala Ala Asp Asp Pro Asp Ser Ser 215 220 225 Met Val Leu Leu Cys Leu Leu Leu Val Pro Leu Leu Leu Ser Leu 230 235 240 Phe Val Leu Gly Leu Phe Leu Trp Phe Leu Lys Arg Glu Arg Gln 245 250 255 Glu Glu Tyr Ile Glu Glu Lys Lys Arg Val Asp Ile Cys Arg Glu 260 265 270 Thr Pro Asn Ile Cys Pro His Ser Gly Glu Asn Thr Glu Tyr Asp 275 280 285 Thr Ile Pro His Thr Asn Arg Thr Ile Leu Lys Glu Asp Pro Ala 290 295 300 Asn Thr Val Tyr Ser Thr Val Glu Ile Pro Lys Lys Met Glu Asn 305 310 315 Pro His Ser Leu Leu Thr Met Pro Asp Thr Pro Arg Leu Phe Ala 320 325 330 Tyr Glu Asn Val Ile 335 47 766 DNA Homo Sapien 47 ggctcgagcg tttctgagcc aggggtgacc atgacctgct gcgaaggatg 50 gacatcctgc aatggattca gcctgctggt tctactgctg ttaggagtag 100 ttctcaatgc gatacctcta attgtcagct tagttgagga agaccaattt 150 tctcaaaacc ccatctcttg ctttgagtgg tggttcccag gaattatagg 200 agcaggtctg atggccattc cagcaacaac aatgtccttg acagcaagaa 250 aaagagcgtg ctgcaacaac agaactggaa tgtttctttc atcatttttc 300 agtgtgatca cagtcattgg tgctctgtat tgcatgctga tatccatcca 350 ggctctctta aaaggtcctc tcatgtgtaa ttctccaagc aacagtaatg 400 ccaattgtga attttcattg aaaaacatca gtgacattca tccagaatcc 450 ttcaacttgc agtggttttt caatgactct tgtgcacctc ctactggttt 500 caataaaccc accagtaacg acaccatggc gagtggctgg agagcatcta 550 gtttccactt cgattctgaa gaaaacaaac ataggcttat ccacttctca 600 gtatttttag gtctattgct tgttggaatt ctggaggtcc tgtttgggct 650 cagtcagata gtcatcggtt tccttggctg tctgtgtgga gtctctaagc 700 gaagaagtca aattgtgtag tttaatggga ataaaatgta agtatcagta 750 gtttgaaaaa aaaaaa 766 48 229 PRT Homo Sapien 48 Met Thr Cys Cys Glu Gly Trp Thr Ser Cys Asn Gly Phe Ser Leu 1 5 10 15 Leu Val Leu Leu Leu Leu Gly Val Val Leu Asn Ala Ile Pro Leu 20 25 30 Ile Val Ser Leu Val Glu Glu Asp Gln Phe Ser Gln Asn Pro Ile 35 40 45 Ser Cys Phe Glu Trp Trp Phe Pro Gly Ile Ile Gly Ala Gly Leu 50 55 60 Met Ala Ile Pro Ala Thr Thr Met Ser Leu Thr Ala Arg Lys Arg 65 70 75 Ala Cys Cys Asn Asn Arg Thr Gly Met Phe Leu Ser Ser Phe Phe 80 85 90 Ser Val Ile Thr Val Ile Gly Ala Leu Tyr Cys Met Leu Ile Ser 95 100 105 Ile Gln Ala Leu Leu Lys Gly Pro Leu Met Cys Asn Ser Pro Ser 110 115 120 Asn Ser Asn Ala Asn Cys Glu Phe Ser Leu Lys Asn Ile Ser Asp 125 130 135 Ile His Pro Glu Ser Phe Asn Leu Gln Trp Phe Phe Asn Asp Ser 140 145 150 Cys Ala Pro Pro Thr Gly Phe Asn Lys Pro Thr Ser Asn Asp Thr 155 160 165 Met Ala Ser Gly Trp Arg Ala Ser Ser Phe His Phe Asp Ser Glu 170 175 180 Glu Asn Lys His Arg Leu Ile His Phe Ser Val Phe Leu Gly Leu 185 190 195 Leu Leu Val Gly Ile Leu Glu Val Leu Phe Gly Leu Ser Gln Ile 200 205 210 Val Ile Gly Phe Leu Gly Cys Leu Cys Gly Val Ser Lys Arg Arg 215 220 225 Ser Gln Ile Val 49 636 DNA Homo Sapien 49 atccgttctc tgcgctgcca gctcaggtga gccctcgcca aggtgacctc 50 gcaggacact ggtgaaggag cagtgaggaa cctgcagagt cacacagttg 100 ctgaccaatt gagctgtgag cctggagcag atccgtgggc tgcagacccc 150 cgccccagtg cctctccccc tgcagccctg cccctcgaac tgtgacatgg 200 agagagtgac cctggccctt ctcctactgg caggcctgac tgccttggaa 250 gccaatgacc catttgccaa taaagacgat cccttctact atgactggaa 300 aaacctgcag ctgagcggac tgatctgcgg agggctcctg gccattgctg 350 ggatcgcggc agttctgagt ggcaaatgca aatacaagag cagccagaag 400 cagcacagtc ctgtacctga gaaggccatc ccactcatca ctccaggctc 450 tgccactact tgctgagcac aggactggcc tccagggatg gcctgaagcc 500 taacactggc ccccagcacc tcctcccctg ggaggcctta tcctcaagga 550 aggacttctc tccaagggca ggctgttagg cccctttctg atcaggaggc 600 ttctttatga attaaactcg ccccaccacc ccctca 636 50 89 PRT Homo Sapien 50 Met Glu Arg Val Thr Leu Ala Leu Leu Leu Leu Ala Gly Leu Thr 1 5 10 15 Ala Leu Glu Ala Asn Asp Pro Phe Ala Asn Lys Asp Asp Pro Phe 20 25 30 Tyr Tyr Asp Trp Lys Asn Leu Gln Leu Ser Gly Leu Ile Cys Gly 35 40 45 Gly Leu Leu Ala Ile Ala Gly Ile Ala Ala Val Leu Ser Gly Lys 50 55 60 Cys Lys Tyr Lys Ser Ser Gln Lys Gln His Ser Pro Val Pro Glu 65 70 75 Lys Ala Ile Pro Leu Ile Thr Pro Gly Ser Ala Thr Thr Cys 80 85 51 1734 DNA Homo Sapien 51 gtggactctg agaagcccag gcagttgagg acaggagaga gaaggctgca 50 gacccagagg gagggaggac agggagtcgg aaggaggagg acagaggagg 100 gcacagagac gcagagcaag ggcggcaagg aggagaccct ggtgggagga 150 agacactctg gagagagagg gggctgggca gagatgaagt tccaggggcc 200 cctggcctgc ctcctgctgg ccctctgcct gggcagtggg gaggctggcc 250 ccctgcagag cggagaggaa agcactggga caaatattgg ggaggccctt 300 ggacatggcc tgggagacgc cctgagcgaa ggggtgggaa aggccattgg 350 caaagaggcc ggaggggcag ctggctctaa agtcagtgag gcccttggcc 400 aagggaccag agaagcagtt ggcactggag tcaggcaggt tccaggcttt 450 ggcgcagcag atgctttggg caacagggtc ggggaagcag cccatgctct 500 gggaaacact gggcacgaga ttggcagaca ggcagaagat gtcattcgac 550 acggagcaga tgctgtccgc ggctcctggc agggggtgcc tggccacagt 600 ggtgcttggg aaacttctgg aggccatggc atctttggct ctcaaggtgg 650 ccttggaggc cagggccagg gcaatcctgg aggtctgggg actccgtggg 700 tccacggata ccccggaaac tcagcaggca gctttggaat gaatcctcag 750 ggagctccct ggggtcaagg aggcaatgga gggccaccaa actttgggac 800 caacactcag ggagctgtgg cccagcctgg ctatggttca gtgagagcca 850 gcaaccagaa tgaagggtgc acgaatcccc caccatctgg ctcaggtgga 900 ggctccagca actctggggg aggcagcggc tcacagtcgg gcagcagtgg 950 cagtggcagc aatggtgaca acaacaatgg cagcagcagt ggtggcagca 1000 gcagtggcag cagcagtggc agcagcagtg gcggcagcag tggcggcagc 1050 agtggtggca gcagtggcaa cagtggtggc agcagaggtg acagcggcag 1100 tgagtcctcc tggggatcca gcaccggctc ctcctccggc aaccacggtg 1150 ggagcggcgg aggaaatgga cataaacccg ggtgtgaaaa gccagggaat 1200 gaagcccgcg ggagcgggga atctgggatt cagggcttca gaggacaggg 1250 agtttccagc aacatgaggg aaataagcaa agagggcaat cgcctccttg 1300 gaggctctgg agacaattat cgggggcaag ggtcgagctg gggcagtgga 1350 ggaggtgacg ctgttggtgg agtcaatact gtgaactctg agacgtctcc 1400 tgggatgttt aactttgaca ctttctggaa gaattttaaa tccaagctgg 1450 gtttcatcaa ctgggatgcc ataaacaagg accagagaag ctctcgcatc 1500 ccgtgacctc cagacaagga gccaccagat tggatgggag cccccacact 1550 ccctccttaa aacaccaccc tctcatcact aatctcagcc cttgcccttg 1600 aaataaacct tagctgcccc acaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1650 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1700 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaa 1734 52 440 PRT Homo Sapien 52 Met Lys Phe Gln Gly Pro Leu Ala Cys Leu Leu Leu Ala Leu Cys 1 5 10 15 Leu Gly Ser Gly Glu Ala Gly Pro Leu Gln Ser Gly Glu Glu Ser 20 25 30 Thr Gly Thr Asn Ile Gly Glu Ala Leu Gly His Gly Leu Gly Asp 35 40 45 Ala Leu Ser Glu Gly Val Gly Lys Ala Ile Gly Lys Glu Ala Gly 50 55 60 Gly Ala Ala Gly Ser Lys Val Ser Glu Ala Leu Gly Gln Gly Thr 65 70 75 Arg Glu Ala Val Gly Thr Gly Val Arg Gln Val Pro Gly Phe Gly 80 85 90 Ala Ala Asp Ala Leu Gly Asn Arg Val Gly Glu Ala Ala His Ala 95 100 105 Leu Gly Asn Thr Gly His Glu Ile Gly Arg Gln Ala Glu Asp Val 110 115 120 Ile Arg His Gly Ala Asp Ala Val Arg Gly Ser Trp Gln Gly Val 125 130 135 Pro Gly His Ser Gly Ala Trp Glu Thr Ser Gly Gly His Gly Ile 140 145 150 Phe Gly Ser Gln Gly Gly Leu Gly Gly Gln Gly Gln Gly Asn Pro 155 160 165 Gly Gly Leu Gly Thr Pro Trp Val His Gly Tyr Pro Gly Asn Ser 170 175 180 Ala Gly Ser Phe Gly Met Asn Pro Gln Gly Ala Pro Trp Gly Gln 185 190 195 Gly Gly Asn Gly Gly Pro Pro Asn Phe Gly Thr Asn Thr Gln Gly 200 205 210 Ala Val Ala Gln Pro Gly Tyr Gly Ser Val Arg Ala Ser Asn Gln 215 220 225 Asn Glu Gly Cys Thr Asn Pro Pro Pro Ser Gly Ser Gly Gly Gly 230 235 240 Ser Ser Asn Ser Gly Gly Gly Ser Gly Ser Gln Ser Gly Ser Ser 245 250 255 Gly Ser Gly Ser Asn Gly Asp Asn Asn Asn Gly Ser Ser Ser Gly 260 265 270 Gly Ser Ser Ser Gly Ser Ser Ser Gly Ser Ser Ser Gly Gly Ser 275 280 285 Ser Gly Gly Ser Ser Gly Gly Ser Ser Gly Asn Ser Gly Gly Ser 290 295 300 Arg Gly Asp Ser Gly Ser Glu Ser Ser Trp Gly Ser Ser Thr Gly 305 310 315 Ser Ser Ser Gly Asn His Gly Gly Ser Gly Gly Gly Asn Gly His 320 325 330 Lys Pro Gly Cys Glu Lys Pro Gly Asn Glu Ala Arg Gly Ser Gly 335 340 345 Glu Ser Gly Ile Gln Gly Phe Arg Gly Gln Gly Val Ser Ser Asn 350 355 360 Met Arg Glu Ile Ser Lys Glu Gly Asn Arg Leu Leu Gly Gly Ser 365 370 375 Gly Asp Asn Tyr Arg Gly Gln Gly Ser Ser Trp Gly Ser Gly Gly 380 385 390 Gly Asp Ala Val Gly Gly Val Asn Thr Val Asn Ser Glu Thr Ser 395 400 405 Pro Gly Met Phe Asn Phe Asp Thr Phe Trp Lys Asn Phe Lys Ser 410 415 420 Lys Leu Gly Phe Ile Asn Trp Asp Ala Ile Asn Lys Asp Gln Arg 425 430 435 Ser Ser Arg Ile Pro 440 53 1676 DNA Homo Sapien 53 ggagaagagg ttgtgtggga caagctgctc ccgacagaag gatgtcgctg 50 ctgagcctgc cctggctggg cctcagaccg gtggcaatgt ccccatggct 100 actcctgctg ctggttgtgg gctcctggct actcgcccgc atcctggctt 150 ggacctatgc cttctataac aactgccgcc ggctccagtg tttcccacag 200 cccccaaaac ggaactggtt ttggggtcac ctgggcctga tcactcctac 250 agaggagggc ttgaaggact cgacccagat gtcggccacc tattcccagg 300 gctttacggt atggctgggt cccatcatcc ccttcatcgt tttatgccac 350 cctgacacca tccggtctat caccaatgcc tcagctgcca ttgcacccaa 400 ggataatctc ttcatcaggt tcctgaagcc ctggctggga gaagggatac 450 tgctgagtgg cggtgacaag tggagccgcc accgtcggat gctgacgccc 500 gccttccatt tcaacatcct gaagtcctat ataacgatct tcaacaagag 550 tgcaaacatc atgcttgaca agtggcagca cctggcctca gagggcagca 600 gtcgtctgga catgtttgag cacatcagcc tcatgacctt ggacagtcta 650 cagaaatgca tcttcagctt tgacagccat tgtcaggaga ggcccagtga 700 atatattgcc accatcttgg agctcagtgc ccttgtagag aaaagaagcc 750 agcatatcct ccagcacatg gactttctgt attacctctc ccatgacggg 800 cggcgcttcc acagggcctg ccgcctggtg catgacttca cagacgctgt 850 catccgggag cggcgtcgca ccctccccac tcagggtatt gatgattttt 900 tcaaagacaa agccaagtcc aagactttgg atttcattga tgtgcttctg 950 ctgagcaagg atgaagatgg gaaggcattg tcagatgagg atataagagc 1000 agaggctgac accttcatgt ttggaggcca tgacaccacg gccagtggcc 1050 tctcctgggt cctgtacaac cttgcgaggc acccagaata ccaggagcgc 1100 tgccgacagg aggtgcaaga gcttctgaag gaccgcgatc ctaaagagat 1150 tgaatgggac gacctggccc agctgccctt cctgaccatg tgcgtgaagg 1200 agagcctgag gttacatccc ccagctccct tcatctcccg atgctgcacc 1250 caggacattg ttctcccaga tggccgagtc atccccaaag gcattacctg 1300 cctcatcgat attatagggg tccatcacaa cccaactgtg tggccggatc 1350 ctgaggtcta cgaccccttc cgctttgacc cagagaacag caaggggagg 1400 tcacctctgg cttttattcc tttctccgca gggcccagga actgcatcgg 1450 gcaggcgttc gccatggcgg agatgaaagt ggtcctggcg ttgatgctgc 1500 tgcacttccg gttcctgcca gaccacactg agccccgcag gaagctggaa 1550 ttgatcatgc gcgccgaggg cgggctttgg ctgcgggtgg agcccctgaa 1600 tgtaggcttg cagtgacttt ctgacccatc cacctgtttt tttgcagatt 1650 gtcatgaata aaacggtgct gtcaaa 1676 54 524 PRT Homo Sapien 54 Met Ser Leu Leu Ser Leu Pro Trp Leu Gly Leu Arg Pro Val Ala 1 5 10 15 Met Ser Pro Trp Leu Leu Leu Leu Leu Val Val Gly Ser Trp Leu 20 25 30 Leu Ala Arg Ile Leu Ala Trp Thr Tyr Ala Phe Tyr Asn Asn Cys 35 40 45 Arg Arg Leu Gln Cys Phe Pro Gln Pro Pro Lys Arg Asn Trp Phe 50 55 60 Trp Gly His Leu Gly Leu Ile Thr Pro Thr Glu Glu Gly Leu Lys 65 70 75 Asp Ser Thr Gln Met Ser Ala Thr Tyr Ser Gln Gly Phe Thr Val 80 85 90 Trp Leu Gly Pro Ile Ile Pro Phe Ile Val Leu Cys His Pro Asp 95 100 105 Thr Ile Arg Ser Ile Thr Asn Ala Ser Ala Ala Ile Ala Pro Lys 110 115 120 Asp Asn Leu Phe Ile Arg Phe Leu Lys Pro Trp Leu Gly Glu Gly 125 130 135 Ile Leu Leu Ser Gly Gly Asp Lys Trp Ser Arg His Arg Arg Met 140 145 150 Leu Thr Pro Ala Phe His Phe Asn Ile Leu Lys Ser Tyr Ile Thr 155 160 165 Ile Phe Asn Lys Ser Ala Asn Ile Met Leu Asp Lys Trp Gln His 170 175 180 Leu Ala Ser Glu Gly Ser Ser Arg Leu Asp Met Phe Glu His Ile 185 190 195 Ser Leu Met Thr Leu Asp Ser Leu Gln Lys Cys Ile Phe Ser Phe 200 205 210 Asp Ser His Cys Gln Glu Arg Pro Ser Glu Tyr Ile Ala Thr Ile 215 220 225 Leu Glu Leu Ser Ala Leu Val Glu Lys Arg Ser Gln His Ile Leu 230 235 240 Gln His Met Asp Phe Leu Tyr Tyr Leu Ser His Asp Gly Arg Arg 245 250 255 Phe His Arg Ala Cys Arg Leu Val His Asp Phe Thr Asp Ala Val 260 265 270 Ile Arg Glu Arg Arg Arg Thr Leu Pro Thr Gln Gly Ile Asp Asp 275 280 285 Phe Phe Lys Asp Lys Ala Lys Ser Lys Thr Leu Asp Phe Ile Asp 290 295 300 Val Leu Leu Leu Ser Lys Asp Glu Asp Gly Lys Ala Leu Ser Asp 305 310 315 Glu Asp Ile Arg Ala Glu Ala Asp Thr Phe Met Phe Gly Gly His 320 325 330 Asp Thr Thr Ala Ser Gly Leu Ser Trp Val Leu Tyr Asn Leu Ala 335 340 345 Arg His Pro Glu Tyr Gln Glu Arg Cys Arg Gln Glu Val Gln Glu 350 355 360 Leu Leu Lys Asp Arg Asp Pro Lys Glu Ile Glu Trp Asp Asp Leu 365 370 375 Ala Gln Leu Pro Phe Leu Thr Met Cys Val Lys Glu Ser Leu Arg 380 385 390 Leu His Pro Pro Ala Pro Phe Ile Ser Arg Cys Cys Thr Gln Asp 395 400 405 Ile Val Leu Pro Asp Gly Arg Val Ile Pro Lys Gly Ile Thr Cys 410 415 420 Leu Ile Asp Ile Ile Gly Val His His Asn Pro Thr Val Trp Pro 425 430 435 Asp Pro Glu Val Tyr Asp Pro Phe Arg Phe Asp Pro Glu Asn Ser 440 445 450 Lys Gly Arg Ser Pro Leu Ala Phe Ile Pro Phe Ser Ala Gly Pro 455 460 465 Arg Asn Cys Ile Gly Gln Ala Phe Ala Met Ala Glu Met Lys Val 470 475 480 Val Leu Ala Leu Met Leu Leu His Phe Arg Phe Leu Pro Asp His 485 490 495 Thr Glu Pro Arg Arg Lys Leu Glu Leu Ile Met Arg Ala Glu Gly 500 505 510 Gly Leu Trp Leu Arg Val Glu Pro Leu Asn Val Gly Leu Gln 515 520 55 644 DNA Homo Sapien 55 atcgcatcaa ttgggagtac catcttcctc atgggaccag tgaaacagct 50 gaagcgaatg tttgagccta ctcgtttgat tgcaactatc atggtgctgt 100 tgtgttttgc acttaccctg tgttctgcct tttggtggca taacaaggga 150 cttgcactta tcttctgcat tttgcagtct ttggcattga cgtggtacag 200 cctttccttc ataccatttg caagggatgc tgtgaagaag tgttttgccg 250 tgtgtcttgc ataattcatg gccagtttta tgaagctttg gaaggcacta 300 tggacagaag ctggtggaca gttttgtaac tatcttcgaa acctctgtct 350 tacagacatg tgccttttat cttgcagcaa tgtgttgctt gtgattcgaa 400 catttgaggg ttacttttgg aagcaacaat acattctcga acctgaatgt 450 cagtagcaca ggatgagaag tgggttctgt atcttgtgga gtggaatctt 500 cctcatgtac ctgtttcctc tctggatgtt gtcccactga attcccatga 550 atacaaacct attcagcaac agcaaaaaaa aaaaaaaaaa aaaaaaaaaa 600 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaa 644 56 77 PRT Homo Sapien 56 Met Gly Pro Val Lys Gln Leu Lys Arg Met Phe Glu Pro Thr Arg 1 5 10 15 Leu Ile Ala Thr Ile Met Val Leu Leu Cys Phe Ala Leu Thr Leu 20 25 30 Cys Ser Ala Phe Trp Trp His Asn Lys Gly Leu Ala Leu Ile Phe 35 40 45 Cys Ile Leu Gln Ser Leu Ala Leu Thr Trp Tyr Ser Leu Ser Phe 50 55 60 Ile Pro Phe Ala Arg Asp Ala Val Lys Lys Cys Phe Ala Val Cys 65 70 75 Leu Ala 57 3334 DNA Homo Sapien 57 cggctcgagc tcgagccgaa tcggctcgag gggcagtgga gcacccagca 50 ggccgccaac atgctctgtc tgtgcctgta cgtgccggtc atcggggaag 100 cccagaccga gttccagtac tttgagtcga aggggctccc tgccgagctg 150 aagtccattt tcaagctcag tgtcttcatc ccctcccagg aattctccac 200 ctaccgccag tggaagcaga aaattgtaca agctggagat aaggaccttg 250 atgggcagct agactttgaa gaatttgtcc attatctcca agatcatgag 300 aagaagctga ggctggtgtt taagattttg gacaaaaaga atgatggacg 350 cattgacgcg caggagatca tgcagtccct gcgggacttg ggagtcaaga 400 tatctgaaca gcaggcagaa aaaattctca agagcatgga taaaaacggc 450 acgatgacca tcgactggaa cgagtggaga gactaccacc tcctccaccc 500 cgtggaaaac atccccgaga tcatcctcta ctggaagcat tccacgatct 550 ttgatgtggg tgagaatcta acggtcccgg atgagttcac agtggaggag 600 aggcagacgg ggatgtggtg gagacacctg gtggcaggag gtggggcagg 650 ggccgtatcc agaacctgca cggcccccct ggacaggctc aaggtgctca 700 tgcaggtcca tgcctcccgc agcaacaaca tgggcatcgt tggtggcttc 750 actcagatga ttcgagaagg aggggccagg tcactctggc ggggcaatgg 800 catcaacgtc ctcaaaattg cccccgaatc agccatcaaa ttcatggcct 850 atgagcagat caagcgcctt gttggtagtg accaggagac tctgaggatt 900 cacgagaggc ttgtggcagg gtccttggca ggggccatcg cccagagcag 950 catctaccca atggaggtcc tgaagacccg gatggcgctg cggaagacag 1000 gccagtactc aggaatgctg gactgcgcca ggaggatcct ggccagagag 1050 ggggtggccg ccttctacaa aggctatgtc cccaacatgc tgggcatcat 1100 cccctatgcc ggcatcgacc ttgcagtcta cgagacgctc aagaatgcct 1150 ggctgcagca ctatgcagtg aacagcgcgg accccggcgt gtttgtgctc 1200 ctggcctgtg gcaccatgtc cagtacctgt ggccagctgg ccagctaccc 1250 cctggcccta gtcaggaccc ggatgcaggc gcaagcctct attgagggcg 1300 ctccggaggt gaccatgagc agcctcttca aacatatcct gcggaccgag 1350 ggggccttcg ggctgtacag ggggctggcc cccaacttca tgaaggtcat 1400 cccagctgtg agcatcagct acgtggtcta cgagaacctg aagatcaccc 1450 tgggcgtgca gtcgcggtga cggggggagg gccgcccggc agtggactcg 1500 ctgatcctgg gccgcagcct ggggtgtgca gccatctcat tctgtgaatg 1550 tgccaacact aagctgtctc gagccaagct gtgaaaaccc tagacgcacc 1600 cgcagggagg gtggggagag ctggcaggcc cagggcttgt cctgctgacc 1650 ccagcagacc ctcctgttgg ttccagcgaa gaccacaggc attccttagg 1700 gtccagggtc agcaggctcc gggctcacat gtgtaaggac aggacatttt 1750 ctgcagtgcc tgccaatagt gagcttggag cctggaggcc ggcttagttc 1800 ttccatttca cccttgcagc cagctgttgg ccacggcccc tgccctctgg 1850 tctgccgtgc atctccctgt gccctcttgc tgcctgcctg tctgctgagg 1900 taaggtggga ggagggctac agcccacatc ccaccccctc gtccaatccc 1950 ataatccatg atgaaaggtg aggtcacgtg gcctcccagg cctgacttcc 2000 caacctacag cattgacgcc aacttggctg tgaaggaaga ggaaaggatc 2050 tggccttgtg gtcactggca tctgagccct gctgatggct ggggctctcg 2100 ggcatgcttg ggagtgcagg gggctcgggc tgcctggcct ggctgcacag 2150 aaggcaagtg ctggggctca tggtgctctg agctggcctg gaccctgtca 2200 ggatgggccc cacctcagaa ccaaactcac tgtccccact gtggcatgag 2250 ggcagtggag caccatgttt gagggcgaag ggcagagcgt ttgtgtgttc 2300 tggggaggga aggaaaaggt gttggaggcc ttaattatgg actgttggga 2350 aaagggtttt gtccagaagg acaagccgga caaatgagcg acttctgtgc 2400 ttccagagga agacgaggga gcaggagctt ggctgactgc tcagagtctg 2450 ttctgacgcc ctgggggttc ctgtccaacc ccagcagggg cgcagcggga 2500 ccagccccac attccacttg tgtcactgct tggaacctat ttattttgta 2550 tttatttgaa cagagttatg tcctaactat ttttatagat ttgtttaatt 2600 aatagcttgt cattttcaag ttcatttttt attcatattt atgttcatgg 2650 ttgattgtac cttcccaagc ccgcccagtg ggatgggagg aggaggagaa 2700 ggggggcctt gggccgctgc agtcacatct gtccagagaa attccttttg 2750 ggactggagg cagaaaagcg gccagaaggc agcagccctg gctcctttcc 2800 tttggcaggt tggggaaggg cttgccccca gccttaggat ttcagggttt 2850 gactgggggc gtggagagag agggaggaac ctcaataacc ttgaaggtgg 2900 aatccagtta tttcctgcgc tgcgagggtt tctttatttc actcttttct 2950 gaatgtcaag gcagtgaggt gcctctcact gtgaatttgt ggtgggcggg 3000 ggctggagga gagggtgggg ggctggctcc gtccctccca gccttctgct 3050 gcccttgctt aacaatgccg gccaactggc gacctcacgg ttgcacttcc 3100 attccaccag aatgacctga tgaggaaatc ttcaatagga tgcaaagatc 3150 aatgcaaaaa ttgttatata tgaacatata actggagtcg tcaaaaagca 3200 aattaagaaa gaattggacg ttagaagttg tcatttaaag cagccttcta 3250 ataaagttgt ttcaaagctg aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 3300 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaa 3334 58 469 PRT Homo Sapien 58 Met Leu Cys Leu Cys Leu Tyr Val Pro Val Ile Gly Glu Ala Gln 1 5 10 15 Thr Glu Phe Gln Tyr Phe Glu Ser Lys Gly Leu Pro Ala Glu Leu 20 25 30 Lys Ser Ile Phe Lys Leu Ser Val Phe Ile Pro Ser Gln Glu Phe 35 40 45 Ser Thr Tyr Arg Gln Trp Lys Gln Lys Ile Val Gln Ala Gly Asp 50 55 60 Lys Asp Leu Asp Gly Gln Leu Asp Phe Glu Glu Phe Val His Tyr 65 70 75 Leu Gln Asp His Glu Lys Lys Leu Arg Leu Val Phe Lys Ile Leu 80 85 90 Asp Lys Lys Asn Asp Gly Arg Ile Asp Ala Gln Glu Ile Met Gln 95 100 105 Ser Leu Arg Asp Leu Gly Val Lys Ile Ser Glu Gln Gln Ala Glu 110 115 120 Lys Ile Leu Lys Ser Met Asp Lys Asn Gly Thr Met Thr Ile Asp 125 130 135 Trp Asn Glu Trp Arg Asp Tyr His Leu Leu His Pro Val Glu Asn 140 145 150 Ile Pro Glu Ile Ile Leu Tyr Trp Lys His Ser Thr Ile Phe Asp 155 160 165 Val Gly Glu Asn Leu Thr Val Pro Asp Glu Phe Thr Val Glu Glu 170 175 180 Arg Gln Thr Gly Met Trp Trp Arg His Leu Val Ala Gly Gly Gly 185 190 195 Ala Gly Ala Val Ser Arg Thr Cys Thr Ala Pro Leu Asp Arg Leu 200 205 210 Lys Val Leu Met Gln Val His Ala Ser Arg Ser Asn Asn Met Gly 215 220 225 Ile Val Gly Gly Phe Thr Gln Met Ile Arg Glu Gly Gly Ala Arg 230 235 240 Ser Leu Trp Arg Gly Asn Gly Ile Asn Val Leu Lys Ile Ala Pro 245 250 255 Glu Ser Ala Ile Lys Phe Met Ala Tyr Glu Gln Ile Lys Arg Leu 260 265 270 Val Gly Ser Asp Gln Glu Thr Leu Arg Ile His Glu Arg Leu Val 275 280 285 Ala Gly Ser Leu Ala Gly Ala Ile Ala Gln Ser Ser Ile Tyr Pro 290 295 300 Met Glu Val Leu Lys Thr Arg Met Ala Leu Arg Lys Thr Gly Gln 305 310 315 Tyr Ser Gly Met Leu Asp Cys Ala Arg Arg Ile Leu Ala Arg Glu 320 325 330 Gly Val Ala Ala Phe Tyr Lys Gly Tyr Val Pro Asn Met Leu Gly 335 340 345 Ile Ile Pro Tyr Ala Gly Ile Asp Leu Ala Val Tyr Glu Thr Leu 350 355 360 Lys Asn Ala Trp Leu Gln His Tyr Ala Val Asn Ser Ala Asp Pro 365 370 375 Gly Val Phe Val Leu Leu Ala Cys Gly Thr Met Ser Ser Thr Cys 380 385 390 Gly Gln Leu Ala Ser Tyr Pro Leu Ala Leu Val Arg Thr Arg Met 395 400 405 Gln Ala Gln Ala Ser Ile Glu Gly Ala Pro Glu Val Thr Met Ser 410 415 420 Ser Leu Phe Lys His Ile Leu Arg Thr Glu Gly Ala Phe Gly Leu 425 430 435 Tyr Arg Gly Leu Ala Pro Asn Phe Met Lys Val Ile Pro Ala Val 440 445 450 Ser Ile Ser Tyr Val Val Tyr Glu Asn Leu Lys Ile Thr Leu Gly 455 460 465 Val Gln Ser Arg 59 1658 DNA Homo Sapien 59 ggaaggcagc ggcagctcca ctcagccagt acccagatac gctgggaacc 50 ttccccagcc atggcttccc tggggcagat cctcttctgg agcataatta 100 gcatcatcat tattctggct ggagcaattg cactcatcat tggctttggt 150 atttcaggga gacactccat cacagtcact actgtcgcct cagctgggaa 200 cattggggag gatggaatcc tgagctgcac ttttgaacct gacatcaaac 250 tttctgatat cgtgatacaa tggctgaagg aaggtgtttt aggcttggtc 300 catgagttca aagaaggcaa agatgagctg tcggagcagg atgaaatgtt 350 cagaggccgg acagcagtgt ttgctgatca agtgatagtt ggcaatgcct 400 ctttgcggct gaaaaacgtg caactcacag atgctggcac ctacaaatgt 450 tatatcatca cttctaaagg caaggggaat gctaaccttg agtataaaac 500 tggagccttc agcatgccgg aagtgaatgt ggactataat gccagctcag 550 agaccttgcg gtgtgaggct ccccgatggt tcccccagcc cacagtggtc 600 tgggcatccc aagttgacca gggagccaac ttctcggaag tctccaatac 650 cagctttgag ctgaactctg agaatgtgac catgaaggtt gtgtctgtgc 700 tctacaatgt tacgatcaac aacacatact cctgtatgat tgaaaatgac 750 attgccaaag caacagggga tatcaaagtg acagaatcgg agatcaaaag 800 gcggagtcac ctacagctgc taaactcaaa ggcttctctg tgtgtctctt 850 ctttctttgc catcagctgg gcacttctgc ctctcagccc ttacctgatg 900 ctaaaataat gtgccttggc cacaaaaaag catgcaaagt cattgttaca 950 acagggatct acagaactat ttcaccacca gatatgacct agttttatat 1000 ttctgggagg aaatgaattc atatctagaa gtctggagtg agcaaacaag 1050 agcaagaaac aaaaagaagc caaaagcaga aggctccaat atgaacaaga 1100 taaatctatc ttcaaagaca tattagaagt tgggaaaata attcatgtga 1150 actagacaag tgtgttaaga gtgataagta aaatgcacgt ggagacaagt 1200 gcatccccag atctcaggga cctccccctg cctgtcacct ggggagtgag 1250 aggacaggat agtgcatgtt ctttgtctct gaatttttag ttatatgtgc 1300 tgtaatgttg ctctgaggaa gcccctggaa agtctatccc aacatatcca 1350 catcttatat tccacaaatt aagctgtagt atgtacccta agacgctgct 1400 aattgactgc cacttcgcaa ctcaggggcg gctgcatttt agtaatgggt 1450 caaatgattc actttttatg atgcttccaa aggtgccttg gcttctcttc 1500 ccaactgaca aatgccaaag ttgagaaaaa tgatcataat tttagcataa 1550 acagagcagt cggggacacc gattttataa ataaactgag caccttcttt 1600 ttaaacaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1650 aaaaaaaa 1658 60 282 PRT Homo Sapien 60 Met Ala Ser Leu Gly Gln Ile Leu Phe Trp Ser Ile Ile Ser Ile 1 5 10 15 Ile Ile Ile Leu Ala Gly Ala Ile Ala Leu Ile Ile Gly Phe Gly 20 25 30 Ile Ser Gly Arg His Ser Ile Thr Val Thr Thr Val Ala Ser Ala 35 40 45 Gly Asn Ile Gly Glu Asp Gly Ile Leu Ser Cys Thr Phe Glu Pro 50 55 60 Asp Ile Lys Leu Ser Asp Ile Val Ile Gln Trp Leu Lys Glu Gly 65 70 75 Val Leu Gly Leu Val His Glu Phe Lys Glu Gly Lys Asp Glu Leu 80 85 90 Ser Glu Gln Asp Glu Met Phe Arg Gly Arg Thr Ala Val Phe Ala 95 100 105 Asp Gln Val Ile Val Gly Asn Ala Ser Leu Arg Leu Lys Asn Val 110 115 120 Gln Leu Thr Asp Ala Gly Thr Tyr Lys Cys Tyr Ile Ile Thr Ser 125 130 135 Lys Gly Lys Gly Asn Ala Asn Leu Glu Tyr Lys Thr Gly Ala Phe 140 145 150 Ser Met Pro Glu Val Asn Val Asp Tyr Asn Ala Ser Ser Glu Thr 155 160 165 Leu Arg Cys Glu Ala Pro Arg Trp Phe Pro Gln Pro Thr Val Val 170 175 180 Trp Ala Ser Gln Val Asp Gln Gly Ala Asn Phe Ser Glu Val Ser 185 190 195 Asn Thr Ser Phe Glu Leu Asn Ser Glu Asn Val Thr Met Lys Val 200 205 210 Val Ser Val Leu Tyr Asn Val Thr Ile Asn Asn Thr Tyr Ser Cys 215 220 225 Met Ile Glu Asn Asp Ile Ala Lys Ala Thr Gly Asp Ile Lys Val 230 235 240 Thr Glu Ser Glu Ile Lys Arg Arg Ser His Leu Gln Leu Leu Asn 245 250 255 Ser Lys Ala Ser Leu Cys Val Ser Ser Phe Phe Ala Ile Ser Trp 260 265 270 Ala Leu Leu Pro Leu Ser Pro Tyr Leu Met Leu Lys 275 280 61 1617 DNA Homo Sapien 61 tgacgtcaga atcaccatgg ccagctatcc ttaccggcag ggctgcccag 50 gagctgcagg acaagcacca ggagcccctc cgggtagcta ctaccctgga 100 ccccccaata gtggagggca gtatggtagt gggctacccc ctggtggtgg 150 ttatgggggt cctgcccctg gagggcctta tggaccacca gctggtggag 200 ggccctatgg acaccccaat cctgggatgt tcccctctgg aactccagga 250 ggaccatatg gcggtgcagc tcccgggggc ccctatggtc agccacctcc 300 aagttcctac ggtgcccagc agcctgggct ttatggacag ggtggcgccc 350 ctcccaatgt ggatcctgag gcctactcct ggttccagtc ggtggactca 400 gatcacagtg gctatatctc catgaaggag ctaaagcagg ccctggtcaa 450 ctgcaattgg tcttcattca atgatgagac ctgcctcatg atgataaaca 500 tgtttgacaa gaccaagtca ggccgcatcg atgtctacgg cttctcagcc 550 ctgtggaaat tcatccagca gtggaagaac ctcttccagc agtatgaccg 600 ggaccgctcg ggctccatta gctacacaga gctgcagcaa gctctgtccc 650 aaatgggcta caacctgagc ccccagttca cccagcttct ggtctcccgc 700 tactgcccac gctctgccaa tcctgccatg cagcttgacc gcttcatcca 750 ggtgtgcacc cagctgcagg tgctgacaga ggccttccgg gagaaggaca 800 cagctgtaca aggcaacatc cggctcagct tcgaggactt cgtcaccatg 850 acagcttctc ggatgctatg acccaaccat ctgtggagag tggagtgcac 900 cagggacctt tcctggcttc ttagagtgag agaagtatgt ggacatctct 950 tcttttcctg tccctctaga agaacattct cccttgcttg atgcaacact 1000 gttccaaaag agggtggaga gtcctgcatc atagccacca aatagtgagg 1050 accggggctg aggccacaca gataggggcc tgatggagga gaggatagaa 1100 gttgaatgtc ctgatggcca tgagcagttg agtggcacag cctggcacca 1150 ggagcaggtc cttgtaatgg agttagtgtc cagtcagctg agctccaccc 1200 tgatgccagt ggtgagtgtt catcggcctg ttaccgttag tacctgtgtt 1250 ccctcaccag gccatcctgt caaacgagcc cattttctcc aaagtggaat 1300 ctgaccaagc atgagagaga tctgtctatg ggaccagtgg cttggattct 1350 gccacaccca taaatccttg tgtgttaact tctagctgcc tggggctggc 1400 cctgctcaga caaatctgct ccctgggcat ctttggccag gcttctgccc 1450 cctgcagctg ggacccctca cttgcctgcc atgctctgct cggcttcagt 1500 ctccaggaga cagtggtcac ctctccctgc caatactttt tttaatttgc 1550 attttttttc atttggggcc aaaagtccag tgaaattgta agcttcaata 1600 aaaggatgaa actctga 1617 62 284 PRT Homo Sapien 62 Met Ala Ser Tyr Pro Tyr Arg Gln Gly Cys Pro Gly Ala Ala Gly 1 5 10 15 Gln Ala Pro Gly Ala Pro Pro Gly Ser Tyr Tyr Pro Gly Pro Pro 20 25 30 Asn Ser Gly Gly Gln Tyr Gly Ser Gly Leu Pro Pro Gly Gly Gly 35 40 45 Tyr Gly Gly Pro Ala Pro Gly Gly Pro Tyr Gly Pro Pro Ala Gly 50 55 60 Gly Gly Pro Tyr Gly His Pro Asn Pro Gly Met Phe Pro Ser Gly 65 70 75 Thr Pro Gly Gly Pro Tyr Gly Gly Ala Ala Pro Gly Gly Pro Tyr 80 85 90 Gly Gln Pro Pro Pro Ser Ser Tyr Gly Ala Gln Gln Pro Gly Leu 95 100 105 Tyr Gly Gln Gly Gly Ala Pro Pro Asn Val Asp Pro Glu Ala Tyr 110 115 120 Ser Trp Phe Gln Ser Val Asp Ser Asp His Ser Gly Tyr Ile Ser 125 130 135 Met Lys Glu Leu Lys Gln Ala Leu Val Asn Cys Asn Trp Ser Ser 140 145 150 Phe Asn Asp Glu Thr Cys Leu Met Met Ile Asn Met Phe Asp Lys 155 160 165 Thr Lys Ser Gly Arg Ile Asp Val Tyr Gly Phe Ser Ala Leu Trp 170 175 180 Lys Phe Ile Gln Gln Trp Lys Asn Leu Phe Gln Gln Tyr Asp Arg 185 190 195 Asp Arg Ser Gly Ser Ile Ser Tyr Thr Glu Leu Gln Gln Ala Leu 200 205 210 Ser Gln Met Gly Tyr Asn Leu Ser Pro Gln Phe Thr Gln Leu Leu 215 220 225 Val Ser Arg Tyr Cys Pro Arg Ser Ala Asn Pro Ala Met Gln Leu 230 235 240 Asp Arg Phe Ile Gln Val Cys Thr Gln Leu Gln Val Leu Thr Glu 245 250 255 Ala Phe Arg Glu Lys Asp Thr Ala Val Gln Gly Asn Ile Arg Leu 260 265 270 Ser Phe Glu Asp Phe Val Thr Met Thr Ala Ser Arg Met Leu 275 280 63 1234 DNA Homo Sapien 63 caggatgcag ggccgcgtgg cagggagctg cgctcctctg ggcctgctcc 50 tggtctgtct tcatctccca ggcctctttg cccggagcat cggtgttgtg 100 gaggagaaag tttcccaaaa cttcgggacc aacttgcctc agctcggaca 150 accttcctcc actggcccct ctaactctga acatccgcag cccgctctgg 200 accctaggtc taatgacttg gcaagggttc ctctgaagct cagcgtgcct 250 ccatcagatg gcttcccacc tgcaggaggt tctgcagtgc agaggtggcc 300 tccatcgtgg gggctgcctg ccatggattc ctggccccct gaggatcctt 350 ggcagatgat ggctgctgcg gctgaggacc gcctggggga agcgctgcct 400 gaagaactct cttacctctc cagtgctgcg gccctcgctc cgggcagtgg 450 ccctttgcct ggggagtctt ctcccgatgc cacaggcctc tcacctgagg 500 cttcactcct ccaccaggac tcggagtcca gacgactgcc ccgttctaat 550 tcactgggag ccgggggaaa aatcctttcc caacgccctc cctggtctct 600 catccacagg gttctgcctg atcacccctg gggtaccctg aatcccagtg 650 tgtcctgggg aggtggaggc cctgggactg gttggggaac gaggcccatg 700 ccacaccctg agggaatctg gggtatcaat aatcaacccc caggtaccag 750 ctggggaaat attaatcggt atccaggagg cagctgggga aatattaatc 800 ggtatccagg aggcagctgg gggaatatta atcggtatcc aggaggcagc 850 tgggggaata ttcatctata cccaggtatc aataacccat ttcctcctgg 900 agttctccgc cctcctggct cttcttggaa catcccagct ggcttcccta 950 atcctccaag ccctaggttg cagtggggct agagcacgat agagggaaac 1000 ccaacattgg gagttagagt cctgctcccg ccccttgctg tgtgggctca 1050 atccaggccc tgttaacatg tttccagcac tatccccact tttcagtgcc 1100 tcccctgctc atctccaata aaataaaagc acttatgaaa aaaaaaaaaa 1150 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1200 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaa 1234 64 325 PRT Homo Sapien 64 Met Gln Gly Arg Val Ala Gly Ser Cys Ala Pro Leu Gly Leu Leu 1 5 10 15 Leu Val Cys Leu His Leu Pro Gly Leu Phe Ala Arg Ser Ile Gly 20 25 30 Val Val Glu Glu Lys Val Ser Gln Asn Phe Gly Thr Asn Leu Pro 35 40 45 Gln Leu Gly Gln Pro Ser Ser Thr Gly Pro Ser Asn Ser Glu His 50 55 60 Pro Gln Pro Ala Leu Asp Pro Arg Ser Asn Asp Leu Ala Arg Val 65 70 75 Pro Leu Lys Leu Ser Val Pro Pro Ser Asp Gly Phe Pro Pro Ala 80 85 90 Gly Gly Ser Ala Val Gln Arg Trp Pro Pro Ser Trp Gly Leu Pro 95 100 105 Ala Met Asp Ser Trp Pro Pro Glu Asp Pro Trp Gln Met Met Ala 110 115 120 Ala Ala Ala Glu Asp Arg Leu Gly Glu Ala Leu Pro Glu Glu Leu 125 130 135 Ser Tyr Leu Ser Ser Ala Ala Ala Leu Ala Pro Gly Ser Gly Pro 140 145 150 Leu Pro Gly Glu Ser Ser Pro Asp Ala Thr Gly Leu Ser Pro Glu 155 160 165 Ala Ser Leu Leu His Gln Asp Ser Glu Ser Arg Arg Leu Pro Arg 170 175 180 Ser Asn Ser Leu Gly Ala Gly Gly Lys Ile Leu Ser Gln Arg Pro 185 190 195 Pro Trp Ser Leu Ile His Arg Val Leu Pro Asp His Pro Trp Gly 200 205 210 Thr Leu Asn Pro Ser Val Ser Trp Gly Gly Gly Gly Pro Gly Thr 215 220 225 Gly Trp Gly Thr Arg Pro Met Pro His Pro Glu Gly Ile Trp Gly 230 235 240 Ile Asn Asn Gln Pro Pro Gly Thr Ser Trp Gly Asn Ile Asn Arg 245 250 255 Tyr Pro Gly Gly Ser Trp Gly Asn Ile Asn Arg Tyr Pro Gly Gly 260 265 270 Ser Trp Gly Asn Ile Asn Arg Tyr Pro Gly Gly Ser Trp Gly Asn 275 280 285 Ile His Leu Tyr Pro Gly Ile Asn Asn Pro Phe Pro Pro Gly Val 290 295 300 Leu Arg Pro Pro Gly Ser Ser Trp Asn Ile Pro Ala Gly Phe Pro 305 310 315 Asn Pro Pro Ser Pro Arg Leu Gln Trp Gly 320 325 65 422 DNA Homo Sapien 65 aaggagaggc caccgggact tcagtgtctc ctccatccca ggagcgcagt 50 ggccactatg gggtctgggc tgccccttgt cctcctcttg accctccttg 100 gcagctcaca tggaacaggg ccgggtatga ctttgcaact gaagctgaag 150 gagtcttttc tgacaaattc ctcctatgag tccagcttcc tggaattgct 200 tgaaaagctc tgcctcctcc tccatctccc ttcagggacc agcgtcaccc 250 tccaccatgc aagatctcaa caccatgttg tctgcaacac atgacagcca 300 ttgaagcctg tgtccttctt ggcccgggct tttgggccgg ggatgcagga 350 ggcaggcccc gaccctgtct ttcagcaggc ccccaccctc ctgagtggca 400 ataaataaaa ttcggtatgc tg 422 66 78 PRT Homo Sapien 66 Met Gly Ser Gly Leu Pro Leu Val Leu Leu Leu Thr Leu Leu Gly 1 5 10 15 Ser Ser His Gly Thr Gly Pro Gly Met Thr Leu Gln Leu Lys Leu 20 25 30 Lys Glu Ser Phe Leu Thr Asn Ser Ser Tyr Glu Ser Ser Phe Leu 35 40 45 Glu Leu Leu Glu Lys Leu Cys Leu Leu Leu His Leu Pro Ser Gly 50 55 60 Thr Ser Val Thr Leu His His Ala Arg Ser Gln His His Val Val 65 70 75 Cys Asn Thr 67 744 DNA Homo Sapien 67 acggaccgag ggttcgaggg agggacacgg accaggaacc tgagctaggt 50 caaagacgcc cgggccaggt gccccgtcgc aggtgcccct ggccggagat 100 gcggtaggag gggcgagcgc gagaagcccc ttcctcggcg ctgccaaccc 150 gccacccagc ccatggcgaa ccccgggctg gggctgcttc tggcgctggg 200 cctgccgttc ctgctggccc gctggggccg agcctggggg caaatacaga 250 ccacttctgc aaatgagaat agcactgttt tgccttcatc caccagctcc 300 agctccgatg gcaacctgcg tccggaagcc atcactgcta tcatcgtggt 350 cttctccctc ttggctgcct tgctcctggc tgtggggctg gcactgttgg 400 tgcggaagct tcgggagaag cggcagacgg agggcaccta ccggcccagt 450 agcgaggagc agttctccca tgcagccgag gcccgggccc ctcaggactc 500 caaggagacg gtgcagggct gcctgcccat ctaggtcccc tctcctgcat 550 ctgtctccct tcattgctgt gtgaccttgg ggaaaggcag tgccctctct 600 gggcagtcag atccacccag tgcttaatag cagggaagaa ggtacttcaa 650 agactctgcc cctgaggtca agagaggatg gggctattca cttttatata 700 tttatataaa attagtagtg agatgtaaaa aaaaaaaaaa aaaa 744 68 123 PRT Homo Sapien 68 Met Ala Asn Pro Gly Leu Gly Leu Leu Leu Ala Leu Gly Leu Pro 1 5 10 15 Phe Leu Leu Ala Arg Trp Gly Arg Ala Trp Gly Gln Ile Gln Thr 20 25 30 Thr Ser Ala Asn Glu Asn Ser Thr Val Leu Pro Ser Ser Thr Ser 35 40 45 Ser Ser Ser Asp Gly Asn Leu Arg Pro Glu Ala Ile Thr Ala Ile 50 55 60 Ile Val Val Phe Ser Leu Leu Ala Ala Leu Leu Leu Ala Val Gly 65 70 75 Leu Ala Leu Leu Val Arg Lys Leu Arg Glu Lys Arg Gln Thr Glu 80 85 90 Gly Thr Tyr Arg Pro Ser Ser Glu Glu Gln Phe Ser His Ala Ala 95 100 105 Glu Ala Arg Ala Pro Gln Asp Ser Lys Glu Thr Val Gln Gly Cys 110 115 120 Leu Pro Ile 69 3265 DNA Homo Sapien 69 gccaggaata actagagagg aacaatgggg ttattcagag gttttgtttt 50 cctcttagtt ctgtgcctgc tgcaccagtc aaatacttcc ttcattaagc 100 tgaataataa tggctttgaa gatattgtca ttgttataga tcctagtgtg 150 ccagaagatg aaaaaataat tgaacaaata gaggatatgg tgactacagc 200 ttctacgtac ctgtttgaag ccacagaaaa aagatttttt ttcaaaaatg 250 tatctatatt aattcctgag aattggaagg aaaatcctca gtacaaaagg 300 ccaaaacatg aaaaccataa acatgctgat gttatagttg caccacctac 350 actcccaggt agagatgaac catacaccaa gcagttcaca gaatgtggag 400 agaaaggcga atacattcac ttcacccctg accttctact tggaaaaaaa 450 caaaatgaat atggaccacc aggcaaactg tttgtccatg agtgggctca 500 cctccggtgg ggagtgtttg atgagtacaa tgaagatcag cctttctacc 550 gtgctaagtc aaaaaaaatc gaagcaacaa ggtgttccgc aggtatctct 600 ggtagaaata gagtttataa gtgtcaagga ggcagctgtc ttagtagagc 650 atgcagaatt gattctacaa caaaactgta tggaaaagat tgtcaattct 700 ttcctgataa agtacaaaca gaaaaagcat ccataatgtt tatgcaaagt 750 attgattctg ttgttgaatt ttgtaacgaa aaaacccata atcaagaagc 800 tccaagccta caaaacataa agtgcaattt tagaagtaca tgggaggtga 850 ttagcaattc tgaggatttt aaaaacacca tacccatggt gacaccacct 900 cctccacctg tcttctcatt gctgaagatc agtcaaagaa ttgtgtgctt 950 agttcttgat aagtctggaa gcatgggggg taaggaccgc ctaaatcgaa 1000 tgaatcaagc agcaaaacat ttcctgctgc agactgttga aaatggatcc 1050 tgggtgggga tggttcactt tgatagtact gccactattg taaataagct 1100 aatccaaata aaaagcagtg atgaaagaaa cacactcatg gcaggattac 1150 ctacatatcc tctgggagga acttccatct gctctggaat taaatatgca 1200 tttcaggtga ttggagagct acattcccaa ctcgatggat ccgaagtact 1250 gctgctgact gatggggagg ataacactgc aagttcttgt attgatgaag 1300 tgaaacaaag tggggccatt gttcatttta ttgctttggg aagagctgct 1350 gatgaagcag taatagagat gagcaagata acaggaggaa gtcattttta 1400 tgtttcagat gaagctcaga acaatggcct cattgatgct tttggggctc 1450 ttacatcagg aaatactgat ctctcccaga agtcccttca gctcgaaagt 1500 aagggattaa cactgaatag taatgcctgg atgaacgaca ctgtcataat 1550 tgatagtaca gtgggaaagg acacgttctt tctcatcaca tggaacagtc 1600 tgcctcccag tatttctctc tgggatccca gtggaacaat aatggaaaat 1650 ttcacagtgg atgcaacttc caaaatggcc tatctcagta ttccaggaac 1700 tgcaaaggtg ggcacttggg catacaatct tcaagccaaa gcgaacccag 1750 aaacattaac tattacagta acttctcgag cagcaaattc ttctgtgcct 1800 ccaatcacag tgaatgctaa aatgaataag gacgtaaaca gtttccccag 1850 cccaatgatt gtttacgcag aaattctaca aggatatgta cctgttcttg 1900 gagccaatgt gactgctttc attgaatcac agaatggaca tacagaagtt 1950 ttggaacttt tggataatgg tgcaggcgct gattctttca agaatgatgg 2000 agtctactcc aggtatttta cagcatatac agaaaatggc agatatagct 2050 taaaagttcg ggctcatgga ggagcaaaca ctgccaggct aaaattacgg 2100 cctccactga atagagccgc gtacatacca ggctgggtag tgaacgggga 2150 aattgaagca aacccgccaa gacctgaaat tgatgaggat actcagacca 2200 ccttggagga tttcagccga acagcatccg gaggtgcatt tgtggtatca 2250 caagtcccaa gccttccctt gcctgaccaa tacccaccaa gtcaaatcac 2300 agaccttgat gccacagttc atgaggataa gattattctt acatggacag 2350 caccaggaga taattttgat gttggaaaag ttcaacgtta tatcataaga 2400 ataagtgcaa gtattcttga tctaagagac agttttgatg atgctcttca 2450 agtaaatact actgatctgt caccaaagga ggccaactcc aaggaaagct 2500 ttgcatttaa accagaaaat atctcagaag aaaatgcaac ccacatattt 2550 attgccatta aaagtataga taaaagcaat ttgacatcaa aagtatccaa 2600 cattgcacaa gtaactttgt ttatccctca agcaaatcct gatgacattg 2650 atcctacacc tactcctact cctactccta ctcctgataa aagtcataat 2700 tctggagtta atatttctac gctggtattg tctgtgattg ggtctgttgt 2750 aattgttaac tttattttaa gtaccaccat ttgaacctta acgaagaaaa 2800 aaatcttcaa gtagacctag aagagagttt taaaaaacaa aacaatgtaa 2850 gtaaaggata tttctgaatc ttaaaattca tcccatgtgt gatcataaac 2900 tcataaaaat aattttaaga tgtcggaaaa ggatactttg attaaataaa 2950 aacactcatg gatatgtaaa aactgtcaag attaaaattt aatagtttca 3000 tttatttgtt attttatttg taagaaatag tgatgaacaa agatcctttt 3050 tcatactgat acctggttgt atattatttg atgcaacagt tttctgaaat 3100 gatatttcaa attgcatcaa gaaattaaaa tcatctatct gagtagtcaa 3150 aatacaagta aaggagagca aataaacaac atttggaaaa aaaaaaaaaa 3200 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 3250 aaaaaaaaaa aaaaa 3265 70 919 PRT Homo Sapien 70 Met Gly Leu Phe Arg Gly Phe Val Phe Leu Leu Val Leu Cys Leu 1 5 10 15 Leu His Gln Ser Asn Thr Ser Phe Ile Lys Leu Asn Asn Asn Gly 20 25 30 Phe Glu Asp Ile Val Ile Val Ile Asp Pro Ser Val Pro Glu Asp 35 40 45 Glu Lys Ile Ile Glu Gln Ile Glu Asp Met Val Thr Thr Ala Ser 50 55 60 Thr Tyr Leu Phe Glu Ala Thr Glu Lys Arg Phe Phe Phe Lys Asn 65 70 75 Val Ser Ile Leu Ile Pro Glu Asn Trp Lys Glu Asn Pro Gln Tyr 80 85 90 Lys Arg Pro Lys His Glu Asn His Lys His Ala Asp Val Ile Val 95 100 105 Ala Pro Pro Thr Leu Pro Gly Arg Asp Glu Pro Tyr Thr Lys Gln 110 115 120 Phe Thr Glu Cys Gly Glu Lys Gly Glu Tyr Ile His Phe Thr Pro 125 130 135 Asp Leu Leu Leu Gly Lys Lys Gln Asn Glu Tyr Gly Pro Pro Gly 140 145 150 Lys Leu Phe Val His Glu Trp Ala His Leu Arg Trp Gly Val Phe 155 160 165 Asp Glu Tyr Asn Glu Asp Gln Pro Phe Tyr Arg Ala Lys Ser Lys 170 175 180 Lys Ile Glu Ala Thr Arg Cys Ser Ala Gly Ile Ser Gly Arg Asn 185 190 195 Arg Val Tyr Lys Cys Gln Gly Gly Ser Cys Leu Ser Arg Ala Cys 200 205 210 Arg Ile Asp Ser Thr Thr Lys Leu Tyr Gly Lys Asp Cys Gln Phe 215 220 225 Phe Pro Asp Lys Val Gln Thr Glu Lys Ala Ser Ile Met Phe Met 230 235 240 Gln Ser Ile Asp Ser Val Val Glu Phe Cys Asn Glu Lys Thr His 245 250 255 Asn Gln Glu Ala Pro Ser Leu Gln Asn Ile Lys Cys Asn Phe Arg 260 265 270 Ser Thr Trp Glu Val Ile Ser Asn Ser Glu Asp Phe Lys Asn Thr 275 280 285 Ile Pro Met Val Thr Pro Pro Pro Pro Pro Val Phe Ser Leu Leu 290 295 300 Lys Ile Ser Gln Arg Ile Val Cys Leu Val Leu Asp Lys Ser Gly 305 310 315 Ser Met Gly Gly Lys Asp Arg Leu Asn Arg Met Asn Gln Ala Ala 320 325 330 Lys His Phe Leu Leu Gln Thr Val Glu Asn Gly Ser Trp Val Gly 335 340 345 Met Val His Phe Asp Ser Thr Ala Thr Ile Val Asn Lys Leu Ile 350 355 360 Gln Ile Lys Ser Ser Asp Glu Arg Asn Thr Leu Met Ala Gly Leu 365 370 375 Pro Thr Tyr Pro Leu Gly Gly Thr Ser Ile Cys Ser Gly Ile Lys 380 385 390 Tyr Ala Phe Gln Val Ile Gly Glu Leu His Ser Gln Leu Asp Gly 395 400 405 Ser Glu Val Leu Leu Leu Thr Asp Gly Glu Asp Asn Thr Ala Ser 410 415 420 Ser Cys Ile Asp Glu Val Lys Gln Ser Gly Ala Ile Val His Phe 425 430 435 Ile Ala Leu Gly Arg Ala Ala Asp Glu Ala Val Ile Glu Met Ser 440 445 450 Lys Ile Thr Gly Gly Ser His Phe Tyr Val Ser Asp Glu Ala Gln 455 460 465 Asn Asn Gly Leu Ile Asp Ala Phe Gly Ala Leu Thr Ser Gly Asn 470 475 480 Thr Asp Leu Ser Gln Lys Ser Leu Gln Leu Glu Ser Lys Gly Leu 485 490 495 Thr Leu Asn Ser Asn Ala Trp Met Asn Asp Thr Val Ile Ile Asp 500 505 510 Ser Thr Val Gly Lys Asp Thr Phe Phe Leu Ile Thr Trp Asn Ser 515 520 525 Leu Pro Pro Ser Ile Ser Leu Trp Asp Pro Ser Gly Thr Ile Met 530 535 540 Glu Asn Phe Thr Val Asp Ala Thr Ser Lys Met Ala Tyr Leu Ser 545 550 555 Ile Pro Gly Thr Ala Lys Val Gly Thr Trp Ala Tyr Asn Leu Gln 560 565 570 Ala Lys Ala Asn Pro Glu Thr Leu Thr Ile Thr Val Thr Ser Arg 575 580 585 Ala Ala Asn Ser Ser Val Pro Pro Ile Thr Val Asn Ala Lys Met 590 595 600 Asn Lys Asp Val Asn Ser Phe Pro Ser Pro Met Ile Val Tyr Ala 605 610 615 Glu Ile Leu Gln Gly Tyr Val Pro Val Leu Gly Ala Asn Val Thr 620 625 630 Ala Phe Ile Glu Ser Gln Asn Gly His Thr Glu Val Leu Glu Leu 635 640 645 Leu Asp Asn Gly Ala Gly Ala Asp Ser Phe Lys Asn Asp Gly Val 650 655 660 Tyr Ser Arg Tyr Phe Thr Ala Tyr Thr Glu Asn Gly Arg Tyr Ser 665 670 675 Leu Lys Val Arg Ala His Gly Gly Ala Asn Thr Ala Arg Leu Lys 680 685 690 Leu Arg Pro Pro Leu Asn Arg Ala Ala Tyr Ile Pro Gly Trp Val 695 700 705 Val Asn Gly Glu Ile Glu Ala Asn Pro Pro Arg Pro Glu Ile Asp 710 715 720 Glu Asp Thr Gln Thr Thr Leu Glu Asp Phe Ser Arg Thr Ala Ser 725 730 735 Gly Gly Ala Phe Val Val Ser Gln Val Pro Ser Leu Pro Leu Pro 740 745 750 Asp Gln Tyr Pro Pro Ser Gln Ile Thr Asp Leu Asp Ala Thr Val 755 760 765 His Glu Asp Lys Ile Ile Leu Thr Trp Thr Ala Pro Gly Asp Asn 770 775 780 Phe Asp Val Gly Lys Val Gln Arg Tyr Ile Ile Arg Ile Ser Ala 785 790 795 Ser Ile Leu Asp Leu Arg Asp Ser Phe Asp Asp Ala Leu Gln Val 800 805 810 Asn Thr Thr Asp Leu Ser Pro Lys Glu Ala Asn Ser Lys Glu Ser 815 820 825 Phe Ala Phe Lys Pro Glu Asn Ile Ser Glu Glu Asn Ala Thr His 830 835 840 Ile Phe Ile Ala Ile Lys Ser Ile Asp Lys Ser Asn Leu Thr Ser 845 850 855 Lys Val Ser Asn Ile Ala Gln Val Thr Leu Phe Ile Pro Gln Ala 860 865 870 Asn Pro Asp Asp Ile Asp Pro Thr Pro Thr Pro Thr Pro Thr Pro 875 880 885 Thr Pro Asp Lys Ser His Asn Ser Gly Val Asn Ile Ser Thr Leu 890 895 900 Val Leu Ser Val Ile Gly Ser Val Val Ile Val Asn Phe Ile Leu 905 910 915 Ser Thr Thr Ile 71 3877 DNA Homo Sapien 71 ctccttaggt ggaaaccctg ggagtagagt actgacagca aagaccggga 50 aagaccatac gtccccgggc aggggtgaca acaggtgtca tctttttgat 100 ctcgtgtgtg gctgccttcc tatttcaagg aaagacgcca aggtaatttt 150 gacccagagg agcaatgatg tagccacctc ctaaccttcc cttcttgaac 200 ccccagttat gccaggattt actagagagt gtcaactcaa ccagcaagcg 250 gctccttcgg cttaacttgt ggttggagga gagaaccttt gtggggctgc 300 gttctcttag cagtgctcag aagtgacttg cctgagggtg gaccagaaga 350 aaggaaaggt cccctcttgc tgttggctgc acatcaggaa ggctgtgatg 400 ggaatgaagg tgaaaacttg gagatttcac ttcagtcatt gcttctgcct 450 gcaagatcat cctttaaaag tagagaagct gctctgtgtg gtggttaact 500 ccaagaggca gaactcgttc tagaaggaaa tggatgcaag cagctccggg 550 ggccccaaac gcatgcttcc tgtggtctag cccagggaag cccttccgtg 600 ggggccccgg ctttgaggga tgccaccggt tctggacgca tggctgattc 650 ctgaatgatg atggttcgcc gggggctgct tgcgtggatt tcccgggtgg 700 tggttttgct ggtgctcctc tgctgtgcta tctctgtcct gtacatgttg 750 gcctgcaccc caaaaggtga cgaggagcag ctggcactgc ccagggccaa 800 cagccccacg gggaaggagg ggtaccaggc cgtccttcag gagtgggagg 850 agcagcaccg caactacgtg agcagcctga agcggcagat cgcacagctc 900 aaggaggagc tgcaggagag gagtgagcag ctcaggaatg ggcagtacca 950 agccagcgat gctgctggcc tgggtctgga caggagcccc ccagagaaaa 1000 cccaggccga cctcctggcc ttcctgcact cgcaggtgga caaggcagag 1050 gtgaatgctg gcgtcaagct ggccacagag tatgcagcag tgcctttcga 1100 tagctttact ctacagaagg tgtaccagct ggagactggc cttacccgcc 1150 accccgagga gaagcctgtg aggaaggaca agcgggatga gttggtggaa 1200 gccattgaat cagccttgga gaccctgaac aatcctgcag agaacagccc 1250 caatcaccgt ccttacacgg cctctgattt catagaaggg atctaccgaa 1300 cagaaaggga caaagggaca ttgtatgagc tcaccttcaa aggggaccac 1350 aaacacgaat tcaaacggct catcttattt cgaccattca gccccatcat 1400 gaaagtgaaa aatgaaaagc tcaacatggc caacacgctt atcaatgtta 1450 tcgtgcctct agcaaaaagg gtggacaagt tccggcagtt catgcagaat 1500 ttcagggaga tgtgcattga gcaggatggg agagtccatc tcactgttgt 1550 ttactttggg aaagaagaaa taaatgaagt caaaggaata cttgaaaaca 1600 cttccaaagc tgccaacttc aggaacttta ccttcatcca gctgaatgga 1650 gaattttctc ggggaaaggg acttgatgtt ggagcccgct tctggaaggg 1700 aagcaacgtc cttctctttt tctgtgatgt ggacatctac ttcacatctg 1750 aattcctcaa tacgtgtagg ctgaatacac agccagggaa gaaggtattt 1800 tatccagttc ttttcagtca gtacaatcct ggcataatat acggccacca 1850 tgatgcagtc cctcccttgg aacagcagct ggtcataaag aaggaaactg 1900 gattttggag agactttgga tttgggatga cgtgtcagta tcggtcagac 1950 ttcatcaata taggtgggtt tgatctggac atcaaaggct ggggcggaga 2000 ggatgtgcac ctttatcgca agtatctcca cagcaacctc atagtggtac 2050 ggacgcctgt gcgaggactc ttccacctct ggcatgagaa gcgctgcatg 2100 gacgagctga cccccgagca gtacaagatg tgcatgcagt ccaaggccat 2150 gaacgaggca tcccacggcc agctgggcat gctggtgttc aggcacgaga 2200 tagaggctca ccttcgcaaa cagaaacaga agacaagtag caaaaaaaca 2250 tgaactccca gagaaggatt gtgggagaca ctttttcttt ccttttgcaa 2300 ttactgaaag tggctgcaac agagaaaaga cttccataaa ggacgacaaa 2350 agaattggac tgatgggtca gagatgagaa agcctccgat ttctctctgt 2400 tgggcttttt acaacagaaa tcaaaatctc cgctttgcct gcaaaagtaa 2450 cccagttgca ccctgtgaag tgtctgacaa aggcagaatg cttgtgagat 2500 tataagccta atggtgtgga ggttttgatg gtgtttacaa tacactgaga 2550 cctgttgttt tgtgtgctca ttgaaatatt catgatttaa gagcagtttt 2600 gtaaaaaatt cattagcatg aaaggcaagc atatttctcc tcatatgaat 2650 gagcctatca gcagggctct agtttctagg aatgctaaaa tatcagaagg 2700 caggagagga gataggctta ttatgatact agtgagtaca ttaagtaaaa 2750 taaaatggac cagaaaagaa aagaaaccat aaatatcgtg tcatattttc 2800 cccaagatta accaaaaata atctgcttat ctttttggtt gtccttttaa 2850 ctgtctccgt ttttttcttt tatttaaaaa tgcacttttt ttcccttgtg 2900 agttatagtc tgcttattta attaccactt tgcaagcctt acaagagagc 2950 acaagttggc ctacattttt atatttttta agaagatact ttgagatgca 3000 ttatgagaac tttcagttca aagcatcaaa ttgatgccat atccaaggac 3050 atgccaaatg ctgattctgt caggcactga atgtcaggca ttgagacata 3100 gggaaggaat ggtttgtact aatacagacg tacagatact ttctctgaag 3150 agtattttcg aagaggagca actgaacact ggaggaaaag aaaatgacac 3200 tttctgcttt acagaaaagg aaactcattc agactggtga tatcgtgatg 3250 tacctaaaag tcagaaacca cattttctcc tcagaagtag ggaccgcttt 3300 cttacctgtt taaataaacc aaagtatacc gtgtgaacca aacaatctct 3350 tttcaaaaca gggtgctcct cctggcttct ggcttccata agaagaaatg 3400 gagaaaaata tatatatata tatatatatt gtgaaagatc aatccatctg 3450 ccagaatcta gtgggatgga agtttttgct acatgttatc caccccaggc 3500 caggtggaag taactgaatt attttttaaa ttaagcagtt ctactcaatc 3550 accaagatgc ttctgaaaat tgcattttat taccatttca aactattttt 3600 taaaaataaa tacagttaac atagagtggt ttcttcattc atgtgaaaat 3650 tattagccag caccagatgc atgagctaat tatctctttg agtccttgct 3700 tctgtttgct cacagtaaac tcattgttta aaagcttcaa gaacattcaa 3750 gctgttggtg tgttaaaaaa tgcattgtat tgatttgtac tggtagttta 3800 tgaaatttaa ttaaaacaca ggccatgaat ggaaggtggt attgcacagc 3850 taataaaata tgatttgtgg atatgaa 3877 72 532 PRT Homo Sapien 72 Met Met Met Val Arg Arg Gly Leu Leu Ala Trp Ile Ser Arg Val 1 5 10 15 Val Val Leu Leu Val Leu Leu Cys Cys Ala Ile Ser Val Leu Tyr 20 25 30 Met Leu Ala Cys Thr Pro Lys Gly Asp Glu Glu Gln Leu Ala Leu 35 40 45 Pro Arg Ala Asn Ser Pro Thr Gly Lys Glu Gly Tyr Gln Ala Val 50 55 60 Leu Gln Glu Trp Glu Glu Gln His Arg Asn Tyr Val Ser Ser Leu 65 70 75 Lys Arg Gln Ile Ala Gln Leu Lys Glu Glu Leu Gln Glu Arg Ser 80 85 90 Glu Gln Leu Arg Asn Gly Gln Tyr Gln Ala Ser Asp Ala Ala Gly 95 100 105 Leu Gly Leu Asp Arg Ser Pro Pro Glu Lys Thr Gln Ala Asp Leu 110 115 120 Leu Ala Phe Leu His Ser Gln Val Asp Lys Ala Glu Val Asn Ala 125 130 135 Gly Val Lys Leu Ala Thr Glu Tyr Ala Ala Val Pro Phe Asp Ser 140 145 150 Phe Thr Leu Gln Lys Val Tyr Gln Leu Glu Thr Gly Leu Thr Arg 155 160 165 His Pro Glu Glu Lys Pro Val Arg Lys Asp Lys Arg Asp Glu Leu 170 175 180 Val Glu Ala Ile Glu Ser Ala Leu Glu Thr Leu Asn Asn Pro Ala 185 190 195 Glu Asn Ser Pro Asn His Arg Pro Tyr Thr Ala Ser Asp Phe Ile 200 205 210 Glu Gly Ile Tyr Arg Thr Glu Arg Asp Lys Gly Thr Leu Tyr Glu 215 220 225 Leu Thr Phe Lys Gly Asp His Lys His Glu Phe Lys Arg Leu Ile 230 235 240 Leu Phe Arg Pro Phe Ser Pro Ile Met Lys Val Lys Asn Glu Lys 245 250 255 Leu Asn Met Ala Asn Thr Leu Ile Asn Val Ile Val Pro Leu Ala 260 265 270 Lys Arg Val Asp Lys Phe Arg Gln Phe Met Gln Asn Phe Arg Glu 275 280 285 Met Cys Ile Glu Gln Asp Gly Arg Val His Leu Thr Val Val Tyr 290 295 300 Phe Gly Lys Glu Glu Ile Asn Glu Val Lys Gly Ile Leu Glu Asn 305 310 315 Thr Ser Lys Ala Ala Asn Phe Arg Asn Phe Thr Phe Ile Gln Leu 320 325 330 Asn Gly Glu Phe Ser Arg Gly Lys Gly Leu Asp Val Gly Ala Arg 335 340 345 Phe Trp Lys Gly Ser Asn Val Leu Leu Phe Phe Cys Asp Val Asp 350 355 360 Ile Tyr Phe Thr Ser Glu Phe Leu Asn Thr Cys Arg Leu Asn Thr 365 370 375 Gln Pro Gly Lys Lys Val Phe Tyr Pro Val Leu Phe Ser Gln Tyr 380 385 390 Asn Pro Gly Ile Ile Tyr Gly His His Asp Ala Val Pro Pro Leu 395 400 405 Glu Gln Gln Leu Val Ile Lys Lys Glu Thr Gly Phe Trp Arg Asp 410 415 420 Phe Gly Phe Gly Met Thr Cys Gln Tyr Arg Ser Asp Phe Ile Asn 425 430 435 Ile Gly Gly Phe Asp Leu Asp Ile Lys Gly Trp Gly Gly Glu Asp 440 445 450 Val His Leu Tyr Arg Lys Tyr Leu His Ser Asn Leu Ile Val Val 455 460 465 Arg Thr Pro Val Arg Gly Leu Phe His Leu Trp His Glu Lys Arg 470 475 480 Cys Met Asp Glu Leu Thr Pro Glu Gln Tyr Lys Met Cys Met Gln 485 490 495 Ser Lys Ala Met Asn Glu Ala Ser His Gly Gln Leu Gly Met Leu 500 505 510 Val Phe Arg His Glu Ile Glu Ala His Leu Arg Lys Gln Lys Gln 515 520 525 Lys Thr Ser Ser Lys Lys Thr 530 73 1701 DNA Homo Sapien unsure 1528 unknown base 73 gagactgcag agggagataa agagagaggg caaagaggca gcaagagatt 50 tgtcctgggg atccagaaac ccatgatacc ctactgaaca ccgaatcccc 100 tggaagccca cagagacaga gacagcaaga gaagcagaga taaatacact 150 cacgccagga gctcgctcgc tctctctctc tctctctcac tcctccctcc 200 ctctctctct gcctgtccta gtcctctagt cctcaaattc ccagtcccct 250 gcaccccttc ctgggacact atgttgttct ccgccctcct gctggaggtg 300 atttggatcc tggctgcaga tgggggtcaa cactggacgt atgagggccc 350 acatggtcag gaccattggc cagcctctta ccctgagtgt ggaaacaatg 400 cccagtcgcc catcgatatt cagacagaca gtgtgacatt tgaccctgat 450 ttgcctgctc tgcagcccca cggatatgac cagcctggca ccgagccttt 500 ggacctgcac aacaatggcc acacagtgca actctctctg ccctctaccc 550 tgtatctggg tggacttccc cgaaaatatg tagctgccca gctccacctg 600 cactggggtc agaaaggatc cccagggggg tcagaacacc agatcaacag 650 tgaagccaca tttgcagagc tccacattgt acattatgac tctgattcct 700 atgacagctt gagtgaggct gctgagaggc ctcagggcct ggctgtcctg 750 ggcatcctaa ttgaggtggg tgagactaag aatatagctt atgaacacat 800 tctgagtcac ttgcatgaag tcaggcataa agatcagaag acctcagtgc 850 ctcccttcaa cctaagagag ctgctcccca aacagctggg gcagtacttc 900 cgctacaatg gctcgctcac aactccccct tgctaccaga gtgtgctctg 950 gacagttttt tatagaaggt cccagatttc aatggaacag ctggaaaagc 1000 ttcaggggac attgttctcc acagaagagg agccctctaa gcttctggta 1050 cagaactacc gagcccttca gcctctcaat cagcgcatgg tctttgcttc 1100 tttcatccaa gcaggatcct cgtataccac aggtgaaatg ctgagtctag 1150 gtgtaggaat cttggttggc tgtctctgcc ttctcctggc tgtttatttc 1200 attgctagaa agattcggaa gaagaggctg gaaaaccgaa agagtgtggt 1250 cttcacctca gcacaagcca cgactgaggc ataaattcct tctcagatac 1300 catggatgtg gatgacttcc cttcatgcct atcaggaagc ctctaaaatg 1350 gggtgtagga tctggccaga aacactgtag gagtagtaag cagatgtcct 1400 ccttcccctg gacatctctt agagaggaat ggacccaggc tgtcattcca 1450 ggaagaactg cagagccttc agcctctcca aacatgtagg aggaaatgag 1500 gaaatcgctg tgttgttaat gcagaganca aactctgttt agttgcaggg 1550 gaagtttggg atatacccca aagtcctcta ccccctcact tttatggccc 1600 tttccctaga tatactgcgg gatctctcct taggataaag agttgctgtt 1650 gaagttgtat atttttgatc aatatatttg gaaattaaag tttctgactt 1700 t 1701 74 337 PRT Homo Sapien 74 Met Leu Phe Ser Ala Leu Leu Leu Glu Val Ile Trp Ile Leu Ala 1 5 10 15 Ala Asp Gly Gly Gln His Trp Thr Tyr Glu Gly Pro His Gly Gln 20 25 30 Asp His Trp Pro Ala Ser Tyr Pro Glu Cys Gly Asn Asn Ala Gln 35 40 45 Ser Pro Ile Asp Ile Gln Thr Asp Ser Val Thr Phe Asp Pro Asp 50 55 60 Leu Pro Ala Leu Gln Pro His Gly Tyr Asp Gln Pro Gly Thr Glu 65 70 75 Pro Leu Asp Leu His Asn Asn Gly His Thr Val Gln Leu Ser Leu 80 85 90 Pro Ser Thr Leu Tyr Leu Gly Gly Leu Pro Arg Lys Tyr Val Ala 95 100 105 Ala Gln Leu His Leu His Trp Gly Gln Lys Gly Ser Pro Gly Gly 110 115 120 Ser Glu His Gln Ile Asn Ser Glu Ala Thr Phe Ala Glu Leu His 125 130 135 Ile Val His Tyr Asp Ser Asp Ser Tyr Asp Ser Leu Ser Glu Ala 140 145 150 Ala Glu Arg Pro Gln Gly Leu Ala Val Leu Gly Ile Leu Ile Glu 155 160 165 Val Gly Glu Thr Lys Asn Ile Ala Tyr Glu His Ile Leu Ser His 170 175 180 Leu His Glu Val Arg His Lys Asp Gln Lys Thr Ser Val Pro Pro 185 190 195 Phe Asn Leu Arg Glu Leu Leu Pro Lys Gln Leu Gly Gln Tyr Phe 200 205 210 Arg Tyr Asn Gly Ser Leu Thr Thr Pro Pro Cys Tyr Gln Ser Val 215 220 225 Leu Trp Thr Val Phe Tyr Arg Arg Ser Gln Ile Ser Met Glu Gln 230 235 240 Leu Glu Lys Leu Gln Gly Thr Leu Phe Ser Thr Glu Glu Glu Pro 245 250 255 Ser Lys Leu Leu Val Gln Asn Tyr Arg Ala Leu Gln Pro Leu Asn 260 265 270 Gln Arg Met Val Phe Ala Ser Phe Ile Gln Ala Gly Ser Ser Tyr 275 280 285 Thr Thr Gly Glu Met Leu Ser Leu Gly Val Gly Ile Leu Val Gly 290 295 300 Cys Leu Cys Leu Leu Leu Ala Val Tyr Phe Ile Ala Arg Lys Ile 305 310 315 Arg Lys Lys Arg Leu Glu Asn Arg Lys Ser Val Val Phe Thr Ser 320 325 330 Ala Gln Ala Thr Thr Glu Ala 335 75 1743 DNA Homo Sapien 75 tgccgctgcc gccgctgctg ctgttgctcc tggcggcgcc ttggggacgg 50 gcagttccct gtgtctctgg tggtttgcct aaacctgcaa acatcacctt 100 cttatccatc aacatgaaga atgtcctaca atggactcca ccagagggtc 150 ttcaaggagt taaagttact tacactgtgc agtatttcat cacaaattgg 200 cccaccagag gtggcactga ctacagatga gaagtccatt tctgttgtcc 250 tgacagctcc agagaagtgg aagagaaatc cagaagacct tcctgtttcc 300 atgcaacaaa tatactccaa tctgaagtat aacgtgtctg tgttgaatac 350 taaatcaaac agaacgtggt cccagtgtgt gaccaaccac acgctggtgc 400 tcacctggct ggagccgaac actctttact gcgtacacgt ggagtccttc 450 gtcccagggc cccctcgccg tgctcagcct tctgagaagc agtgtgccag 500 gactttgaaa gatcaatcat cagagttcaa ggctaaaatc atcttctggt 550 atgttttgcc catatctatt accgtgtttc ttttttctgt gatgggctat 600 tccatctacc gatatatcca cgttggcaaa gagaaacacc cagcaaattt 650 gattttgatt tatggaaatg aatttgacaa aagattcttt gtgcctgctg 700 aaaaaatcgt gattaacttt atcaccctca atatctcgga tgattctaaa 750 atttctcatc aggatatgag tttactggga aaaagcagtg atgtatccag 800 ccttaatgat cctcagccca gcgggaacct gaggccccct caggaggaag 850 aggaggtgaa acatttaggg tatgcttcgc atttgatgga aattttttgt 900 gactctgaag aaaacacgga aggtacttct ctcacccagc aagagtccct 950 cagcagaaca atacccccgg ataaaacagt cattgaatat gaatatgatg 1000 tcagaaccac tgacatttgt gcggggcctg aagagcagga gctcagtttg 1050 caggaggagg tgtccacaca aggaacatta ttggagtcgc aggcagcgtt 1100 ggcagtcttg ggcccgcaaa cgttacagta ctcatacacc cctcagctcc 1150 aagacttaga ccccctggcg caggagcaca cagactcgga ggaggggccg 1200 gaggaagagc catcgacgac cctggtcgac tgggatcccc aaactggcag 1250 gctgtgtatt ccttcgctgt ccagcttcga ccaggattca gagggctgcg 1300 agccttctga gggggatggg ctcggagagg agggtcttct atctagactc 1350 tatgaggagc cggctccaga caggccacca ggagaaaatg aaacctatct 1400 catgcaattc atggaggaat gggggttata tgtgcagatg gaaaactgat 1450 gccaacactt ccttttgcct tttgtttcct gtgcaaacaa gtgagtcacc 1500 cctttgatcc cagccataaa gtacctggga tgaaagaagt tttttccagt 1550 ttgtcagtgt ctgtgagaat tacttatttc ttttctctat tctcatagca 1600 cgtgtgtgat tggttcatgc atgtaggtct cttaacaatg atggtgggcc 1650 tctggagtcc aggggctggc cggttgttct atgcagagaa agcagtcaat 1700 aaatgtttgc cagactgggt gcagaattta ttcaggtggg tgt 1743 76 442 PRT Homo Sapien 76 Met Ser Tyr Asn Gly Leu His Gln Arg Val Phe Lys Glu Leu Lys 1 5 10 15 Leu Leu Thr Leu Cys Ser Ile Ser Ser Gln Ile Gly Pro Pro Glu 20 25 30 Val Ala Leu Thr Thr Asp Glu Lys Ser Ile Ser Val Val Leu Thr 35 40 45 Ala Pro Glu Lys Trp Lys Arg Asn Pro Glu Asp Leu Pro Val Ser 50 55 60 Met Gln Gln Ile Tyr Ser Asn Leu Lys Tyr Asn Val Ser Val Leu 65 70 75 Asn Thr Lys Ser Asn Arg Thr Trp Ser Gln Cys Val Thr Asn His 80 85 90 Thr Leu Val Leu Thr Trp Leu Glu Pro Asn Thr Leu Tyr Cys Val 95 100 105 His Val Glu Ser Phe Val Pro Gly Pro Pro Arg Arg Ala Gln Pro 110 115 120 Ser Glu Lys Gln Cys Ala Arg Thr Leu Lys Asp Gln Ser Ser Glu 125 130 135 Phe Lys Ala Lys Ile Ile Phe Trp Tyr Val Leu Pro Ile Ser Ile 140 145 150 Thr Val Phe Leu Phe Ser Val Met Gly Tyr Ser Ile Tyr Arg Tyr 155 160 165 Ile His Val Gly Lys Glu Lys His Pro Ala Asn Leu Ile Leu Ile 170 175 180 Tyr Gly Asn Glu Phe Asp Lys Arg Phe Phe Val Pro Ala Glu Lys 185 190 195 Ile Val Ile Asn Phe Ile Thr Leu Asn Ile Ser Asp Asp Ser Lys 200 205 210 Ile Ser His Gln Asp Met Ser Leu Leu Gly Lys Ser Ser Asp Val 215 220 225 Ser Ser Leu Asn Asp Pro Gln Pro Ser Gly Asn Leu Arg Pro Pro 230 235 240 Gln Glu Glu Glu Glu Val Lys His Leu Gly Tyr Ala Ser His Leu 245 250 255 Met Glu Ile Phe Cys Asp Ser Glu Glu Asn Thr Glu Gly Thr Ser 260 265 270 Leu Thr Gln Gln Glu Ser Leu Ser Arg Thr Ile Pro Pro Asp Lys 275 280 285 Thr Val Ile Glu Tyr Glu Tyr Asp Val Arg Thr Thr Asp Ile Cys 290 295 300 Ala Gly Pro Glu Glu Gln Glu Leu Ser Leu Gln Glu Glu Val Ser 305 310 315 Thr Gln Gly Thr Leu Leu Glu Ser Gln Ala Ala Leu Ala Val Leu 320 325 330 Gly Pro Gln Thr Leu Gln Tyr Ser Tyr Thr Pro Gln Leu Gln Asp 335 340 345 Leu Asp Pro Leu Ala Gln Glu His Thr Asp Ser Glu Glu Gly Pro 350 355 360 Glu Glu Glu Pro Ser Thr Thr Leu Val Asp Trp Asp Pro Gln Thr 365 370 375 Gly Arg Leu Cys Ile Pro Ser Leu Ser Ser Phe Asp Gln Asp Ser 380 385 390 Glu Gly Cys Glu Pro Ser Glu Gly Asp Gly Leu Gly Glu Glu Gly 395 400 405 Leu Leu Ser Arg Leu Tyr Glu Glu Pro Ala Pro Asp Arg Pro Pro 410 415 420 Gly Glu Asn Glu Thr Tyr Leu Met Gln Phe Met Glu Glu Trp Gly 425 430 435 Leu Tyr Val Gln Met Glu Asn 440 77 1636 DNA Homo Sapien 77 gaggagcggg ccgaggactc cagcgtgccc aggtctggca tcctgcactt 50 gctgccctct gacacctggg aagatggccg gcccgtggac cttcaccctt 100 ctctgtggtt tgctggcagc caccttgatc caagccaccc tcagtcccac 150 tgcagttctc atcctcggcc caaaagtcat caaagaaaag ctgacacagg 200 agctgaagga ccacaacgcc accagcatcc tgcagcagct gccgctgctc 250 agtgccatgc gggaaaagcc agccggaggc atccctgtgc tgggcagcct 300 ggtgaacacc gtcctgaagc acatcatctg gctgaaggtc atcacagcta 350 acatcctcca gctgcaggtg aagccctcgg ccaatgacca ggagctgcta 400 gtcaagatcc ccctggacat ggtggctgga ttcaacacgc ccctggtcaa 450 gaccatcgtg gagttccaca tgacgactga ggcccaagcc accatccgca 500 tggacaccag tgcaagtggc cccacccgcc tggtcctcag tgactgtgcc 550 accagccatg ggagcctgcg catccaactg ctgtataagc tctccttcct 600 ggtgaacgcc ttagctaagc aggtcatgaa cctcctagtg ccatccctgc 650 ccaatctagt gaaaaaccag ctgtgtcccg tgatcgaggc ttccttcaat 700 ggcatgtatg cagacctcct gcagctggtg aaggtgccca tttccctcag 750 cattgaccgt ctggagtttg accttctgta tcctgccatc aagggtgaca 800 ccattcagct ctacctgggg gccaagttgt tggactcaca gggaaaggtg 850 accaagtggt tcaataactc tgcagcttcc ctgacaatgc ccaccctgga 900 caacatcccg ttcagcctca tcgtgagtca ggacgtggtg aaagctgcag 950 tggctgctgt gctctctcca gaagaattca tggtcctgtt ggactctgtg 1000 cttcctgaga gtgcccatcg gctgaagtca agcatcgggc tgatcaatga 1050 aaaggctgca gataagctgg gatctaccca gatcgtgaag atcctaactc 1100 aggacactcc cgagtttttt atagaccaag gccatgccaa ggtggcccaa 1150 ctgatcgtgc tggaagtgtt tccctccagt gaagccctcc gccctttgtt 1200 caccctgggc atcgaagcca gctcggaagc tcagttttac accaaaggtg 1250 accaacttat actcaacttg aataacatca gctctgatcg gatccagctg 1300 atgaactctg ggattggctg gttccaacct gatgttctga aaaacatcat 1350 cactgagatc atccactcca tcctgctgcc gaaccagaat ggcaaattaa 1400 gatctggggt cccagtgtca ttggtgaagg ccttgggatt cgaggcagct 1450 gagtcctcac tgaccaagga tgcccttgtg cttactccag cctccttgtg 1500 gaaacccagc tctcctgtct cccagtgaag acttggatgg cagccatcag 1550 ggaaggctgg gtcccagctg ggagtatggg tgtgagctct atagaccatc 1600 cctctctgca atcaataaac acttgcctgt gaaaaa 1636 78 484 PRT Homo Sapien 78 Met Ala Gly Pro Trp Thr Phe Thr Leu Leu Cys Gly Leu Leu Ala 1 5 10 15 Ala Thr Leu Ile Gln Ala Thr Leu Ser Pro Thr Ala Val Leu Ile 20 25 30 Leu Gly Pro Lys Val Ile Lys Glu Lys Leu Thr Gln Glu Leu Lys 35 40 45 Asp His Asn Ala Thr Ser Ile Leu Gln Gln Leu Pro Leu Leu Ser 50 55 60 Ala Met Arg Glu Lys Pro Ala Gly Gly Ile Pro Val Leu Gly Ser 65 70 75 Leu Val Asn Thr Val Leu Lys His Ile Ile Trp Leu Lys Val Ile 80 85 90 Thr Ala Asn Ile Leu Gln Leu Gln Val Lys Pro Ser Ala Asn Asp 95 100 105 Gln Glu Leu Leu Val Lys Ile Pro Leu Asp Met Val Ala Gly Phe 110 115 120 Asn Thr Pro Leu Val Lys Thr Ile Val Glu Phe His Met Thr Thr 125 130 135 Glu Ala Gln Ala Thr Ile Arg Met Asp Thr Ser Ala Ser Gly Pro 140 145 150 Thr Arg Leu Val Leu Ser Asp Cys Ala Thr Ser His Gly Ser Leu 155 160 165 Arg Ile Gln Leu Leu Tyr Lys Leu Ser Phe Leu Val Asn Ala Leu 170 175 180 Ala Lys Gln Val Met Asn Leu Leu Val Pro Ser Leu Pro Asn Leu 185 190 195 Val Lys Asn Gln Leu Cys Pro Val Ile Glu Ala Ser Phe Asn Gly 200 205 210 Met Tyr Ala Asp Leu Leu Gln Leu Val Lys Val Pro Ile Ser Leu 215 220 225 Ser Ile Asp Arg Leu Glu Phe Asp Leu Leu Tyr Pro Ala Ile Lys 230 235 240 Gly Asp Thr Ile Gln Leu Tyr Leu Gly Ala Lys Leu Leu Asp Ser 245 250 255 Gln Gly Lys Val Thr Lys Trp Phe Asn Asn Ser Ala Ala Ser Leu 260 265 270 Thr Met Pro Thr Leu Asp Asn Ile Pro Phe Ser Leu Ile Val Ser 275 280 285 Gln Asp Val Val Lys Ala Ala Val Ala Ala Val Leu Ser Pro Glu 290 295 300 Glu Phe Met Val Leu Leu Asp Ser Val Leu Pro Glu Ser Ala His 305 310 315 Arg Leu Lys Ser Ser Ile Gly Leu Ile Asn Glu Lys Ala Ala Asp 320 325 330 Lys Leu Gly Ser Thr Gln Ile Val Lys Ile Leu Thr Gln Asp Thr 335 340 345 Pro Glu Phe Phe Ile Asp Gln Gly His Ala Lys Val Ala Gln Leu 350 355 360 Ile Val Leu Glu Val Phe Pro Ser Ser Glu Ala Leu Arg Pro Leu 365 370 375 Phe Thr Leu Gly Ile Glu Ala Ser Ser Glu Ala Gln Phe Tyr Thr 380 385 390 Lys Gly Asp Gln Leu Ile Leu Asn Leu Asn Asn Ile Ser Ser Asp 395 400 405 Arg Ile Gln Leu Met Asn Ser Gly Ile Gly Trp Phe Gln Pro Asp 410 415 420 Val Leu Lys Asn Ile Ile Thr Glu Ile Ile His Ser Ile Leu Leu 425 430 435 Pro Asn Gln Asn Gly Lys Leu Arg Ser Gly Val Pro Val Ser Leu 440 445 450 Val Lys Ala Leu Gly Phe Glu Ala Ala Glu Ser Ser Leu Thr Lys 455 460 465 Asp Ala Leu Val Leu Thr Pro Ala Ser Leu Trp Lys Pro Ser Ser 470 475 480 Pro Val Ser Gln 79 1475 DNA Homo Sapien 79 gagagaagtc agcctggcag agagactctg aaatgaggga ttagaggtgt 50 tcaaggagca agagcttcag cctgaagaca agggagcagt ccctgaagac 100 gcttctactg agaggtctgc catggcctct cttggcctcc aacttgtggg 150 ctacatccta ggccttctgg ggcttttggg cacactggtt gccatgctgc 200 tccccagctg gaaaacaagt tcttatgtcg gtgccagcat tgtgacagca 250 gttggcttct ccaagggcct ctggatggaa tgtgccacac acagcacagg 300 catcacccag tgtgacatct atagcaccct tctgggcctg cccgctgaca 350 tccaggctgc ccaggccatg atggtgacat ccagtgcaat ctcctccctg 400 gcctgcatta tctctgtggt gggcatgaga tgcacagtct tctgccagga 450 atcccgagcc aaagacagag tggcggtagc aggtggagtc tttttcatcc 500 ttggaggcct cctgggattc attcctgttg cctggaatct tcatgggatc 550 ctacgggact tctactcacc actggtgcct gacagcatga aatttgagat 600 tggagaggct ctttacttgg gcattatttc ttccctgttc tccctgatag 650 ctggaatcat cctctgcttt tcctgctcat cccagagaaa tcgctccaac 700 tactacgatg cctaccaagc ccaacctctt gccacaagga gctctccaag 750 gcctggtcaa cctcccaaag tcaagagtga gttcaattcc tacagcctga 800 cagggtatgt gtgaagaacc aggggccaga gctggggggt ggctgggtct 850 gtgaaaaaca gtggacagca ccccgagggc cacaggtgag ggacactacc 900 actggatcgt gtcagaaggt gctgctgagg atagactgac tttggccatt 950 ggattgagca aaggcagaaa tgggggctag tgtaacagca tgcaggttga 1000 attgccaagg atgctcgcca tgccagcctt tctgttttcc tcaccttgct 1050 gctcccctgc cctaagtccc caaccctcaa cttgaaaccc cattccctta 1100 agccaggact cagaggatcc ctttgccctc tggtttacct gggactccat 1150 ccccaaaccc actaatcaca tcccactgac tgaccctctg tgatcaaaga 1200 ccctctctct ggctgaggtt ggctcttagc tcattgctgg ggatgggaag 1250 gagaagcagt ggcttttgtg ggcattgctc taacctactt ctcaagcttc 1300 cctccaaaga aactgattgg ccctggaacc tccatcccac tcttgttatg 1350 actccacagt gtccagacta atttgtgcat gaactgaaat aaaaccatcc 1400 tacggtatcc agggaacaga aagcaggatg caggatggga ggacaggaag 1450 gcagcctggg acatttaaaa aaata 1475 80 230 PRT Homo Sapien 80 Met Ala Ser Leu Gly Leu Gln Leu Val Gly Tyr Ile Leu Gly Leu 1 5 10 15 Leu Gly Leu Leu Gly Thr Leu Val Ala Met Leu Leu Pro Ser Trp 20 25 30 Lys Thr Ser Ser Tyr Val Gly Ala Ser Ile Val Thr Ala Val Gly 35 40 45 Phe Ser Lys Gly Leu Trp Met Glu Cys Ala Thr His Ser Thr Gly 50 55 60 Ile Thr Gln Cys Asp Ile Tyr Ser Thr Leu Leu Gly Leu Pro Ala 65 70 75 Asp Ile Gln Ala Ala Gln Ala Met Met Val Thr Ser Ser Ala Ile 80 85 90 Ser Ser Leu Ala Cys Ile Ile Ser Val Val Gly Met Arg Cys Thr 95 100 105 Val Phe Cys Gln Glu Ser Arg Ala Lys Asp Arg Val Ala Val Ala 110 115 120 Gly Gly Val Phe Phe Ile Leu Gly Gly Leu Leu Gly Phe Ile Pro 125 130 135 Val Ala Trp Asn Leu His Gly Ile Leu Arg Asp Phe Tyr Ser Pro 140 145 150 Leu Val Pro Asp Ser Met Lys Phe Glu Ile Gly Glu Ala Leu Tyr 155 160 165 Leu Gly Ile Ile Ser Ser Leu Phe Ser Leu Ile Ala Gly Ile Ile 170 175 180 Leu Cys Phe Ser Cys Ser Ser Gln Arg Asn Arg Ser Asn Tyr Tyr 185 190 195 Asp Ala Tyr Gln Ala Gln Pro Leu Ala Thr Arg Ser Ser Pro Arg 200 205 210 Pro Gly Gln Pro Pro Lys Val Lys Ser Glu Phe Asn Ser Tyr Ser 215 220 225 Leu Thr Gly Tyr Val 230 81 1732 DNA Homo Sapien 81 cccacgcgtc cgcgcctctc ccttctgctg gaccttcctt cgtctctcca 50 tctctccctc ctttccccgc gttctctttc cacctttctc ttcttcccac 100 cttagacctc ccttcctgcc ctcctttcct gcccaccgct gcttcctggc 150 ccttctccga ccccgctcta gcagcagacc tcctggggtc tgtgggttga 200 tctgtggccc ctgtgcctcc gtgtcctttt cgtctccctt cctcccgact 250 ccgctcccgg accagcggcc tgaccctggg gaaaggatgg ttcccgaggt 300 gagggtcctc tcctccttgc tgggactcgc gctgctctgg ttccccctgg 350 actcccacgc tcgagcccgc ccagacatgt tctgcctttt ccatgggaag 400 agatactccc ccggcgagag ctggcacccc tacttggagc cacaaggcct 450 gatgtactgc ctgcgctgta cctgctcaga gggcgcccat gtgagttgtt 500 accgcctcca ctgtccgcct gtccactgcc cccagcctgt gacggagcca 550 cagcaatgct gtcccaagtg tgtggaacct cacactccct ctggactccg 600 ggccccacca aagtcctgcc agcacaacgg gaccatgtac caacacggag 650 agatcttcag tgcccatgag ctgttcccct cccgcctgcc caaccagtgt 700 gtcctctgca gctgcacaga gggccagatc tactgcggcc tcacaacctg 750 ccccgaacca ggctgcccag cacccctccc actgccagac tcctgctgcc 800 aagcctgcaa agatgaggca agtgagcaat cggatgaaga ggacagtgtg 850 cagtcgctcc atggggtgag acatcctcag gatccatgtt ccagtgatgc 900 tgggagaaag agaggcccgg gcaccccagc ccccactggc ctcagcgccc 950 ctctgagctt catccctcgc cacttcagac ccaagggagc aggcagcaca 1000 actgtcaaga tcgtcctgaa ggagaaacat aagaaagcct gtgtgcatgg 1050 cgggaagacg tactcccacg gggaggtgtg gcacccggcc ttccgtgcct 1100 tcggcccctt gccctgcatc ctatgcacct gtgaggatgg ccgccaggac 1150 tgccagcgtg tgacctgtcc caccgagtac ccctgccgtc accccgagaa 1200 agtggctggg aagtgctgca agatttgccc agaggacaaa gcagaccctg 1250 gccacagtga gatcagttct accaggtgtc ccaaggcacc gggccgggtc 1300 ctcgtccaca catcggtatc cccaagccca gacaacctgc gtcgctttgc 1350 cctggaacac gaggcctcgg acttggtgga gatctacctc tggaagctgg 1400 taaaagatga ggaaactgag gctcagagag gtgaagtacc tggcccaagg 1450 ccacacagcc agaatcttcc acttgactca gatcaagaaa gtcaggaagc 1500 aagacttcca gaaagaggca cagcacttcc gactgctcgc tggcccccac 1550 gaaggtcact ggaacgtctt cctagcccag accctggagc tgaaggtcac 1600 ggccagtcca gacaaagtga ccaagacata acaaagacct aacagttgca 1650 gatatgagct gtataattgt tgttattata tattaataaa taagaagttg 1700 cattaccctc aaaaaaaaaa aaaaaaaaaa aa 1732 82 451 PRT Homo Sapien 82 Met Val Pro Glu Val Arg Val Leu Ser Ser Leu Leu Gly Leu Ala 1 5 10 15 Leu Leu Trp Phe Pro Leu Asp Ser His Ala Arg Ala Arg Pro Asp 20 25 30 Met Phe Cys Leu Phe His Gly Lys Arg Tyr Ser Pro Gly Glu Ser 35 40 45 Trp His Pro Tyr Leu Glu Pro Gln Gly Leu Met Tyr Cys Leu Arg 50 55 60 Cys Thr Cys Ser Glu Gly Ala His Val Ser Cys Tyr Arg Leu His 65 70 75 Cys Pro Pro Val His Cys Pro Gln Pro Val Thr Glu Pro Gln Gln 80 85 90 Cys Cys Pro Lys Cys Val Glu Pro His Thr Pro Ser Gly Leu Arg 95 100 105 Ala Pro Pro Lys Ser Cys Gln His Asn Gly Thr Met Tyr Gln His 110 115 120 Gly Glu Ile Phe Ser Ala His Glu Leu Phe Pro Ser Arg Leu Pro 125 130 135 Asn Gln Cys Val Leu Cys Ser Cys Thr Glu Gly Gln Ile Tyr Cys 140 145 150 Gly Leu Thr Thr Cys Pro Glu Pro Gly Cys Pro Ala Pro Leu Pro 155 160 165 Leu Pro Asp Ser Cys Cys Gln Ala Cys Lys Asp Glu Ala Ser Glu 170 175 180 Gln Ser Asp Glu Glu Asp Ser Val Gln Ser Leu His Gly Val Arg 185 190 195 His Pro Gln Asp Pro Cys Ser Ser Asp Ala Gly Arg Lys Arg Gly 200 205 210 Pro Gly Thr Pro Ala Pro Thr Gly Leu Ser Ala Pro Leu Ser Phe 215 220 225 Ile Pro Arg His Phe Arg Pro Lys Gly Ala Gly Ser Thr Thr Val 230 235 240 Lys Ile Val Leu Lys Glu Lys His Lys Lys Ala Cys Val His Gly 245 250 255 Gly Lys Thr Tyr Ser His Gly Glu Val Trp His Pro Ala Phe Arg 260 265 270 Ala Phe Gly Pro Leu Pro Cys Ile Leu Cys Thr Cys Glu Asp Gly 275 280 285 Arg Gln Asp Cys Gln Arg Val Thr Cys Pro Thr Glu Tyr Pro Cys 290 295 300 Arg His Pro Glu Lys Val Ala Gly Lys Cys Cys Lys Ile Cys Pro 305 310 315 Glu Asp Lys Ala Asp Pro Gly His Ser Glu Ile Ser Ser Thr Arg 320 325 330 Cys Pro Lys Ala Pro Gly Arg Val Leu Val His Thr Ser Val Ser 335 340 345 Pro Ser Pro Asp Asn Leu Arg Arg Phe Ala Leu Glu His Glu Ala 350 355 360 Ser Asp Leu Val Glu Ile Tyr Leu Trp Lys Leu Val Lys Asp Glu 365 370 375 Glu Thr Glu Ala Gln Arg Gly Glu Val Pro Gly Pro Arg Pro His 380 385 390 Ser Gln Asn Leu Pro Leu Asp Ser Asp Gln Glu Ser Gln Glu Ala 395 400 405 Arg Leu Pro Glu Arg Gly Thr Ala Leu Pro Thr Ala Arg Trp Pro 410 415 420 Pro Arg Arg Ser Leu Glu Arg Leu Pro Ser Pro Asp Pro Gly Ala 425 430 435 Glu Gly His Gly Gln Ser Arg Gln Ser Asp Gln Asp Ile Thr Lys 440 445 450 Thr 83 2052 DNA Homo Sapien 83 gacagctgtg tctcgatgga gtagactctc agaacagcgc agtttgccct 50 ccgctcacgc agagcctctc cgtggcttcc gcaccttgag cattaggcca 100 gttctcctct tctctctaat ccatccgtca cctctcctgt catccgtttc 150 catgccgtga ggtccattca cagaacacat ccatggctct catgctcagt 200 ttggttctga gtctcctcaa gctgggatca gggcagtggc aggtgtttgg 250 gccagacaag cctgtccagg ccttggtggg ggaggacgca gcattctcct 300 gtttcctgtc tcctaagacc aatgcagagg ccatggaagt gcggttcttc 350 aggggccagt tctctagcgt ggtccacctc tacagggacg ggaaggacca 400 gccatttatg cagatgccac agtatcaagg caggacaaaa ctggtgaagg 450 attctattgc ggaggggcgc atctctctga ggctggaaaa cattactgtg 500 ttggatgctg gcctctatgg gtgcaggatt agttcccagt cttactacca 550 gaaggccatc tgggagctac aggtgtcagc actgggctca gttcctctca 600 tttccatcac gggatatgtt gatagagaca tccagctact ctgtcagtcc 650 tcgggctggt tcccccggcc cacagcgaag tggaaaggtc cacaaggaca 700 ggatttgtcc acagactcca ggacaaacag agacatgcat ggcctgtttg 750 atgtggagat ctctctgacc gtccaagaga acgccgggag catatcctgt 800 tccatgcggc atgctcatct gagccgagag gtggaatcca gggtacagat 850 aggagatacc tttttcgagc ctatatcgtg gcacctggct accaaagtac 900 tgggaatact ctgctgtggc ctattttttg gcattgttgg actgaagatt 950 ttcttctcca aattccagtg gaaaatccag gcggaactgg actggagaag 1000 aaagcacgga caggcagaat tgagagacgc ccggaaacac gcagtggagg 1050 tgactctgga tccagagacg gctcacccga agctctgcgt ttctgatctg 1100 aaaactgtaa cccatagaaa agctccccag gaggtgcctc actctgagaa 1150 gagatttaca aggaagagtg tggtggcttc tcagagtttc caagcaggga 1200 aacattactg ggaggtggac ggaggacaca ataaaaggtg gcgcgtggga 1250 gtgtgccggg atgatgtgga caggaggaag gagtacgtga ctttgtctcc 1300 cgatcatggg tactgggtcc tcagactgaa tggagaacat ttgtatttca 1350 cattaaatcc ccgttttatc agcgtcttcc ccaggacccc acctacaaaa 1400 ataggggtct tcctggacta tgagtgtggg accatctcct tcttcaacat 1450 aaatgaccag tcccttattt ataccctgac atgtcggttt gaaggcttat 1500 tgaggcccta cattgagtat ccgtcctata atgagcaaaa tggaactccc 1550 atagtcatct gcccagtcac ccaggaatca gagaaagagg cctcttggca 1600 aagggcctct gcaatcccag agacaagcaa cagtgagtcc tcctcacagg 1650 caaccacgcc cttcctcccc aggggtgaaa tgtaggatga atcacatccc 1700 acattcttct ttagggatat taaggtctct ctcccagatc caaagtcccg 1750 cagcagccgg ccaaggtggc ttccagatga agggggactg gcctgtccac 1800 atgggagtca ggtgtcatgg ctgccctgag ctgggaggga agaaggctga 1850 cattacattt agtttgctct cactccatct ggctaagtga tcttgaaata 1900 ccacctctca ggtgaagaac cgtcaggaat tcccatctca caggctgtgg 1950 tgtagattaa gtagacaagg aatgtgaata atgcttagat cttattgatg 2000 acagagtgta tcctaatggt ttgttcatta tattacactt tcagtaaaaa 2050 aa 2052 84 500 PRT Homo Sapien 84 Met Ala Leu Met Leu Ser Leu Val Leu Ser Leu Leu Lys Leu Gly 1 5 10 15 Ser Gly Gln Trp Gln Val Phe Gly Pro Asp Lys Pro Val Gln Ala 20 25 30 Leu Val Gly Glu Asp Ala Ala Phe Ser Cys Phe Leu Ser Pro Lys 35 40 45 Thr Asn Ala Glu Ala Met Glu Val Arg Phe Phe Arg Gly Gln Phe 50 55 60 Ser Ser Val Val His Leu Tyr Arg Asp Gly Lys Asp Gln Pro Phe 65 70 75 Met Gln Met Pro Gln Tyr Gln Gly Arg Thr Lys Leu Val Lys Asp 80 85 90 Ser Ile Ala Glu Gly Arg Ile Ser Leu Arg Leu Glu Asn Ile Thr 95 100 105 Val Leu Asp Ala Gly Leu Tyr Gly Cys Arg Ile Ser Ser Gln Ser 110 115 120 Tyr Tyr Gln Lys Ala Ile Trp Glu Leu Gln Val Ser Ala Leu Gly 125 130 135 Ser Val Pro Leu Ile Ser Ile Thr Gly Tyr Val Asp Arg Asp Ile 140 145 150 Gln Leu Leu Cys Gln Ser Ser Gly Trp Phe Pro Arg Pro Thr Ala 155 160 165 Lys Trp Lys Gly Pro Gln Gly Gln Asp Leu Ser Thr Asp Ser Arg 170 175 180 Thr Asn Arg Asp Met His Gly Leu Phe Asp Val Glu Ile Ser Leu 185 190 195 Thr Val Gln Glu Asn Ala Gly Ser Ile Ser Cys Ser Met Arg His 200 205 210 Ala His Leu Ser Arg Glu Val Glu Ser Arg Val Gln Ile Gly Asp 215 220 225 Thr Phe Phe Glu Pro Ile Ser Trp His Leu Ala Thr Lys Val Leu 230 235 240 Gly Ile Leu Cys Cys Gly Leu Phe Phe Gly Ile Val Gly Leu Lys 245 250 255 Ile Phe Phe Ser Lys Phe Gln Trp Lys Ile Gln Ala Glu Leu Asp 260 265 270 Trp Arg Arg Lys His Gly Gln Ala Glu Leu Arg Asp Ala Arg Lys 275 280 285 His Ala Val Glu Val Thr Leu Asp Pro Glu Thr Ala His Pro Lys 290 295 300 Leu Cys Val Ser Asp Leu Lys Thr Val Thr His Arg Lys Ala Pro 305 310 315 Gln Glu Val Pro His Ser Glu Lys Arg Phe Thr Arg Lys Ser Val 320 325 330 Val Ala Ser Gln Ser Phe Gln Ala Gly Lys His Tyr Trp Glu Val 335 340 345 Asp Gly Gly His Asn Lys Arg Trp Arg Val Gly Val Cys Arg Asp 350 355 360 Asp Val Asp Arg Arg Lys Glu Tyr Val Thr Leu Ser Pro Asp His 365 370 375 Gly Tyr Trp Val Leu Arg Leu Asn Gly Glu His Leu Tyr Phe Thr 380 385 390 Leu Asn Pro Arg Phe Ile Ser Val Phe Pro Arg Thr Pro Pro Thr 395 400 405 Lys Ile Gly Val Phe Leu Asp Tyr Glu Cys Gly Thr Ile Ser Phe 410 415 420 Phe Asn Ile Asn Asp Gln Ser Leu Ile Tyr Thr Leu Thr Cys Arg 425 430 435 Phe Glu Gly Leu Leu Arg Pro Tyr Ile Glu Tyr Pro Ser Tyr Asn 440 445 450 Glu Gln Asn Gly Thr Pro Ile Val Ile Cys Pro Val Thr Gln Glu 455 460 465 Ser Glu Lys Glu Ala Ser Trp Gln Arg Ala Ser Ala Ile Pro Glu 470 475 480 Thr Ser Asn Ser Glu Ser Ser Ser Gln Ala Thr Thr Pro Phe Leu 485 490 495 Pro Arg Gly Glu Met 500 85 1665 DNA Homo Sapien 85 aacagacgtt ccctcgcggc cctggcacct ctaaccccag acatgctgct 50 gctgctgctg cccctgctct gggggaggga gagggcggaa ggacagacaa 100 gtaaactgct gacgatgcag agttccgtga cggtgcagga aggcctgtgt 150 gtccatgtgc cctgctcctt ctcctacccc tcgcatggct ggatttaccc 200 tggcccagta gttcatggct actggttccg ggaaggggcc aatacagacc 250 aggatgctcc agtggccaca aacaacccag ctcgggcagt gtgggaggag 300 actcgggacc gattccacct ccttggggac ccacatacca agaattgcac 350 cctgagcatc agagatgcca gaagaagtga tgcggggaga tacttctttc 400 gtatggagaa aggaagtata aaatggaatt ataaacatca ccggctctct 450 gtgaatgtga cagccttgac ccacaggccc aacatcctca tcccaggcac 500 cctggagtcc ggctgccccc agaatctgac ctgctctgtg ccctgggcct 550 gtgagcaggg gacaccccct atgatctcct ggatagggac ctccgtgtcc 600 cccctggacc cctccaccac ccgctcctcg gtgctcaccc tcatcccaca 650 gccccaggac catggcacca gcctcacctg tcaggtgacc ttccctgggg 700 ccagcgtgac cacgaacaag accgtccatc tcaacgtgtc ctacccgcct 750 cagaacttga ccatgactgt cttccaagga gacggcacag tatccacagt 800 cttgggaaat ggctcatctc tgtcactccc agagggccag tctctgcgcc 850 tggtctgtgc agttgatgca gttgacagca atccccctgc caggctgagc 900 ctgagctgga gaggcctgac cctgtgcccc tcacagccct caaacccggg 950 ggtgctggag ctgccttggg tgcacctgag ggatgcagct gaattcacct 1000 gcagagctca gaaccctctc ggctctcagc aggtctacct gaacgtctcc 1050 ctgcagagca aagccacatc aggagtgact cagggggtgg tcgggggagc 1100 tggagccaca gccctggtct tcctgtcctt ctgcgtcatc ttcgttgtag 1150 tgaggtcctg caggaagaaa tcggcaaggc cagcagcggg cgtgggagat 1200 acgggcatag aggatgcaaa cgctgtcagg ggttcagcct ctcaggggcc 1250 cctgactgaa ccttgggcag aagacagtcc cccagaccag cctcccccag 1300 cttctgcccg ctcctcagtg ggggaaggag agctccagta tgcatccctc 1350 agcttccaga tggtgaagcc ttgggactcg cggggacagg aggccactga 1400 caccgagtac tcggagatca agatccacag atgagaaact gcagagactc 1450 accctgattg agggatcaca gcccctccag gcaagggaga agtcagaggc 1500 tgattcttgt agaattaaca gccctcaacg tgatgagcta tgataacact 1550 atgaattatg tgcagagtga aaagcacaca ggctttagag tcaaagtatc 1600 tcaaacctga atccacactg tgccctccct tttatttttt taactaaaag 1650 acagacaaat tccta 1665 86 463 PRT Homo Sapien 86 Met Leu Leu Leu Leu Leu Pro Leu Leu Trp Gly Arg Glu Arg Ala 1 5 10 15 Glu Gly Gln Thr Ser Lys Leu Leu Thr Met Gln Ser Ser Val Thr 20 25 30 Val Gln Glu Gly Leu Cys Val His Val Pro Cys Ser Phe Ser Tyr 35 40 45 Pro Ser His Gly Trp Ile Tyr Pro Gly Pro Val Val His Gly Tyr 50 55 60 Trp Phe Arg Glu Gly Ala Asn Thr Asp Gln Asp Ala Pro Val Ala 65 70 75 Thr Asn Asn Pro Ala Arg Ala Val Trp Glu Glu Thr Arg Asp Arg 80 85 90 Phe His Leu Leu Gly Asp Pro His Thr Lys Asn Cys Thr Leu Ser 95 100 105 Ile Arg Asp Ala Arg Arg Ser Asp Ala Gly Arg Tyr Phe Phe Arg 110 115 120 Met Glu Lys Gly Ser Ile Lys Trp Asn Tyr Lys His His Arg Leu 125 130 135 Ser Val Asn Val Thr Ala Leu Thr His Arg Pro Asn Ile Leu Ile 140 145 150 Pro Gly Thr Leu Glu Ser Gly Cys Pro Gln Asn Leu Thr Cys Ser 155 160 165 Val Pro Trp Ala Cys Glu Gln Gly Thr Pro Pro Met Ile Ser Trp 170 175 180 Ile Gly Thr Ser Val Ser Pro Leu Asp Pro Ser Thr Thr Arg Ser 185 190 195 Ser Val Leu Thr Leu Ile Pro Gln Pro Gln Asp His Gly Thr Ser 200 205 210 Leu Thr Cys Gln Val Thr Phe Pro Gly Ala Ser Val Thr Thr Asn 215 220 225 Lys Thr Val His Leu Asn Val Ser Tyr Pro Pro Gln Asn Leu Thr 230 235 240 Met Thr Val Phe Gln Gly Asp Gly Thr Val Ser Thr Val Leu Gly 245 250 255 Asn Gly Ser Ser Leu Ser Leu Pro Glu Gly Gln Ser Leu Arg Leu 260 265 270 Val Cys Ala Val Asp Ala Val Asp Ser Asn Pro Pro Ala Arg Leu 275 280 285 Ser Leu Ser Trp Arg Gly Leu Thr Leu Cys Pro Ser Gln Pro Ser 290 295 300 Asn Pro Gly Val Leu Glu Leu Pro Trp Val His Leu Arg Asp Ala 305 310 315 Ala Glu Phe Thr Cys Arg Ala Gln Asn Pro Leu Gly Ser Gln Gln 320 325 330 Val Tyr Leu Asn Val Ser Leu Gln Ser Lys Ala Thr Ser Gly Val 335 340 345 Thr Gln Gly Val Val Gly Gly Ala Gly Ala Thr Ala Leu Val Phe 350 355 360 Leu Ser Phe Cys Val Ile Phe Val Val Val Arg Ser Cys Arg Lys 365 370 375 Lys Ser Ala Arg Pro Ala Ala Gly Val Gly Asp Thr Gly Ile Glu 380 385 390 Asp Ala Asn Ala Val Arg Gly Ser Ala Ser Gln Gly Pro Leu Thr 395 400 405 Glu Pro Trp Ala Glu Asp Ser Pro Pro Asp Gln Pro Pro Pro Ala 410 415 420 Ser Ala Arg Ser Ser Val Gly Glu Gly Glu Leu Gln Tyr Ala Ser 425 430 435 Leu Ser Phe Gln Met Val Lys Pro Trp Asp Ser Arg Gly Gln Glu 440 445 450 Ala Thr Asp Thr Glu Tyr Ser Glu Ile Lys Ile His Arg 455 460 87 1176 DNA Homo Sapien 87 agaaagctgc actctgttga gctccagggc gcagtggagg gagggagtga 50 aggagctctc tgtacccaag gaaagtgcag ctgagactca gacaagatta 100 caatgaacca actcagcttc ctgctgtttc tcatagcgac caccagagga 150 tggagtacag atgaggctaa tacttacttc aaggaatgga cctgttcttc 200 gtctccatct ctgcccagaa gctgcaagga aatcaaagac gaatgtccta 250 gtgcatttga tggcctgtat tttctccgca ctgagaatgg tgttatctac 300 cagaccttct gtgacatgac ctctgggggt ggcggctgga ccctggtggc 350 cagcgtgcat gagaatgaca tgcgtgggaa gtgcacggtg ggcgatcgct 400 ggtccagtca gcagggcagc aaagcagact acccagaggg ggacggcaac 450 tgggccaact acaacacctt tggatctgca gaggcggcca cgagcgatga 500 ctacaagaac cctggctact acgacatcca ggccaaggac ctgggcatct 550 ggcacgtgcc caataagtcc cccatgcagc actggagaaa cagctccctg 600 ctgaggtacc gcacggacac tggcttcctc cagacactgg gacataatct 650 gtttggcatc taccagaaat atccagtgaa atatggagaa ggaaagtgtt 700 ggactgacaa cggcccggtg atccctgtgg tctatgattt tggcgacgcc 750 cagaaaacag catcttatta ctcaccctat ggccagcggg aattcactgc 800 gggatttgtt cagttcaggg tatttaataa cgagagagca gccaacgcct 850 tgtgtgctgg aatgagggtc accggatgta acactgagca tcactgcatt 900 ggtggaggag gatactttcc agaggccagt ccccagcagt gtggagattt 950 ttctggtttt gattggagtg gatatggaac tcatgttggt tacagcagca 1000 gccgtgagat aactgaggca gctgtgcttc tattctatcg ttgagagttt 1050 tgtgggaggg aacccagacc tctcctccca accatgagat cccaaggatg 1100 gagaacaact tacccagtag ctagaatgtt aatggcagaa gagaaaacaa 1150 taaatcatat tgactcaaga aaaaaa 1176 88 313 PRT Homo Sapien 88 Met Asn Gln Leu Ser Phe Leu Leu Phe Leu Ile Ala Thr Thr Arg 1 5 10 15 Gly Trp Ser Thr Asp Glu Ala Asn Thr Tyr Phe Lys Glu Trp Thr 20 25 30 Cys Ser Ser Ser Pro Ser Leu Pro Arg Ser Cys Lys Glu Ile Lys 35 40 45 Asp Glu Cys Pro Ser Ala Phe Asp Gly Leu Tyr Phe Leu Arg Thr 50 55 60 Glu Asn Gly Val Ile Tyr Gln Thr Phe Cys Asp Met Thr Ser Gly 65 70 75 Gly Gly Gly Trp Thr Leu Val Ala Ser Val His Glu Asn Asp Met 80 85 90 Arg Gly Lys Cys Thr Val Gly Asp Arg Trp Ser Ser Gln Gln Gly 95 100 105 Ser Lys Ala Asp Tyr Pro Glu Gly Asp Gly Asn Trp Ala Asn Tyr 110 115 120 Asn Thr Phe Gly Ser Ala Glu Ala Ala Thr Ser Asp Asp Tyr Lys 125 130 135 Asn Pro Gly Tyr Tyr Asp Ile Gln Ala Lys Asp Leu Gly Ile Trp 140 145 150 His Val Pro Asn Lys Ser Pro Met Gln His Trp Arg Asn Ser Ser 155 160 165 Leu Leu Arg Tyr Arg Thr Asp Thr Gly Phe Leu Gln Thr Leu Gly 170 175 180 His Asn Leu Phe Gly Ile Tyr Gln Lys Tyr Pro Val Lys Tyr Gly 185 190 195 Glu Gly Lys Cys Trp Thr Asp Asn Gly Pro Val Ile Pro Val Val 200 205 210 Tyr Asp Phe Gly Asp Ala Gln Lys Thr Ala Ser Tyr Tyr Ser Pro 215 220 225 Tyr Gly Gln Arg Glu Phe Thr Ala Gly Phe Val Gln Phe Arg Val 230 235 240 Phe Asn Asn Glu Arg Ala Ala Asn Ala Leu Cys Ala Gly Met Arg 245 250 255 Val Thr Gly Cys Asn Thr Glu His His Cys Ile Gly Gly Gly Gly 260 265 270 Tyr Phe Pro Glu Ala Ser Pro Gln Gln Cys Gly Asp Phe Ser Gly 275 280 285 Phe Asp Trp Ser Gly Tyr Gly Thr His Val Gly Tyr Ser Ser Ser 290 295 300 Arg Glu Ile Thr Glu Ala Ala Val Leu Leu Phe Tyr Arg 305 310 89 759 DNA Homo Sapien 89 ctagatttgt cggcttgcgg ggagacttca ggagtcgctg tctctgaact 50 tccagcctca gagaccgccg cccttgtccc cgagggccat gggccgggtc 100 tcagggcttg tgccctctcg cttcctgacg ctcctggcgc atctggtggt 150 cgtcatcacc ttattctggt cccgggacag caacatacag gcctgcctgc 200 ctctcacgtt cacccccgag gagtatgaca agcaggacat tcagctggtg 250 gccgcgctct ctgtcaccct gggcctcttt gcagtggagc tggccggttt 300 cctctcagga gtctccatgt tcaacagcac ccagagcctc atctccattg 350 gggctcactg tagtgcatcc gtggccctgt ccttcttcat attcgagcgt 400 tgggagtgca ctacgtattg gtacattttt gtcttctgca gtgcccttcc 450 agctgtcact gaaatggctt tattcgtcac cgtctttggg ctgaaaaaga 500 aacccttctg attaccttca tgacgggaac ctaaggacga agcctacagg 550 ggcaagggcc gcttcgtatt cctggaagaa ggaaggcata ggcttcggtt 600 ttcccctcgg aaactgcttc tgctggagga tatgtgttgg aataattacg 650 tcttgagtct gggattatcc gcattgtatt tagtgctttg taataaaata 700 tgttttgtag taacattaag acttatatac agttttaggg gacaattaaa 750 aaaaaaaaa 759 90 140 PRT Homo Sapien 90 Met Gly Arg Val Ser Gly Leu Val Pro Ser Arg Phe Leu Thr Leu 1 5 10 15 Leu Ala His Leu Val Val Val Ile Thr Leu Phe Trp Ser Arg Asp 20 25 30 Ser Asn Ile Gln Ala Cys Leu Pro Leu Thr Phe Thr Pro Glu Glu 35 40 45 Tyr Asp Lys Gln Asp Ile Gln Leu Val Ala Ala Leu Ser Val Thr 50 55 60 Leu Gly Leu Phe Ala Val Glu Leu Ala Gly Phe Leu Ser Gly Val 65 70 75 Ser Met Phe Asn Ser Thr Gln Ser Leu Ile Ser Ile Gly Ala His 80 85 90 Cys Ser Ala Ser Val Ala Leu Ser Phe Phe Ile Phe Glu Arg Trp 95 100 105 Glu Cys Thr Thr Tyr Trp Tyr Ile Phe Val Phe Cys Ser Ala Leu 110 115 120 Pro Ala Val Thr Glu Met Ala Leu Phe Val Thr Val Phe Gly Leu 125 130 135 Lys Lys Lys Pro Phe 140 91 1871 DNA Homo Sapien 91 ctgggacccc gaaaagagaa ggggagagcg aggggacgag agcggaggag 50 gaagatgcaa ctgactcgct gctgcttcgt gttcctggtg cagggtagcc 100 tctatctggt catctgtggc caggatgatg gtcctcccgg ctcagaggac 150 cctgagcgtg atgaccacga gggccagccc cggccccggg tgcctcggaa 200 gcggggccac atctcaccta agtcccgccc catggccaat tccactctcc 250 tagggctgct ggccccgcct ggggaggctt ggggcattct tgggcagccc 300 cccaaccgcc cgaaccacag ccccccaccc tcagccaagg tgaagaaaat 350 ctttggctgg ggcgacttct actccaacat caagacggtg gccctgaacc 400 tgctcgtcac agggaagatt gtggaccatg gcaatgggac cttcagcgtc 450 cacttccaac acaatgccac aggccaggga aacatctcca tcagcctcgt 500 gccccccagt aaagctgtag agttccacca ggaacagcag atcttcatcg 550 aagccaaggc ctccaaaatc ttcaactgcc ggatggagtg ggagaaggta 600 gaacggggcc gccggacctc gctttgcacc cacgacccag ccaagatctg 650 ctcccgagac cacgctcaga gctcagccac ctggagctgc tcccagccct 700 tcaaagtcgt ctgtgtctac atcgccttct acagcacgga ctatcggctg 750 gtccagaagg tgtgcccaga ttacaactac catagtgata ccccctacta 800 cccatctggg tgacccgggg caggccacag aggccaggcc agggctggaa 850 ggacaggcct gcccatgcag gagaccatct ggacaccggg cagggaaggg 900 gttgggcctc aggcagggag gggggtggag acgaggagat gccaagtggg 950 gccagggcca agtctcaagt ggcagagaaa gggtcccaag tgctggtccc 1000 aacctgaagc tgtggagtga ctagatcaca ggagcactgg aggaggagtg 1050 ggctctctgt gcagcctcac agggctttgc cacggagcca cagagagatg 1100 ctgggtcccc gaggcctgtg ggcaggccga tcagtgtggc cccagatcaa 1150 gtcatgggag gaagctaagc ccttggttct tgccatcctg aggaaagata 1200 gcaacaggga gggggagatt tcatcagtgt ggacagcctg tcaacttagg 1250 atggatggct gagagggctt cctaggagcc agtcagcagg gtggggtggg 1300 gccagaggag ctctccagcc ctgcctagtg ggcgccctga gccccttgtc 1350 gtgtgctgag catggcatga ggctgaagtg gcaaccctgg ggtctttgat 1400 gtcttgacag attgaccatc tgtctccagc caggccaccc ctttccaaaa 1450 ttccctcttc tgccagtact ccccctgtac cacccattgc tgatggcaca 1500 cccatcctta agctaagaca ggacgattgt ggtcctccca cactaaggcc 1550 acagcccatc cgcgtgctgt gtgtccctct tccaccccaa cccctgctgg 1600 ctcctctggg agcatccatg tcccggagag gggtccctca acagtcagcc 1650 tcacctgtca gaccggggtt ctcccggatc tggatggcgc cgccctctca 1700 gcagcgggca cgggtggggc ggggccgggc cgcagagcat gtgctggatc 1750 tgttctgtgt gtctgtctgt gggtgggggg aggggaggga agtcttgtga 1800 aaccgctgat tgctgacttt tgtgtgaaga atcgtgttct tggagcagga 1850 aataaagctt gccccggggc a 1871 92 252 PRT Homo Sapien 92 Met Gln Leu Thr Arg Cys Cys Phe Val Phe Leu Val Gln Gly Ser 1 5 10 15 Leu Tyr Leu Val Ile Cys Gly Gln Asp Asp Gly Pro Pro Gly Ser 20 25 30 Glu Asp Pro Glu Arg Asp Asp His Glu Gly Gln Pro Arg Pro Arg 35 40 45 Val Pro Arg Lys Arg Gly His Ile Ser Pro Lys Ser Arg Pro Met 50 55 60 Ala Asn Ser Thr Leu Leu Gly Leu Leu Ala Pro Pro Gly Glu Ala 65 70 75 Trp Gly Ile Leu Gly Gln Pro Pro Asn Arg Pro Asn His Ser Pro 80 85 90 Pro Pro Ser Ala Lys Val Lys Lys Ile Phe Gly Trp Gly Asp Phe 95 100 105 Tyr Ser Asn Ile Lys Thr Val Ala Leu Asn Leu Leu Val Thr Gly 110 115 120 Lys Ile Val Asp His Gly Asn Gly Thr Phe Ser Val His Phe Gln 125 130 135 His Asn Ala Thr Gly Gln Gly Asn Ile Ser Ile Ser Leu Val Pro 140 145 150 Pro Ser Lys Ala Val Glu Phe His Gln Glu Gln Gln Ile Phe Ile 155 160 165 Glu Ala Lys Ala Ser Lys Ile Phe Asn Cys Arg Met Glu Trp Glu 170 175 180 Lys Val Glu Arg Gly Arg Arg Thr Ser Leu Cys Thr His Asp Pro 185 190 195 Ala Lys Ile Cys Ser Arg Asp His Ala Gln Ser Ser Ala Thr Trp 200 205 210 Ser Cys Ser Gln Pro Phe Lys Val Val Cys Val Tyr Ile Ala Phe 215 220 225 Tyr Ser Thr Asp Tyr Arg Leu Val Gln Lys Val Cys Pro Asp Tyr 230 235 240 Asn Tyr His Ser Asp Thr Pro Tyr Tyr Pro Ser Gly 245 250 93 902 DNA Homo Sapien 93 cggtggccat gactgcggcc gtgttcttcg gctgcgcctt cattgccttc 50 gggcctgcgc tcgcccttta tgtcttcacc atcgccatcg agccgttgcg 100 tatcatcttc ctcatcgccg gagctttctt ctggttggtg tctctactga 150 tttcgtccct tgtttggttc atggcaagag tcattattga caacaaagat 200 ggaccaacac agaaatatct gctgatcttt ggagcgtttg tctctgtcta 250 tatccaagaa atgttccgat ttgcatatta taaactctta aaaaaagcca 300 gtgaaggttt gaagagtata aacccaggtg agacagcacc ctctatgcga 350 ctgctggcct atgtttctgg cttgggcttt ggaatcatga gtggagtatt 400 ttcctttgtg aataccctat ctgactcctt ggggccaggc acagtgggca 450 ttcatggaga ttctcctcaa ttcttccttt attcagcttt catgacgctg 500 gtcattatct tgctgcatgt attctggggc attgtatttt ttgatggctg 550 tgagaagaaa aagtggggca tcctccttat cgttctcctg acccacctgc 600 tggtgtcagc ccagaccttc ataagttctt attatggaat aaacctggcg 650 tcagcattta taatcctggt gctcatgggc acctgggcat tcttagctgc 700 gggaggcagc tgccgaagcc tgaaactctg cctgctctgc caagacaaga 750 actttcttct ttacaaccag cgctccagat aacctcaggg aaccagcact 800 tcccaaaccg cagactacat ctttagagga agcacaactg tgcctttttc 850 tgaaaatccc tttttctggt ggaattgaga aagaaataaa actatgcaga 900 ta 902 94 257 PRT Homo Sapien 94 Met Thr Ala Ala Val Phe Phe Gly Cys Ala Phe Ile Ala Phe Gly 1 5 10 15 Pro Ala Leu Ala Leu Tyr Val Phe Thr Ile Ala Ile Glu Pro Leu 20 25 30 Arg Ile Ile Phe Leu Ile Ala Gly Ala Phe Phe Trp Leu Val Ser 35 40 45 Leu Leu Ile Ser Ser Leu Val Trp Phe Met Ala Arg Val Ile Ile 50 55 60 Asp Asn Lys Asp Gly Pro Thr Gln Lys Tyr Leu Leu Ile Phe Gly 65 70 75 Ala Phe Val Ser Val Tyr Ile Gln Glu Met Phe Arg Phe Ala Tyr 80 85 90 Tyr Lys Leu Leu Lys Lys Ala Ser Glu Gly Leu Lys Ser Ile Asn 95 100 105 Pro Gly Glu Thr Ala Pro Ser Met Arg Leu Leu Ala Tyr Val Ser 110 115 120 Gly Leu Gly Phe Gly Ile Met Ser Gly Val Phe Ser Phe Val Asn 125 130 135 Thr Leu Ser Asp Ser Leu Gly Pro Gly Thr Val Gly Ile His Gly 140 145 150 Asp Ser Pro Gln Phe Phe Leu Tyr Ser Ala Phe Met Thr Leu Val 155 160 165 Ile Ile Leu Leu His Val Phe Trp Gly Ile Val Phe Phe Asp Gly 170 175 180 Cys Glu Lys Lys Lys Trp Gly Ile Leu Leu Ile Val Leu Leu Thr 185 190 195 His Leu Leu Val Ser Ala Gln Thr Phe Ile Ser Ser Tyr Tyr Gly 200 205 210 Ile Asn Leu Ala Ser Ala Phe Ile Ile Leu Val Leu Met Gly Thr 215 220 225 Trp Ala Phe Leu Ala Ala Gly Gly Ser Cys Arg Ser Leu Lys Leu 230 235 240 Cys Leu Leu Cys Gln Asp Lys Asn Phe Leu Leu Tyr Asn Gln Arg 245 250 255 Ser Arg 95 1073 DNA Homo Sapien 95 aatttttcac cagagtaaac ttgagaaacc aactggacct tgagtattgt 50 acattttgcc tcgtggaccc aaaggtagca atctgaaaca tgaggagtac 100 gattctactg ttttgtcttc taggatcaac tcggtcatta ccacagctca 150 aacctgcttt gggactccct cccacaaaac tggctccgga tcagggaaca 200 ctaccaaacc aacagcagtc aaatcaggtc tttccttctt taagtctgat 250 accattaaca cagatgctca cactggggcc agatctgcat ctgttaaatc 300 ctgctgcagg aatgacacct ggtacccaga cccacccatt gaccctggga 350 gggttgaatg tacaacagca actgcaccca catgtgttac caatttttgt 400 cacacaactt ggagcccagg gcactatcct aagctcagag gaattgccac 450 aaatcttcac gagcctcatc atccattcct tgttcccggg aggcatcctg 500 cccaccagtc aggcaggggc taatccagat gtccaggatg gaagccttcc 550 agcaggagga gcaggtgtaa atcctgccac ccagggaacc ccagcaggcc 600 gcctcccaac tcccagtggc acagatgacg actttgcagt gaccacccct 650 gcaggcatcc aaaggagcac acatgccatc gaggaagcca ccacagaatc 700 agcaaatgga attcagtaag ctgtttcaaa ttttttcaac taagctgcct 750 cgaatttggt gatacatgtg aatctttatc attgattata ttatggaata 800 gattgagaca cattggatag tcttagaaga aattaattct taatttacct 850 gaaaatattc ttgaaatttc agaaaatatg ttctatgtag agaatcccaa 900 cttttaaaaa caataattca atggataaat ctgtctttga aatataacat 950 tatgctgcct ggatgatatg catattaaaa catatttgga aaactggaaa 1000 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1050 aaaaaaaaaa aaaaaaaaaa aaa 1073 96 209 PRT Homo Sapien 96 Met Arg Ser Thr Ile Leu Leu Phe Cys Leu Leu Gly Ser Thr Arg 1 5 10 15 Ser Leu Pro Gln Leu Lys Pro Ala Leu Gly Leu Pro Pro Thr Lys 20 25 30 Leu Ala Pro Asp Gln Gly Thr Leu Pro Asn Gln Gln Gln Ser Asn 35 40 45 Gln Val Phe Pro Ser Leu Ser Leu Ile Pro Leu Thr Gln Met Leu 50 55 60 Thr Leu Gly Pro Asp Leu His Leu Leu Asn Pro Ala Ala Gly Met 65 70 75 Thr Pro Gly Thr Gln Thr His Pro Leu Thr Leu Gly Gly Leu Asn 80 85 90 Val Gln Gln Gln Leu His Pro His Val Leu Pro Ile Phe Val Thr 95 100 105 Gln Leu Gly Ala Gln Gly Thr Ile Leu Ser Ser Glu Glu Leu Pro 110 115 120 Gln Ile Phe Thr Ser Leu Ile Ile His Ser Leu Phe Pro Gly Gly 125 130 135 Ile Leu Pro Thr Ser Gln Ala Gly Ala Asn Pro Asp Val Gln Asp 140 145 150 Gly Ser Leu Pro Ala Gly Gly Ala Gly Val Asn Pro Ala Thr Gln 155 160 165 Gly Thr Pro Ala Gly Arg Leu Pro Thr Pro Ser Gly Thr Asp Asp 170 175 180 Asp Phe Ala Val Thr Thr Pro Ala Gly Ile Gln Arg Ser Thr His 185 190 195 Ala Ile Glu Glu Ala Thr Thr Glu Ser Ala Asn Gly Ile Gln 200 205 97 2848 DNA Homo Sapien 97 gctcaagtgc cctgccttgc cccacccagc ccagcctggc cagagccccc 50 tggagaagga gctctcttct tgcttggcag ctggaccaag ggagccagtc 100 ttgggcgctg gagggcctgt cctgaccatg gtccctgcct ggctgtggct 150 gctttgtgtc tccgtccccc aggctctccc caaggcccag cctgcagagc 200 tgtctgtgga agttccagaa aactatggtg gaaatttccc tttatacctg 250 accaagttgc cgctgccccg tgagggggct gaaggccaga tcgtgctgtc 300 aggggactca ggcaaggcaa ctgagggccc atttgctatg gatccagatt 350 ctggcttcct gctggtgacc agggccctgg accgagagga gcaggcagag 400 taccagctac aggtcaccct ggagatgcag gatggacatg tcttgtgggg 450 tccacagcct gtgcttgtgc acgtgaagga tgagaatgac caggtgcccc 500 atttctctca agccatctac agagctcggc tgagccgggg taccaggcct 550 ggcatcccct tcctcttcct tgaggcttca gaccgggatg agccaggcac 600 agccaactcg gatcttcgat tccacatcct gagccaggct ccagcccagc 650 cttccccaga catgttccag ctggagcctc ggctgggggc tctggccctc 700 agccccaagg ggagcaccag ccttgaccac gccctggaga ggacctacca 750 gctgttggta caggtcaagg acatgggtga ccaggcctca ggccaccagg 800 ccactgccac cgtggaagtc tccatcatag agagcacctg ggtgtcccta 850 gagcctatcc acctggcaga gaatctcaaa gtcctatacc cgcaccacat 900 ggcccaggta cactggagtg ggggtgatgt gcactatcac ctggagagcc 950 atcccccggg accctttgaa gtgaatgcag agggaaacct ctacgtgacc 1000 agagagctgg acagagaagc ccaggctgag tacctgctcc aggtgcgggc 1050 tcagaattcc catggcgagg actatgcggc ccctctggag ctgcacgtgc 1100 tggtgatgga tgagaatgac aacgtgccta tctgccctcc ccgtgacccc 1150 acagtcagca tccctgagct cagtccacca ggtactgaag tgactagact 1200 gtcagcagag gatgcagatg cccccggctc ccccaattcc cacgttgtgt 1250 atcagctcct gagccctgag cctgaggatg gggtagaggg gagagccttc 1300 caggtggacc ccacttcagg cagtgtgacg ctgggggtgc tcccactccg 1350 agcaggccag aacatcctgc ttctggtgct ggccatggac ctggcaggcg 1400 cagagggtgg cttcagcagc acgtgtgaag tcgaagtcgc agtcacagat 1450 atcaatgatc acgcccctga gttcatcact tcccagattg ggcctataag 1500 cctccctgag gatgtggagc ccgggactct ggtggccatg ctaacagcca 1550 ttgatgctga cctcgagccc gccttccgcc tcatggattt tgccattgag 1600 aggggagaca cagaagggac ttttggcctg gattgggagc cagactctgg 1650 gcatgttaga ctcagactct gcaagaacct cagttatgag gcagctccaa 1700 gtcatgaggt ggtggtggtg gtgcagagtg tggcgaagct ggtggggcca 1750 ggcccaggcc ctggagccac cgccacggtg actgtgctag tggagagagt 1800 gatgccaccc cccaagttgg accaggagag ctacgaggcc agtgtcccca 1850 tcagtgcccc agccggctct ttcctgctga ccatccagcc ctccgacccc 1900 atcagccgaa ccctcaggtt ctccctagtc aatgactcag agggctggct 1950 ctgcattgag aaattctccg gggaggtgca caccgcccag tccctgcagg 2000 gcgcccagcc tggggacacc tacacggtgc ttgtggaggc ccaggataca 2050 gccctgactc ttgcccctgt gccctcccaa tacctctgca caccccgcca 2100 agaccatggc ttgatcgtga gtggacccag caaggacccc gatctggcca 2150 gtgggcacgg tccctacagc ttcacccttg gtcccaaccc cacggtgcaa 2200 cgggattggc gcctccagac tctcaatggt tcccatgcct acctcacctt 2250 ggccctgcat tgggtggagc cacgtgaaca cataatcccc gtggtggtca 2300 gccacaatgc ccagatgtgg cagctcctgg ttcgagtgat cgtgtgtcgc 2350 tgcaacgtgg aggggcagtg catgcgcaag gtgggccgca tgaagggcat 2400 gcccacgaag ctgtcggcag tgggcatcct tgtaggcacc ctggtagcaa 2450 taggaatctt cctcatcctc attttcaccc actggaccat gtcaaggaag 2500 aaggacccgg atcaaccagc agacagcgtg cccctgaagg cgactgtctg 2550 aatggcccag gcagctctag ctgggagctt ggcctctggc tccatctgag 2600 tcccctggga gagagcccag cacccaagat ccagcagggg acaggacaga 2650 gtagaagccc ctccatctgc cctggggtgg aggcaccatc accatcacca 2700 ggcatgtctg cagagcctgg acaccaactt tatggactgc ccatgggagt 2750 gctccaaatg tcagggtgtt tgcccaataa taaagcccca gagaactggg 2800 ctgggcccta tgggaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaag 2848 98 807 PRT Homo Sapien 98 Met Val Pro Ala Trp Leu Trp Leu Leu Cys Val Ser Val Pro Gln 1 5 10 15 Ala Leu Pro Lys Ala Gln Pro Ala Glu Leu Ser Val Glu Val Pro 20 25 30 Glu Asn Tyr Gly Gly Asn Phe Pro Leu Tyr Leu Thr Lys Leu Pro 35 40 45 Leu Pro Arg Glu Gly Ala Glu Gly Gln Ile Val Leu Ser Gly Asp 50 55 60 Ser Gly Lys Ala Thr Glu Gly Pro Phe Ala Met Asp Pro Asp Ser 65 70 75 Gly Phe Leu Leu Val Thr Arg Ala Leu Asp Arg Glu Glu Gln Ala 80 85 90 Glu Tyr Gln Leu Gln Val Thr Leu Glu Met Gln Asp Gly His Val 95 100 105 Leu Trp Gly Pro Gln Pro Val Leu Val His Val Lys Asp Glu Asn 110 115 120 Asp Gln Val Pro His Phe Ser Gln Ala Ile Tyr Arg Ala Arg Leu 125 130 135 Ser Arg Gly Thr Arg Pro Gly Ile Pro Phe Leu Phe Leu Glu Ala 140 145 150 Ser Asp Arg Asp Glu Pro Gly Thr Ala Asn Ser Asp Leu Arg Phe 155 160 165 His Ile Leu Ser Gln Ala Pro Ala Gln Pro Ser Pro Asp Met Phe 170 175 180 Gln Leu Glu Pro Arg Leu Gly Ala Leu Ala Leu Ser Pro Lys Gly 185 190 195 Ser Thr Ser Leu Asp His Ala Leu Glu Arg Thr Tyr Gln Leu Leu 200 205 210 Val Gln Val Lys Asp Met Gly Asp Gln Ala Ser Gly His Gln Ala 215 220 225 Thr Ala Thr Val Glu Val Ser Ile Ile Glu Ser Thr Trp Val Ser 230 235 240 Leu Glu Pro Ile His Leu Ala Glu Asn Leu Lys Val Leu Tyr Pro 245 250 255 His His Met Ala Gln Val His Trp Ser Gly Gly Asp Val His Tyr 260 265 270 His Leu Glu Ser His Pro Pro Gly Pro Phe Glu Val Asn Ala Glu 275 280 285 Gly Asn Leu Tyr Val Thr Arg Glu Leu Asp Arg Glu Ala Gln Ala 290 295 300 Glu Tyr Leu Leu Gln Val Arg Ala Gln Asn Ser His Gly Glu Asp 305 310 315 Tyr Ala Ala Pro Leu Glu Leu His Val Leu Val Met Asp Glu Asn 320 325 330 Asp Asn Val Pro Ile Cys Pro Pro Arg Asp Pro Thr Val Ser Ile 335 340 345 Pro Glu Leu Ser Pro Pro Gly Thr Glu Val Thr Arg Leu Ser Ala 350 355 360 Glu Asp Ala Asp Ala Pro Gly Ser Pro Asn Ser His Val Val Tyr 365 370 375 Gln Leu Leu Ser Pro Glu Pro Glu Asp Gly Val Glu Gly Arg Ala 380 385 390 Phe Gln Val Asp Pro Thr Ser Gly Ser Val Thr Leu Gly Val Leu 395 400 405 Pro Leu Arg Ala Gly Gln Asn Ile Leu Leu Leu Val Leu Ala Met 410 415 420 Asp Leu Ala Gly Ala Glu Gly Gly Phe Ser Ser Thr Cys Glu Val 425 430 435 Glu Val Ala Val Thr Asp Ile Asn Asp His Ala Pro Glu Phe Ile 440 445 450 Thr Ser Gln Ile Gly Pro Ile Ser Leu Pro Glu Asp Val Glu Pro 455 460 465 Gly Thr Leu Val Ala Met Leu Thr Ala Ile Asp Ala Asp Leu Glu 470 475 480 Pro Ala Phe Arg Leu Met Asp Phe Ala Ile Glu Arg Gly Asp Thr 485 490 495 Glu Gly Thr Phe Gly Leu Asp Trp Glu Pro Asp Ser Gly His Val 500 505 510 Arg Leu Arg Leu Cys Lys Asn Leu Ser Tyr Glu Ala Ala Pro Ser 515 520 525 His Glu Val Val Val Val Val Gln Ser Val Ala Lys Leu Val Gly 530 535 540 Pro Gly Pro Gly Pro Gly Ala Thr Ala Thr Val Thr Val Leu Val 545 550 555 Glu Arg Val Met Pro Pro Pro Lys Leu Asp Gln Glu Ser Tyr Glu 560 565 570 Ala Ser Val Pro Ile Ser Ala Pro Ala Gly Ser Phe Leu Leu Thr 575 580 585 Ile Gln Pro Ser Asp Pro Ile Ser Arg Thr Leu Arg Phe Ser Leu 590 595 600 Val Asn Asp Ser Glu Gly Trp Leu Cys Ile Glu Lys Phe Ser Gly 605 610 615 Glu Val His Thr Ala Gln Ser Leu Gln Gly Ala Gln Pro Gly Asp 620 625 630 Thr Tyr Thr Val Leu Val Glu Ala Gln Asp Thr Ala Leu Thr Leu 635 640 645 Ala Pro Val Pro Ser Gln Tyr Leu Cys Thr Pro Arg Gln Asp His 650 655 660 Gly Leu Ile Val Ser Gly Pro Ser Lys Asp Pro Asp Leu Ala Ser 665 670 675 Gly His Gly Pro Tyr Ser Phe Thr Leu Gly Pro Asn Pro Thr Val 680 685 690 Gln Arg Asp Trp Arg Leu Gln Thr Leu Asn Gly Ser His Ala Tyr 695 700 705 Leu Thr Leu Ala Leu His Trp Val Glu Pro Arg Glu His Ile Ile 710 715 720 Pro Val Val Val Ser His Asn Ala Gln Met Trp Gln Leu Leu Val 725 730 735 Arg Val Ile Val Cys Arg Cys Asn Val Glu Gly Gln Cys Met Arg 740 745 750 Lys Val Gly Arg Met Lys Gly Met Pro Thr Lys Leu Ser Ala Val 755 760 765 Gly Ile Leu Val Gly Thr Leu Val Ala Ile Gly Ile Phe Leu Ile 770 775 780 Leu Ile Phe Thr His Trp Thr Met Ser Arg Lys Lys Asp Pro Asp 785 790 795 Gln Pro Ala Asp Ser Val Pro Leu Lys Ala Thr Val 800 805 99 2436 DNA Homo Sapien 99 ggctgaccgt gctacattgc ctggaggaag cctaaggaac ccaggcatcc 50 agctgcccac gcctgagtcc aagattcttc ccaggaacac aaacgtagga 100 gacccacgct cctggaagca ccagccttta tctcttcacc ttcaagtccc 150 ctttctcaag aatcctctgt tctttgccct ctaaagtctt ggtacatcta 200 ggacccaggc atcttgcttt ccagccacaa agagacagat gaagatgcag 250 aaaggaaatg ttctccttat gtttggtcta ctattgcatt tagaagctgc 300 aacaaattcc aatgagacta gcacctctgc caacactgga tccagtgtga 350 tctccagtgg agccagcaca gccaccaact ctgggtccag tgtgacctcc 400 agtggggtca gcacagccac catctcaggg tccagcgtga cctccaatgg 450 ggtcagcata gtcaccaact ctgagttcca tacaacctcc agtgggatca 500 gcacagccac caactctgag ttcagcacag cgtccagtgg gatcagcata 550 gccaccaact ctgagtccag cacaacctcc agtggggcca gcacagccac 600 caactctgag tccagcacac cctccagtgg ggccagcaca gtcaccaact 650 ctgggtccag tgtgacctcc agtggagcca gcactgccac caactctgag 700 tccagcacag tgtccagtag ggccagcact gccaccaact ctgagtctag 750 cacactctcc agtggggcca gcacagccac caactctgac tccagcacaa 800 cctccagtgg ggctagcaca gccaccaact ctgagtccag cacaacctcc 850 agtggggcca gcacagccac caactctgag tccagcacag tgtccagtag 900 ggccagcact gccaccaact ctgagtccag cacaacctcc agtggggcca 950 gcacagccac caactctgag tccagaacga cctccaatgg ggctggcaca 1000 gccaccaact ctgagtccag cacgacctcc agtggggcca gcacagccac 1050 caactctgac tccagcacag tgtccagtgg ggccagcact gccaccaact 1100 ctgagtccag cacgacctcc agtggggcca gcacagccac caactctgag 1150 tccagcacga cctccagtgg ggctagcaca gccaccaact ctgactccag 1200 cacaacctcc agtggggccg gcacagccac caactctgag tccagcacag 1250 tgtccagtgg gatcagcaca gtcaccaatt ctgagtccag cacaccctcc 1300 agtggggcca acacagccac caactctgag tccagtacga cctccagtgg 1350 ggccaacaca gccaccaact ctgagtccag cacagtgtcc agtggggcca 1400 gcactgccac caactctgag tccagcacaa cctccagtgg ggtcagcaca 1450 gccaccaact ctgagtccag cacaacctcc agtggggcta gcacagccac 1500 caactctgac tccagcacaa cctccagtga ggccagcaca gccaccaact 1550 ctgagtctag cacagtgtcc agtgggatca gcacagtcac caattctgag 1600 tccagcacaa cctccagtgg ggccaacaca gccaccaact ctgggtccag 1650 tgtgacctct gcaggctctg gaacagcagc tctgactgga atgcacacaa 1700 cttcccatag tgcatctact gcagtgagtg aggcaaagcc tggtgggtcc 1750 ctggtgccgt gggaaatctt cctcatcacc ctggtctcgg ttgtggcggc 1800 cgtggggctc tttgctgggc tcttcttctg tgtgagaaac agcctgtccc 1850 tgagaaacac ctttaacaca gctgtctacc accctcatgg cctcaaccat 1900 ggccttggtc caggccctgg agggaatcat ggagcccccc acaggcccag 1950 gtggagtcct aactggttct ggaggagacc agtatcatcg atagccatgg 2000 agatgagcgg gaggaacagc gggccctgag cagccccgga agcaagtgcc 2050 gcattcttca ggaaggaaga gacctgggca cccaagacct ggtttccttt 2100 cattcatccc aggagacccc tcccagcttt gtttgagatc ctgaaaatct 2150 tgaagaaggt attcctcacc tttcttgcct ttaccagaca ctggaaagag 2200 aatactatat tgctcattta gctaagaaat aaatacatct catctaacac 2250 acacgacaaa gagaagctgt gcttgccccg gggtgggtat ctagctctga 2300 gatgaactca gttataggag aaaacctcca tgctggactc catctggcat 2350 tcaaaatctc cacagtaaaa tccaaagacc tcaaaaaaaa aaaaaaaaaa 2400 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaa 2436 100 596 PRT Homo Sapien 100 Met Lys Met Gln Lys Gly Asn Val Leu Leu Met Phe Gly Leu Leu 1 5 10 15 Leu His Leu Glu Ala Ala Thr Asn Ser Asn Glu Thr Ser Thr Ser 20 25 30 Ala Asn Thr Gly Ser Ser Val Ile Ser Ser Gly Ala Ser Thr Ala 35 40 45 Thr Asn Ser Gly Ser Ser Val Thr Ser Ser Gly Val Ser Thr Ala 50 55 60 Thr Ile Ser Gly Ser Ser Val Thr Ser Asn Gly Val Ser Ile Val 65 70 75 Thr Asn Ser Glu Phe His Thr Thr Ser Ser Gly Ile Ser Thr Ala 80 85 90 Thr Asn Ser Glu Phe Ser Thr Ala Ser Ser Gly Ile Ser Ile Ala 95 100 105 Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala 110 115 120 Thr Asn Ser Glu Ser Ser Thr Pro Ser Ser Gly Ala Ser Thr Val 125 130 135 Thr Asn Ser Gly Ser Ser Val Thr Ser Ser Gly Ala Ser Thr Ala 140 145 150 Thr Asn Ser Glu Ser Ser Thr Val Ser Ser Arg Ala Ser Thr Ala 155 160 165 Thr Asn Ser Glu Ser Ser Thr Leu Ser Ser Gly Ala Ser Thr Ala 170 175 180 Thr Asn Ser Asp Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala 185 190 195 Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala 200 205 210 Thr Asn Ser Glu Ser Ser Thr Val Ser Ser Arg Ala Ser Thr Ala 215 220 225 Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala 230 235 240 Thr Asn Ser Glu Ser Arg Thr Thr Ser Asn Gly Ala Gly Thr Ala 245 250 255 Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala 260 265 270 Thr Asn Ser Asp Ser Ser Thr Val Ser Ser Gly Ala Ser Thr Ala 275 280 285 Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala 290 295 300 Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala 305 310 315 Thr Asn Ser Asp Ser Ser Thr Thr Ser Ser Gly Ala Gly Thr Ala 320 325 330 Thr Asn Ser Glu Ser Ser Thr Val Ser Ser Gly Ile Ser Thr Val 335 340 345 Thr Asn Ser Glu Ser Ser Thr Pro Ser Ser Gly Ala Asn Thr Ala 350 355 360 Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Asn Thr Ala 365 370 375 Thr Asn Ser Glu Ser Ser Thr Val Ser Ser Gly Ala Ser Thr Ala 380 385 390 Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Val Ser Thr Ala 395 400 405 Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala 410 415 420 Thr Asn Ser Asp Ser Ser Thr Thr Ser Ser Glu Ala Ser Thr Ala 425 430 435 Thr Asn Ser Glu Ser Ser Thr Val Ser Ser Gly Ile Ser Thr Val 440 445 450 Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Asn Thr Ala 455 460 465 Thr Asn Ser Gly Ser Ser Val Thr Ser Ala Gly Ser Gly Thr Ala 470 475 480 Ala Leu Thr Gly Met His Thr Thr Ser His Ser Ala Ser Thr Ala 485 490 495 Val Ser Glu Ala Lys Pro Gly Gly Ser Leu Val Pro Trp Glu Ile 500 505 510 Phe Leu Ile Thr Leu Val Ser Val Val Ala Ala Val Gly Leu Phe 515 520 525 Ala Gly Leu Phe Phe Cys Val Arg Asn Ser Leu Ser Leu Arg Asn 530 535 540 Thr Phe Asn Thr Ala Val Tyr His Pro His Gly Leu Asn His Gly 545 550 555 Leu Gly Pro Gly Pro Gly Gly Asn His Gly Ala Pro His Arg Pro 560 565 570 Arg Trp Ser Pro Asn Trp Phe Trp Arg Arg Pro Val Ser Ser Ile 575 580 585 Ala Met Glu Met Ser Gly Arg Asn Ser Gly Pro 590 595 101 1728 DNA Homo Sapien 101 ggccggacgc ctccgcgtta cgggatgaat taacggcggg ttccgcacgg 50 aggttgtgac ccctacggag ccccagcttg cccacgcacc ccactcggcg 100 tcgcgcggcg tgccctgctt gtcacaggtg ggaggctgga actatcaggc 150 tgaaaaacag agtgggtact ctcttctggg aagctggcaa caaatggatg 200 atgtgatata tgcattccag gggaagggaa attgtggtgc ttctgaaccc 250 atggtcaatt aacgaggcag tttctagcta ctgcacgtac ttcataaagc 300 aggactctaa aagctttgga atcatggtgt catggaaagg gatttacttt 350 atactgactc tgttttgggg aagctttttt ggaagcattt tcatgctgag 400 tcccttttta cctttgatgt ttgtaaaccc atcttggtat cgctggatca 450 acaaccgcct tgtggcaaca tggctcaccc tacctgtggc attattggag 500 accatgtttg gtgtaaaagt gattataact ggggatgcat ttgttcctgg 550 agaaagaagt gtcattatca tgaaccatcg gacaagaatg gactggatgt 600 tcctgtggaa ttgcctgatg cgatatagct acctcagatt ggagaaaatt 650 tgcctcaaag cgagtctcaa aggtgttcct ggatttggtt gggccatgca 700 ggctgctgcc tatatcttca ttcataggaa atggaaggat gacaagagcc 750 atttcgaaga catgattgat tacttttgtg atattcacga accacttcaa 800 ctcctcatat tcccagaagg gactgatctc acagaaaaca gcaagtctcg 850 aagtaatgca tttgctgaaa aaaatggact tcagaaatat gaatatgttt 900 tacatccaag aactacaggc tttacttttg tggtagaccg tctaagagaa 950 ggtaagaacc ttgatgctgt ccatgatatc actgtggcgt atcctcacaa 1000 cattcctcaa tcagagaagc acctcctcca aggagacttt cccagggaaa 1050 tccactttca cgtccaccgg tatccaatag acaccctccc cacatccaag 1100 gaggaccttc aactctggtg ccacaaacgg tgggaagaga aagaagagag 1150 gctgcgttcc ttctatcaag gggagaagaa tttttatttt accggacaga 1200 gtgtcattcc accttgcaag tctgaactca gggtccttgt ggtcaaattg 1250 ctctctatac tgtattggac cctgttcagc cctgcaatgt gcctactcat 1300 atatttgtac agtcttgtta agtggtattt tataatcacc attgtaatct 1350 ttgtgctgca agagagaata tttggtggac tggagatcat agaacttgca 1400 tgttaccgac ttttacacaa acagccacat ttaaattcaa agaaaaatga 1450 gtaagattat aaggtttgcc atgtgaaaac ctagagcata ttttggaaat 1500 gttctaaacc tttctaagct cagatgcatt tttgcatgac tatgtcgaat 1550 atttcttact gccatcatta tttgttaaag atattttgca cttaattttg 1600 tgggaaaaat attgctacaa ttttttttaa tctctgaatg taatttcgat 1650 actgtgtaca tagcagggag tgatcggggt gaaataactt gggccagaat 1700 attattaaac aatcatcagg cttttaaa 1728 102 414 PRT Homo Sapien 102 Met His Ser Arg Gly Arg Glu Ile Val Val Leu Leu Asn Pro Trp 1 5 10 15 Ser Ile Asn Glu Ala Val Ser Ser Tyr Cys Thr Tyr Phe Ile Lys 20 25 30 Gln Asp Ser Lys Ser Phe Gly Ile Met Val Ser Trp Lys Gly Ile 35 40 45 Tyr Phe Ile Leu Thr Leu Phe Trp Gly Ser Phe Phe Gly Ser Ile 50 55 60 Phe Met Leu Ser Pro Phe Leu Pro Leu Met Phe Val Asn Pro Ser 65 70 75 Trp Tyr Arg Trp Ile Asn Asn Arg Leu Val Ala Thr Trp Leu Thr 80 85 90 Leu Pro Val Ala Leu Leu Glu Thr Met Phe Gly Val Lys Val Ile 95 100 105 Ile Thr Gly Asp Ala Phe Val Pro Gly Glu Arg Ser Val Ile Ile 110 115 120 Met Asn His Arg Thr Arg Met Asp Trp Met Phe Leu Trp Asn Cys 125 130 135 Leu Met Arg Tyr Ser Tyr Leu Arg Leu Glu Lys Ile Cys Leu Lys 140 145 150 Ala Ser Leu Lys Gly Val Pro Gly Phe Gly Trp Ala Met Gln Ala 155 160 165 Ala Ala Tyr Ile Phe Ile His Arg Lys Trp Lys Asp Asp Lys Ser 170 175 180 His Phe Glu Asp Met Ile Asp Tyr Phe Cys Asp Ile His Glu Pro 185 190 195 Leu Gln Leu Leu Ile Phe Pro Glu Gly Thr Asp Leu Thr Glu Asn 200 205 210 Ser Lys Ser Arg Ser Asn Ala Phe Ala Glu Lys Asn Gly Leu Gln 215 220 225 Lys Tyr Glu Tyr Val Leu His Pro Arg Thr Thr Gly Phe Thr Phe 230 235 240 Val Val Asp Arg Leu Arg Glu Gly Lys Asn Leu Asp Ala Val His 245 250 255 Asp Ile Thr Val Ala Tyr Pro His Asn Ile Pro Gln Ser Glu Lys 260 265 270 His Leu Leu Gln Gly Asp Phe Pro Arg Glu Ile His Phe His Val 275 280 285 His Arg Tyr Pro Ile Asp Thr Leu Pro Thr Ser Lys Glu Asp Leu 290 295 300 Gln Leu Trp Cys His Lys Arg Trp Glu Glu Lys Glu Glu Arg Leu 305 310 315 Arg Ser Phe Tyr Gln Gly Glu Lys Asn Phe Tyr Phe Thr Gly Gln 320 325 330 Ser Val Ile Pro Pro Cys Lys Ser Glu Leu Arg Val Leu Val Val 335 340 345 Lys Leu Leu Ser Ile Leu Tyr Trp Thr Leu Phe Ser Pro Ala Met 350 355 360 Cys Leu Leu Ile Tyr Leu Tyr Ser Leu Val Lys Trp Tyr Phe Ile 365 370 375 Ile Thr Ile Val Ile Phe Val Leu Gln Glu Arg Ile Phe Gly Gly 380 385 390 Leu Glu Ile Ile Glu Leu Ala Cys Tyr Arg Leu Leu His Lys Gln 395 400 405 Pro His Leu Asn Ser Lys Lys Asn Glu 410 103 2403 DNA Homo Sapien 103 cggctcgagc ggctcgagtg aagagcctct ccacggctcc tgcgcctgag 50 acagctggcc tgacctccaa atcatccatc cacccctgct gtcatctgtt 100 ttcatagtgt gagatcaacc cacaggaata tccatggctt ttgtgctcat 150 tttggttctc agtttctacg agctggtgtc aggacagtgg caagtcactg 200 gaccgggcaa gtttgtccag gccttggtgg gggaggacgc cgtgttctcc 250 tgctccctct ttcctgagac cagtgcagag gctatggaag tgcggttctt 300 caggaatcag ttccatgctg tggtccacct ctacagagat ggggaagact 350 gggaatctaa gcagatgcca cagtatcgag ggagaactga gtttgtgaag 400 gactccattg caggggggcg tgtctctcta aggctaaaaa acatcactcc 450 ctcggacatc ggcctgtatg ggtgctggtt cagttcccag atttacgatg 500 aggaggccac ctgggagctg cgggtggcag cactgggctc acttcctctc 550 atttccatcg tgggatatgt tgacggaggt atccagttac tctgcctgtc 600 ctcaggctgg ttcccccagc ccacagccaa gtggaaaggt ccacaaggac 650 aggatttgtc ttcagactcc agagcaaatg cagatgggta cagcctgtat 700 gatgtggaga tctccattat agtccaggaa aatgctggga gcatattgtg 750 ttccatccac cttgctgagc agagtcatga ggtggaatcc aaggtattga 800 taggagagac gtttttccag ccctcacctt ggcgcctggc ttctatttta 850 ctcgggttac tctgtggtgc cctgtgtggt gttgtcatgg ggatgataat 900 tgttttcttc aaatccaaag ggaaaatcca ggcggaactg gactggagaa 950 gaaagcacgg acaggcagaa ttgagagacg cccggaaaca cgcagtggag 1000 gtgactctgg atccagagac ggctcacccg aagctctgcg tttctgatct 1050 gaaaactgta acccatagaa aagctcccca ggaggtgcct cactctgaga 1100 agagatttac aaggaagagt gtggtggctt ctcagggttt ccaagcaggg 1150 agacattact gggaggtgga cgtgggacaa aatgtagggt ggtatgtggg 1200 agtgtgtcgg gatgacgtag acagggggaa gaacaatgtg actttgtctc 1250 ccaacaatgg gtattgggtc ctcagactga caacagaaca tttgtatttc 1300 acattcaatc cccattttat cagcctcccc cccagcaccc ctcctacacg 1350 agtaggggtc ttcctggact atgagggtgg gaccatctcc ttcttcaata 1400 caaatgacca gtcccttatt tataccctgc tgacatgtca gtttgaaggc 1450 ttgttgagac cctatatcca gcatgcgatg tatgacgagg aaaaggggac 1500 tcccatattc atatgtccag tgtcctgggg atgagacaga gaagaccctg 1550 cttaaagggc cccacaccac agacccagac acagccaagg gagagtgctc 1600 ccgacaggtg gccccagctt cctctccgga gcctgcgcac agagagtcac 1650 gccccccact ctcctttagg gagctgaggt tcttctgccc tgagccctgc 1700 agcagcggca gtcacagctt ccagatgagg ggggattggc ctgaccctgt 1750 gggagtcaga agccatggct gccctgaagt ggggacggaa tagactcaca 1800 ttaggtttag tttgtgaaaa ctccatccag ctaagcgatc ttgaacaagt 1850 cacaacctcc caggctcctc atttgctagt cacggacagt gattcctgcc 1900 tcacaggtga agattaaaga gacaacgaat gtgaatcatg cttgcaggtt 1950 tgagggcaca gtgtttgcta atgatgtgtt tttatattat acattttccc 2000 accataaact ctgtttgctt attccacatt aatttacttt tctctatacc 2050 aaatcaccca tggaatagtt attgaacacc tgctttgtga ggctcaaaga 2100 ataaagagga ggtaggattt ttcactgatt ctataagccc agcattacct 2150 gataccaaaa ccaggcaaag aaaacagaag aagaggaagg aaaactacag 2200 gtccatatcc ctcattaaca cagacacaaa aattctaaat aaaattttaa 2250 caaattaaac taaacaatat atttaaagat gatatataac tactcagtgt 2300 ggtttgtccc acaaatgcag agttggttta atatttaaat atcaaccagt 2350 gtaattcagc acattaataa agtaaaaaag aaaaccataa aaaaaaaaaa 2400 aaa 2403 104 466 PRT Homo Sapien 104 Met Ala Phe Val Leu Ile Leu Val Leu Ser Phe Tyr Glu Leu Val 1 5 10 15 Ser Gly Gln Trp Gln Val Thr Gly Pro Gly Lys Phe Val Gln Ala 20 25 30 Leu Val Gly Glu Asp Ala Val Phe Ser Cys Ser Leu Phe Pro Glu 35 40 45 Thr Ser Ala Glu Ala Met Glu Val Arg Phe Phe Arg Asn Gln Phe 50 55 60 His Ala Val Val His Leu Tyr Arg Asp Gly Glu Asp Trp Glu Ser 65 70 75 Lys Gln Met Pro Gln Tyr Arg Gly Arg Thr Glu Phe Val Lys Asp 80 85 90 Ser Ile Ala Gly Gly Arg Val Ser Leu Arg Leu Lys Asn Ile Thr 95 100 105 Pro Ser Asp Ile Gly Leu Tyr Gly Cys Trp Phe Ser Ser Gln Ile 110 115 120 Tyr Asp Glu Glu Ala Thr Trp Glu Leu Arg Val Ala Ala Leu Gly 125 130 135 Ser Leu Pro Leu Ile Ser Ile Val Gly Tyr Val Asp Gly Gly Ile 140 145 150 Gln Leu Leu Cys Leu Ser Ser Gly Trp Phe Pro Gln Pro Thr Ala 155 160 165 Lys Trp Lys Gly Pro Gln Gly Gln Asp Leu Ser Ser Asp Ser Arg 170 175 180 Ala Asn Ala Asp Gly Tyr Ser Leu Tyr Asp Val Glu Ile Ser Ile 185 190 195 Ile Val Gln Glu Asn Ala Gly Ser Ile Leu Cys Ser Ile His Leu 200 205 210 Ala Glu Gln Ser His Glu Val Glu Ser Lys Val Leu Ile Gly Glu 215 220 225 Thr Phe Phe Gln Pro Ser Pro Trp Arg Leu Ala Ser Ile Leu Leu 230 235 240 Gly Leu Leu Cys Gly Ala Leu Cys Gly Val Val Met Gly Met Ile 245 250 255 Ile Val Phe Phe Lys Ser Lys Gly Lys Ile Gln Ala Glu Leu Asp 260 265 270 Trp Arg Arg Lys His Gly Gln Ala Glu Leu Arg Asp Ala Arg Lys 275 280 285 His Ala Val Glu Val Thr Leu Asp Pro Glu Thr Ala His Pro Lys 290 295 300 Leu Cys Val Ser Asp Leu Lys Thr Val Thr His Arg Lys Ala Pro 305 310 315 Gln Glu Val Pro His Ser Glu Lys Arg Phe Thr Arg Lys Ser Val 320 325 330 Val Ala Ser Gln Gly Phe Gln Ala Gly Arg His Tyr Trp Glu Val 335 340 345 Asp Val Gly Gln Asn Val Gly Trp Tyr Val Gly Val Cys Arg Asp 350 355 360 Asp Val Asp Arg Gly Lys Asn Asn Val Thr Leu Ser Pro Asn Asn 365 370 375 Gly Tyr Trp Val Leu Arg Leu Thr Thr Glu His Leu Tyr Phe Thr 380 385 390 Phe Asn Pro His Phe Ile Ser Leu Pro Pro Ser Thr Pro Pro Thr 395 400 405 Arg Val Gly Val Phe Leu Asp Tyr Glu Gly Gly Thr Ile Ser Phe 410 415 420 Phe Asn Thr Asn Asp Gln Ser Leu Ile Tyr Thr Leu Leu Thr Cys 425 430 435 Gln Phe Glu Gly Leu Leu Arg Pro Tyr Ile Gln His Ala Met Tyr 440 445 450 Asp Glu Glu Lys Gly Thr Pro Ile Phe Ile Cys Pro Val Ser Trp 455 460 465 Gly 105 2103 DNA Homo Sapien 105 ccttcacagg actcttcatt gctggttggc aatgatgtat cggccagatg 50 tggtgagggc taggaaaaga gtttgttggg aaccctgggt tatcggcctc 100 gtcatcttca tatccctgat tgtcctggca gtgtgcattg gactcactgt 150 tcattatgtg agatataatc aaaagaagac ctacaattac tatagcacat 200 tgtcatttac aactgacaaa ctatatgctg agtttggcag agaggcttct 250 aacaatttta cagaaatgag ccagagactt gaatcaatgg tgaaaaatgc 300 attttataaa tctccattaa gggaagaatt tgtcaagtct caggttatca 350 agttcagtca acagaagcat ggagtgttgg ctcatatgct gttgatttgt 400 agatttcact ctactgagga tcctgaaact gtagataaaa ttgttcaact 450 tgttttacat gaaaagctgc aagatgctgt aggaccccct aaagtagatc 500 ctcactcagt taaaattaaa aaaatcaaca agacagaaac agacagctat 550 ctaaaccatt gctgcggaac acgaagaagt aaaactctag gtcagagtct 600 caggatcgtt ggtgggacag aagtagaaga gggtgaatgg ccctggcagg 650 ctagcctgca gtgggatggg agtcatcgct gtggagcaac cttaattaat 700 gccacatggc ttgtgagtgc tgctcactgt tttacaacat ataagaaccc 750 tgccagatgg actgcttcct ttggagtaac aataaaacct tcgaaaatga 800 aacggggtct ccggagaata attgtccatg aaaaatacaa acacccatca 850 catgactatg atatttctct tgcagagctt tctagccctg ttccctacac 900 aaatgcagta catagagttt gtctccctga tgcatcctat gagtttcaac 950 caggtgatgt gatgtttgtg acaggatttg gagcactgaa aaatgatggt 1000 tacagtcaaa atcatcttcg acaagcacag gtgactctca tagacgctac 1050 aacttgcaat gaacctcaag cttacaatga cgccataact cctagaatgt 1100 tatgtgctgg ctccttagaa ggaaaaacag atgcatgcca gggtgactct 1150 ggaggaccac tggttagttc agatgctaga gatatctggt accttgctgg 1200 aatagtgagc tggggagatg aatgtgcgaa acccaacaag cctggtgttt 1250 atactagagt tacggccttg cgggactgga ttacttcaaa aactggtatc 1300 taagagacaa aagcctcatg gaacagataa catttttttt tgttttttgg 1350 gtgtggaggc catttttaga gatacagaat tggagaagac ttgcaaaaca 1400 gctagatttg actgatctca ataaactgtt tgcttgatgc atgtattttc 1450 ttcccagctc tgttccgcac gtaagcatcc tgcttctgcc agatcaactc 1500 tgtcatctgt gagcaatagt tgaaacttta tgtacataga gaaatagata 1550 atacaatatt acattacagc ctgtattcat ttgttctcta gaagttttgt 1600 cagaattttg acttgttgac ataaatttgt aatgcatata tacaatttga 1650 agcactcctt ttcttcagtt cctcagctcc tctcatttca gcaaatatcc 1700 attttcaagg tgcagaacaa ggagtgaaag aaaatataag aagaaaaaaa 1750 tcccctacat tttattggca cagaaaagta ttaggtgttt ttcttagtgg 1800 aatattagaa atgatcatat tcattatgaa aggtcaagca aagacagcag 1850 aataccaatc acttcatcat ttaggaagta tgggaactaa gttaaggaag 1900 tccagaaaga agccaagata tatccttatt ttcatttcca aacaactact 1950 atgataaatg tgaagaagat tctgtttttt tgtgacctat aataattata 2000 caaacttcat gcaatgtact tgttctaagc aaattaaagc aaatatttat 2050 ttaacattgt tactgaggat gtcaacatat aacaataaaa tataaatcac 2100 cca 2103 106 423 PRT Homo Sapien 106 Met Met Tyr Arg Pro Asp Val Val Arg Ala Arg Lys Arg Val Cys 1 5 10 15 Trp Glu Pro Trp Val Ile Gly Leu Val Ile Phe Ile Ser Leu Ile 20 25 30 Val Leu Ala Val Cys Ile Gly Leu Thr Val His Tyr Val Arg Tyr 35 40 45 Asn Gln Lys Lys Thr Tyr Asn Tyr Tyr Ser Thr Leu Ser Phe Thr 50 55 60 Thr Asp Lys Leu Tyr Ala Glu Phe Gly Arg Glu Ala Ser Asn Asn 65 70 75 Phe Thr Glu Met Ser Gln Arg Leu Glu Ser Met Val Lys Asn Ala 80 85 90 Phe Tyr Lys Ser Pro Leu Arg Glu Glu Phe Val Lys Ser Gln Val 95 100 105 Ile Lys Phe Ser Gln Gln Lys His Gly Val Leu Ala His Met Leu 110 115 120 Leu Ile Cys Arg Phe His Ser Thr Glu Asp Pro Glu Thr Val Asp 125 130 135 Lys Ile Val Gln Leu Val Leu His Glu Lys Leu Gln Asp Ala Val 140 145 150 Gly Pro Pro Lys Val Asp Pro His Ser Val Lys Ile Lys Lys Ile 155 160 165 Asn Lys Thr Glu Thr Asp Ser Tyr Leu Asn His Cys Cys Gly Thr 170 175 180 Arg Arg Ser Lys Thr Leu Gly Gln Ser Leu Arg Ile Val Gly Gly 185 190 195 Thr Glu Val Glu Glu Gly Glu Trp Pro Trp Gln Ala Ser Leu Gln 200 205 210 Trp Asp Gly Ser His Arg Cys Gly Ala Thr Leu Ile Asn Ala Thr 215 220 225 Trp Leu Val Ser Ala Ala His Cys Phe Thr Thr Tyr Lys Asn Pro 230 235 240 Ala Arg Trp Thr Ala Ser Phe Gly Val Thr Ile Lys Pro Ser Lys 245 250 255 Met Lys Arg Gly Leu Arg Arg Ile Ile Val His Glu Lys Tyr Lys 260 265 270 His Pro Ser His Asp Tyr Asp Ile Ser Leu Ala Glu Leu Ser Ser 275 280 285 Pro Val Pro Tyr Thr Asn Ala Val His Arg Val Cys Leu Pro Asp 290 295 300 Ala Ser Tyr Glu Phe Gln Pro Gly Asp Val Met Phe Val Thr Gly 305 310 315 Phe Gly Ala Leu Lys Asn Asp Gly Tyr Ser Gln Asn His Leu Arg 320 325 330 Gln Ala Gln Val Thr Leu Ile Asp Ala Thr Thr Cys Asn Glu Pro 335 340 345 Gln Ala Tyr Asn Asp Ala Ile Thr Pro Arg Met Leu Cys Ala Gly 350 355 360 Ser Leu Glu Gly Lys Thr Asp Ala Cys Gln Gly Asp Ser Gly Gly 365 370 375 Pro Leu Val Ser Ser Asp Ala Arg Asp Ile Trp Tyr Leu Ala Gly 380 385 390 Ile Val Ser Trp Gly Asp Glu Cys Ala Lys Pro Asn Lys Pro Gly 395 400 405 Val Tyr Thr Arg Val Thr Ala Leu Arg Asp Trp Ile Thr Ser Lys 410 415 420 Thr Gly Ile 107 2397 DNA Homo Sapien 107 agagaaagaa gcgtctccag ctgaagccaa tgcagccctc cggctctccg 50 cgaagaagtt ccctgccccg atgagccccc gccgtgcgtc cccgactatc 100 cccaggcggg cgtggggcac cgggcccagc gccgacgatc gctgccgttt 150 tgcccttggg agtaggatgt ggtgaaagga tggggcttct cccttacggg 200 gctcacaatg gccagagaag attccgtgaa gtgtctgcgc tgcctgctct 250 acgccctcaa tctgctcttt tggttaatgt ccatcagtgt gttggcagtt 300 tctgcttgga tgagggacta cctaaataat gttctcactt taactgcaga 350 aacgagggta gaggaagcag tcattttgac ttactttcct gtggttcatc 400 cggtcatgat tgctgtttgc tgtttcctta tcattgtggg gatgttagga 450 tattgtggaa cggtgaaaag aaatctgttg cttcttgcat ggtactttgg 500 aagtttgctt gtcattttct gtgtagaact ggcttgtggc gtttggacat 550 atgaacagga acttatggtt ccagtacaat ggtcagatat ggtcactttg 600 aaagccagga tgacaaatta tggattacct agatatcggt ggcttactca 650 tgcttggaat ttttttcaga gagagtttaa gtgctgtgga gtagtatatt 700 tcactgactg gttggaaatg acagagatgg actggccccc agattcctgc 750 tgtgttagag aattcccagg atgttccaaa caggcccacc aggaagatct 800 cagtgacctt tatcaagagg gttgtgggaa gaaaatgtat tcctttttga 850 gaggaaccaa acaactgcag gtgctgaggt ttctgggaat ctccattggg 900 gtgacacaaa tcctggccat gattctcacc attactctgc tctgggctct 950 gtattatgat agaagggagc ctgggacaga ccaaatgatg tccttgaaga 1000 atgacaactc tcagcacctg tcatgtccct cagtagaact gttgaaacca 1050 agcctgtcaa gaatctttga acacacatcc atggcaaaca gctttaatac 1100 acactttgag atggaggagt tataaaaaga aatgtcacag aagaaaacca 1150 caaacttgtt ttattggact tgtgaatttt tgagtacata ctatgtgttt 1200 cagaaatatg tagaaataaa aatgttgcca taaaataaca cctaagcata 1250 tactattcta tgctttaaaa tgaggatgga aaagtttcat gtcataagtc 1300 accacctgga caataattga tgcccttaaa atgctgaaga cagatgtcat 1350 acccactgtg tagcctgtgt atgactttta ctgaacacag ttatgttttg 1400 aggcagcatg gtttgattag catttccgca tccatgcaaa cgagtcacat 1450 atggtgggac tggagccata gtaaaggttg atttacttct accaactagt 1500 atataaagta ctaattaaat gctaacatag gaagttagaa aatactaata 1550 acttttatta ctcagcgatc tattcttctg atgctaaata aattatatat 1600 cagaaaactt tcaatattgg tgactaccta aatgtgattt ttgctggtta 1650 ctaaaatatt cttaccactt aaaagagcaa gctaacacat tgtcttaagc 1700 tgatcaggga ttttttgtat ataagtctgt gttaaatctg tataattcag 1750 tcgatttcag ttctgataat gttaagaata accattatga aaaggaaaat 1800 ttgtcctgta tagcatcatt atttttagcc tttcctgtta ataaagcttt 1850 actattctgt cctgggctta tattacacat ataactgtta tttaaatact 1900 taaccactaa ttttgaaaat taccagtgtg atacatagga atcattattc 1950 agaatgtagt ctggtcttta ggaagtatta ataagaaaat ttgcacataa 2000 cttagttgat tcagaaagga cttgtatgct gtttttctcc caaatgaaga 2050 ctctttttga cactaaacac tttttaaaaa gcttatcttt gccttctcca 2100 aacaagaagc aatagtctcc aagtcaatat aaattctaca gaaaatagtg 2150 ttctttttct ccagaaaaat gcttgtgaga atcattaaaa catgtgacaa 2200 tttagagatt ctttgtttta tttcactgat taatatactg tggcaaatta 2250 cacagattat taaatttttt tacaagagta tagtatattt atttgaaatg 2300 ggaaaagtgc attttactgt attttgtgta ttttgtttat ttctcagaat 2350 atggaaagaa aattaaaatg tgtcaataaa tattttctag agagtaa 2397 108 305 PRT Homo Sapien 108 Met Ala Arg Glu Asp Ser Val Lys Cys Leu Arg Cys Leu Leu Tyr 1 5 10 15 Ala Leu Asn Leu Leu Phe Trp Leu Met Ser Ile Ser Val Leu Ala 20 25 30 Val Ser Ala Trp Met Arg Asp Tyr Leu Asn Asn Val Leu Thr Leu 35 40 45 Thr Ala Glu Thr Arg Val Glu Glu Ala Val Ile Leu Thr Tyr Phe 50 55 60 Pro Val Val His Pro Val Met Ile Ala Val Cys Cys Phe Leu Ile 65 70 75 Ile Val Gly Met Leu Gly Tyr Cys Gly Thr Val Lys Arg Asn Leu 80 85 90 Leu Leu Leu Ala Trp Tyr Phe Gly Ser Leu Leu Val Ile Phe Cys 95 100 105 Val Glu Leu Ala Cys Gly Val Trp Thr Tyr Glu Gln Glu Leu Met 110 115 120 Val Pro Val Gln Trp Ser Asp Met Val Thr Leu Lys Ala Arg Met 125 130 135 Thr Asn Tyr Gly Leu Pro Arg Tyr Arg Trp Leu Thr His Ala Trp 140 145 150 Asn Phe Phe Gln Arg Glu Phe Lys Cys Cys Gly Val Val Tyr Phe 155 160 165 Thr Asp Trp Leu Glu Met Thr Glu Met Asp Trp Pro Pro Asp Ser 170 175 180 Cys Cys Val Arg Glu Phe Pro Gly Cys Ser Lys Gln Ala His Gln 185 190 195 Glu Asp Leu Ser Asp Leu Tyr Gln Glu Gly Cys Gly Lys Lys Met 200 205 210 Tyr Ser Phe Leu Arg Gly Thr Lys Gln Leu Gln Val Leu Arg Phe 215 220 225 Leu Gly Ile Ser Ile Gly Val Thr Gln Ile Leu Ala Met Ile Leu 230 235 240 Thr Ile Thr Leu Leu Trp Ala Leu Tyr Tyr Asp Arg Arg Glu Pro 245 250 255 Gly Thr Asp Gln Met Met Ser Leu Lys Asn Asp Asn Ser Gln His 260 265 270 Leu Ser Cys Pro Ser Val Glu Leu Leu Lys Pro Ser Leu Ser Arg 275 280 285 Ile Phe Glu His Thr Ser Met Ala Asn Ser Phe Asn Thr His Phe 290 295 300 Glu Met Glu Glu Leu 305 109 2339 DNA Homo Sapien 109 ccaaggccag agctgtggac accttatccc actcatcctc atcctcttcc 50 tctgataaag cccctaccag tgctgataaa gtctttctcg tgagagccta 100 gaggccttaa aaaaaaaagt gcttgaaaga gaaggggaca aaggaacacc 150 agtattaaga ggattttcca gtgtttctgg cagttggtcc agaaggatgc 200 ctccattcct gcttctcacc tgcctcttca tcacaggcac ctccgtgtca 250 cccgtggccc tagatccttg ttctgcttac atcagcctga atgagccctg 300 gaggaacact gaccaccagt tggatgagtc tcaaggtcct cctctatgtg 350 acaaccatgt gaatggggag tggtaccact tcacgggcat ggcgggagat 400 gccatgccta ccttctgcat accagaaaac cactgtggaa cccacgcacc 450 tgtctggctc aatggcagcc accccctaga aggcgacggc attgtgcaac 500 gccaggcttg tgccagcttc aatgggaact gctgtctctg gaacaccacg 550 gtggaagtca aggcttgccc tggaggctac tatgtgtatc gtctgaccaa 600 gcccagcgtc tgcttccacg tctactgtgg tcatttttat gacatctgcg 650 acgaggactg ccatggcagc tgctcagata ccagcgagtg cacatgcgct 700 ccaggaactg tgctaggccc tgacaggcag acatgctttg atgaaaatga 750 atgtgagcaa aacaacggtg gctgcagtga gatctgtgtg aacctcaaaa 800 actcctaccg ctgtgagtgt ggggttggcc gtgtgctaag aagtgatggc 850 aagacttgtg aagacgttga aggatgccac aataacaatg gtggctgcag 900 ccactcttgc cttggatctg agaaaggcta ccagtgtgaa tgtccccggg 950 gcctggtgct gtctgaggat aaccacactt gccaagtccc tgtgttgtgc 1000 aaatcaaatg ccattgaagt gaacatcccc agggagctgg ttggtggcct 1050 ggagctcttc ctgaccaaca cctcctgccg aggagtgtcc aacggcaccc 1100 atgtcaacat cctcttctct ctcaagacat gtggtacagt ggtcgatgtg 1150 gtgaatgaca agattgtggc cagcaacctc gtgacaggtc tacccaagca 1200 gaccccgggg agcagcgggg acttcatcat ccgaaccagc aagctgctga 1250 tcccggtgac ctgcgagttt ccacgcctgt acaccatttc tgaaggatac 1300 gttcccaacc ttcgaaactc cccactggaa atcatgagcc gaaatcatgg 1350 gatcttccca ttcactctgg agatcttcaa ggacaatgag tttgaagagc 1400 cttaccggga agctctgccc accctcaagc ttcgtgactc cctctacttt 1450 ggcattgagc ccgtggtgca cgtgagcggc ttggaaagct tggtggagag 1500 ctgctttgcc acccccacct ccaagatcga cgaggtcctg aaatactacc 1550 tcatccggga tggctgtgtt tcagatgact cggtaaagca gtacacatcc 1600 cgggatcacc tagcaaagca cttccaggtc cctgtcttca agtttgtggg 1650 caaagaccac aaggaagtgt ttctgcactg ccgggttctt gtctgtggag 1700 tgttggacga gcgttcccgc tgtgcccagg gttgccaccg gcgaatgcgt 1750 cgtggggcag gaggagagga ctcagccggt ctacagggcc agacgctaac 1800 aggcggcccg atccgcatcg actgggagga ctagttcgta gccatacctc 1850 gagtccctgc attggacggc tctgctcttt ggagcttctc cccccaccgc 1900 cctctaagaa catctgccaa cagctgggtt cagacttcac actgtgagtt 1950 cagactccca gcaccaactc actctgattc tggtccattc agtgggcaca 2000 ggtcacagca ctgctgaaca atgtggcctg ggtggggttt catctttcta 2050 gggttgaaaa ctaaactgtc cacccagaaa gacactcacc ccatttccct 2100 catttctttc ctacacttaa atacctcgtg tatggtgcaa tcagaccaca 2150 aaatcagaag ctgggtataa tatttcaagt tacaaaccct agaaaaatta 2200 aacagttact gaaattatga cttaaatacc caatgactcc ttaaatatgt 2250 aaattatagt tataccttga aatttcaatt caaatgcaga ctaattatag 2300 ggaatttgga agtgtatcaa taaaacagta tataatttt 2339 110 545 PRT Homo Sapien 110 Met Pro Pro Phe Leu Leu Leu Thr Cys Leu Phe Ile Thr Gly Thr 1 5 10 15 Ser Val Ser Pro Val Ala Leu Asp Pro Cys Ser Ala Tyr Ile Ser 20 25 30 Leu Asn Glu Pro Trp Arg Asn Thr Asp His Gln Leu Asp Glu Ser 35 40 45 Gln Gly Pro Pro Leu Cys Asp Asn His Val Asn Gly Glu Trp Tyr 50 55 60 His Phe Thr Gly Met Ala Gly Asp Ala Met Pro Thr Phe Cys Ile 65 70 75 Pro Glu Asn His Cys Gly Thr His Ala Pro Val Trp Leu Asn Gly 80 85 90 Ser His Pro Leu Glu Gly Asp Gly Ile Val Gln Arg Gln Ala Cys 95 100 105 Ala Ser Phe Asn Gly Asn Cys Cys Leu Trp Asn Thr Thr Val Glu 110 115 120 Val Lys Ala Cys Pro Gly Gly Tyr Tyr Val Tyr Arg Leu Thr Lys 125 130 135 Pro Ser Val Cys Phe His Val Tyr Cys Gly His Phe Tyr Asp Ile 140 145 150 Cys Asp Glu Asp Cys His Gly Ser Cys Ser Asp Thr Ser Glu Cys 155 160 165 Thr Cys Ala Pro Gly Thr Val Leu Gly Pro Asp Arg Gln Thr Cys 170 175 180 Phe Asp Glu Asn Glu Cys Glu Gln Asn Asn Gly Gly Cys Ser Glu 185 190 195 Ile Cys Val Asn Leu Lys Asn Ser Tyr Arg Cys Glu Cys Gly Val 200 205 210 Gly Arg Val Leu Arg Ser Asp Gly Lys Thr Cys Glu Asp Val Glu 215 220 225 Gly Cys His Asn Asn Asn Gly Gly Cys Ser His Ser Cys Leu Gly 230 235 240 Ser Glu Lys Gly Tyr Gln Cys Glu Cys Pro Arg Gly Leu Val Leu 245 250 255 Ser Glu Asp Asn His Thr Cys Gln Val Pro Val Leu Cys Lys Ser 260 265 270 Asn Ala Ile Glu Val Asn Ile Pro Arg Glu Leu Val Gly Gly Leu 275 280 285 Glu Leu Phe Leu Thr Asn Thr Ser Cys Arg Gly Val Ser Asn Gly 290 295 300 Thr His Val Asn Ile Leu Phe Ser Leu Lys Thr Cys Gly Thr Val 305 310 315 Val Asp Val Val Asn Asp Lys Ile Val Ala Ser Asn Leu Val Thr 320 325 330 Gly Leu Pro Lys Gln Thr Pro Gly Ser Ser Gly Asp Phe Ile Ile 335 340 345 Arg Thr Ser Lys Leu Leu Ile Pro Val Thr Cys Glu Phe Pro Arg 350 355 360 Leu Tyr Thr Ile Ser Glu Gly Tyr Val Pro Asn Leu Arg Asn Ser 365 370 375 Pro Leu Glu Ile Met Ser Arg Asn His Gly Ile Phe Pro Phe Thr 380 385 390 Leu Glu Ile Phe Lys Asp Asn Glu Phe Glu Glu Pro Tyr Arg Glu 395 400 405 Ala Leu Pro Thr Leu Lys Leu Arg Asp Ser Leu Tyr Phe Gly Ile 410 415 420 Glu Pro Val Val His Val Ser Gly Leu Glu Ser Leu Val Glu Ser 425 430 435 Cys Phe Ala Thr Pro Thr Ser Lys Ile Asp Glu Val Leu Lys Tyr 440 445 450 Tyr Leu Ile Arg Asp Gly Cys Val Ser Asp Asp Ser Val Lys Gln 455 460 465 Tyr Thr Ser Arg Asp His Leu Ala Lys His Phe Gln Val Pro Val 470 475 480 Phe Lys Phe Val Gly Lys Asp His Lys Glu Val Phe Leu His Cys 485 490 495 Arg Val Leu Val Cys Gly Val Leu Asp Glu Arg Ser Arg Cys Ala 500 505 510 Gln Gly Cys His Arg Arg Met Arg Arg Gly Ala Gly Gly Glu Asp 515 520 525 Ser Ala Gly Leu Gln Gly Gln Thr Leu Thr Gly Gly Pro Ile Arg 530 535 540 Ile Asp Trp Glu Asp 545 111 2063 DNA Homo Sapien 111 gagagaggca gcagcttgct cagcggacaa ggatgctggg cgtgagggac 50 caaggcctgc cctgcactcg ggcctcctcc agccagtgct gaccagggac 100 ttctgacctg ctggccagcc aggacctgtg tggggaggcc ctcctgctgc 150 cttggggtga caatctcagc tccaggctac agggagaccg ggaggatcac 200 agagccagca tgttacagga tcctgacagt gatcaacctc tgaacagcct 250 cgatgtcaaa cccctgcgca aaccccgtat ccccatggag accttcagaa 300 aggtggggat ccccatcatc atagcactac tgagcctggc gagtatcatc 350 attgtggttg tcctcatcaa ggtgattctg gataaatact acttcctctg 400 cgggcagcct ctccacttca tcccgaggaa gcagctgtgt gacggagagc 450 tggactgtcc cttgggggag gacgaggagc actgtgtcaa gagcttcccc 500 gaagggcctg cagtggcagt ccgcctctcc aaggaccgat ccacactgca 550 ggtgctggac tcggccacag ggaactggtt ctctgcctgt ttcgacaact 600 tcacagaagc tctcgctgag acagcctgta ggcagatggg ctacagcaga 650 gctgtggaga ttggcccaga ccaggatctg gatgttgttg aaatcacaga 700 aaacagccag gagcttcgca tgcggaactc aagtgggccc tgtctctcag 750 gctccctggt ctccctgcac tgtcttgcct gtgggaagag cctgaagacc 800 ccccgtgtgg tgggtgggga ggaggcctct gtggattctt ggccttggca 850 ggtcagcatc cagtacgaca aacagcacgt ctgtggaggg agcatcctgg 900 acccccactg ggtcctcacg gcagcccact gcttcaggaa acataccgat 950 gtgttcaact ggaaggtgcg ggcaggctca gacaaactgg gcagcttccc 1000 atccctggct gtggccaaga tcatcatcat tgaattcaac cccatgtacc 1050 ccaaagacaa tgacatcgcc ctcatgaagc tgcagttccc actcactttc 1100 tcaggcacag tcaggcccat ctgtctgccc ttctttgatg aggagctcac 1150 tccagccacc ccactctgga tcattggatg gggctttacg aagcagaatg 1200 gagggaagat gtctgacata ctgctgcagg cgtcagtcca ggtcattgac 1250 agcacacggt gcaatgcaga cgatgcgtac cagggggaag tcaccgagaa 1300 gatgatgtgt gcaggcatcc cggaaggggg tgtggacacc tgccagggtg 1350 acagtggtgg gcccctgatg taccaatctg accagtggca tgtggtgggc 1400 atcgttagct ggggctatgg ctgcgggggc ccgagcaccc caggagtata 1450 caccaaggtc tcagcctatc tcaactggat ctacaatgtc tggaaggctg 1500 agctgtaatg ctgctgcccc tttgcagtgc tgggagccgc ttccttcctg 1550 ccctgcccac ctggggatcc cccaaagtca gacacagagc aagagtcccc 1600 ttgggtacac ccctctgccc acagcctcag catttcttgg agcagcaaag 1650 ggcctcaatt cctgtaagag accctcgcag cccagaggcg cccagaggaa 1700 gtcagcagcc ctagctcggc cacacttggt gctcccagca tcccagggag 1750 agacacagcc cactgaacaa ggtctcaggg gtattgctaa gccaagaagg 1800 aactttccca cactactgaa tggaagcagg ctgtcttgta aaagcccaga 1850 tcactgtggg ctggagagga gaaggaaagg gtctgcgcca gccctgtccg 1900 tcttcaccca tccccaagcc tactagagca agaaaccagt tgtaatataa 1950 aatgcactgc cctactgttg gtatgactac cgttacctac tgttgtcatt 2000 gttattacag ctatggccac tattattaaa gagctgtgta acatctctgg 2050 caaaaaaaaa aaa 2063 112 432 PRT Homo Sapien 112 Met Leu Gln Asp Pro Asp Ser Asp Gln Pro Leu Asn Ser Leu Asp 1 5 10 15 Val Lys Pro Leu Arg Lys Pro Arg Ile Pro Met Glu Thr Phe Arg 20 25 30 Lys Val Gly Ile Pro Ile Ile Ile Ala Leu Leu Ser Leu Ala Ser 35 40 45 Ile Ile Ile Val Val Val Leu Ile Lys Val Ile Leu Asp Lys Tyr 50 55 60 Tyr Phe Leu Cys Gly Gln Pro Leu His Phe Ile Pro Arg Lys Gln 65 70 75 Leu Cys Asp Gly Glu Leu Asp Cys Pro Leu Gly Glu Asp Glu Glu 80 85 90 His Cys Val Lys Ser Phe Pro Glu Gly Pro Ala Val Ala Val Arg 95 100 105 Leu Ser Lys Asp Arg Ser Thr Leu Gln Val Leu Asp Ser Ala Thr 110 115 120 Gly Asn Trp Phe Ser Ala Cys Phe Asp Asn Phe Thr Glu Ala Leu 125 130 135 Ala Glu Thr Ala Cys Arg Gln Met Gly Tyr Ser Arg Ala Val Glu 140 145 150 Ile Gly Pro Asp Gln Asp Leu Asp Val Val Glu Ile Thr Glu Asn 155 160 165 Ser Gln Glu Leu Arg Met Arg Asn Ser Ser Gly Pro Cys Leu Ser 170 175 180 Gly Ser Leu Val Ser Leu His Cys Leu Ala Cys Gly Lys Ser Leu 185 190 195 Lys Thr Pro Arg Val Val Gly Gly Glu Glu Ala Ser Val Asp Ser 200 205 210 Trp Pro Trp Gln Val Ser Ile Gln Tyr Asp Lys Gln His Val Cys 215 220 225 Gly Gly Ser Ile Leu Asp Pro His Trp Val Leu Thr Ala Ala His 230 235 240 Cys Phe Arg Lys His Thr Asp Val Phe Asn Trp Lys Val Arg Ala 245 250 255 Gly Ser Asp Lys Leu Gly Ser Phe Pro Ser Leu Ala Val Ala Lys 260 265 270 Ile Ile Ile Ile Glu Phe Asn Pro Met Tyr Pro Lys Asp Asn Asp 275 280 285 Ile Ala Leu Met Lys Leu Gln Phe Pro Leu Thr Phe Ser Gly Thr 290 295 300 Val Arg Pro Ile Cys Leu Pro Phe Phe Asp Glu Glu Leu Thr Pro 305 310 315 Ala Thr Pro Leu Trp Ile Ile Gly Trp Gly Phe Thr Lys Gln Asn 320 325 330 Gly Gly Lys Met Ser Asp Ile Leu Leu Gln Ala Ser Val Gln Val 335 340 345 Ile Asp Ser Thr Arg Cys Asn Ala Asp Asp Ala Tyr Gln Gly Glu 350 355 360 Val Thr Glu Lys Met Met Cys Ala Gly Ile Pro Glu Gly Gly Val 365 370 375 Asp Thr Cys Gln Gly Asp Ser Gly Gly Pro Leu Met Tyr Gln Ser 380 385 390 Asp Gln Trp His Val Val Gly Ile Val Ser Trp Gly Tyr Gly Cys 395 400 405 Gly Gly Pro Ser Thr Pro Gly Val Tyr Thr Lys Val Ser Ala Tyr 410 415 420 Leu Asn Trp Ile Tyr Asn Val Trp Lys Ala Glu Leu 425 430 113 1768 DNA Homo Sapien 113 ggctggactg gaactcctgg tcccaagtga tccacccgcc tcagcctccc 50 aaggtgctgt gattataggt gtaagccacc gtgtctggcc tctgaacaac 100 tttttcagca actaaaaaag ccacaggagt tgaactgcta ggattctgac 150 tatgctgtgg tggctagtgc tcctactcct acctacatta aaatctgttt 200 tttgttctct tgtaactagc ctttaccttc ctaacacaga ggatctgtca 250 ctgtggctct ggcccaaacc tgaccttcac tctggaacga gaacagaggt 300 ttctacccac accgtcccct cgaagccggg gacagcctca ccttgctggc 350 ctctcgctgg agcagtgccc tcaccaactg tctcacgtct ggaggcactg 400 actcgggcag tgcaggtagc tgagcctctt ggtagctgcg gctttcaagg 450 tgggccttgc cctggccgta gaagggattg acaagcccga agatttcata 500 ggcgatggct cccactgccc aggcatcagc cttgctgtag tcaatcactg 550 ccctggggcc aggacgggcc gtggacacct gctcagaagc agtgggtgag 600 acatcacgct gcccgcccat ctaacctttt catgtcctgc acatcacctg 650 atccatgggc taatctgaac tctgtcccaa ggaacccaga gcttgagtga 700 gctgtggctc agacccagaa ggggtctgct tagaccacct ggtttatgtg 750 acaggacttg cattctcctg gaacatgagg gaacgccgga ggaaagcaaa 800 gtggcaggga aggaacttgt gccaaattat gggtcagaaa agatggaggt 850 gttgggttat cacaaggcat cgagtctcct gcattcagtg gacatgtggg 900 ggaagggctg ccgatggcgc atgacacact cgggactcac ctctggggcc 950 atcagacagc cgtttccgcc ccgatccacg taccagctgc tgaagggcaa 1000 ctgcaggccg atgctctcat cagccaggca gcagccaaaa tctgcgatca 1050 ccagccaggg gcagccgtct gggaaggagc aagcaaagtg accatttctc 1100 ctcccctcct tccctctgag aggccctcct atgtccctac taaagccacc 1150 agcaagacat agctgacagg ggctaatggc tcagtgttgg cccaggaggt 1200 cagcaaggcc tgagagctga tcagaagggc ctgctgtgcg aacacggaaa 1250 tgcctccagt aagcacaggc tgcaaaatcc ccaggcaaag gactgtgtgg 1300 ctcaatttaa atcatgttct agtaattgga gctgtcccca agaccaaagg 1350 agctagagct tggttcaaat gatctccaag ggcccttata ccccaggaga 1400 ctttgatttg aatttgaaac cccaaatcca aacctaagaa ccaggtgcat 1450 taagaatcag ttattgccgg gtgtggtggc ctgtaatgcc aacattttgg 1500 gaggccgagg cgggtagatc acctgaggtc aggagttcaa gaccagcctg 1550 gccaacatgg tgaaacccct gtctctacta aaaatacaaa aaaactagcc 1600 aggcatggtg gtgtgtgcct gtatcccagc tactcgggag gctgagacag 1650 gagaattact tgaacctggg aggtgaagga ggctgagaca ggagaatcac 1700 ttcagcctga gcaacacagc gagactctgt ctcagaaaaa ataaaaaaag 1750 aattatggtt atttgtaa 1768 114 109 PRT Homo Sapien 114 Met Leu Trp Trp Leu Val Leu Leu Leu Leu Pro Thr Leu Lys Ser 1 5 10 15 Val Phe Cys Ser Leu Val Thr Ser Leu Tyr Leu Pro Asn Thr Glu 20 25 30 Asp Leu Ser Leu Trp Leu Trp Pro Lys Pro Asp Leu His Ser Gly 35 40 45 Thr Arg Thr Glu Val Ser Thr His Thr Val Pro Ser Lys Pro Gly 50 55 60 Thr Ala Ser Pro Cys Trp Pro Leu Ala Gly Ala Val Pro Ser Pro 65 70 75 Thr Val Ser Arg Leu Glu Ala Leu Thr Arg Ala Val Gln Val Ala 80 85 90 Glu Pro Leu Gly Ser Cys Gly Phe Gln Gly Gly Pro Cys Pro Gly 95 100 105 Arg Arg Arg Asp 115 1197 DNA Homo Sapien 115 cagcagtggt ctctcagtcc tctcaaagca aggaaagagt actgtgtgct 50 gagagaccat ggcaaagaat cctccagaga attgtgaaga ctgtcacatt 100 ctaaatgcag aagcttttaa atccaagaaa atatgtaaat cacttaagat 150 ttgtggactg gtgtttggta tcctggccct aactctaatt gtcctgtttt 200 gggggagcaa gcacttctgg ccggaggtac ccaaaaaagc ctatgacatg 250 gagcacactt tctacagcaa tggagagaag aagaagattt acatggaaat 300 tgatcctgtg accagaactg aaatattcag aagcggaaat ggcactgatg 350 aaacattgga agtgcacgac tttaaaaacg gatacactgg catctacttc 400 gtgggtcttc aaaaatgttt tatcaaaact cagattaaag tgattcctga 450 attttctgaa ccagaagagg aaatagatga gaatgaagaa attaccacaa 500 ctttctttga acagtcagtg atttgggtcc cagcagaaaa gcctattgaa 550 aaccgagatt ttcttaaaaa ttccaaaatt ctggagattt gtgataacgt 600 gaccatgtat tggatcaatc ccactctaat atcagtttct gagttacaag 650 actttgagga ggagggagaa gatcttcact ttcctgccaa cgaaaaaaaa 700 gggattgaac aaaatgaaca gtgggtggtc cctcaagtga aagtagagaa 750 gacccgtcac gccagacaag caagtgagga agaacttcca ataaatgact 800 atactgaaaa tggaatagaa tttgatccca tgctggatga gagaggttat 850 tgttgtattt actgccgtcg aggcaaccgc tattgccgcc gcgtctgtga 900 acctttacta ggctactacc catatccata ctgctaccaa ggaggacgag 950 tcatctgtcg tgtcatcatg ccttgtaact ggtgggtggc ccgcatgctg 1000 gggagggtct aataggaggt ttgagctcaa atgcttaaac tgctggcaac 1050 atataataaa tgcatgctat tcaatgaatt tctgcctatg aggcatctgg 1100 cccctggtag ccagctctcc agaattactt gtaggtaatt cctctcttca 1150 tgttctaata aacttctaca ttatcaccaa aaaaaaaaaa aaaaaaa 1197 116 317 PRT Homo Sapien 116 Met Ala Lys Asn Pro Pro Glu Asn Cys Glu Asp Cys His Ile Leu 1 5 10 15 Asn Ala Glu Ala Phe Lys Ser Lys Lys Ile Cys Lys Ser Leu Lys 20 25 30 Ile Cys Gly Leu Val Phe Gly Ile Leu Ala Leu Thr Leu Ile Val 35 40 45 Leu Phe Trp Gly Ser Lys His Phe Trp Pro Glu Val Pro Lys Lys 50 55 60 Ala Tyr Asp Met Glu His Thr Phe Tyr Ser Asn Gly Glu Lys Lys 65 70 75 Lys Ile Tyr Met Glu Ile Asp Pro Val Thr Arg Thr Glu Ile Phe 80 85 90 Arg Ser Gly Asn Gly Thr Asp Glu Thr Leu Glu Val His Asp Phe 95 100 105 Lys Asn Gly Tyr Thr Gly Ile Tyr Phe Val Gly Leu Gln Lys Cys 110 115 120 Phe Ile Lys Thr Gln Ile Lys Val Ile Pro Glu Phe Ser Glu Pro 125 130 135 Glu Glu Glu Ile Asp Glu Asn Glu Glu Ile Thr Thr Thr Phe Phe 140 145 150 Glu Gln Ser Val Ile Trp Val Pro Ala Glu Lys Pro Ile Glu Asn 155 160 165 Arg Asp Phe Leu Lys Asn Ser Lys Ile Leu Glu Ile Cys Asp Asn 170 175 180 Val Thr Met Tyr Trp Ile Asn Pro Thr Leu Ile Ser Val Ser Glu 185 190 195 Leu Gln Asp Phe Glu Glu Glu Gly Glu Asp Leu His Phe Pro Ala 200 205 210 Asn Glu Lys Lys Gly Ile Glu Gln Asn Glu Gln Trp Val Val Pro 215 220 225 Gln Val Lys Val Glu Lys Thr Arg His Ala Arg Gln Ala Ser Glu 230 235 240 Glu Glu Leu Pro Ile Asn Asp Tyr Thr Glu Asn Gly Ile Glu Phe 245 250 255 Asp Pro Met Leu Asp Glu Arg Gly Tyr Cys Cys Ile Tyr Cys Arg 260 265 270 Arg Gly Asn Arg Tyr Cys Arg Arg Val Cys Glu Pro Leu Leu Gly 275 280 285 Tyr Tyr Pro Tyr Pro Tyr Cys Tyr Gln Gly Gly Arg Val Ile Cys 290 295 300 Arg Val Ile Met Pro Cys Asn Trp Trp Val Ala Arg Met Leu Gly 305 310 315 Arg Val 117 2121 DNA Homo Sapien 117 gagctcccct caggagcgcg ttagcttcac accttcggca gcaggagggc 50 ggcagcttct cgcaggcggc agggcgggcg gccaggatca tgtccaccac 100 cacatgccaa gtggtggcgt tcctcctgtc catcctgggg ctggccggct 150 gcatcgcggc caccgggatg gacatgtgga gcacccagga cctgtacgac 200 aaccccgtca cctccgtgtt ccagtacgaa gggctctgga ggagctgcgt 250 gaggcagagt tcaggcttca ccgaatgcag gccctatttc accatcctgg 300 gacttccagc catgctgcag gcagtgcgag ccctgatgat cgtaggcatc 350 gtcctgggtg ccattggcct cctggtatcc atctttgccc tgaaatgcat 400 ccgcattggc agcatggagg actctgccaa agccaacatg acactgacct 450 ccgggatcat gttcattgtc tcaggtcttt gtgcaattgc tggagtgtct 500 gtgtttgcca acatgctggt gactaacttc tggatgtcca cagctaacat 550 gtacaccggc atgggtggga tggtgcagac tgttcagacc aggtacacat 600 ttggtgcggc tctgttcgtg ggctgggtcg ctggaggcct cacactaatt 650 gggggtgtga tgatgtgcat cgcctgccgg ggcctggcac cagaagaaac 700 caactacaaa gccgtttctt atcatgcctc aggccacagt gttgcctaca 750 agcctggagg cttcaaggcc agcactggct ttgggtccaa caccaaaaac 800 aagaagatat acgatggagg tgcccgcaca gaggacgagg tacaatctta 850 tccttccaag cacgactatg tgtaatgctc taagacctct cagcacgggc 900 ggaagaaact cccggagagc tcacccaaaa aacaaggaga tcccatctag 950 atttcttctt gcttttgact cacagctgga agttagaaaa gcctcgattt 1000 catctttgga gaggccaaat ggtcttagcc tcagtctctg tctctaaata 1050 ttccaccata aaacagctga gttatttatg aattagaggc tatagctcac 1100 attttcaatc ctctatttct ttttttaaat ataactttct actctgatga 1150 gagaatgtgg ttttaatctc tctctcacat tttgatgatt tagacagact 1200 ccccctcttc ctcctagtca ataaacccat tgatgatcta tttcccagct 1250 tatccccaag aaaacttttg aaaggaaaga gtagacccaa agatgttatt 1300 ttctgctgtt tgaattttgt ctccccaccc ccaacttggc tagtaataaa 1350 cacttactga agaagaagca ataagagaaa gatatttgta atctctccag 1400 cccatgatct cggttttctt acactgtgat cttaaaagtt accaaaccaa 1450 agtcattttc agtttgaggc aaccaaacct ttctactgct gttgacatct 1500 tcttattaca gcaacaccat tctaggagtt tcctgagctc tccactggag 1550 tcctctttct gtcgcgggtc agaaattgtc cctagatgaa tgagaaaatt 1600 atttttttta atttaagtcc taaatatagt taaaataaat aatgttttag 1650 taaaatgata cactatctct gtgaaatagc ctcaccccta catgtggata 1700 gaaggaaatg aaaaaataat tgctttgaca ttgtctatat ggtactttgt 1750 aaagtcatgc ttaagtacaa attccatgaa aagctcacac ctgtaatcct 1800 agcactttgg gaggctgagg aggaaggatc acttgagccc agaagttcga 1850 gactagcctg ggcaacatgg agaagccctg tctctacaaa atacagagag 1900 aaaaaatcag ccagtcatgg tggcatacac ctgtagtccc agcattccgg 1950 gaggctgagg tgggaggatc acttgagccc agggaggttg gggctgcagt 2000 gagccatgat cacaccactg cactccagcc aggtgacata gcgagatcct 2050 gtctaaaaaa ataaaaaata aataatggaa cacagcaagt cctaggaagt 2100 aggttaaaac taattcttta a 2121 118 261 PRT Homo Sapien 118 Met Ser Thr Thr Thr Cys Gln Val Val Ala Phe Leu Leu Ser Ile 1 5 10 15 Leu Gly Leu Ala Gly Cys Ile Ala Ala Thr Gly Met Asp Met Trp 20 25 30 Ser Thr Gln Asp Leu Tyr Asp Asn Pro Val Thr Ser Val Phe Gln 35 40 45 Tyr Glu Gly Leu Trp Arg Ser Cys Val Arg Gln Ser Ser Gly Phe 50 55 60 Thr Glu Cys Arg Pro Tyr Phe Thr Ile Leu Gly Leu Pro Ala Met 65 70 75 Leu Gln Ala Val Arg Ala Leu Met Ile Val Gly Ile Val Leu Gly 80 85 90 Ala Ile Gly Leu Leu Val Ser Ile Phe Ala Leu Lys Cys Ile Arg 95 100 105 Ile Gly Ser Met Glu Asp Ser Ala Lys Ala Asn Met Thr Leu Thr 110 115 120 Ser Gly Ile Met Phe Ile Val Ser Gly Leu Cys Ala Ile Ala Gly 125 130 135 Val Ser Val Phe Ala Asn Met Leu Val Thr Asn Phe Trp Met Ser 140 145 150 Thr Ala Asn Met Tyr Thr Gly Met Gly Gly Met Val Gln Thr Val 155 160 165 Gln Thr Arg Tyr Thr Phe Gly Ala Ala Leu Phe Val Gly Trp Val 170 175 180 Ala Gly Gly Leu Thr Leu Ile Gly Gly Val Met Met Cys Ile Ala 185 190 195 Cys Arg Gly Leu Ala Pro Glu Glu Thr Asn Tyr Lys Ala Val Ser 200 205 210 Tyr His Ala Ser Gly His Ser Val Ala Tyr Lys Pro Gly Gly Phe 215 220 225 Lys Ala Ser Thr Gly Phe Gly Ser Asn Thr Lys Asn Lys Lys Ile 230 235 240 Tyr Asp Gly Gly Ala Arg Thr Glu Asp Glu Val Gln Ser Tyr Pro 245 250 255 Ser Lys His Asp Tyr Val 260 119 2010 DNA Homo Sapien 119 ggaaaaactg ttctcttctg tggcacagag aaccctgctt caaagcagaa 50 gtagcagttc cggagtccag ctggctaaaa ctcatcccag aggataatgg 100 caacccatgc cttagaaatc gctgggctgt ttcttggtgg tgttggaatg 150 gtgggcacag tggctgtcac tgtcatgcct cagtggagag tgtcggcctt 200 cattgaaaac aacatcgtgg tttttgaaaa cttctgggaa ggactgtgga 250 tgaattgcgt gaggcaggct aacatcagga tgcagtgcaa aatctatgat 300 tccctgctgg ctctttctcc ggacctacag gcagccagag gactgatgtg 350 tgctgcttcc gtgatgtcct tcttggcttt catgatggcc atccttggca 400 tgaaatgcac caggtgcacg ggggacaatg agaaggtgaa ggctcacatt 450 ctgctgacgg ctggaatcat cttcatcatc acgggcatgg tggtgctcat 500 ccctgtgagc tgggttgcca atgccatcat cagagatttc tataactcaa 550 tagtgaatgt tgcccaaaaa cgtgagcttg gagaagctct ctacttagga 600 tggaccacgg cactggtgct gattgttgga ggagctctgt tctgctgcgt 650 tttttgttgc aacgaaaaga gcagtagcta cagatactcg ataccttccc 700 atcgcacaac ccaaaaaagt tatcacaccg gaaagaagtc accgagcgtc 750 tactccagaa gtcagtatgt gtagttgtgt atgttttttt aactttacta 800 taaagccatg caaatgacaa aaatctatat tactttctca aaatggaccc 850 caaagaaact ttgatttact gttcttaact gcctaatctt aattacagga 900 actgtgcatc agctatttat gattctataa gctatttcag cagaatgaga 950 tattaaaccc aatgctttga ttgttctaga aagtatagta atttgttttc 1000 taaggtggtt caagcatcta ctctttttat catttacttc aaaatgacat 1050 tgctaaagac tgcattattt tactactgta atttctccac gacatagcat 1100 tatgtacata gatgagtgta acatttatat ctcacataga gacatgctta 1150 tatggtttta tttaaaatga aatgccagtc cattacactg aataaataga 1200 actcaactat tgcttttcag ggaaatcatg gatagggttg aagaaggtta 1250 ctattaattg tttaaaaaca gcttagggat taatgtcctc catttataat 1300 gaagattaaa atgaaggctt taatcagcat tgtaaaggaa attgaatggc 1350 tttctgatat gctgtttttt agcctaggag ttagaaatcc taacttcttt 1400 atcctcttct cccagaggct ttttttttct tgtgtattaa attaacattt 1450 ttaaaacgca gatattttgt caaggggctt tgcattcaaa ctgcttttcc 1500 agggctatac tcagaagaaa gataaaagtg tgatctaaga aaaagtgatg 1550 gttttaggaa agtgaaaata tttttgtttt tgtatttgaa gaagaatgat 1600 gcattttgac aagaaatcat atatgtatgg atatatttta ataagtattt 1650 gagtacagac tttgaggttt catcaatata aataaaagag cagaaaaata 1700 tgtcttggtt ttcatttgct taccaaaaaa acaacaacaa aaaaagttgt 1750 cctttgagaa cttcacctgc tcctatgtgg gtacctgagt caaaattgtc 1800 atttttgttc tgtgaaaaat aaatttcctt cttgtaccat ttctgtttag 1850 ttttactaaa atctgtaaat actgtatttt tctgtttatt ccaaatttga 1900 tgaaactgac aatccaattt gaaagtttgt gtcgacgtct gtctagctta 1950 aatgaatgtg ttctatttgc tttatacatt tatattaata aattgtacat 2000 ttttctaatt 2010 120 225 PRT Homo Sapien 120 Met Ala Thr His Ala Leu Glu Ile Ala Gly Leu Phe Leu Gly Gly 1 5 10 15 Val Gly Met Val Gly Thr Val Ala Val Thr Val Met Pro Gln Trp 20 25 30 Arg Val Ser Ala Phe Ile Glu Asn Asn Ile Val Val Phe Glu Asn 35 40 45 Phe Trp Glu Gly Leu Trp Met Asn Cys Val Arg Gln Ala Asn Ile 50 55 60 Arg Met Gln Cys Lys Ile Tyr Asp Ser Leu Leu Ala Leu Ser Pro 65 70 75 Asp Leu Gln Ala Ala Arg Gly Leu Met Cys Ala Ala Ser Val Met 80 85 90 Ser Phe Leu Ala Phe Met Met Ala Ile Leu Gly Met Lys Cys Thr 95 100 105 Arg Cys Thr Gly Asp Asn Glu Lys Val Lys Ala His Ile Leu Leu 110 115 120 Thr Ala Gly Ile Ile Phe Ile Ile Thr Gly Met Val Val Leu Ile 125 130 135 Pro Val Ser Trp Val Ala Asn Ala Ile Ile Arg Asp Phe Tyr Asn 140 145 150 Ser Ile Val Asn Val Ala Gln Lys Arg Glu Leu Gly Glu Ala Leu 155 160 165 Tyr Leu Gly Trp Thr Thr Ala Leu Val Leu Ile Val Gly Gly Ala 170 175 180 Leu Phe Cys Cys Val Phe Cys Cys Asn Glu Lys Ser Ser Ser Tyr 185 190 195 Arg Tyr Ser Ile Pro Ser His Arg Thr Thr Gln Lys Ser Tyr His 200 205 210 Thr Gly Lys Lys Ser Pro Ser Val Tyr Ser Arg Ser Gln Tyr Val 215 220 225 121 1257 DNA Homo Sapien 121 ggagagaggc gcgcgggtga aaggcgcatt gatgcagcct gcggcggcct 50 cggagcgcgg cggagccaga cgctgaccac gttcctctcc tcggtctcct 100 ccgcctccag ctccgcgctg cccggcagcc gggagccatg cgaccccagg 150 gccccgccgc ctccccgcag cggctccgcg gcctcctgct gctcctgctg 200 ctgcagctgc ccgcgccgtc gagcgcctct gagatcccca aggggaagca 250 aaaggcgcag ctccggcaga gggaggtggt ggacctgtat aatggaatgt 300 gcttacaagg gccagcagga gtgcctggtc gagacgggag ccctggggcc 350 aatgttattc cgggtacacc tgggatccca ggtcgggatg gattcaaagg 400 agaaaagggg gaatgtctga gggaaagctt tgaggagtcc tggacaccca 450 actacaagca gtgttcatgg agttcattga attatggcat agatcttggg 500 aaaattgcgg agtgtacatt tacaaagatg cgttcaaata gtgctctaag 550 agttttgttc agtggctcac ttcggctaaa atgcagaaat gcatgctgtc 600 agcgttggta tttcacattc aatggagctg aatgttcagg acctcttccc 650 attgaagcta taatttattt ggaccaagga agccctgaaa tgaattcaac 700 aattaatatt catcgcactt cttctgtgga aggactttgt gaaggaattg 750 gtgctggatt agtggatgtt gctatctggg ttggcacttg ttcagattac 800 ccaaaaggag atgcttctac tggatggaat tcagtttctc gcatcattat 850 tgaagaacta ccaaaataaa tgctttaatt ttcatttgct acctcttttt 900 ttattatgcc ttggaatggt tcacttaaat gacattttaa ataagtttat 950 gtatacatct gaatgaaaag caaagctaaa tatgtttaca gaccaaagtg 1000 tgatttcaca ctgtttttaa atctagcatt attcattttg cttcaatcaa 1050 aagtggtttc aatatttttt ttagttggtt agaatacttt cttcatagtc 1100 acattctctc aacctataat ttggaatatt gttgtggtct tttgtttttt 1150 ctcttagtat agcattttta aaaaaatata aaagctacca atctttgtac 1200 aatttgtaaa tgttaagaat tttttttata tctgttaaat aaaaattatt 1250 tccaaca 1257 122 243 PRT Homo Sapien 122 Met Arg Pro Gln Gly Pro Ala Ala Ser Pro Gln Arg Leu Arg Gly 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Gln Leu Pro Ala Pro Ser Ser Ala 20 25 30 Ser Glu Ile Pro Lys Gly Lys Gln Lys Ala Gln Leu Arg Gln Arg 35 40 45 Glu Val Val Asp Leu Tyr Asn Gly Met Cys Leu Gln Gly Pro Ala 50 55 60 Gly Val Pro Gly Arg Asp Gly Ser Pro Gly Ala Asn Val Ile Pro 65 70 75 Gly Thr Pro Gly Ile Pro Gly Arg Asp Gly Phe Lys Gly Glu Lys 80 85 90 Gly Glu Cys Leu Arg Glu Ser Phe Glu Glu Ser Trp Thr Pro Asn 95 100 105 Tyr Lys Gln Cys Ser Trp Ser Ser Leu Asn Tyr Gly Ile Asp Leu 110 115 120 Gly Lys Ile Ala Glu Cys Thr Phe Thr Lys Met Arg Ser Asn Ser 125 130 135 Ala Leu Arg Val Leu Phe Ser Gly Ser Leu Arg Leu Lys Cys Arg 140 145 150 Asn Ala Cys Cys Gln Arg Trp Tyr Phe Thr Phe Asn Gly Ala Glu 155 160 165 Cys Ser Gly Pro Leu Pro Ile Glu Ala Ile Ile Tyr Leu Asp Gln 170 175 180 Gly Ser Pro Glu Met Asn Ser Thr Ile Asn Ile His Arg Thr Ser 185 190 195 Ser Val Glu Gly Leu Cys Glu Gly Ile Gly Ala Gly Leu Val Asp 200 205 210 Val Ala Ile Trp Val Gly Thr Cys Ser Asp Tyr Pro Lys Gly Asp 215 220 225 Ala Ser Thr Gly Trp Asn Ser Val Ser Arg Ile Ile Ile Glu Glu 230 235 240 Leu Pro Lys 123 2379 DNA Homo Sapien 123 gctgagcgtg tgcgcggtac ggggctctcc tgccttctgg gctccaacgc 50 agctctgtgg ctgaactggg tgctcatcac gggaactgct gggctatgga 100 atacagatgt ggcagctcag gtagccccaa attgcctgga agaatacatc 150 atgtttttcg ataagaagaa attgtaggat ccagtttttt ttttaaccgc 200 cccctcccca ccccccaaaa aaactgtaaa gatgcaaaaa cgtaatatcc 250 atgaagatcc tattacctag gaagattttg atgttttgct gcgaatgcgg 300 tgttgggatt tatttgttct tggagtgttc tgcgtggctg gcaaagaata 350 atgttccaaa atcggtccat ctcccaaggg gtccaatttt tcttcctggg 400 tgtcagcgag ccctgactca ctacagtgca gctgacaggg gctgtcatgc 450 aactggcccc taagccaaag caaaagacct aaggacgacc tttgaacaat 500 acaaaggatg ggtttcaatg taattaggct actgagcgga tcagctgtag 550 cactggttat agcccccact gtcttactga caatgctttc ttctgccgaa 600 cgaggatgcc ctaagggctg taggtgtgaa ggcaaaatgg tatattgtga 650 atctcagaaa ttacaggaga taccctcaag tatatctgct ggttgcttag 700 gtttgtccct tcgctataac agccttcaaa aacttaagta taatcaattt 750 aaagggctca accagctcac ctggctatac cttgaccata accatatcag 800 caatattgac gaaaatgctt ttaatggaat acgcagactc aaagagctga 850 ttcttagttc caatagaatc tcctattttc ttaacaatac cttcagacct 900 gtgacaaatt tacggaactt ggatctgtcc tataatcagc tgcattctct 950 gggatctgaa cagtttcggg gcttgcggaa gctgctgagt ttacatttac 1000 ggtctaactc cctgagaacc atccctgtgc gaatattcca agactgccgc 1050 aacctggaac ttttggacct gggatataac cggatccgaa gtttagccag 1100 gaatgtcttt gctggcatga tcagactcaa agaacttcac ctggagcaca 1150 atcaattttc caagctcaac ctggcccttt ttccaaggtt ggtcagcctt 1200 cagaaccttt acttgcagtg gaataaaatc agtgtcatag gacagaccat 1250 gtcctggacc tggagctcct tacaaaggct tgatttatca ggcaatgaga 1300 tcgaagcttt cagtggaccc agtgttttcc agtgtgtccc gaatctgcag 1350 cgcctcaacc tggattccaa caagctcaca tttattggtc aagagatttt 1400 ggattcttgg atatccctca atgacatcag tcttgctggg aatatatggg 1450 aatgcagcag aaatatttgc tcccttgtaa actggctgaa aagttttaaa 1500 ggtctaaggg agaatacaat tatctgtgcc agtcccaaag agctgcaagg 1550 agtaaatgtg atcgatgcag tgaagaacta cagcatctgt ggcaaaagta 1600 ctacagagag gtttgatctg gccagggctc tcccaaagcc gacgtttaag 1650 cccaagctcc ccaggccgaa gcatgagagc aaaccccctt tgcccccgac 1700 ggtgggagcc acagagcccg gcccagagac cgatgctgac gccgagcaca 1750 tctctttcca taaaatcatc gcgggcagcg tggcgctttt cctgtccgtg 1800 ctcgtcatcc tgctggttat ctacgtgtca tggaagcggt accctgcgag 1850 catgaagcag ctgcagcagc gctccctcat gcgaaggcac aggaaaaaga 1900 aaagacagtc cctaaagcaa atgactccca gcacccagga attttatgta 1950 gattataaac ccaccaacac ggagaccagc gagatgctgc tgaatgggac 2000 gggaccctgc acctataaca aatcgggctc cagggagtgt gaggtatgaa 2050 ccattgtgat aaaaagagct cttaaaagct gggaaataag tggtgcttta 2100 ttgaactctg gtgactatca agggaacgcg atgccccccc tccccttccc 2150 tctccctctc actttggtgg caagatcctt ccttgtccgt tttagtgcat 2200 tcataatact ggtcattttc ctctcataca taatcaaccc attgaaattt 2250 aaataccaca atcaatgtga agcttgaact ccggtttaat ataataccta 2300 ttgtataaga ccctttactg attccattaa tgtcgcattt gttttaagat 2350 aaaacttctt tcataggtaa aaaaaaaaa 2379 124 513 PRT Homo Sapien 124 Met Gly Phe Asn Val Ile Arg Leu Leu Ser Gly Ser Ala Val Ala 1 5 10 15 Leu Val Ile Ala Pro Thr Val Leu Leu Thr Met Leu Ser Ser Ala 20 25 30 Glu Arg Gly Cys Pro Lys Gly Cys Arg Cys Glu Gly Lys Met Val 35 40 45 Tyr Cys Glu Ser Gln Lys Leu Gln Glu Ile Pro Ser Ser Ile Ser 50 55 60 Ala Gly Cys Leu Gly Leu Ser Leu Arg Tyr Asn Ser Leu Gln Lys 65 70 75 Leu Lys Tyr Asn Gln Phe Lys Gly Leu Asn Gln Leu Thr Trp Leu 80 85 90 Tyr Leu Asp His Asn His Ile Ser Asn Ile Asp Glu Asn Ala Phe 95 100 105 Asn Gly Ile Arg Arg Leu Lys Glu Leu Ile Leu Ser Ser Asn Arg 110 115 120 Ile Ser Tyr Phe Leu Asn Asn Thr Phe Arg Pro Val Thr Asn Leu 125 130 135 Arg Asn Leu Asp Leu Ser Tyr Asn Gln Leu His Ser Leu Gly Ser 140 145 150 Glu Gln Phe Arg Gly Leu Arg Lys Leu Leu Ser Leu His Leu Arg 155 160 165 Ser Asn Ser Leu Arg Thr Ile Pro Val Arg Ile Phe Gln Asp Cys 170 175 180 Arg Asn Leu Glu Leu Leu Asp Leu Gly Tyr Asn Arg Ile Arg Ser 185 190 195 Leu Ala Arg Asn Val Phe Ala Gly Met Ile Arg Leu Lys Glu Leu 200 205 210 His Leu Glu His Asn Gln Phe Ser Lys Leu Asn Leu Ala Leu Phe 215 220 225 Pro Arg Leu Val Ser Leu Gln Asn Leu Tyr Leu Gln Trp Asn Lys 230 235 240 Ile Ser Val Ile Gly Gln Thr Met Ser Trp Thr Trp Ser Ser Leu 245 250 255 Gln Arg Leu Asp Leu Ser Gly Asn Glu Ile Glu Ala Phe Ser Gly 260 265 270 Pro Ser Val Phe Gln Cys Val Pro Asn Leu Gln Arg Leu Asn Leu 275 280 285 Asp Ser Asn Lys Leu Thr Phe Ile Gly Gln Glu Ile Leu Asp Ser 290 295 300 Trp Ile Ser Leu Asn Asp Ile Ser Leu Ala Gly Asn Ile Trp Glu 305 310 315 Cys Ser Arg Asn Ile Cys Ser Leu Val Asn Trp Leu Lys Ser Phe 320 325 330 Lys Gly Leu Arg Glu Asn Thr Ile Ile Cys Ala Ser Pro Lys Glu 335 340 345 Leu Gln Gly Val Asn Val Ile Asp Ala Val Lys Asn Tyr Ser Ile 350 355 360 Cys Gly Lys Ser Thr Thr Glu Arg Phe Asp Leu Ala Arg Ala Leu 365 370 375 Pro Lys Pro Thr Phe Lys Pro Lys Leu Pro Arg Pro Lys His Glu 380 385 390 Ser Lys Pro Pro Leu Pro Pro Thr Val Gly Ala Thr Glu Pro Gly 395 400 405 Pro Glu Thr Asp Ala Asp Ala Glu His Ile Ser Phe His Lys Ile 410 415 420 Ile Ala Gly Ser Val Ala Leu Phe Leu Ser Val Leu Val Ile Leu 425 430 435 Leu Val Ile Tyr Val Ser Trp Lys Arg Tyr Pro Ala Ser Met Lys 440 445 450 Gln Leu Gln Gln Arg Ser Leu Met Arg Arg His Arg Lys Lys Lys 455 460 465 Arg Gln Ser Leu Lys Gln Met Thr Pro Ser Thr Gln Glu Phe Tyr 470 475 480 Val Asp Tyr Lys Pro Thr Asn Thr Glu Thr Ser Glu Met Leu Leu 485 490 495 Asn Gly Thr Gly Pro Cys Thr Tyr Asn Lys Ser Gly Ser Arg Glu 500 505 510 Cys Glu Val 125 998 DNA Homo Sapien 125 ccgttatcgt cttgcgctac tgctgaatgt ccgtcccgga ggaggaggag 50 aggcttttgc cgctgaccca gagatggccc cgagcgagca aattcctact 100 gtccggctgc gcggctaccg tggccgagct agcaaccttt cccctggatc 150 tcacaaaaac tcgactccaa atgcaaggag aagcagctct tgctcggttg 200 ggagacggtg caagagaatc tgccccctat aggggaatgg tgcgcacagc 250 cctagggatc attgaagagg aaggctttct aaagctttgg caaggagtga 300 cacccgccat ttacagacac gtagtgtatt ctggaggtcg aatggtcaca 350 tatgaacatc tccgagaggt tgtgtttggc aaaagtgaag atgagcatta 400 tcccctttgg aaatcagtca ttggagggat gatggctggt gttattggcc 450 agtttttagc caatccaact gacctagtga aggttcagat gcaaatggaa 500 ggaaaaagga aactggaagg aaaaccattg cgatttcgtg gtgtacatca 550 tgcatttgca aaaatcttag ctgaaggagg aatacgaggg ctttgggcag 600 gctgggtacc caatatacaa agagcagcac tggtgaatat gggagattta 650 accacttatg atacagtgaa acactacttg gtattgaata caccacttga 700 ggacaatatc atgactcacg gtttatcaag tttatgttct ggactggtag 750 cttctattct gggaacacca gccgatgtca tcaaaagcag aataatgaat 800 caaccacgag ataaacaagg aaggggactt ttgtataaat catcgactga 850 ctgcttgatt caggctgttc aaggtgaagg attcatgagt ctatataaag 900 gctttttacc atcttggctg agaatgaccc cttggtcaat ggtgttctgg 950 cttacttatg aaaaaatcag agagatgagt ggagtcagtc cattttaa 998 126 323 PRT Homo Sapien 126 Met Ser Val Pro Glu Glu Glu Glu Arg Leu Leu Pro Leu Thr Gln 1 5 10 15 Arg Trp Pro Arg Ala Ser Lys Phe Leu Leu Ser Gly Cys Ala Ala 20 25 30 Thr Val Ala Glu Leu Ala Thr Phe Pro Leu Asp Leu Thr Lys Thr 35 40 45 Arg Leu Gln Met Gln Gly Glu Ala Ala Leu Ala Arg Leu Gly Asp 50 55 60 Gly Ala Arg Glu Ser Ala Pro Tyr Arg Gly Met Val Arg Thr Ala 65 70 75 Leu Gly Ile Ile Glu Glu Glu Gly Phe Leu Lys Leu Trp Gln Gly 80 85 90 Val Thr Pro Ala Ile Tyr Arg His Val Val Tyr Ser Gly Gly Arg 95 100 105 Met Val Thr Tyr Glu His Leu Arg Glu Val Val Phe Gly Lys Ser 110 115 120 Glu Asp Glu His Tyr Pro Leu Trp Lys Ser Val Ile Gly Gly Met 125 130 135 Met Ala Gly Val Ile Gly Gln Phe Leu Ala Asn Pro Thr Asp Leu 140 145 150 Val Lys Val Gln Met Gln Met Glu Gly Lys Arg Lys Leu Glu Gly 155 160 165 Lys Pro Leu Arg Phe Arg Gly Val His His Ala Phe Ala Lys Ile 170 175 180 Leu Ala Glu Gly Gly Ile Arg Gly Leu Trp Ala Gly Trp Val Pro 185 190 195 Asn Ile Gln Arg Ala Ala Leu Val Asn Met Gly Asp Leu Thr Thr 200 205 210 Tyr Asp Thr Val Lys His Tyr Leu Val Leu Asn Thr Pro Leu Glu 215 220 225 Asp Asn Ile Met Thr His Gly Leu Ser Ser Leu Cys Ser Gly Leu 230 235 240 Val Ala Ser Ile Leu Gly Thr Pro Ala Asp Val Ile Lys Ser Arg 245 250 255 Ile Met Asn Gln Pro Arg Asp Lys Gln Gly Arg Gly Leu Leu Tyr 260 265 270 Lys Ser Ser Thr Asp Cys Leu Ile Gln Ala Val Gln Gly Glu Gly 275 280 285 Phe Met Ser Leu Tyr Lys Gly Phe Leu Pro Ser Trp Leu Arg Met 290 295 300 Thr Pro Trp Ser Met Val Phe Trp Leu Thr Tyr Glu Lys Ile Arg 305 310 315 Glu Met Ser Gly Val Ser Pro Phe 320 127 1505 DNA Homo Sapien 127 cgcggatcgg acccaagcag gtcggcggcg gcggcaggag agcggccggg 50 cgtcagctcc tcgacccccg tgtcgggcta gtccagcgag gcggacgggc 100 ggcgtgggcc catggccagg cccggcatgg agcggtggcg cgaccggctg 150 gcgctggtga cgggggcctc ggggggcatc ggcgcggccg tggcccgggc 200 cctggtccag cagggactga aggtggtggg ctgcgcccgc actgtgggca 250 acatcgagga gctggctgct gaatgtaaga gtgcaggcta ccccgggact 300 ttgatcccct acagatgtga cctatcaaat gaagaggaca tcctctccat 350 gttctcagct atccgttctc agcacagcgg tgtagacatc tgcatcaaca 400 atgctggctt ggcccggcct gacaccctgc tctcaggcag caccagtggt 450 tggaaggaca tgttcaatgt gaacgtgctg gccctcagca tctgcacacg 500 ggaagcctac cagtccatga aggagcggaa tgtggacgat gggcacatca 550 ttaacatcaa tagcatgtct ggccaccgag tgttacccct gtctgtgacc 600 cacttctata gtgccaccaa gtatgccgtc actgcgctga cagagggact 650 gaggcaagag cttcgggagg cccagaccca catccgagcc acgtgcatct 700 ctccaggtgt ggtggagaca caattcgcct tcaaactcca cgacaaggac 750 cctgagaagg cagctgccac ctatgagcaa atgaagtgtc tcaaacccga 800 ggatgtggcc gaggctgtta tctacgtcct cagcaccccc gcacacatcc 850 agattggaga catccagatg aggcccacgg agcaggtgac ctagtgactg 900 tgggagctcc tccttccctc cccacccttc atggcttgcc tcctgcctct 950 ggattttagg tgttgatttc tggatcacgg gataccactt cctgtccaca 1000 ccccgaccag gggctagaaa atttgtttga gatttttata tcatcttgtc 1050 aaattgcttc agttgtaaat gtgaaaaatg ggctggggaa aggaggtggt 1100 gtccctaatt gttttacttg ttaacttgtt cttgtgcccc tgggcacttg 1150 gcctttgtct gctctcagtg tcttcccttt gacatgggaa aggagttgtg 1200 gccaaaatcc ccatcttctt gcacctcaac gtctgtggct cagggctggg 1250 gtggcagagg gaggccttca ccttatatct gtgttgttat ccagggctcc 1300 agacttcctc ctctgcctgc cccactgcac cctctccccc ttatctatct 1350 ccttctcggc tccccagccc agtcttggct tcttgtcccc tcctggggtc 1400 atccctccac tctgactctg actatggcag cagaacacca gggcctggcc 1450 cagtggattt catggtgatc attaaaaaag aaaaatcgca accaaaaaaa 1500 aaaaa 1505 128 260 PRT Homo Sapien 128 Met Ala Arg Pro Gly Met Glu Arg Trp Arg Asp Arg Leu Ala Leu 1 5 10 15 Val Thr Gly Ala Ser Gly Gly Ile Gly Ala Ala Val Ala Arg Ala 20 25 30 Leu Val Gln Gln Gly Leu Lys Val Val Gly Cys Ala Arg Thr Val 35 40 45 Gly Asn Ile Glu Glu Leu Ala Ala Glu Cys Lys Ser Ala Gly Tyr 50 55 60 Pro Gly Thr Leu Ile Pro Tyr Arg Cys Asp Leu Ser Asn Glu Glu 65 70 75 Asp Ile Leu Ser Met Phe Ser Ala Ile Arg Ser Gln His Ser Gly 80 85 90 Val Asp Ile Cys Ile Asn Asn Ala Gly Leu Ala Arg Pro Asp Thr 95 100 105 Leu Leu Ser Gly Ser Thr Ser Gly Trp Lys Asp Met Phe Asn Val 110 115 120 Asn Val Leu Ala Leu Ser Ile Cys Thr Arg Glu Ala Tyr Gln Ser 125 130 135 Met Lys Glu Arg Asn Val Asp Asp Gly His Ile Ile Asn Ile Asn 140 145 150 Ser Met Ser Gly His Arg Val Leu Pro Leu Ser Val Thr His Phe 155 160 165 Tyr Ser Ala Thr Lys Tyr Ala Val Thr Ala Leu Thr Glu Gly Leu 170 175 180 Arg Gln Glu Leu Arg Glu Ala Gln Thr His Ile Arg Ala Thr Cys 185 190 195 Ile Ser Pro Gly Val Val Glu Thr Gln Phe Ala Phe Lys Leu His 200 205 210 Asp Lys Asp Pro Glu Lys Ala Ala Ala Thr Tyr Glu Gln Met Lys 215 220 225 Cys Leu Lys Pro Glu Asp Val Ala Glu Ala Val Ile Tyr Val Leu 230 235 240 Ser Thr Pro Ala His Ile Gln Ile Gly Asp Ile Gln Met Arg Pro 245 250 255 Thr Glu Gln Val Thr 260 129 1177 DNA Homo Sapien 129 aacttctaca tgggcctcct gctgctggtg ctcttcctca gcctcctgcc 50 ggtggcctac accatcatgt ccctcccacc ctcctttgac tgcgggccgt 100 tcaggtgcag agtctcagtt gcccgggagc acctcccctc ccgaggcagt 150 ctgctcagag ggcctcggcc cagaattcca gttctggttt catgccagcc 200 tgtaaaaggc catggaactt tgggtgaatc accgatgcca tttaagaggg 250 ttttctgcca ggatggaaat gttaggtcgt tctgtgtctg cgctgttcat 300 ttcagtagcc accagccacc tgtggccgtt gagtgcttga aatgaggaac 350 tgagaaaatt aatttctcat gtatttttct catttattta ttaattttta 400 actgatagtt gtacatattt gggggtacat gtgatatttg gatacatgta 450 tacaatatat aatgatcaaa tcagggtaac tgggatatcc atcacatcaa 500 acatttattt tttattcttt ttagacagag tctcactctg tcacccaggc 550 tggagtgcag tggtgccatc tcagcttact gcaacctctg cctgccaggt 600 tcaagcgatt ctcatgcctc cacctcccaa gtagctggga ctacaggcat 650 gcaccacaat gcccaactaa tttttgtatt tttagtagag acggggtttt 700 gccatgttgc ccaggctggc cttgaactcc tggcctcaaa caatccactt 750 gcctcggcct cccaaagtgt tatgattaca ggcgtgagcc accgtgcctg 800 gcctaaacat ttatcttttc tttgtgttgg gaactttgaa attatacaat 850 gaattattgt taactgtcat ctccctgctg tgctatggaa cactgggact 900 tcttccctct atctaactgt atatttgtac cagttaacca accgtacttc 950 atccccactc ctctctatcc ttcccaacct ctgatcacct cattctactc 1000 tctacctcca tgagatccac ttttttagct cccacatgtg agtaagaaaa 1050 tgcaatattt gtctttctgt gcctggctta tttcacttaa cataatgact 1100 tcctgttcca tccatgttgc tgcaaatgac aggatttcgt tcttaatttc 1150 aattaaaata accacacatg gcaaaaa 1177 130 111 PRT Homo Sapien 130 Met Gly Leu Leu Leu Leu Val Leu Phe Leu Ser Leu Leu Pro Val 1 5 10 15 Ala Tyr Thr Ile Met Ser Leu Pro Pro Ser Phe Asp Cys Gly Pro 20 25 30 Phe Arg Cys Arg Val Ser Val Ala Arg Glu His Leu Pro Ser Arg 35 40 45 Gly Ser Leu Leu Arg Gly Pro Arg Pro Arg Ile Pro Val Leu Val 50 55 60 Ser Cys Gln Pro Val Lys Gly His Gly Thr Leu Gly Glu Ser Pro 65 70 75 Met Pro Phe Lys Arg Val Phe Cys Gln Asp Gly Asn Val Arg Ser 80 85 90 Phe Cys Val Cys Ala Val His Phe Ser Ser His Gln Pro Pro Val 95 100 105 Ala Val Glu Cys Leu Lys 110 131 2061 DNA Homo Sapien 131 ttctgaagta acggaagcta ccttgtataa agacctcaac actgctgacc 50 atgatcagcg cagcctggag catcttcctc atcgggacta aaattgggct 100 gttccttcaa gtagcacctc tatcagttat ggctaaatcc tgtccatctg 150 tgtgtcgctg cgatgcgggt ttcatttact gtaatgatcg ctttctgaca 200 tccattccaa caggaatacc agaggatgct acaactctct accttcagaa 250 caaccaaata aataatgctg ggattccttc agatttgaaa aacttgctga 300 aagtagaaag aatataccta taccacaaca gtttagatga atttcctacc 350 aacctcccaa agtatgtaaa agagttacat ttgcaagaaa ataacataag 400 gactatcact tatgattcac tttcaaaaat tccctatctg gaagaattac 450 atttagatga caactctgtc tctgcagtta gcatagaaga gggagcattc 500 cgagacagca actatctccg actgcttttc ctgtcccgta atcaccttag 550 cacaattccc tggggtttgc ccaggactat agaagaacta cgcttggatg 600 ataatcgcat atccactatt tcatcaccat ctcttcaagg tctcactagt 650 ctaaaacgcc tggttctaga tggaaacctg ttgaacaatc atggtttagg 700 tgacaaagtt ttcttcaacc tagttaattt gacagagctg tccctggtgc 750 ggaattccct gactgctgca ccagtaaacc ttccaggcac aaacctgagg 800 aagctttatc ttcaagataa ccacatcaat cgggtgcccc caaatgcttt 850 ttcttatcta aggcagctct atcgactgga tatgtccaat aataacctaa 900 gtaatttacc tcagggtatc tttgatgatt tggacaatat aacacaactg 950 attcttcgca acaatccctg gtattgcggg tgcaagatga aatgggtacg 1000 tgactggtta caatcactac ctgtgaaggt caacgtgcgt gggctcatgt 1050 gccaagcccc agaaaaggtt cgtgggatgg ctattaagga tctcaatgca 1100 gaactgtttg attgtaagga cagtgggatt gtaagcacca ttcagataac 1150 cactgcaata cccaacacag tgtatcctgc ccaaggacag tggccagctc 1200 cagtgaccaa acagccagat attaagaacc ccaagctcac taaggatcaa 1250 caaaccacag ggagtccctc aagaaaaaca attacaatta ctgtgaagtc 1300 tgtcacctct gataccattc atatctcttg gaaacttgct ctacctatga 1350 ctgctttgag actcagctgg cttaaactgg gccatagccc ggcatttgga 1400 tctataacag aaacaattgt aacaggggaa cgcagtgagt acttggtcac 1450 agccctggag cctgattcac cctataaagt atgcatggtt cccatggaaa 1500 ccagcaacct ctacctattt gatgaaactc ctgtttgtat tgagactgaa 1550 actgcacccc ttcgaatgta caaccctaca accaccctca atcgagagca 1600 agagaaagaa ccttacaaaa accccaattt acctttggct gccatcattg 1650 gtggggctgt ggccctggtt accattgccc ttcttgcttt agtgtgttgg 1700 tatgttcata ggaatggatc gctcttctca aggaactgtg catatagcaa 1750 agggaggaga agaaaggatg actatgcaga agctggcact aagaaggaca 1800 actctatcct ggaaatcagg gaaacttctt ttcagatgtt accaataagc 1850 aatgaaccca tctcgaagga ggagtttgta atacacacca tatttcctcc 1900 taatggaatg aatctgtaca aaaacaatca cagtgaaagc agtagtaacc 1950 gaagctacag agacagtggt attccagact cagatcactc acactcatga 2000 tgctgaagga ctcacagcag acttgtgttt tgggtttttt aaacctaagg 2050 gaggtgatgg t 2061 132 649 PRT Homo Sapien 132 Met Ile Ser Ala Ala Trp Ser Ile Phe Leu Ile Gly Thr Lys Ile 1 5 10 15 Gly Leu Phe Leu Gln Val Ala Pro Leu Ser Val Met Ala Lys Ser 20 25 30 Cys Pro Ser Val Cys Arg Cys Asp Ala Gly Phe Ile Tyr Cys Asn 35 40 45 Asp Arg Phe Leu Thr Ser Ile Pro Thr Gly Ile Pro Glu Asp Ala 50 55 60 Thr Thr Leu Tyr Leu Gln Asn Asn Gln Ile Asn Asn Ala Gly Ile 65 70 75 Pro Ser Asp Leu Lys Asn Leu Leu Lys Val Glu Arg Ile Tyr Leu 80 85 90 Tyr His Asn Ser Leu Asp Glu Phe Pro Thr Asn Leu Pro Lys Tyr 95 100 105 Val Lys Glu Leu His Leu Gln Glu Asn Asn Ile Arg Thr Ile Thr 110 115 120 Tyr Asp Ser Leu Ser Lys Ile Pro Tyr Leu Glu Glu Leu His Leu 125 130 135 Asp Asp Asn Ser Val Ser Ala Val Ser Ile Glu Glu Gly Ala Phe 140 145 150 Arg Asp Ser Asn Tyr Leu Arg Leu Leu Phe Leu Ser Arg Asn His 155 160 165 Leu Ser Thr Ile Pro Trp Gly Leu Pro Arg Thr Ile Glu Glu Leu 170 175 180 Arg Leu Asp Asp Asn Arg Ile Ser Thr Ile Ser Ser Pro Ser Leu 185 190 195 Gln Gly Leu Thr Ser Leu Lys Arg Leu Val Leu Asp Gly Asn Leu 200 205 210 Leu Asn Asn His Gly Leu Gly Asp Lys Val Phe Phe Asn Leu Val 215 220 225 Asn Leu Thr Glu Leu Ser Leu Val Arg Asn Ser Leu Thr Ala Ala 230 235 240 Pro Val Asn Leu Pro Gly Thr Asn Leu Arg Lys Leu Tyr Leu Gln 245 250 255 Asp Asn His Ile Asn Arg Val Pro Pro Asn Ala Phe Ser Tyr Leu 260 265 270 Arg Gln Leu Tyr Arg Leu Asp Met Ser Asn Asn Asn Leu Ser Asn 275 280 285 Leu Pro Gln Gly Ile Phe Asp Asp Leu Asp Asn Ile Thr Gln Leu 290 295 300 Ile Leu Arg Asn Asn Pro Trp Tyr Cys Gly Cys Lys Met Lys Trp 305 310 315 Val Arg Asp Trp Leu Gln Ser Leu Pro Val Lys Val Asn Val Arg 320 325 330 Gly Leu Met Cys Gln Ala Pro Glu Lys Val Arg Gly Met Ala Ile 335 340 345 Lys Asp Leu Asn Ala Glu Leu Phe Asp Cys Lys Asp Ser Gly Ile 350 355 360 Val Ser Thr Ile Gln Ile Thr Thr Ala Ile Pro Asn Thr Val Tyr 365 370 375 Pro Ala Gln Gly Gln Trp Pro Ala Pro Val Thr Lys Gln Pro Asp 380 385 390 Ile Lys Asn Pro Lys Leu Thr Lys Asp Gln Gln Thr Thr Gly Ser 395 400 405 Pro Ser Arg Lys Thr Ile Thr Ile Thr Val Lys Ser Val Thr Ser 410 415 420 Asp Thr Ile His Ile Ser Trp Lys Leu Ala Leu Pro Met Thr Ala 425 430 435 Leu Arg Leu Ser Trp Leu Lys Leu Gly His Ser Pro Ala Phe Gly 440 445 450 Ser Ile Thr Glu Thr Ile Val Thr Gly Glu Arg Ser Glu Tyr Leu 455 460 465 Val Thr Ala Leu Glu Pro Asp Ser Pro Tyr Lys Val Cys Met Val 470 475 480 Pro Met Glu Thr Ser Asn Leu Tyr Leu Phe Asp Glu Thr Pro Val 485 490 495 Cys Ile Glu Thr Glu Thr Ala Pro Leu Arg Met Tyr Asn Pro Thr 500 505 510 Thr Thr Leu Asn Arg Glu Gln Glu Lys Glu Pro Tyr Lys Asn Pro 515 520 525 Asn Leu Pro Leu Ala Ala Ile Ile Gly Gly Ala Val Ala Leu Val 530 535 540 Thr Ile Ala Leu Leu Ala Leu Val Cys Trp Tyr Val His Arg Asn 545 550 555 Gly Ser Leu Phe Ser Arg Asn Cys Ala Tyr Ser Lys Gly Arg Arg 560 565 570 Arg Lys Asp Asp Tyr Ala Glu Ala Gly Thr Lys Lys Asp Asn Ser 575 580 585 Ile Leu Glu Ile Arg Glu Thr Ser Phe Gln Met Leu Pro Ile Ser 590 595 600 Asn Glu Pro Ile Ser Lys Glu Glu Phe Val Ile His Thr Ile Phe 605 610 615 Pro Pro Asn Gly Met Asn Leu Tyr Lys Asn Asn His Ser Glu Ser 620 625 630 Ser Ser Asn Arg Ser Tyr Arg Asp Ser Gly Ile Pro Asp Ser Asp 635 640 645 His Ser His Ser 133 1882 DNA Homo Sapien 133 ccgtcatccc cctgcagcca cccttcccag agtcctttgc ccaggccacc 50 ccaggcttct tggcagccct gccgggccac ttgtcttcat gtctgccagg 100 gggaggtggg aaggaggtgg gaggagggcg tgcagaggca gtctgggctt 150 ggccagagct cagggtgctg agcgtgtgac cagcagtgag cagaggccgg 200 ccatggccag cctggggctg ctgctcctgc tcttactgac agcactgcca 250 ccgctgtggt cctcctcact gcctgggctg gacactgctg aaagtaaagc 300 caccattgca gacctgatcc tgtctgcgct ggagagagcc accgtcttcc 350 tagaacagag gctgcctgaa atcaacctgg atggcatggt gggggtccga 400 gtgctggaag agcagctaaa aagtgtccgg gagaagtggg cccaggagcc 450 cctgctgcag ccgctgagcc tgcgcgtggg gatgctgggg gagaagctgg 500 aggctgccat ccagagatcc ctccactacc tcaagctgag tgatcccaag 550 tacctaagag agttccagct gaccctccag cccgggtttt ggaagctccc 600 acatgcctgg atccacactg atgcctcctt ggtgtacccc acgttcgggc 650 cccaggactc attctcagag gagagaagtg acgtgtgcct ggtgcagctg 700 ctgggaaccg ggacggacag cagcgagccc tgcggcctct cagacctctg 750 caggagcctc atgaccaagc ccggctgctc aggctactgc ctgtcccacc 800 aactgctctt cttcctctgg gccagaatga ggggatgcac acagggacca 850 ctccaacaga gccaggacta tatcaacctc ttctgcgcca acatgatgga 900 cttgaaccgc agagctgagg ccatcggata cgcctaccct acccgggaca 950 tcttcatgga aaacatcatg ttctgtggaa tgggcggctt ctccgacttc 1000 tacaagctcc ggtggctgga ggccattctc agctggcaga aacagcagga 1050 aggatgcttc ggggagcctg atgctgaaga tgaagaatta tctaaagcta 1100 ttcaatatca gcagcatttt tcgaggagag tgaagaggcg agaaaaacaa 1150 tttccagatt ctcgctctgt tgctcaggct ggagtacagt ggcgcaatct 1200 cggctcactg caacctttgc ctcctgggtt caagcaattc tcttgcctca 1250 tcctcccgag tagctgggac tacaggagcg tgccaccata cctggctaat 1300 ttttatattt ttttagtaga gacagggttt catcatgttg ctcatgctgg 1350 tctcgaactc ctgatctcaa gagatccgcc cacctcaggc tcccaaagtg 1400 tgggattata ggtgtgagcc accgtgtctg gctgaaaagc actttcaaag 1450 agactgtgtt gaataaaggg ccaaggttct tgccacccag cactcatggg 1500 ggctctctcc cctagatggc tgctcctccc acaacacagc cacagcagtg 1550 gcagccctgg gtggcttcct atacatcctg gcagaatacc ccccagcaaa 1600 cagagagcca cacccatcca caccgccacc accaagcagc cgctgagacg 1650 gacggttcca tgccagctgc ctggaggagg aacagacccc tttagtcctc 1700 atcccttaga tcctggaggg cacggatcac atcctgggaa gaaggcatct 1750 ggaggataag caaagccacc ccgacaccca atcttggaag ccctgagtag 1800 gcagggccag ggtaggtggg ggccgggagg gacccaggtg tgaacggatg 1850 aataaagttc aactgcaact gaaaaaaaaa aa 1882 134 440 PRT Homo Sapien 134 Met Ser Ala Arg Gly Arg Trp Glu Gly Gly Gly Arg Arg Ala Cys 1 5 10 15 Arg Gly Ser Leu Gly Leu Ala Arg Ala Gln Gly Ala Glu Arg Val 20 25 30 Thr Ser Ser Glu Gln Arg Pro Ala Met Ala Ser Leu Gly Leu Leu 35 40 45 Leu Leu Leu Leu Leu Thr Ala Leu Pro Pro Leu Trp Ser Ser Ser 50 55 60 Leu Pro Gly Leu Asp Thr Ala Glu Ser Lys Ala Thr Ile Ala Asp 65 70 75 Leu Ile Leu Ser Ala Leu Glu Arg Ala Thr Val Phe Leu Glu Gln 80 85 90 Arg Leu Pro Glu Ile Asn Leu Asp Gly Met Val Gly Val Arg Val 95 100 105 Leu Glu Glu Gln Leu Lys Ser Val Arg Glu Lys Trp Ala Gln Glu 110 115 120 Pro Leu Leu Gln Pro Leu Ser Leu Arg Val Gly Met Leu Gly Glu 125 130 135 Lys Leu Glu Ala Ala Ile Gln Arg Ser Leu His Tyr Leu Lys Leu 140 145 150 Ser Asp Pro Lys Tyr Leu Arg Glu Phe Gln Leu Thr Leu Gln Pro 155 160 165 Gly Phe Trp Lys Leu Pro His Ala Trp Ile His Thr Asp Ala Ser 170 175 180 Leu Val Tyr Pro Thr Phe Gly Pro Gln Asp Ser Phe Ser Glu Glu 185 190 195 Arg Ser Asp Val Cys Leu Val Gln Leu Leu Gly Thr Gly Thr Asp 200 205 210 Ser Ser Glu Pro Cys Gly Leu Ser Asp Leu Cys Arg Ser Leu Met 215 220 225 Thr Lys Pro Gly Cys Ser Gly Tyr Cys Leu Ser His Gln Leu Leu 230 235 240 Phe Phe Leu Trp Ala Arg Met Arg Gly Cys Thr Gln Gly Pro Leu 245 250 255 Gln Gln Ser Gln Asp Tyr Ile Asn Leu Phe Cys Ala Asn Met Met 260 265 270 Asp Leu Asn Arg Arg Ala Glu Ala Ile Gly Tyr Ala Tyr Pro Thr 275 280 285 Arg Asp Ile Phe Met Glu Asn Ile Met Phe Cys Gly Met Gly Gly 290 295 300 Phe Ser Asp Phe Tyr Lys Leu Arg Trp Leu Glu Ala Ile Leu Ser 305 310 315 Trp Gln Lys Gln Gln Glu Gly Cys Phe Gly Glu Pro Asp Ala Glu 320 325 330 Asp Glu Glu Leu Ser Lys Ala Ile Gln Tyr Gln Gln His Phe Ser 335 340 345 Arg Arg Val Lys Arg Arg Glu Lys Gln Phe Pro Asp Ser Arg Ser 350 355 360 Val Ala Gln Ala Gly Val Gln Trp Arg Asn Leu Gly Ser Leu Gln 365 370 375 Pro Leu Pro Pro Gly Phe Lys Gln Phe Ser Cys Leu Ile Leu Pro 380 385 390 Ser Ser Trp Asp Tyr Arg Ser Val Pro Pro Tyr Leu Ala Asn Phe 395 400 405 Tyr Ile Phe Leu Val Glu Thr Gly Phe His His Val Ala His Ala 410 415 420 Gly Leu Glu Leu Leu Ile Ser Arg Asp Pro Pro Thr Ser Gly Ser 425 430 435 Gln Ser Val Gly Leu 440 135 884 DNA Homo Sapien 135 ggtctgagtg cagagctgct gtcatggcgg ccgctctgtg gggcttcttt 50 cccgtcctgc tgctgctgct gctatcgggg gatgtccaga gctcggaggt 100 gcccggggct gctgctgagg gatcgggagg gagtggggtc ggcataggag 150 atcgcttcaa gattgagggg cgtgcagttg ttccaggggt gaagcctcag 200 gactggatct cggcggcccg agtgctggta gacggagaag agcacgtcgg 250 tttccttaag acagatggga gttttgtggt tcatgatata ccttctggat 300 cttatgtagt ggaagttgta tctccagctt acagatttga tcccgttcga 350 gtggatatca cttcgaaagg aaaaatgaga gcaagatatg tgaattacat 400 caaaacatca gaggttgtca gactgcccta tcctctccaa atgaaatctt 450 caggtccacc ttcttacttt attaaaaggg aatcgtgggg ctggacagac 500 tttctaatga acccaatggt tatgatgatg gttcttcctt tattgatatt 550 tgtgcttctg cctaaagtgg tcaacacaag tgatcctgac atgagacggg 600 aaatggagca gtcaatgaat atgctgaatt ccaaccatga gttgcctgat 650 gtttctgagt tcatgacaag actcttctct tcaaaatcat ctggcaaatc 700 tagcagcggc agcagtaaaa caggcaaaag tggggctggc aaaaggaggt 750 agtcaggccg tccagagctg gcatttgcac aaacacggca acactgggtg 800 gcatccaagt cttggaaaac cgtgtgaagc aactactata aacttgagtc 850 atcccgacgt tgatctctta caactgtgta tgtt 884 136 242 PRT Homo Sapien 136 Met Ala Ala Ala Leu Trp Gly Phe Phe Pro Val Leu Leu Leu Leu 1 5 10 15 Leu Leu Ser Gly Asp Val Gln Ser Ser Glu Val Pro Gly Ala Ala 20 25 30 Ala Glu Gly Ser Gly Gly Ser Gly Val Gly Ile Gly Asp Arg Phe 35 40 45 Lys Ile Glu Gly Arg Ala Val Val Pro Gly Val Lys Pro Gln Asp 50 55 60 Trp Ile Ser Ala Ala Arg Val Leu Val Asp Gly Glu Glu His Val 65 70 75 Gly Phe Leu Lys Thr Asp Gly Ser Phe Val Val His Asp Ile Pro 80 85 90 Ser Gly Ser Tyr Val Val Glu Val Val Ser Pro Ala Tyr Arg Phe 95 100 105 Asp Pro Val Arg Val Asp Ile Thr Ser Lys Gly Lys Met Arg Ala 110 115 120 Arg Tyr Val Asn Tyr Ile Lys Thr Ser Glu Val Val Arg Leu Pro 125 130 135 Tyr Pro Leu Gln Met Lys Ser Ser Gly Pro Pro Ser Tyr Phe Ile 140 145 150 Lys Arg Glu Ser Trp Gly Trp Thr Asp Phe Leu Met Asn Pro Met 155 160 165 Val Met Met Met Val Leu Pro Leu Leu Ile Phe Val Leu Leu Pro 170 175 180 Lys Val Val Asn Thr Ser Asp Pro Asp Met Arg Arg Glu Met Glu 185 190 195 Gln Ser Met Asn Met Leu Asn Ser Asn His Glu Leu Pro Asp Val 200 205 210 Ser Glu Phe Met Thr Arg Leu Phe Ser Ser Lys Ser Ser Gly Lys 215 220 225 Ser Ser Ser Gly Ser Ser Lys Thr Gly Lys Ser Gly Ala Gly Lys 230 235 240 Arg Arg 137 1571 DNA Homo Sapien 137 gatggcgcag ccacagcttc tgtgagattc gatttctccc cagttcccct 50 gtgggtctga ggggaccaga agggtgagct acgttggctt tctggaaggg 100 gaggctatat gcgtcaattc cccaaaacaa gttttgacat ttcccctgaa 150 atgtcattct ctatctattc actgcaagtg cctgctgttc caggccttac 200 ctgctgggca ctaacggcgg agccaggatg gggacagaat aaaggagcca 250 cgacctgtgc caccaactcg cactcagact ctgaactcag acctgaaatc 300 ttctcttcac gggaggcttg gcagtttttc ttactcctgt ggtctccaga 350 tttcaggcct aagatgaaag cctctagtct tgccttcagc cttctctctg 400 ctgcgtttta tctcctatgg actccttcca ctggactgaa gacactcaat 450 ttgggaagct gtgtgatcgc cacaaacctt caggaaatac gaaatggatt 500 ttctgagata cggggcagtg tgcaagccaa agatggaaac attgacatca 550 gaatcttaag gaggactgag tctttgcaag acacaaagcc tgcgaatcga 600 tgctgcctcc tgcgccattt gctaagactc tatctggaca gggtatttaa 650 aaactaccag acccctgacc attatactct ccggaagatc agcagcctcg 700 ccaattcctt tcttaccatc aagaaggacc tccggctctc tcatgcccac 750 atgacatgcc attgtgggga ggaagcaatg aagaaataca gccagattct 800 gagtcacttt gaaaagctgg aacctcaggc agcagttgtg aaggctttgg 850 gggaactaga cattcttctg caatggatgg aggagacaga ataggaggaa 900 agtgatgctg ctgctaagaa tattcgaggt caagagctcc agtcttcaat 950 acctgcagag gaggcatgac cccaaaccac catctcttta ctgtactagt 1000 cttgtgctgg tcacagtgta tcttatttat gcattacttg cttccttgca 1050 tgattgtctt tatgcatccc caatcttaat tgagaccata cttgtataag 1100 atttttgtaa tatctttctg ctattggata tatttattag ttaatatatt 1150 tatttatttt ttgctattta atgtatttat ttttttactt ggacatgaaa 1200 ctttaaaaaa attcacagat tatatttata acctgactag agcaggtgat 1250 gtatttttat acagtaaaaa aaaaaaacct tgtaaattct agaagagtgg 1300 ctaggggggt tattcatttg tattcaacta aggacatatt tactcatgct 1350 gatgctctgt gagatatttg aaattgaacc aatgactact taggatgggt 1400 tgtggaataa gttttgatgt ggaattgcac atctacctta caattactga 1450 ccatccccag tagactcccc agtcccataa ttgtgtatct tccagccagg 1500 aatcctacac ggccagcatg tatttctaca aataaagttt tctttgcata 1550 ccaaaaaaaa aaaaaaaaaa a 1571 138 261 PRT Homo Sapien 138 Met Arg Gln Phe Pro Lys Thr Ser Phe Asp Ile Ser Pro Glu Met 1 5 10 15 Ser Phe Ser Ile Tyr Ser Leu Gln Val Pro Ala Val Pro Gly Leu 20 25 30 Thr Cys Trp Ala Leu Thr Ala Glu Pro Gly Trp Gly Gln Asn Lys 35 40 45 Gly Ala Thr Thr Cys Ala Thr Asn Ser His Ser Asp Ser Glu Leu 50 55 60 Arg Pro Glu Ile Phe Ser Ser Arg Glu Ala Trp Gln Phe Phe Leu 65 70 75 Leu Leu Trp Ser Pro Asp Phe Arg Pro Lys Met Lys Ala Ser Ser 80 85 90 Leu Ala Phe Ser Leu Leu Ser Ala Ala Phe Tyr Leu Leu Trp Thr 95 100 105 Pro Ser Thr Gly Leu Lys Thr Leu Asn Leu Gly Ser Cys Val Ile 110 115 120 Ala Thr Asn Leu Gln Glu Ile Arg Asn Gly Phe Ser Glu Ile Arg 125 130 135 Gly Ser Val Gln Ala Lys Asp Gly Asn Ile Asp Ile Arg Ile Leu 140 145 150 Arg Arg Thr Glu Ser Leu Gln Asp Thr Lys Pro Ala Asn Arg Cys 155 160 165 Cys Leu Leu Arg His Leu Leu Arg Leu Tyr Leu Asp Arg Val Phe 170 175 180 Lys Asn Tyr Gln Thr Pro Asp His Tyr Thr Leu Arg Lys Ile Ser 185 190 195 Ser Leu Ala Asn Ser Phe Leu Thr Ile Lys Lys Asp Leu Arg Leu 200 205 210 Ser His Ala His Met Thr Cys His Cys Gly Glu Glu Ala Met Lys 215 220 225 Lys Tyr Ser Gln Ile Leu Ser His Phe Glu Lys Leu Glu Pro Gln 230 235 240 Ala Ala Val Val Lys Ala Leu Gly Glu Leu Asp Ile Leu Leu Gln 245 250 255 Trp Met Glu Glu Thr Glu 260 139 2395 DNA Homo Sapien 139 cctggagccg gaagcgcggc tgcagcaggg cgaggctcca ggtggggtcg 50 gttccgcatc cagcctagcg tgtccacgat gcggctgggc tccgggactt 100 tcgctacctg ttgcgtagcg atcgaggtgc tagggatcgc ggtcttcctt 150 cggggattct tcccggctcc cgttcgttcc tctgccagag cggaacacgg 200 agcggagccc ccagcgcccg aaccctcggc tggagccagt tctaactgga 250 ccacgctgcc accacctctc ttcagtaaag ttgttattgt tctgatagat 300 gccttgagag atgattttgt gtttgggtca aagggtgtga aatttatgcc 350 ctacacaact taccttgtgg aaaaaggagc atctcacagt tttgtggctg 400 aagcaaagcc acctacagtt actatgcctc gaatcaaggc attgatgacg 450 gggagccttc ctggctttgt cgacgtcatc aggaacctca attctcctgc 500 actgctggaa gacagtgtga taagacaagc aaaagcagct ggaaaaagaa 550 tagtctttta tggagatgaa acctgggtta aattattccc aaagcatttt 600 gtggaatatg atggaacaac ctcatttttc gtgtcagatt acacagaggt 650 ggataataat gtcacgaggc atttggataa agtattaaaa agaggagatt 700 gggacatatt aatcctccac tacctggggc tggaccacat tggccacatt 750 tcagggccca acagccccct gattgggcag aagctgagcg agatggacag 800 cgtgctgatg aagatccaca cctcactgca gtcgaaggag agagagacgc 850 ctttacccaa tttgctggtt ctttgtggtg accatggcat gtctgaaaca 900 ggaagtcacg gggcctcctc caccgaggag gtgaatacac ctctgatttt 950 aatcagttct gcgtttgaaa ggaaacccgg tgatatccga catccaaagc 1000 acgtccaata gacggatgtg gctgcgacac tggcgatagc acttggctta 1050 ccgattccaa aagacagtgt agggagcctc ctattcccag ttgtggaagg 1100 aagaccaatg agagagcagt tgagattttt acatttgaat acagtgcagc 1150 ttagtaaact gttgcaagag aatgtgccgt catatgaaaa agatcctggg 1200 tttgagcagt ttaaaatgtc agaaagattg catgggaact ggatcagact 1250 gtacttggag gaaaagcatt cagaagtcct attcaacctg ggctccaagg 1300 ttctcaggca gtacctggat gctctgaaga cgctgagctt gtccctgagt 1350 gcacaagtgg cccagttctc accctgctcc tgctcagcgt cccacaggca 1400 ctgcacagaa aggctgagct ggaagtccca ctgtcatctc ctgggttttc 1450 tctgctcttt tatttggtga tcctggttct ttcggccgtt cacgtcattg 1500 tgtgcacctc agctgaaagt tcgtgctact tctgtggcct ctcgtggctg 1550 gcggcaggct gcctttcgtt taccagactc tggttgaaca cctggtgtgt 1600 gccaagtgct ggcagtgccc tggacagggg gcctcaggga aggacgtgga 1650 gcagccttat cccaggcctc tgggtgtccc gacacaggtg ttcacatctg 1700 tgctgtcagg tcagatgcct cagttcttgg aaagctaggt tcctgcgact 1750 gttaccaagg tgattgtaaa gagctggcgg tcacagagga acaagccccc 1800 cagctgaggg ggtgtgtgaa tcggacagcc tcccagcaga ggtgtgggag 1850 ctgcagctga gggaagaaga gacaatcggc ctggacactc aggagggtca 1900 aaaggagact tggtcgcacc actcatcctg ccacccccag aatgcatcct 1950 gcctcatcag gtccagattt ctttccaagg cggacgtttt ctgttggaat 2000 tcttagtcct tggcctcgga caccttcatt cgttagctgg ggagtggtgg 2050 tgaggcagtg aagaagaggc ggatggtcac actcagatcc acagagccca 2100 ggatcaaggg acccactgca gtggcagcag gactgttggg cccccacccc 2150 aaccctgcac agccctcatc ccctcttggc ttgagccgtc agaggccctg 2200 tgctgagtgt ctgaccgaga cactcacagc tttgtcatca gggcacaggc 2250 ttcctcggag ccaggatgat ctgtgccacg cttgcacctc gggcccatct 2300 gggctcatgc tctctctcct gctattgaat tagtacctag ctgcacacag 2350 tatgtagtta ccaaaagaat aaacggcaat aattgagaaa aaaaa 2395 140 310 PRT Homo Sapien 140 Met Arg Leu Gly Ser Gly Thr Phe Ala Thr Cys Cys Val Ala Ile 1 5 10 15 Glu Val Leu Gly Ile Ala Val Phe Leu Arg Gly Phe Phe Pro Ala 20 25 30 Pro Val Arg Ser Ser Ala Arg Ala Glu His Gly Ala Glu Pro Pro 35 40 45 Ala Pro Glu Pro Ser Ala Gly Ala Ser Ser Asn Trp Thr Thr Leu 50 55 60 Pro Pro Pro Leu Phe Ser Lys Val Val Ile Val Leu Ile Asp Ala 65 70 75 Leu Arg Asp Asp Phe Val Phe Gly Ser Lys Gly Val Lys Phe Met 80 85 90 Pro Tyr Thr Thr Tyr Leu Val Glu Lys Gly Ala Ser His Ser Phe 95 100 105 Val Ala Glu Ala Lys Pro Pro Thr Val Thr Met Pro Arg Ile Lys 110 115 120 Ala Leu Met Thr Gly Ser Leu Pro Gly Phe Val Asp Val Ile Arg 125 130 135 Asn Leu Asn Ser Pro Ala Leu Leu Glu Asp Ser Val Ile Arg Gln 140 145 150 Ala Lys Ala Ala Gly Lys Arg Ile Val Phe Tyr Gly Asp Glu Thr 155 160 165 Trp Val Lys Leu Phe Pro Lys His Phe Val Glu Tyr Asp Gly Thr 170 175 180 Thr Ser Phe Phe Val Ser Asp Tyr Thr Glu Val Asp Asn Asn Val 185 190 195 Thr Arg His Leu Asp Lys Val Leu Lys Arg Gly Asp Trp Asp Ile 200 205 210 Leu Ile Leu His Tyr Leu Gly Leu Asp His Ile Gly His Ile Ser 215 220 225 Gly Pro Asn Ser Pro Leu Ile Gly Gln Lys Leu Ser Glu Met Asp 230 235 240 Ser Val Leu Met Lys Ile His Thr Ser Leu Gln Ser Lys Glu Arg 245 250 255 Glu Thr Pro Leu Pro Asn Leu Leu Val Leu Cys Gly Asp His Gly 260 265 270 Met Ser Glu Thr Gly Ser His Gly Ala Ser Ser Thr Glu Glu Val 275 280 285 Asn Thr Pro Leu Ile Leu Ile Ser Ser Ala Phe Glu Arg Lys Pro 290 295 300 Gly Asp Ile Arg His Pro Lys His Val Gln 305 310 141 754 DNA Homo Sapien 141 ggcacgaggc aagccttcca ggttatcgtg acgcaccttg aaagtctgag 50 agctactgcc ctacagaaag ttactagtgc cctaaagctg gcgctggcac 100 tgatgttact gctgctgttg gagtacaact tccctataga aaacaactgc 150 cagcacctta agaccactca caccttcaga gtgaagaact taaacccgaa 200 gaaattcagc attcatgacc aggatcacaa agtactggtc ctggactctg 250 ggaatctcat agcagttcca gataaaaact acatacgccc agagatcttc 300 tttgcattag cctcatcctt gagctcagcc tctgcggaga aaggaagtcc 350 gattctcctg ggggtctcta aaggggagtt ttgtctctac tgtgacaagg 400 ataaaggaca aagtcatcca tcccttcagc tgaagaagga gaaactgatg 450 aagctggctg cccaaaagga atcagcacgc cggcccttca tcttttatag 500 ggctcaggtg ggctcctgga acatgctgga gtcggcggct caccccggat 550 ggttcatctg cacctcctgc aattgtaatg agcctgttgg ggtgacagat 600 aaatttgaga acaggaaaca cattgaattt tcatttcaac cagtttgcaa 650 agctgaaatg agccccagtg aggtcagcga ttaggaaact gccccattga 700 acgccttcct cgctaatttg aactaattgt ataaaaacac caaacctgct 750 cact 754 142 193 PRT Homo Sapien 142 Met Leu Leu Leu Leu Leu Glu Tyr Asn Phe Pro Ile Glu Asn Asn 1 5 10 15 Cys Gln His Leu Lys Thr Thr His Thr Phe Arg Val Lys Asn Leu 20 25 30 Asn Pro Lys Lys Phe Ser Ile His Asp Gln Asp His Lys Val Leu 35 40 45 Val Leu Asp Ser Gly Asn Leu Ile Ala Val Pro Asp Lys Asn Tyr 50 55 60 Ile Arg Pro Glu Ile Phe Phe Ala Leu Ala Ser Ser Leu Ser Ser 65 70 75 Ala Ser Ala Glu Lys Gly Ser Pro Ile Leu Leu Gly Val Ser Lys 80 85 90 Gly Glu Phe Cys Leu Tyr Cys Asp Lys Asp Lys Gly Gln Ser His 95 100 105 Pro Ser Leu Gln Leu Lys Lys Glu Lys Leu Met Lys Leu Ala Ala 110 115 120 Gln Lys Glu Ser Ala Arg Arg Pro Phe Ile Phe Tyr Arg Ala Gln 125 130 135 Val Gly Ser Trp Asn Met Leu Glu Ser Ala Ala His Pro Gly Trp 140 145 150 Phe Ile Cys Thr Ser Cys Asn Cys Asn Glu Pro Val Gly Val Thr 155 160 165 Asp Lys Phe Glu Asn Arg Lys His Ile Glu Phe Ser Phe Gln Pro 170 175 180 Val Cys Lys Ala Glu Met Ser Pro Ser Glu Val Ser Asp 185 190 143 961 DNA Homo Sapien 143 ctagagagta tagggcagaa ggatggcaga tgagtgactc cacatccaga 50 gctgcctccc tttaatccag gatcctgtcc ttcctgtcct gtaggagtgc 100 ctgttgccag tgtggggtga gacaagtttg tcccacaggg ctgtctgagc 150 agataagatt aagggctggg tctgtgctca attaactcct gtgggcacgg 200 gggctgggaa gagcaaagtc agcggtgcct acagtcagca ccatgctggg 250 cctgccgtgg aagggaggtc tgtcctgggc gctgctgctg cttctcttag 300 gctcccagat cctgctgatc tatgcctggc atttccacga gcaaagggac 350 tgtgatgaac acaatgtcat ggctcgttac ctccctgcca cagtggagtt 400 tgctgtccac acattcaacc aacagagcaa ggactactat gcctacagac 450 tggggcacat cttgaattcc tggaaggagc aggtggagtc caagactgta 500 ttctcaatgg agctactgct ggggagaact aggtgtggga aatttgaaga 550 cgacattgac aactgccatt tccaagaaag cacagagctg aacaatactt 600 tcacctgctt cttcaccatc agcaccaggc cctggatgac tcagttcagc 650 ctcctgaaca agacctgctt ggagggattc cactgagtga aacccactca 700 caggcttgtc catgtgctgc tcccacattc cgtggacatc agcactactc 750 tcctgaggac tcttcagtgg ctgagcagct ttggacttgt ttgttatcct 800 attttgcatg tgtttgagat ctcagatcag tgttttagaa aatccacaca 850 tcttgagcct aatcatgtag tgtagatcat taaacatcag cattttaaga 900 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 950 aaaaaaaaaa a 961 144 147 PRT Homo Sapien 144 Met Leu Gly Leu Pro Trp Lys Gly Gly Leu Ser Trp Ala Leu Leu 1 5 10 15 Leu Leu Leu Leu Gly Ser Gln Ile Leu Leu Ile Tyr Ala Trp His 20 25 30 Phe His Glu Gln Arg Asp Cys Asp Glu His Asn Val Met Ala Arg 35 40 45 Tyr Leu Pro Ala Thr Val Glu Phe Ala Val His Thr Phe Asn Gln 50 55 60 Gln Ser Lys Asp Tyr Tyr Ala Tyr Arg Leu Gly His Ile Leu Asn 65 70 75 Ser Trp Lys Glu Gln Val Glu Ser Lys Thr Val Phe Ser Met Glu 80 85 90 Leu Leu Leu Gly Arg Thr Arg Cys Gly Lys Phe Glu Asp Asp Ile 95 100 105 Asp Asn Cys His Phe Gln Glu Ser Thr Glu Leu Asn Asn Thr Phe 110 115 120 Thr Cys Phe Phe Thr Ile Ser Thr Arg Pro Trp Met Thr Gln Phe 125 130 135 Ser Leu Leu Asn Lys Thr Cys Leu Glu Gly Phe His 140 145 145 1157 DNA Homo Sapien 145 ctgtgcagct cgaggctcca gaggcacact ccagagagag ccaaggttct 50 gacgcgatga ggaagcacct gagctggtgg tggctggcca ctgtctgcat 100 gctgctcttc agccacctct ctgcggtcca gacgaggggc atcaagcaca 150 gaatcaagtg gaaccggaag gccctgccca gcactgccca gatcactgag 200 gcccaggtgg ctgagaaccg cccgggagcc ttcatcaagc aaggccgcaa 250 gctcgacatt gacttcggag ccgagggcaa caggtactac gaggccaact 300 actggcagtt ccccgatggc atccactaca acggctgctc tgaggctaat 350 gtgaccaagg aggcatttgt caccggctgc atcaatgcca cccaggcggc 400 gaaccagggg gagttccaga agccagacaa caagctccac cagcaggtgc 450 tctggcggct ggtccaggag ctctgctccc tcaagcattg cgagttttgg 500 ttggagaggg gcgcaggact tcgggtcacc atgcaccagc cagtgctcct 550 ctgccttctg gctttgatct ggctcatggt gaaataagct tgccaggagg 600 ctggcagtac agagcgcagc agcgagcaaa tcctggcaag tgacccagct 650 cttctccccc aaacccacgc gtgttctgaa ggtgcccagg agcggcgatg 700 cactcgcact gcaaatgccg ctcccacgta tgcgccctgg tatgtgcctg 750 cgttctgata gatgggggac tgtggcttct ccgtcactcc attctcagcc 800 cctagcagag cgtctggcac actagattag tagtaaatgc ttgatgagaa 850 gaacacatca ggcactgcgc cacctgcttc acagtacttc ccaacaactc 900 ttagaggtag gtgtattccc gttttacaga taaggaaact gaggcccaga 950 gagctgaagt actgcaccca gcatcaccag ctagaaagtg gcagagccag 1000 gattcaaccc tggcttgtct aaccccaggt tttctgctct gtccaattcc 1050 agagctgtct ggtgatcact ttatgtctca cagggaccca catccaaaca 1100 tgtatctcta atgaaattgt gaaagctcca tgtttagaaa taaatgaaaa 1150 cacctga 1157 146 176 PRT Homo Sapien 146 Met Arg Lys His Leu Ser Trp Trp Trp Leu Ala Thr Val Cys Met 1 5 10 15 Leu Leu Phe Ser His Leu Ser Ala Val Gln Thr Arg Gly Ile Lys 20 25 30 His Arg Ile Lys Trp Asn Arg Lys Ala Leu Pro Ser Thr Ala Gln 35 40 45 Ile Thr Glu Ala Gln Val Ala Glu Asn Arg Pro Gly Ala Phe Ile 50 55 60 Lys Gln Gly Arg Lys Leu Asp Ile Asp Phe Gly Ala Glu Gly Asn 65 70 75 Arg Tyr Tyr Glu Ala Asn Tyr Trp Gln Phe Pro Asp Gly Ile His 80 85 90 Tyr Asn Gly Cys Ser Glu Ala Asn Val Thr Lys Glu Ala Phe Val 95 100 105 Thr Gly Cys Ile Asn Ala Thr Gln Ala Ala Asn Gln Gly Glu Phe 110 115 120 Gln Lys Pro Asp Asn Lys Leu His Gln Gln Val Leu Trp Arg Leu 125 130 135 Val Gln Glu Leu Cys Ser Leu Lys His Cys Glu Phe Trp Leu Glu 140 145 150 Arg Gly Ala Gly Leu Arg Val Thr Met His Gln Pro Val Leu Leu 155 160 165 Cys Leu Leu Ala Leu Ile Trp Leu Met Val Lys 170 175 147 333 DNA Homo Sapien 147 gccttggcct cccaaagggc tgggattata ggcgtgacca ccatgtctgg 50 tccagagtct catttcctga tgatttatag actcaaagaa aactcatgtt 100 cagaagctct cttctcttct ggcctcctct ctgtcttctt tccctctttc 150 ttcttatttt aattagtagc atctactcag agtcatgcaa gctggaaatc 200 tttcattttg cttgtcagtg gggtaggtca ctgagtctta gtttttattt 250 tttgaaattt caactttcag attcaggggg tacatgtgaa ggtttgtttt 300 atgagtatat tgcatgatgc tgaggtttgg ggt 333 148 73 PRT Homo Sapien 148 Met Phe Arg Ser Ser Leu Leu Phe Trp Pro Pro Leu Cys Leu Leu 1 5 10 15 Ser Leu Phe Leu Leu Ile Leu Ile Ser Ser Ile Tyr Ser Glu Ser 20 25 30 Cys Lys Leu Glu Ile Phe His Phe Ala Cys Gln Trp Gly Arg Ser 35 40 45 Leu Ser Leu Ser Phe Tyr Phe Leu Lys Phe Gln Leu Ser Asp Ser 50 55 60 Gly Gly Thr Cys Glu Gly Leu Phe Tyr Glu Tyr Ile Ala 65 70 149 1893 DNA Homo Sapien 149 gtctccgcgt cacaggaact tcagcaccca cagggcggac agcgctcccc 50 tctacctgga gacttgactc ccgcgcgccc caaccctgct tatcccttga 100 ccgtcgagtg tcagagatcc tgcagccgcc cagtcccggc ccctctcccg 150 ccccacaccc accctcctgg ctcttcctgt ttttactcct ccttttcatt 200 cataacaaaa gctacagctc caggagccca gcgccgggct gtgacccaag 250 ccgagcgtgg aagaatgggg ttcctcggga ccggcacttg gattctggtg 300 ttagtgctcc cgattcaagc tttccccaaa cctggaggaa gccaagacaa 350 atctctacat aatagagaat taagtgcaga aagacctttg aatgaacaga 400 ttgctgaagc agaagaagac aagattaaaa aaacatatcc tccagaaaac 450 aagccaggtc agagcaacta ttcttttgtt gataacttga acctgctaaa 500 ggcaataaca gaaaaggaaa aaattgagaa agaaagacaa tctataagaa 550 gctccccact tgataataag ttgaatgtgg aagatgttga ttcaaccaag 600 aatcgaaaac tgatcgatga ttatgactct actaagagtg gattggatca 650 taaatttcaa gatgatccag atggtcttca tcaactagac gggactcctt 700 taaccgctga agacattgtc cataaaatcg ctgccaggat ttatgaagaa 750 aatgacagag ccgtgtttga caagattgtt tctaaactac ttaatctcgg 800 ccttatcaca gaaagccaag cacatacact ggaagatgaa gtagcagagg 850 ttttacaaaa attaatctca aaggaagcca acaattatga ggaggatccc 900 aataagccca caagctggac tgagaatcag gctggaaaaa taccagagaa 950 agtgactcca atggcagcaa ttcaagatgg tcttgctaag ggagaaaacg 1000 atgaaacagt atctaacaca ttaaccttga caaatggctt ggaaaggaga 1050 actaaaacct acagtgaaga caactttgag gaactccaat atttcccaaa 1100 tttctatgcg ctactgaaaa gtattgattc agaaaaagaa gcaaaagaga 1150 aagaaacact gattactatc atgaaaacac tgattgactt tgtgaagatg 1200 atggtgaaat atggaacaat atctccagaa gaaggtgttt cctaccttga 1250 aaacttggat gaaatgattg ctcttcagac caaaaacaag ctagaaaaaa 1300 atgctactga caatataagc aagcttttcc cagcaccatc agagaagagt 1350 catgaagaaa cagacagtac caaggaagaa gcagctaaga tggaaaagga 1400 atatggaagc ttgaaggatt ccacaaaaga tgataactcc aacccaggag 1450 gaaagacaga tgaacccaaa ggaaaaacag aagcctattt ggaagccatc 1500 agaaaaaata ttgaatggtt gaagaaacat gacaaaaagg gaaataaaga 1550 agattatgac ctttcaaaga tgagagactt catcaataaa caagctgatg 1600 cttatgtgga gaaaggcatc cttgacaagg aagaagccga ggccatcaag 1650 cgcatttata gcagcctgta aaaatggcaa aagatccagg agtctttcaa 1700 ctgtttcaga aaacataata tagcttaaaa cacttctaat tctgtgatta 1750 aaattttttg acccaagggt tattagaaag tgctgaattt acagtagtta 1800 accttttaca agtggttaaa acatagcttt cttcccgtaa aaactatctg 1850 aaagtaaagt tgtatgtaag ctgaaaaaaa aaaaaaaaaa aaa 1893 150 468 PRT Homo Sapien 150 Met Gly Phe Leu Gly Thr Gly Thr Trp Ile Leu Val Leu Val Leu 1 5 10 15 Pro Ile Gln Ala Phe Pro Lys Pro Gly Gly Ser Gln Asp Lys Ser 20 25 30 Leu His Asn Arg Glu Leu Ser Ala Glu Arg Pro Leu Asn Glu Gln 35 40 45 Ile Ala Glu Ala Glu Glu Asp Lys Ile Lys Lys Thr Tyr Pro Pro 50 55 60 Glu Asn Lys Pro Gly Gln Ser Asn Tyr Ser Phe Val Asp Asn Leu 65 70 75 Asn Leu Leu Lys Ala Ile Thr Glu Lys Glu Lys Ile Glu Lys Glu 80 85 90 Arg Gln Ser Ile Arg Ser Ser Pro Leu Asp Asn Lys Leu Asn Val 95 100 105 Glu Asp Val Asp Ser Thr Lys Asn Arg Lys Leu Ile Asp Asp Tyr 110 115 120 Asp Ser Thr Lys Ser Gly Leu Asp His Lys Phe Gln Asp Asp Pro 125 130 135 Asp Gly Leu His Gln Leu Asp Gly Thr Pro Leu Thr Ala Glu Asp 140 145 150 Ile Val His Lys Ile Ala Ala Arg Ile Tyr Glu Glu Asn Asp Arg 155 160 165 Ala Val Phe Asp Lys Ile Val Ser Lys Leu Leu Asn Leu Gly Leu 170 175 180 Ile Thr Glu Ser Gln Ala His Thr Leu Glu Asp Glu Val Ala Glu 185 190 195 Val Leu Gln Lys Leu Ile Ser Lys Glu Ala Asn Asn Tyr Glu Glu 200 205 210 Asp Pro Asn Lys Pro Thr Ser Trp Thr Glu Asn Gln Ala Gly Lys 215 220 225 Ile Pro Glu Lys Val Thr Pro Met Ala Ala Ile Gln Asp Gly Leu 230 235 240 Ala Lys Gly Glu Asn Asp Glu Thr Val Ser Asn Thr Leu Thr Leu 245 250 255 Thr Asn Gly Leu Glu Arg Arg Thr Lys Thr Tyr Ser Glu Asp Asn 260 265 270 Phe Glu Glu Leu Gln Tyr Phe Pro Asn Phe Tyr Ala Leu Leu Lys 275 280 285 Ser Ile Asp Ser Glu Lys Glu Ala Lys Glu Lys Glu Thr Leu Ile 290 295 300 Thr Ile Met Lys Thr Leu Ile Asp Phe Val Lys Met Met Val Lys 305 310 315 Tyr Gly Thr Ile Ser Pro Glu Glu Gly Val Ser Tyr Leu Glu Asn 320 325 330 Leu Asp Glu Met Ile Ala Leu Gln Thr Lys Asn Lys Leu Glu Lys 335 340 345 Asn Ala Thr Asp Asn Ile Ser Lys Leu Phe Pro Ala Pro Ser Glu 350 355 360 Lys Ser His Glu Glu Thr Asp Ser Thr Lys Glu Glu Ala Ala Lys 365 370 375 Met Glu Lys Glu Tyr Gly Ser Leu Lys Asp Ser Thr Lys Asp Asp 380 385 390 Asn Ser Asn Pro Gly Gly Lys Thr Asp Glu Pro Lys Gly Lys Thr 395 400 405 Glu Ala Tyr Leu Glu Ala Ile Arg Lys Asn Ile Glu Trp Leu Lys 410 415 420 Lys His Asp Lys Lys Gly Asn Lys Glu Asp Tyr Asp Leu Ser Lys 425 430 435 Met Arg Asp Phe Ile Asn Lys Gln Ala Asp Ala Tyr Val Glu Lys 440 445 450 Gly Ile Leu Asp Lys Glu Glu Ala Glu Ala Ile Lys Arg Ile Tyr 455 460 465 Ser Ser Leu 151 2598 DNA Homo Sapien 151 cggctcgagg ctcccgccag gagaaaggaa cattctgagg ggagtctaca 50 ccctgtggag ctcaagatgg tcctgagtgg ggcgctgtgc ttccgaatga 100 aggactcggc attgaaggtg ctttatctgc ataataacca gcttctagct 150 ggagggctgc atgcagggaa ggtcattaaa ggtgaagaga tcagcgtggt 200 ccccaatcgg tggctggatg ccagcctgtc ccccgtcatc ctgggtgtcc 250 agggtggaag ccagtgcctg tcatgtgggg tggggcagga gccgactcta 300 acactagagc cagtgaacat catggagctc tatcttggtg ccaaggaatc 350 caagagcttc accttctacc ggcgggacat ggggctcacc tccagcttcg 400 agtcggctgc ctacccgggc tggttcctgt gcacggtgcc tgaagccgat 450 cagcctgtca gactcaccca gcttcccgag aatggtggct ggaatgcccc 500 catcacagac ttctacttcc agcagtgtga ctagggcaac gtgcccccca 550 gaactccctg ggcagagcca gctcgggtga ggggtgagtg gaggagaccc 600 atggcggaca atcactctct ctgctctcag gacccccacg tctgacttag 650 tgggcacctg accactttgt cttctggttc ccagtttgga taaattctga 700 gatttggagc tcagtccacg gtcctccccc actggatggt gctactgctg 750 tggaaccttg taaaaaccat gtggggtaaa ctgggaataa catgaaaaga 800 tttctgtggg ggtggggtgg gggagtggtg ggaatcattc ctgcttaatg 850 gtaactgaca agtgttaccc tgagccccgc aggccaaccc atccccagtt 900 gagccttata gggtcagtag ctctccacat gaagtcctgt cactcaccac 950 tgtgcaggag agggaggtgg tcatagagtc agggatctat ggcccttggc 1000 ccagccccac ccccttccct ttaatcctgc cactgtcata tgctaccttt 1050 cctatctctt ccctcatcat cttgttgtgg gcatgaggag gtggtgatgt 1100 cagaagaaat ggctcgagct cagaagataa aagataagta gggtatgctg 1150 atcctctttt aaaaacccaa gatacaatca aaatcccaga tgctggtctc 1200 tattcccatg aaaaagtgct catgacatat tgagaagacc tacttacaaa 1250 gtggcatata ttgcaattta ttttaattaa aagataccta tttatatatt 1300 tctttataga aaaaagtctg gaagagttta cttcaattgt agcaatgtca 1350 gggtggtggc agtataggtg atttttcttt taattctgtt aatttatctg 1400 tatttcctaa tttttctaca atgaagatga attccttgta taaaaataag 1450 aaaagaaatt aatcttgagg taagcagagc agacatcatc tctgattgtc 1500 ctcagcctcc acttccccag agtaaattca aattgaatcg agctctgctg 1550 ctctggttgg ttgtagtagt gatcaggaaa cagatctcag caaagccact 1600 gaggaggagg ctgtgctgag tttgtgtggc tggaatctct gggtaaggaa 1650 cttaaagaac aaaaatcatc tggtaattct ttcctagaag gatcacagcc 1700 cctgggattc caaggcattg gatccagtct ctaagaaggc tgctgtactg 1750 gttgaattgt gtccccctca aattcacatc cttcttggaa tctcagtctg 1800 tgagtttatt tggagataag gtctctgcag atgtagttag ttaagacaag 1850 gtcatgctgg atgaaggtag acctaaattc aatatgactg gtttccttgt 1900 atgaaaagga gaggacacag agacagagga gacgcgggga agactatgta 1950 aagatgaagg cagagatcgg agttttgcag ccacaagcta agaaacacca 2000 aggattgtgg caaccatcag aagcttggaa gaggcaaaga agaattcttc 2050 cctagaggct ttagagggat aacggctctg ctgaaacctt aatctcagac 2100 ttccagcctc ctgaacgaag aaagaataaa tttcggctgt tttaagccac 2150 caaggataat tggttacagc agctctagga aactaataca gctgctaaaa 2200 tgatccctgt ctcctcgtgt ttacattctg tgtgtgtccc ctcccacaat 2250 gtaccaaagt tgtctttgtg accaatagaa tatggcagaa gtgatggcat 2300 gccacttcca agattaggtt ataaaagaca ctgcagcttc tacttgagcc 2350 ctctctctct gccacccacc gcccccaatc tatcttggct cactcgctct 2400 gggggaagct agctgccatg ctatgagcag gcctataaag agacttacgt 2450 ggtaaaaaat gaagtctcct gcccacagcc acattagtga acctagaagc 2500 agagactctg tgagataatc gatgtttgtt gttttaagtt gctcagtttt 2550 ggtctaactt gttatgcagc aatagataaa taatatgcag agaaagag 2598 152 155 PRT Homo Sapien 152 Met Val Leu Ser Gly Ala Leu Cys Phe Arg Met Lys Asp Ser Ala 1 5 10 15 Leu Lys Val Leu Tyr Leu His Asn Asn Gln Leu Leu Ala Gly Gly 20 25 30 Leu His Ala Gly Lys Val Ile Lys Gly Glu Glu Ile Ser Val Val 35 40 45 Pro Asn Arg Trp Leu Asp Ala Ser Leu Ser Pro Val Ile Leu Gly 50 55 60 Val Gln Gly Gly Ser Gln Cys Leu Ser Cys Gly Val Gly Gln Glu 65 70 75 Pro Thr Leu Thr Leu Glu Pro Val Asn Ile Met Glu Leu Tyr Leu 80 85 90 Gly Ala Lys Glu Ser Lys Ser Phe Thr Phe Tyr Arg Arg Asp Met 95 100 105 Gly Leu Thr Ser Ser Phe Glu Ser Ala Ala Tyr Pro Gly Trp Phe 110 115 120 Leu Cys Thr Val Pro Glu Ala Asp Gln Pro Val Arg Leu Thr Gln 125 130 135 Leu Pro Glu Asn Gly Gly Trp Asn Ala Pro Ile Thr Asp Phe Tyr 140 145 150 Phe Gln Gln Cys Asp 155 153 1152 DNA Homo Sapien 153 cttcagaaca ggttctcctt ccccagtcac cagttgctcg agttagaatt 50 gtctgcaatg gccgccctgc agaaatctgt gagctctttc cttatgggga 100 ccctggccac cagctgcctc cttctcttgg ccctcttggt acagggagga 150 gcagctgcgc ccatcagctc ccactgcagg cttgacaagt ccaacttcca 200 gcagccctat atcaccaacc gcaccttcat gctggctaag gaggctagct 250 tggctgataa caacacagac gttcgtctca ttggggagaa actgttccac 300 ggagtcagta tgagtgagcg ctgctatctg atgaagcagg tgctgaactt 350 cacccttgaa gaagtgctgt tccctcaatc tgataggttc cagccttata 400 tgcaggaggt ggtgcccttc ctggccaggc tcagcaacag gctaagcaca 450 tgtcatattg aaggtgatga cctgcatatc cagaggaatg tgcaaaagct 500 gaaggacaca gtgaaaaagc ttggagagag tggagagatc aaagcaattg 550 gagaactgga tttgctgttt atgtctctga gaaatgcctg catttgacca 600 gagcaaagct gaaaaatgaa taactaaccc cctttccctg ctagaaataa 650 caattagatg ccccaaagcg atttttttta accaaaagga agatgggaag 700 ccaaactcca tcatgatggg tggattccaa atgaacccct gcgttagtta 750 caaaggaaac caatgccact tttgtttata agaccagaag gtagactttc 800 taagcataga tatttattga taacatttca ttgtaactgg tgttctatac 850 acagaaaaca atttattttt taaataattg tctttttcca taaaaaagat 900 tactttccat tcctttaggg gaaaaaaccc ctaaatagct tcatgtttcc 950 ataatcagta ctttatattt ataaatgtat ttattattat tataagactg 1000 cattttattt atatcatttt attaatatgg atttatttat agaaacatca 1050 ttcgatattg ctacttgagt gtaaggctaa tattgatatt tatgacaata 1100 attatagagc tataacatgt ttatttgacc tcaataaaca cttggatatc 1150 cc 1152 154 179 PRT Homo Sapien 154 Met Ala Ala Leu Gln Lys Ser Val Ser Ser Phe Leu Met Gly Thr 1 5 10 15 Leu Ala Thr Ser Cys Leu Leu Leu Leu Ala Leu Leu Val Gln Gly 20 25 30 Gly Ala Ala Ala Pro Ile Ser Ser His Cys Arg Leu Asp Lys Ser 35 40 45 Asn Phe Gln Gln Pro Tyr Ile Thr Asn Arg Thr Phe Met Leu Ala 50 55 60 Lys Glu Ala Ser Leu Ala Asp Asn Asn Thr Asp Val Arg Leu Ile 65 70 75 Gly Glu Lys Leu Phe His Gly Val Ser Met Ser Glu Arg Cys Tyr 80 85 90 Leu Met Lys Gln Val Leu Asn Phe Thr Leu Glu Glu Val Leu Phe 95 100 105 Pro Gln Ser Asp Arg Phe Gln Pro Tyr Met Gln Glu Val Val Pro 110 115 120 Phe Leu Ala Arg Leu Ser Asn Arg Leu Ser Thr Cys His Ile Glu 125 130 135 Gly Asp Asp Leu His Ile Gln Arg Asn Val Gln Lys Leu Lys Asp 140 145 150 Thr Val Lys Lys Leu Gly Glu Ser Gly Glu Ile Lys Ala Ile Gly 155 160 165 Glu Leu Asp Leu Leu Phe Met Ser Leu Arg Asn Ala Cys Ile 170 175 155 1320 DNA Homo Sapien 155 ggcttgctga aaataaaatc aggactccta acctgctcca gtcagcctgc 50 ttccacgagg cctgtcagtc agtgcccgac ttgtgactga gtgtgcagtg 100 cccagcatgt accaggtcag tgcagagggc tgcctgaggg ctgtgctgag 150 agggagagga gcagagatgc tgctgagggt ggagggaggc caagctgcca 200 ggtttggggc tgggggccaa gtggagtgag aaactgggat cccaggggga 250 gggtgcagat gagggagcga cccagattag gtgaggacag ttctctcatt 300 agccttttcc tacaggtggt tgcattcttg gcaatggtca tgggaaccca 350 cacctacagc cactggccca gctgctgccc cagcaaaggg caggacacct 400 ctgaggagct gctgaggtgg agcactgtgc ctgtgcctcc cctagagcct 450 gctaggccca accgccaccc agagtcctgt agggccagtg aagatggacc 500 cctcaacagc agggccatct ccccctggag atatgagttg gacagagact 550 tgaaccggct cccccaggac ctgtaccacg cccgttgcct gtgcccgcac 600 tgcgtcagcc tacagacagg ctcccacatg gacccccggg gcaactcgga 650 gctgctctac cacaaccaga ctgtcttcta caggcggcca tgccatggcg 700 agaagggcac ccacaagggc tactgcctgg agcgcaggct gtaccgtgtt 750 tccttagctt gtgtgtgtgt gcggccccgt gtgatgggct agccggacct 800 gctggaggct ggtccctttt tgggaaacct ggagccaggt gtacaaccac 850 ttgccatgaa gggccaggat gcccagatgc ttggcccctg tgaagtgctg 900 tctggagcag caggatcccg ggacaggatg gggggctttg gggaaaacct 950 gcacttctgc acattttgaa aagagcagct gctgcttagg gccgccggaa 1000 gctggtgtcc tgtcattttc tctcaggaaa ggttttcaaa gttctgccca 1050 tttctggagg ccaccactcc tgtctcttcc tcttttccca tcccctgcta 1100 ccctggccca gcacaggcac tttctagata tttccccctt gctggagaag 1150 aaagagcccc tggttttatt tgtttgttta ctcatcactc agtgagcatc 1200 tactttgggt gcattctagt gtagttacta gtcttttgac atggatgatt 1250 ctgaggagga agctgttatt gaatgtatag agatttatcc aaataaatat 1300 ctttatttaa aaatgaaaaa 1320 156 177 PRT Homo Sapien 156 Met Arg Glu Arg Pro Arg Leu Gly Glu Asp Ser Ser Leu Ile Ser 1 5 10 15 Leu Phe Leu Gln Val Val Ala Phe Leu Ala Met Val Met Gly Thr 20 25 30 His Thr Tyr Ser His Trp Pro Ser Cys Cys Pro Ser Lys Gly Gln 35 40 45 Asp Thr Ser Glu Glu Leu Leu Arg Trp Ser Thr Val Pro Val Pro 50 55 60 Pro Leu Glu Pro Ala Arg Pro Asn Arg His Pro Glu Ser Cys Arg 65 70 75 Ala Ser Glu Asp Gly Pro Leu Asn Ser Arg Ala Ile Ser Pro Trp 80 85 90 Arg Tyr Glu Leu Asp Arg Asp Leu Asn Arg Leu Pro Gln Asp Leu 95 100 105 Tyr His Ala Arg Cys Leu Cys Pro His Cys Val Ser Leu Gln Thr 110 115 120 Gly Ser His Met Asp Pro Arg Gly Asn Ser Glu Leu Leu Tyr His 125 130 135 Asn Gln Thr Val Phe Tyr Arg Arg Pro Cys His Gly Glu Lys Gly 140 145 150 Thr His Lys Gly Tyr Cys Leu Glu Arg Arg Leu Tyr Arg Val Ser 155 160 165 Leu Ala Cys Val Cys Val Arg Pro Arg Val Met Gly 170 175 157 1515 DNA Homo Sapien 157 ccggcgatgt cgctcgtgct gctaagcctg gccgcgctgt gcaggagcgc 50 cgtaccccga gagccgaccg ttcaatgtgg ctctgaaact gggccatctc 100 cagagtggat gctacaacat gatctaatcc ccggagactt gagggacctc 150 cgagtagaac ctgttacaac tagtgttgca acaggggact attcaatttt 200 gatgaatgta agctgggtac tccgggcaga tgccagcatc cgcttgttga 250 aggccaccaa gatttgtgtg acgggcaaaa gcaacttcca gtcctacagc 300 tgtgtgaggt gcaattacac agaggccttc cagactcaga ccagaccctc 350 tggtggtaaa tggacatttt cctacatcgg cttccctgta gagctgaaca 400 cagtctattt cattggggcc cataatattc ctaatgcaaa tatgaatgaa 450 gatggccctt ccatgtctgt gaatttcacc tcaccaggct gcctagacca 500 cataatgaaa tataaaaaaa agtgtgtcaa ggccggaagc ctgtgggatc 550 cgaacatcac tgcttgtaag aagaatgagg agacagtaga agtgaacttc 600 acaaccactc ccctgggaaa cagatacatg gctcttatcc aacacagcac 650 tatcatcggg ttttctcagg tgtttgagcc acaccagaag aaacaaacgc 700 gagcttcagt ggtgattcca gtgactgggg atagtgaagg tgctacggtg 750 cagctgactc catattttcc tacttgtggc agcgactgca tccgacataa 800 aggaacagtt gtgctctgcc cacaaacagg cgtccctttc cctctggata 850 acaacaaaag caagccggga ggctggctgc ctctcctcct gctgtctctg 900 ctggtggcca catgggtgct ggtggcaggg atctatctaa tgtggaggca 950 cgaaaggatc aagaagactt ccttttctac caccacacta ctgcccccca 1000 ttaaggttct tgtggtttac ccatctgaaa tatgtttcca tcacacaatt 1050 tgttacttca ctgaatttct tcaaaaccat tgcagaagtg aggtcatcct 1100 tgaaaagtgg cagaaaaaga aaatagcaga gatgggtcca gtgcagtggc 1150 ttgccactca aaagaaggca gcagacaaag tcgtcttcct tctttccaat 1200 gacgtcaaca gtgtgtgcga tggtacctgt ggcaagagcg agggcagtcc 1250 cagtgagaac tctcaagacc tcttccccct tgcctttaac cttttctgca 1300 gtgatctaag aagccagatt catctgcaca aatacgtggt ggtctacttt 1350 agagagattg atacaaaaga cgattacaat gctctcagtg tctgccccaa 1400 gtaccacctc atgaaggatg ccactgcttt ctgtgcagaa cttctccatg 1450 tcaagcagca ggtgtcagca ggaaaaagat cacaagcctg ccacgatggc 1500 tgctgctcct tgtag 1515 158 502 PRT Homo Sapien 158 Met Ser Leu Val Leu Leu Ser Leu Ala Ala Leu Cys Arg Ser Ala 1 5 10 15 Val Pro Arg Glu Pro Thr Val Gln Cys Gly Ser Glu Thr Gly Pro 20 25 30 Ser Pro Glu Trp Met Leu Gln His Asp Leu Ile Pro Gly Asp Leu 35 40 45 Arg Asp Leu Arg Val Glu Pro Val Thr Thr Ser Val Ala Thr Gly 50 55 60 Asp Tyr Ser Ile Leu Met Asn Val Ser Trp Val Leu Arg Ala Asp 65 70 75 Ala Ser Ile Arg Leu Leu Lys Ala Thr Lys Ile Cys Val Thr Gly 80 85 90 Lys Ser Asn Phe Gln Ser Tyr Ser Cys Val Arg Cys Asn Tyr Thr 95 100 105 Glu Ala Phe Gln Thr Gln Thr Arg Pro Ser Gly Gly Lys Trp Thr 110 115 120 Phe Ser Tyr Ile Gly Phe Pro Val Glu Leu Asn Thr Val Tyr Phe 125 130 135 Ile Gly Ala His Asn Ile Pro Asn Ala Asn Met Asn Glu Asp Gly 140 145 150 Pro Ser Met Ser Val Asn Phe Thr Ser Pro Gly Cys Leu Asp His 155 160 165 Ile Met Lys Tyr Lys Lys Lys Cys Val Lys Ala Gly Ser Leu Trp 170 175 180 Asp Pro Asn Ile Thr Ala Cys Lys Lys Asn Glu Glu Thr Val Glu 185 190 195 Val Asn Phe Thr Thr Thr Pro Leu Gly Asn Arg Tyr Met Ala Leu 200 205 210 Ile Gln His Ser Thr Ile Ile Gly Phe Ser Gln Val Phe Glu Pro 215 220 225 His Gln Lys Lys Gln Thr Arg Ala Ser Val Val Ile Pro Val Thr 230 235 240 Gly Asp Ser Glu Gly Ala Thr Val Gln Leu Thr Pro Tyr Phe Pro 245 250 255 Thr Cys Gly Ser Asp Cys Ile Arg His Lys Gly Thr Val Val Leu 260 265 270 Cys Pro Gln Thr Gly Val Pro Phe Pro Leu Asp Asn Asn Lys Ser 275 280 285 Lys Pro Gly Gly Trp Leu Pro Leu Leu Leu Leu Ser Leu Leu Val 290 295 300 Ala Thr Trp Val Leu Val Ala Gly Ile Tyr Leu Met Trp Arg His 305 310 315 Glu Arg Ile Lys Lys Thr Ser Phe Ser Thr Thr Thr Leu Leu Pro 320 325 330 Pro Ile Lys Val Leu Val Val Tyr Pro Ser Glu Ile Cys Phe His 335 340 345 His Thr Ile Cys Tyr Phe Thr Glu Phe Leu Gln Asn His Cys Arg 350 355 360 Ser Glu Val Ile Leu Glu Lys Trp Gln Lys Lys Lys Ile Ala Glu 365 370 375 Met Gly Pro Val Gln Trp Leu Ala Thr Gln Lys Lys Ala Ala Asp 380 385 390 Lys Val Val Phe Leu Leu Ser Asn Asp Val Asn Ser Val Cys Asp 395 400 405 Gly Thr Cys Gly Lys Ser Glu Gly Ser Pro Ser Glu Asn Ser Gln 410 415 420 Asp Leu Phe Pro Leu Ala Phe Asn Leu Phe Cys Ser Asp Leu Arg 425 430 435 Ser Gln Ile His Leu His Lys Tyr Val Val Val Tyr Phe Arg Glu 440 445 450 Ile Asp Thr Lys Asp Asp Tyr Asn Ala Leu Ser Val Cys Pro Lys 455 460 465 Tyr His Leu Met Lys Asp Ala Thr Ala Phe Cys Ala Glu Leu Leu 470 475 480 His Val Lys Gln Gln Val Ser Ala Gly Lys Arg Ser Gln Ala Cys 485 490 495 His Asp Gly Cys Cys Ser Leu 500 159 535 DNA Homo Sapien 159 agccaccagc gcaacatgac agtgaagacc ctgcatggcc cagccatggt 50 caagtacttg ctgctgtcga tattggggct tgcctttctg agtgaggcgg 100 cagctcggaa aatccccaaa gtaggacata cttttttcca aaagcctgag 150 agttgcccgc ctgtgccagg aggtagtatg aagcttgaca ttggcatcat 200 caatgaaaac cagcgcgttt ccatgtcacg taacatcgag agccgctcca 250 cctccccctg gaattacact gtcacttggg accccaaccg gtacccctcg 300 gaagttgtac aggcccagtg taggaacttg ggctgcatca atgctcaagg 350 aaaggaagac atctccatga attccgttcc catccagcaa gagaccctgg 400 tcgtccggag gaagcaccaa ggctgctctg tttctttcca gttggagaag 450 gtgctggtga ctgttggctg cacctgcgtc acccctgtca tccaccatgt 500 gcagtaagag gtgcatatcc actcagctga agaag 535 160 163 PRT Homo Sapien 160 Met Thr Val Lys Thr Leu His Gly Pro Ala Met Val Lys Tyr Leu 1 5 10 15 Leu Leu Ser Ile Leu Gly Leu Ala Phe Leu Ser Glu Ala Ala Ala 20 25 30 Arg Lys Ile Pro Lys Val Gly His Thr Phe Phe Gln Lys Pro Glu 35 40 45 Ser Cys Pro Pro Val Pro Gly Gly Ser Met Lys Leu Asp Ile Gly 50 55 60 Ile Ile Asn Glu Asn Gln Arg Val Ser Met Ser Arg Asn Ile Glu 65 70 75 Ser Arg Ser Thr Ser Pro Trp Asn Tyr Thr Val Thr Trp Asp Pro 80 85 90 Asn Arg Tyr Pro Ser Glu Val Val Gln Ala Gln Cys Arg Asn Leu 95 100 105 Gly Cys Ile Asn Ala Gln Gly Lys Glu Asp Ile Ser Met Asn Ser 110 115 120 Val Pro Ile Gln Gln Glu Thr Leu Val Val Arg Arg Lys His Gln 125 130 135 Gly Cys Ser Val Ser Phe Gln Leu Glu Lys Val Leu Val Thr Val 140 145 150 Gly Cys Thr Cys Val Thr Pro Val Ile His His Val Gln 155 160 161 2380 DNA Homo Sapien 161 acactggcca aacaaaaacg aaagcactcc gtgctggaag taggaggaga 50 gtcaggactc ccaggacaga gagtgcacaa actacccagc acagccccct 100 ccgccccctc tggaggctga agagggattc cagcccctgc cacccacaga 150 cacgggctga ctggggtgtc tgcccccctt gggggggggc agcacagggc 200 ctcaggcctg ggtgccacct ggcacctaga agatgcctgt gccctggttc 250 ttgctgtcct tggcactggg ccgaagccca gtggtccttt ctctggagag 300 gcttgtgggg cctcaggacg ctacccactg ctctccgggc ctctcctgcc 350 gcctctggga cagtgacata ctctgcctgc ctggggacat cgtgcctgct 400 ccgggccccg tgctggcgcc tacgcacctg cagacagagc tggtgctgag 450 gtgccagaag gagaccgact gtgacctctg tctgcgtgtg gctgtccact 500 tggccgtgca tgggcactgg gaagagcctg aagatgagga aaagtttgga 550 ggagcagctg actcaggggt ggaggagcct aggaatgcct ctctccaggc 600 ccaagtcgtg ctctccttcc aggcctaccc tactgcccgc tgcgtcctgc 650 tggaggtgca agtgcctgct gcccttgtgc agtttggtca gtctgtgggc 700 tctgtggtat atgactgctt cgaggctgcc ctagggagtg aggtacgaat 750 ctggtcctat actcagccca ggtacgagaa ggaactcaac cacacacagc 800 agctgcctgc cctgccctgg ctcaacgtgt cagcagatgg tgacaacgtg 850 catctggttc tgaatgtctc tgaggagcag cacttcggcc tctccctgta 900 ctggaatcag gtccagggcc ccccaaaacc ccggtggcac aaaaacctga 950 ctggaccgca gatcattacc ttgaaccaca cagacctggt tccctgcctc 1000 tgtattcagg tgtggcctct ggaacctgac tccgttagga cgaacatctg 1050 ccccttcagg gaggaccccc gcgcacacca gaacctctgg caagccgccc 1100 gactgcgact gctgaccctg cagagctggc tgctggacgc accgtgctcg 1150 ctgcccgcag aagcggcact gtgctggcgg gctccgggtg gggacccctg 1200 ccagccactg gtcccaccgc tttcctggga gaacgtcact gtggacaagg 1250 ttctcgagtt cccattgctg aaaggccacc ctaacctctg tgttcaggtg 1300 aacagctcgg agaagctgca gctgcaggag tgcttgtggg ctgactccct 1350 ggggcctctc aaagacgatg tgctactgtt ggagacacga ggcccccagg 1400 acaacagatc cctctgtgcc ttggaaccca gtggctgtac ttcactaccc 1450 agcaaagcct ccacgagggc agctcgcctt ggagagtact tactacaaga 1500 cctgcagtca ggccagtgtc tgcagctatg ggacgatgac ttgggagcgc 1550 tatgggcctg ccccatggac aaatacatcc acaagcgctg ggccctcgtg 1600 tggctggcct gcctactctt tgccgctgcg ctttccctca tcctccttct 1650 caaaaaggat cacgcgaaag ggtggctgag gctcttgaaa caggacgtcc 1700 gctcgggggc ggccgccagg ggccgcgcgg ctctgctcct ctactcagcc 1750 gatgactcgg gtttcgagcg cctggtgggc gccctggcgt cggccctgtg 1800 ccagctgccg ctgcgcgtgg ccgtagacct gtggagccgt cgtgaactga 1850 gcgcgcaggg gcccgtggct tggtttcacg cgcagcggcg ccagaccctg 1900 caggagggcg gcgtggtggt cttgctcttc tctcccggtg cggtggcgct 1950 gtgcagcgag tggctacagg atggggtgtc cgggcccggg gcgcacggcc 2000 cgcacgacgc cttccgcgcc tcgctcagct gcgtgctgcc cgacttcttg 2050 cagggccggg cgcccggcag ctacgtgggg gcctgcttcg acaggctgct 2100 ccacccggac gccgtacccg cccttttccg caccgtgccc gtcttcacac 2150 tgccctccca actgccagac ttcctggggg ccctgcagca gcctcgcgcc 2200 ccgcgttccg ggcggctcca agagagagcg gagcaagtgt cccgggccct 2250 tcagccagcc ctggatagct acttccatcc cccggggact cccgcgccgg 2300 gacgcggggt gggaccaggg gcgggacctg gggcggggga cgggacttaa 2350 ataaaggcag acgctgtttt tctaaaaaaa 2380 162 705 PRT Homo Sapien 162 Met Pro Val Pro Trp Phe Leu Leu Ser Leu Ala Leu Gly Arg Ser 1 5 10 15 Pro Val Val Leu Ser Leu Glu Arg Leu Val Gly Pro Gln Asp Ala 20 25 30 Thr His Cys Ser Pro Gly Leu Ser Cys Arg Leu Trp Asp Ser Asp 35 40 45 Ile Leu Cys Leu Pro Gly Asp Ile Val Pro Ala Pro Gly Pro Val 50 55 60 Leu Ala Pro Thr His Leu Gln Thr Glu Leu Val Leu Arg Cys Gln 65 70 75 Lys Glu Thr Asp Cys Asp Leu Cys Leu Arg Val Ala Val His Leu 80 85 90 Ala Val His Gly His Trp Glu Glu Pro Glu Asp Glu Glu Lys Phe 95 100 105 Gly Gly Ala Ala Asp Ser Gly Val Glu Glu Pro Arg Asn Ala Ser 110 115 120 Leu Gln Ala Gln Val Val Leu Ser Phe Gln Ala Tyr Pro Thr Ala 125 130 135 Arg Cys Val Leu Leu Glu Val Gln Val Pro Ala Ala Leu Val Gln 140 145 150 Phe Gly Gln Ser Val Gly Ser Val Val Tyr Asp Cys Phe Glu Ala 155 160 165 Ala Leu Gly Ser Glu Val Arg Ile Trp Ser Tyr Thr Gln Pro Arg 170 175 180 Tyr Glu Lys Glu Leu Asn His Thr Gln Gln Leu Pro Ala Leu Pro 185 190 195 Trp Leu Asn Val Ser Ala Asp Gly Asp Asn Val His Leu Val Leu 200 205 210 Asn Val Ser Glu Glu Gln His Phe Gly Leu Ser Leu Tyr Trp Asn 215 220 225 Gln Val Gln Gly Pro Pro Lys Pro Arg Trp His Lys Asn Leu Thr 230 235 240 Gly Pro Gln Ile Ile Thr Leu Asn His Thr Asp Leu Val Pro Cys 245 250 255 Leu Cys Ile Gln Val Trp Pro Leu Glu Pro Asp Ser Val Arg Thr 260 265 270 Asn Ile Cys Pro Phe Arg Glu Asp Pro Arg Ala His Gln Asn Leu 275 280 285 Trp Gln Ala Ala Arg Leu Arg Leu Leu Thr Leu Gln Ser Trp Leu 290 295 300 Leu Asp Ala Pro Cys Ser Leu Pro Ala Glu Ala Ala Leu Cys Trp 305 310 315 Arg Ala Pro Gly Gly Asp Pro Cys Gln Pro Leu Val Pro Pro Leu 320 325 330 Ser Trp Glu Asn Val Thr Val Asp Lys Val Leu Glu Phe Pro Leu 335 340 345 Leu Lys Gly His Pro Asn Leu Cys Val Gln Val Asn Ser Ser Glu 350 355 360 Lys Leu Gln Leu Gln Glu Cys Leu Trp Ala Asp Ser Leu Gly Pro 365 370 375 Leu Lys Asp Asp Val Leu Leu Leu Glu Thr Arg Gly Pro Gln Asp 380 385 390 Asn Arg Ser Leu Cys Ala Leu Glu Pro Ser Gly Cys Thr Ser Leu 395 400 405 Pro Ser Lys Ala Ser Thr Arg Ala Ala Arg Leu Gly Glu Tyr Leu 410 415 420 Leu Gln Asp Leu Gln Ser Gly Gln Cys Leu Gln Leu Trp Asp Asp 425 430 435 Asp Leu Gly Ala Leu Trp Ala Cys Pro Met Asp Lys Tyr Ile His 440 445 450 Lys Arg Trp Ala Leu Val Trp Leu Ala Cys Leu Leu Phe Ala Ala 455 460 465 Ala Leu Ser Leu Ile Leu Leu Leu Lys Lys Asp His Ala Lys Gly 470 475 480 Trp Leu Arg Leu Leu Lys Gln Asp Val Arg Ser Gly Ala Ala Ala 485 490 495 Arg Gly Arg Ala Ala Leu Leu Leu Tyr Ser Ala Asp Asp Ser Gly 500 505 510 Phe Glu Arg Leu Val Gly Ala Leu Ala Ser Ala Leu Cys Gln Leu 515 520 525 Pro Leu Arg Val Ala Val Asp Leu Trp Ser Arg Arg Glu Leu Ser 530 535 540 Ala Gln Gly Pro Val Ala Trp Phe His Ala Gln Arg Arg Gln Thr 545 550 555 Leu Gln Glu Gly Gly Val Val Val Leu Leu Phe Ser Pro Gly Ala 560 565 570 Val Ala Leu Cys Ser Glu Trp Leu Gln Asp Gly Val Ser Gly Pro 575 580 585 Gly Ala His Gly Pro His Asp Ala Phe Arg Ala Ser Leu Ser Cys 590 595 600 Val Leu Pro Asp Phe Leu Gln Gly Arg Ala Pro Gly Ser Tyr Val 605 610 615 Gly Ala Cys Phe Asp Arg Leu Leu His Pro Asp Ala Val Pro Ala 620 625 630 Leu Phe Arg Thr Val Pro Val Phe Thr Leu Pro Ser Gln Leu Pro 635 640 645 Asp Phe Leu Gly Ala Leu Gln Gln Pro Arg Ala Pro Arg Ser Gly 650 655 660 Arg Leu Gln Glu Arg Ala Glu Gln Val Ser Arg Ala Leu Gln Pro 665 670 675 Ala Leu Asp Ser Tyr Phe His Pro Pro Gly Thr Pro Ala Pro Gly 680 685 690 Arg Gly Val Gly Pro Gly Ala Gly Pro Gly Ala Gly Asp Gly Thr 695 700 705 163 2478 DNA Homo Sapien 163 gtcagtgcgg gaggccggtc agccaccaag atgactgaca ggttcagctc 50 tctgcagcac actaccctca agccacctga tgtgacctgt atctccaaag 100 tgagatcgat tcagatgatt gttcatccta cccccacgcc aatccgtgca 150 ggcgatggcc accggctaac cctggaagac atcttccatg acctgttcta 200 ccacttagag ctccaggtca accgcaccta ccaaatgcac cttggaggga 250 agcagagaga atatgagttc ttcggcctga cccctgacac agagttcctt 300 ggcaccatca tgatttgcgt tcccacctgg gccaaggaga gtgcccccta 350 catgtgccga gtgaagacac tgccagaccg gacatggacc tactccttct 400 ccggagcctt cctgttctcc atgggcttcc tcgtcgcagt actctgctac 450 ctgagctaca gatatgtcac caagccgcct gcacctccca actccctgaa 500 cgtccagcga gtcctgactt tccagccgct gcgcttcatc caggagcacg 550 tcctgatccc tgtctttgac ctcagcggcc ccagcagtct ggcccagcct 600 gtccagtact cccagatcag ggtgtctgga cccagggagc ccgcaggagc 650 tccacagcgg catagcctgt ccgagatcac ctacttaggg cagccagaca 700 tctccatcct ccagccctcc aacgtgccac ctccccagat cctctcccca 750 ctgtcctatg ccccaaacgc tgcccctgag gtcgggcccc catcctatgc 800 acctcaggtg acccccgaag ctcaattccc attctacgcc ccacaggcca 850 tctctaaggt ccagccttcc tcctatgccc ctcaagccac tccggacagc 900 tggcctccct cctatggggt atgcatggaa ggttctggca aagactcccc 950 cactgggaca ctttctagtc ctaaacacct taggcctaaa ggtcagcttc 1000 agaaagagcc accagctgga agctgcatgt taggtggcct ttctctgcag 1050 gaggtgacct ccttggctat ggaggaatcc caagaagcaa aatcattgca 1100 ccagcccctg gggatttgca cagacagaac atctgaccca aatgtgctac 1150 acagtgggga ggaagggaca ccacagtacc taaagggcca gctccccctc 1200 ctctcctcag tccagatcga gggccacccc atgtccctcc ctttgcaacc 1250 tccttccggt ccatgttccc cctcggacca aggtccaagt ccctggggcc 1300 tgctggagtc ccttgtgtgt cccaaggatg aagccaagag cccagcccct 1350 gagacctcag acctggagca gcccacagaa ctggattctc ttttcagagg 1400 cctggccctg actgtgcagt gggagtcctg aggggaatgg gaaaggcttg 1450 gtgcttcctc cctgtcccta cccagtgtca catccttggc tgtcaatccc 1500 atgcctgccc atgccacaca ctctgcgatc tggcctcaga cgggtgccct 1550 tgagagaagc agagggagtg gcatgcaggg cccctgccat gggtgcgctc 1600 ctcaccggaa caaagcagca tgataaggac tgcagcgggg gagctctggg 1650 gagcagcttg tgtagacaag cgcgtgctcg ctgagccctg caaggcagaa 1700 atgacagtgc aaggaggaaa tgcagggaaa ctcccgaggt ccagagcccc 1750 acctcctaac accatggatt caaagtgctc agggaatttg cctctccttg 1800 ccccattcct ggccagtttc acaatctagc tcgacagagc atgaggcccc 1850 tgcctcttct gtcattgttc aaaggtggga agagagcctg gaaaagaacc 1900 aggcctggaa aagaaccaga aggaggctgg gcagaaccag aacaacctgc 1950 acttctgcca aggccagggc cagcaggacg gcaggactct agggaggggt 2000 gtggcctgca gctcattccc agccagggca actgcctgac gttgcacgat 2050 ttcagcttca ttcctctgat agaacaaagc gaaatgcagg tccaccaggg 2100 agggagacac acaagccttt tctgcaggca ggagtttcag accctatcct 2150 gagaatgggg tttgaaagga aggtgagggc tgtggcccct ggacgggtac 2200 aataacacac tgtactgatg tcacaacttt gcaagctctg ccttgggttc 2250 agcccatctg ggctcaaatt ccagcctcac cactcacaag ctgtgtgact 2300 tcaaacaaat gaaatcagtg cccagaacct cggtttcctc atctgtaatg 2350 tggggatcat aacacctacc tcatggagtt gtggtgaaga tgaaatgaag 2400 tcatgtcttt aaagtgctta atagtgcctg gtacatgggc agtgcccaat 2450 aaacggtagc tatttaaaaa aaaaaaaa 2478 164 574 PRT Homo Sapien 164 Met Arg Thr Leu Leu Thr Ile Leu Thr Val Gly Ser Leu Ala Ala 1 5 10 15 His Ala Pro Glu Asp Pro Ser Asp Leu Leu Gln His Val Lys Phe 20 25 30 Gln Ser Ser Asn Phe Glu Asn Ile Leu Thr Trp Asp Ser Gly Pro 35 40 45 Glu Gly Thr Pro Asp Thr Val Tyr Ser Ile Glu Tyr Lys Thr Tyr 50 55 60 Gly Glu Arg Asp Trp Val Ala Lys Lys Gly Cys Gln Arg Ile Thr 65 70 75 Arg Lys Ser Cys Asn Leu Thr Val Glu Thr Gly Asn Leu Thr Glu 80 85 90 Leu Tyr Tyr Ala Arg Val Thr Ala Val Ser Ala Gly Gly Arg Ser 95 100 105 Ala Thr Lys Met Thr Asp Arg Phe Ser Ser Leu Gln His Thr Thr 110 115 120 Leu Lys Pro Pro Asp Val Thr Cys Ile Ser Lys Val Arg Ser Ile 125 130 135 Gln Met Ile Val His Pro Thr Pro Thr Pro Ile Arg Ala Gly Asp 140 145 150 Gly His Arg Leu Thr Leu Glu Asp Ile Phe His Asp Leu Phe Tyr 155 160 165 His Leu Glu Leu Gln Val Asn Arg Thr Tyr Gln Met His Leu Gly 170 175 180 Gly Lys Gln Arg Glu Tyr Glu Phe Phe Gly Leu Thr Pro Asp Thr 185 190 195 Glu Phe Leu Gly Thr Ile Met Ile Cys Val Pro Thr Trp Ala Lys 200 205 210 Glu Ser Ala Pro Tyr Met Cys Arg Val Lys Thr Leu Pro Asp Arg 215 220 225 Thr Trp Thr Tyr Ser Phe Ser Gly Ala Phe Leu Phe Ser Met Gly 230 235 240 Phe Leu Val Ala Val Leu Cys Tyr Leu Ser Tyr Arg Tyr Val Thr 245 250 255 Lys Pro Pro Ala Pro Pro Asn Ser Leu Asn Val Gln Arg Val Leu 260 265 270 Thr Phe Gln Pro Leu Arg Phe Ile Gln Glu His Val Leu Ile Pro 275 280 285 Val Phe Asp Leu Ser Gly Pro Ser Ser Leu Ala Gln Pro Val Gln 290 295 300 Tyr Ser Gln Ile Arg Val Ser Gly Pro Arg Glu Pro Ala Gly Ala 305 310 315 Pro Gln Arg His Ser Leu Ser Glu Ile Thr Tyr Leu Gly Gln Pro 320 325 330 Asp Ile Ser Ile Leu Gln Pro Ser Asn Val Pro Pro Pro Gln Ile 335 340 345 Leu Ser Pro Leu Ser Tyr Ala Pro Asn Ala Ala Pro Glu Val Gly 350 355 360 Pro Pro Ser Tyr Ala Pro Gln Val Thr Pro Glu Ala Gln Phe Pro 365 370 375 Phe Tyr Ala Pro Gln Ala Ile Ser Lys Val Gln Pro Ser Ser Tyr 380 385 390 Ala Pro Gln Ala Thr Pro Asp Ser Trp Pro Pro Ser Tyr Gly Val 395 400 405 Cys Met Glu Gly Ser Gly Lys Asp Ser Pro Thr Gly Thr Leu Ser 410 415 420 Ser Pro Lys His Leu Arg Pro Lys Gly Gln Leu Gln Lys Glu Pro 425 430 435 Pro Ala Gly Ser Cys Met Leu Gly Gly Leu Ser Leu Gln Glu Val 440 445 450 Thr Ser Leu Ala Met Glu Glu Ser Gln Glu Ala Lys Ser Leu His 455 460 465 Gln Pro Leu Gly Ile Cys Thr Asp Arg Thr Ser Asp Pro Asn Val 470 475 480 Leu His Ser Gly Glu Glu Gly Thr Pro Gln Tyr Leu Lys Gly Gln 485 490 495 Leu Pro Leu Leu Ser Ser Val Gln Ile Glu Gly His Pro Met Ser 500 505 510 Leu Pro Leu Gln Pro Pro Ser Gly Pro Cys Ser Pro Ser Asp Gln 515 520 525 Gly Pro Ser Pro Trp Gly Leu Leu Glu Ser Leu Val Cys Pro Lys 530 535 540 Asp Glu Ala Lys Ser Pro Ala Pro Glu Thr Ser Asp Leu Glu Gln 545 550 555 Pro Thr Glu Leu Asp Ser Leu Phe Arg Gly Leu Ala Leu Thr Val 560 565 570 Gln Trp Glu Ser 165 1060 DNA Homo Sapien 165 tggcctactg gaaaaaaaaa aaaaaaaaaa aaaagtcacc cgggcccgcg 50 gtggccacaa catggctgcg gcgccggggc tgctcttctg gctgttcgtg 100 ctgggggcgc tctggtgggt cccgggccag tcggatctca gccacggacg 150 gcgtttctcg gacctcaaag tgtgcgggga cgaagagtgc agcatgttaa 200 tgtaccgtgg gaaagctctt gaagacttca cgggccctga ttgtcgtttt 250 gtgaatttta aaaaaggtga cgatgtatat gtctactaca aactggcagg 300 gggatccctt gaactttggg ctggaagtgt tgaacacagt tttggatatt 350 ttccaaaaga tttgatcaag gtacttcata aatacacgga agaagagcta 400 catattccag cagatgagac agactttgtc tgctttgaag gaggaagaga 450 tgattttaat agttataatg tagaagagct tttaggatct ttggaactgg 500 aggactctgt acctgaagag tcgaagaaag ctgaagaagt ttctcagcac 550 agagagaaat ctcctgagga gtctcggggg cgtgaacttg accctgtgcc 600 tgagcccgag gcattcagag ctgattcaga ggatggagaa ggtgctttct 650 cagagagcac cgaggggctg cagggacagc cctcagctca ggagagccac 700 cctcacacca gcggtcctgc ggctaacgct cagggagtgc agtcttcgtt 750 ggacactttt gaagaaattc tgcacgataa attgaaagtg ccgggaagcg 800 aaagcagaac tggcaatagt tctcctgcct cggtggagcg ggagaagaca 850 gatgcttaca aagtcctgaa aacagaaatg agtcagagag gaagtggaca 900 gtgcgttatt cattacagca aaggatttcg ttggcatcaa aatctaagtt 950 tgttttacaa agattgtttt tagtactaag ctgccttggc agtttgcatt 1000 tttgagccaa acaaaaatat attattttcc cttctaagta aaaaaaaaaa 1050 aaaaaaaaaa 1060 166 303 PRT Homo Sapien 166 Met Ala Ala Ala Pro Gly Leu Leu Phe Trp Leu Phe Val Leu Gly 1 5 10 15 Ala Leu Trp Trp Val Pro Gly Gln Ser Asp Leu Ser His Gly Arg 20 25 30 Arg Phe Ser Asp Leu Lys Val Cys Gly Asp Glu Glu Cys Ser Met 35 40 45 Leu Met Tyr Arg Gly Lys Ala Leu Glu Asp Phe Thr Gly Pro Asp 50 55 60 Cys Arg Phe Val Asn Phe Lys Lys Gly Asp Asp Val Tyr Val Tyr 65 70 75 Tyr Lys Leu Ala Gly Gly Ser Leu Glu Leu Trp Ala Gly Ser Val 80 85 90 Glu His Ser Phe Gly Tyr Phe Pro Lys Asp Leu Ile Lys Val Leu 95 100 105 His Lys Tyr Thr Glu Glu Glu Leu His Ile Pro Ala Asp Glu Thr 110 115 120 Asp Phe Val Cys Phe Glu Gly Gly Arg Asp Asp Phe Asn Ser Tyr 125 130 135 Asn Val Glu Glu Leu Leu Gly Ser Leu Glu Leu Glu Asp Ser Val 140 145 150 Pro Glu Glu Ser Lys Lys Ala Glu Glu Val Ser Gln His Arg Glu 155 160 165 Lys Ser Pro Glu Glu Ser Arg Gly Arg Glu Leu Asp Pro Val Pro 170 175 180 Glu Pro Glu Ala Phe Arg Ala Asp Ser Glu Asp Gly Glu Gly Ala 185 190 195 Phe Ser Glu Ser Thr Glu Gly Leu Gln Gly Gln Pro Ser Ala Gln 200 205 210 Glu Ser His Pro His Thr Ser Gly Pro Ala Ala Asn Ala Gln Gly 215 220 225 Val Gln Ser Ser Leu Asp Thr Phe Glu Glu Ile Leu His Asp Lys 230 235 240 Leu Lys Val Pro Gly Ser Glu Ser Arg Thr Gly Asn Ser Ser Pro 245 250 255 Ala Ser Val Glu Arg Glu Lys Thr Asp Ala Tyr Lys Val Leu Lys 260 265 270 Thr Glu Met Ser Gln Arg Gly Ser Gly Gln Cys Val Ile His Tyr 275 280 285 Ser Lys Gly Phe Arg Trp His Gln Asn Leu Ser Leu Phe Tyr Lys 290 295 300 Asp Cys Phe 167 2570 DNA Homo Sapien 167 ccaggaccag ggcgcaccgg ctcagcctct cacttgtcag aggccgggga 50 agagaagcaa agcgcaacgg tgtggtccaa gccggggctt ctgcttcgcc 100 tctaggacat acacgggacc ccctaacttc agtcccccaa acgcgcaccc 150 tcgaagtctt gaactccagc cccgcacatc cacgcgcggc acaggcgcgg 200 caggcggcag gtcccggccg aaggcgatgc gcgcaggggg tcgggcagct 250 gggctcgggc ggcgggagta gggcccggca gggaggcagg gaggctgcat 300 attcagagtc gcgggctgcg ccctgggcag aggccgccct cgctccacgc 350 aacacctgct gctgccaccg cgccgcgatg agccgcgtgg tctcgctgct 400 gctgggcgcc gcgctgctct gcggccacgg agccttctgc cgccgcgtgg 450 tcagcggcca aaaggtgtgt tttgctgact tcaagcatcc ctgctacaaa 500 atggcctact tccatgaact gtccagccga gtgagctttc aggaggcacg 550 cctggcttgt gagagtgagg gaggagtcct cctcagcctt gagaatgaag 600 cagaacagaa gttaatagag agcatgttgc aaaacctgac aaaacccggg 650 acagggattt ctgatggtga tttctggata gggctttgga ggaatggaga 700 tgggcaaaca tctggtgcct gcccagatct ctaccagtgg tctgatggaa 750 gcaattccca gtaccgaaac tggtacacag atgaaccttc ctgcggaagt 800 gaaaagtgtg ttgtgatgta tcaccaacca actgccaatc ctggccttgg 850 gggtccctac ctttaccagt ggaatgatga caggtgtaac atgaagcaca 900 attatatttg caagtatgaa ccagagatta atccaacagc ccctgtagaa 950 aagccttatc ttacaaatca accaggagac acccatcaga atgtggttgt 1000 tactgaagca ggtataattc ccaatctaat ttatgttgtt ataccaacaa 1050 tacccctgct cttactgata ctggttgctt ttggaacctg ttgtttccag 1100 atgctgcata aaagtaaagg aagaacaaaa actagtccaa accagtctac 1150 actgtggatt tcaaagagta ccagaaaaga aagtggcatg gaagtataat 1200 aactcattga cttggttcca gaattttgta attctggatc tgtataagga 1250 atggcatcag aacaatagct tggaatggct tgaaatcaca aaggatctgc 1300 aagatgaact gtaagctccc ccttgaggca aatattaaag taatttttat 1350 atgtctatta tttcatttaa agaatatgct gtgctaataa tggagtgaga 1400 catgcttatt ttgctaaagg atgcacccaa acttcaaact tcaagcaaat 1450 gaaatggaca atgcagataa agttgttatc aacacgtcgg gagtatgtgt 1500 gttagaagca attcctttta tttctttcac ctttcataag ttgttatcta 1550 gtcaatgtaa tgtatattgt attgaaattt acagtgtgca aaagtatttt 1600 acctttgcat aagtgtttga taaaaatgaa ctgttctaat atttattttt 1650 atggcatctc atttttcaat acatgctctt ttgattaaag aaacttatta 1700 ctgttgtcaa ctgaattcac acacacacaa atatagtacc atagaaaaag 1750 tttgttttct cgaaataatt catctttcag cttctctgct tttggtcaat 1800 gtctaggaaa tctcttcaga aataagaagc tatttcatta agtgtgatat 1850 aaacctcctc aaacatttta cttagaggca aggattgtct aatttcaatt 1900 gtgcaagaca tgtgccttat aattattttt agcttaaaat taaacagatt 1950 ttgtaataat gtaactttgt taataggtgc ataaacacta atgcagtcaa 2000 tttgaacaaa agaagtgaca tacacaatat aaatcatatg tcttcacacg 2050 ttgcctatat aatgagaagc agctctctga gggttctgaa atcaatgtgg 2100 tccctctctt gcccactaaa caaagatggt tgttcggggt ttgggattga 2150 cactggaggc agatagttgc aaagttagtc taaggtttcc ctagctgtat 2200 ttagcctctg actatattag tatacaaaga ggtcatgtgg ttgagaccag 2250 gtgaatagtc actatcagtg tggagacaag cacagcacac agacatttta 2300 ggaaggaaag gaactacgaa atcgtgtgaa aatgggttgg aacccatcag 2350 tgatcgcata ttcattgatg agggtttgct tgagatagaa aatggtggct 2400 cctttctgtc ttatctccta gtttcttcaa tgcttacgcc ttgttcttct 2450 caagagaaag ttgtaactct ctggtcttca tatgtccctg tgctcctttt 2500 aaccaaataa agagttcttg tttctggggg aaaaaaaaaa aaaaaaaaaa 2550 aaaaaaaaaa aaaaaaaaaa 2570 168 273 PRT Homo Sapien 168 Met Ser Arg Val Val Ser Leu Leu Leu Gly Ala Ala Leu Leu Cys 1 5 10 15 Gly His Gly Ala Phe Cys Arg Arg Val Val Ser Gly Gln Lys Val 20 25 30 Cys Phe Ala Asp Phe Lys His Pro Cys Tyr Lys Met Ala Tyr Phe 35 40 45 His Glu Leu Ser Ser Arg Val Ser Phe Gln Glu Ala Arg Leu Ala 50 55 60 Cys Glu Ser Glu Gly Gly Val Leu Leu Ser Leu Glu Asn Glu Ala 65 70 75 Glu Gln Lys Leu Ile Glu Ser Met Leu Gln Asn Leu Thr Lys Pro 80 85 90 Gly Thr Gly Ile Ser Asp Gly Asp Phe Trp Ile Gly Leu Trp Arg 95 100 105 Asn Gly Asp Gly Gln Thr Ser Gly Ala Cys Pro Asp Leu Tyr Gln 110 115 120 Trp Ser Asp Gly Ser Asn Ser Gln Tyr Arg Asn Trp Tyr Thr Asp 125 130 135 Glu Pro Ser Cys Gly Ser Glu Lys Cys Val Val Met Tyr His Gln 140 145 150 Pro Thr Ala Asn Pro Gly Leu Gly Gly Pro Tyr Leu Tyr Gln Trp 155 160 165 Asn Asp Asp Arg Cys Asn Met Lys His Asn Tyr Ile Cys Lys Tyr 170 175 180 Glu Pro Glu Ile Asn Pro Thr Ala Pro Val Glu Lys Pro Tyr Leu 185 190 195 Thr Asn Gln Pro Gly Asp Thr His Gln Asn Val Val Val Thr Glu 200 205 210 Ala Gly Ile Ile Pro Asn Leu Ile Tyr Val Val Ile Pro Thr Ile 215 220 225 Pro Leu Leu Leu Leu Ile Leu Val Ala Phe Gly Thr Cys Cys Phe 230 235 240 Gln Met Leu His Lys Ser Lys Gly Arg Thr Lys Thr Ser Pro Asn 245 250 255 Gln Ser Thr Leu Trp Ile Ser Lys Ser Thr Arg Lys Glu Ser Gly 260 265 270 Met Glu Val 169 43 DNA Artificial Sequence Synthetic oligonucleotide probe 169 tgtaaaacga cggccagtta aatagacctg caattattaa tct 43 170 41 DNA Artificial Sequence Synthetic oligonucleotide probe 170 caggaaacag ctatgaccac ctgcacacct gcaaatccat t 41

Claims (6)

1. An antibody that binds to the polypeptide shown in FIG. 60 (SEQ ID NO:60).
2. The antibody of claim 1 which is a monoclonal antibody.
3. The antibody of claim 1 which is a humanized antibody.
4. The antibody of claim 1 which is an antibody fragment.
5. The antibody of claim 1 which is labeled.
6. The antibody of claim 1 which specifically binds to the polypeptide shown in FIG. 60 (SEQ ID NO:60).
US10/063,568 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same Abandoned US20030181668A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US10/063,568 US20030181668A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same

Applications Claiming Priority (52)

Application Number Priority Date Filing Date Title
KR1998-62142 1998-12-30
PCT/US1999/005028 WO1999046281A2 (en) 1998-03-10 1999-03-08 Novel polypeptides and nucleic acids encoding the same
USPCT/US99/05028 1999-03-08
US31183299A 1999-05-14 1999-05-14
USPCT/US99/10733 1999-05-14
PCT/US1999/010733 WO1999060127A2 (en) 1998-05-15 1999-05-14 Il-17 homologous polypeptides and therapeutic uses thereof
US38013899A 1999-08-25 1999-08-25
US38014299A 1999-08-25 1999-08-25
US38013999A 1999-08-25 1999-08-25
US39734299A 1999-09-15 1999-09-15
US40329799A 1999-10-18 1999-10-18
US42384499A 1999-11-12 1999-11-12
USPCT/US99/31274 1999-12-30
PCT/US1999/031274 WO2000053752A2 (en) 1999-03-08 1999-12-30 Promotion or inhibition of angiogenesis and cardiovascularization
PCT/US2000/004341 WO2000053756A2 (en) 1999-03-08 2000-02-18 Secreted and transmembrane polypeptides and nucleic acids encoding the same
USPCT/US00/04341 2000-02-18
USPCT/US00/05601 2000-03-01
PCT/US2000/005601 WO2000056889A2 (en) 1999-03-23 2000-03-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
USPCT/US00/05841 2000-03-02
PCT/US2000/005841 WO2000053758A2 (en) 1999-03-08 2000-03-02 Compositions and methods for the treatment of immune related diseases
PCT/US2000/007532 WO2000070050A1 (en) 1999-05-14 2000-03-21 Compositions and methods for the treatment of immune related diseases
USPCT/US00/07532 2000-03-21
USPCT/US00/14042 2000-05-22
PCT/US2000/014042 WO2000077037A2 (en) 1999-06-15 2000-05-22 Secreted and transmembrane polypeptides and nucleic acids encoding the same
USPCT/US00/15264 2000-06-02
PCT/US2000/015264 WO2000073452A2 (en) 1999-06-02 2000-06-02 Compositions and methods for the treatment of immune related diseases
US64484800A 2000-08-22 2000-08-22
PCT/US2000/023328 WO2001016318A2 (en) 1999-09-01 2000-08-24 Secreted and transmembrane polypeptides and nucleic acids encoding the same
USPCT/US00/23328 2000-08-24
US66535000A 2000-09-18 2000-09-18
US66461000A 2000-09-18 2000-09-18
US70923800A 2000-11-08 2000-11-08
PCT/US2000/030873 WO2001040465A2 (en) 1999-11-30 2000-11-10 Compositions and methods for the treatment of immune related diseases
USPCT/US00/30873 2000-11-10
PCT/US2000/032678 WO2001040466A2 (en) 1999-12-01 2000-12-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
USPCT/US00/32678 2000-12-01
US09/747,259 US6569645B2 (en) 1999-05-14 2000-12-20 IL-17 homologous polypeptides and therapeutic uses thereof
USPCT/US00/34956 2000-12-20
PCT/US2000/034956 WO2001046420A2 (en) 1999-12-23 2000-12-20 Il-17 and il-17r homologous polypeptides and therapeutic uses thereof
PCT/US2001/006520 WO2001068848A2 (en) 2000-03-01 2001-02-28 Secreted and transmembrane polypeptides and nucleic acids encoding the same
USPCT/US01/06520 2001-02-28
US09/816,744 US6579520B2 (en) 1998-05-15 2001-03-22 IL-17 related mammalian cytokine polypeptides (IL-17E)
US09/854,280 US7115398B2 (en) 1998-05-15 2001-05-10 IL-17 homologous polypeptides and therapeutic uses thereof
US09/854,208 US7217412B2 (en) 1998-05-15 2001-05-10 IL-17C related mammalian cytokine polypeptides
US09/870,574 US6551799B2 (en) 1999-12-07 2001-05-30 Interleukin-22 polypeptides, nucleic acids encoding the same and methods for the treatment of pancreatic disorders
PCT/US2001/017800 WO2001093983A1 (en) 2000-06-02 2001-06-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
USPCT/US01/17800 2001-06-01
US09/874,503 US20020177188A1 (en) 1998-05-15 2001-06-05 IL-17 homologous polypeptides and therapeutic uses thereof
US86959901A 2001-06-29 2001-06-29
US09/908,827 US20030054442A1 (en) 1998-05-15 2001-07-18 IL-17 homologous polypeptides and therapeutic uses thereof
US10/006,867 US7160985B2 (en) 1997-10-29 2001-12-06 Pro180 polypeptide
US10/063,568 US20030181668A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/006,867 Continuation US7160985B2 (en) 1997-09-19 2001-12-06 Pro180 polypeptide

Publications (1)

Publication Number Publication Date
US20030181668A1 true US20030181668A1 (en) 2003-09-25

Family

ID=56290278

Family Applications (159)

Application Number Title Priority Date Filing Date
US10/063,517 Expired - Lifetime US7232889B2 (en) 1999-03-08 2002-05-01 PRO300 antibodies
US10/063,518 Expired - Lifetime US7465785B2 (en) 1999-03-08 2002-05-01 Polypeptide encoded by a nucleic acid over-expressed in melanoma
US10/063,510 Expired - Fee Related US7109292B2 (en) 1999-03-08 2002-05-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,520 Abandoned US20030187196A1 (en) 1998-12-30 2002-05-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,521 Abandoned US20030190669A1 (en) 1998-12-30 2002-05-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,519 Granted US20030009013A1 (en) 1998-12-30 2002-05-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,564 Abandoned US20030180794A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,545 Expired - Lifetime US7256261B2 (en) 1999-03-08 2002-05-02 Polypeptides encoded by a nucleic acid over expressed in normal stomach normal skin and kidney tumor
US10/063,547 Granted US20020182638A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,565 Abandoned US20030180904A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,561 Expired - Lifetime US7271247B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptide encoded by a nucleic acid differentially expressed in melanoma
US10/063,532 Expired - Lifetime US7202336B2 (en) 1999-03-08 2002-05-02 Polypeptide encoded by a nucleic acid overexpressed in kidney tumor and underexpressed in lung tumor
US10/063,523 Granted US20030181636A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,524 Granted US20030027992A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,544 Abandoned US20030027212A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,525 Abandoned US20030036634A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,530 Expired - Lifetime US7193059B2 (en) 1999-03-08 2002-05-02 Antibodies that recognize a polypeptide overexpressed in rectal tumors
US10/063,569 Granted US20030018168A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,551 Granted US20020183494A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,566 Abandoned US20030073821A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,541 Abandoned US20030060601A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,540 Granted US20030181667A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,538 Expired - Lifetime US7253255B2 (en) 1999-03-08 2002-05-02 Polypeptide encoded by a nucleic acid underexpressed in esophageal tumor and melanoma
US10/063,523 Expired - Fee Related US7220830B2 (en) 1999-03-08 2002-05-02 Polypeptide underexpressed in stomach tumors
US10/063,553 Granted US20030045684A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,551 Expired - Lifetime US7214777B2 (en) 1999-03-08 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,569 Expired - Lifetime US7378491B2 (en) 1999-03-08 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,547 Expired - Lifetime US7294690B2 (en) 1999-03-08 2002-05-02 Polypeptides encoded by a nucleic acid differentially expressed in lung tumor
US10/063,528 Abandoned US20030181666A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,536 Granted US20030181696A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,545 Granted US20020183505A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,567 Abandoned US20030069394A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,563 Abandoned US20030060602A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,549 Expired - Lifetime US7253256B2 (en) 1999-03-08 2002-05-02 Polypeptides encoded by a nucleic acid are expressed in esophageal and kidney tumor
US10/063,554 Expired - Fee Related US7223841B2 (en) 1999-03-08 2002-05-02 PR0994 antibodies
US10/063,548 Granted US20030187228A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,524 Expired - Lifetime US7205391B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptide suppressed in stomach tumors
US10/063,568 Abandoned US20030181668A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,546 Expired - Lifetime US7435798B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptide encoded by a nucleic acid overexpressed in normal stomach, normal skin and kidney tumor
US10/063,526 Abandoned US20030171550A1 (en) 1998-06-02 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,537 Expired - Lifetime US7276586B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptide encoded by a nucleic acid under-expressed in stomach and lung tumor
US10/063,540 Expired - Lifetime US7193061B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptide encoded by a nucleic acid underexpressed in esophageal tumor and melanoma
US10/063,560 Expired - Fee Related US7232882B2 (en) 1999-03-08 2002-05-02 Polypeptide uder-expressed in melanoma
US10/063,527 Abandoned US20030181637A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,562 Abandoned US20030181697A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,555 Abandoned US20030065143A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,553 Expired - Lifetime US7235630B2 (en) 1999-03-08 2002-05-02 PRO994 polypeptides
US10/063,536 Expired - Lifetime US7259238B2 (en) 1999-03-08 2002-05-02 Polypeptide encoded by a nucleic acid under-expressed in stomach and lung tumor
US10/063,548 Expired - Lifetime US7232892B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptide encoded by a nucleic acid differentailly expressed in stomach, lung and melanoma tumor
US10/063,534 Expired - Lifetime US7193060B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptides encoded by a nucleic acid overexpressed in kidney tumor and underexpressed in lung tumor
US10/063,611 Granted US20030181677A1 (en) 1998-12-30 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,592 Granted US20030181672A1 (en) 1998-10-27 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,589 Abandoned US20030181641A1 (en) 1998-12-30 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,610 Granted US20030180907A1 (en) 1998-12-30 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,610 Expired - Lifetime US7371814B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,597 Expired - Lifetime US7227000B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,577 Expired - Lifetime US7423130B2 (en) 1999-03-08 2002-05-03 PRO1158 polypeptides
US10/063,600 Expired - Fee Related US7230076B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,616 Expired - Lifetime US7358339B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,598 Expired - Fee Related US7223838B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,591 Granted US20030180906A1 (en) 1998-10-27 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,593 Expired - Lifetime US7189805B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,602 Expired - Lifetime US7230082B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,611 Expired - Lifetime US7378501B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,596 Expired - Lifetime US7285624B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,617 Expired - Lifetime US7423119B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,588 Abandoned US20030130483A1 (en) 1998-12-30 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,579 Abandoned US20030181638A1 (en) 1998-12-30 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,591 Expired - Lifetime US7196174B2 (en) 1998-10-27 2002-05-03 PRO1557 polypeptide encoded by a nucleic acid highly expressed in esophageal and kidney tumors
US10/063,583 Expired - Lifetime US7189804B2 (en) 1999-03-08 2002-05-03 PRO1335 polypeptides
US10/063,606 Abandoned US20030181675A1 (en) 1998-12-30 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,578 Expired - Lifetime US7417125B2 (en) 1999-03-08 2002-05-03 Antibodies that bind a PRO1158 polypeptide
US10/063,581 Expired - Lifetime US7189803B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,614 Expired - Lifetime US7393931B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,618 Expired - Lifetime US7468424B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,592 Expired - Lifetime US7220841B2 (en) 1998-10-27 2002-05-03 Antibody to PRO1557 polypeptide encoded by a nucleic acid highly expressed in esophageal and kidney tumors
US10/063,615 Expired - Lifetime US7405269B2 (en) 1998-10-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,607 Expired - Fee Related US7345145B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,582 Expired - Lifetime US7205389B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,604 Expired - Lifetime US7390876B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,640 Expired - Lifetime US7354997B2 (en) 1999-03-08 2002-05-07 Polypeptide encoded by a nucleic acid underexpressed in stomach tumor
US10/063,646 Granted US20030181681A1 (en) 1998-10-20 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,648 Expired - Lifetime US7193062B2 (en) 1998-10-20 2002-05-07 Antibodies to a polypeptide encoded by a nucleic acid over expressed in esoprageal and lung tumor, and under expressed in kidney tumor and melanoma
US10/063,650 Expired - Lifetime US7217787B2 (en) 1999-03-08 2002-05-07 Polypeptide encoded by a nucleic acid underexpressed in rectal tumor
US10/063,652 Expired - Lifetime US7230077B2 (en) 1999-03-08 2002-05-07 Polypeptide encoded by a nucleic acid underexpressed in melanoma
US10/063,653 Expired - Lifetime US7238787B2 (en) 1999-03-08 2002-05-07 Antibodies to a polypeptide encoded by a nucleic acid underexpressed in melanoma
US10/063,638 Expired - Fee Related US7101970B2 (en) 1999-03-08 2002-05-07 PRO1570 polypeptides
US10/063,662 Abandoned US20030180795A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,676 Abandoned US20030180843A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,647 Granted US20030187197A1 (en) 1998-10-20 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,642 Abandoned US20030181650A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,646 Expired - Lifetime US7189821B2 (en) 1998-10-20 2002-05-07 Antibodies to a polypeptide encoded by a nucleic acid underexpressed in lung tumor
US10/063,644 Granted US20030181651A1 (en) 1998-10-20 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,664 Expired - Lifetime US7256262B2 (en) 1999-03-08 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,659 Expired - Lifetime US7186801B2 (en) 1999-03-08 2002-05-07 Polypeptide encoded by a nucleic acid underexpressed in stomach tumor and lung tumor
US10/063,672 Abandoned US20030181700A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,669 Abandoned US20030180838A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,666 Expired - Lifetime US7411037B2 (en) 1999-03-08 2002-05-07 Polypeptides encoded by a nucleic acid underexpressed in melanoma
US10/063,671 Abandoned US20030180840A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,660 Expired - Lifetime US7189822B2 (en) 1999-03-08 2002-05-07 Antibodies to a polypeptide encoded by a nucleic acid underexpressed in stomach and lung tumor
US10/063,675 Abandoned US20030180842A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,677 Abandoned US20030187242A1 (en) 1998-06-02 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,670 Abandoned US20030180839A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,668 Abandoned US20030191290A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,657 Expired - Lifetime US7193063B2 (en) 1999-03-08 2002-05-07 Antibodies to a polypeptide encoded by a nucleic acid overexpressed in esophageal tumor, normal stomach and melanoma
US10/063,674 Abandoned US20030180841A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,661 Expired - Lifetime US7193047B2 (en) 1999-03-08 2002-05-07 Polypeptide encoded by a nucleic acid underexpressed in esophageal tumor
US10/063,644 Expired - Lifetime US7196167B2 (en) 1998-10-20 2002-05-07 Polypeptide underexpressed in lung tumor
US10/063,654 Expired - Lifetime US7202337B2 (en) 1999-03-08 2002-05-07 Polypeptide encoded by a nucleic acid overexpressed in esophageal tumor, normal stomach and melanoma
US10/063,673 Abandoned US20030180908A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,643 Abandoned US20030181680A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,649 Abandoned US20030181652A1 (en) 1998-10-08 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,639 Expired - Fee Related US7081520B2 (en) 1998-10-08 2002-05-07 Anti-pro 1570 antibodies
US10/063,647 Expired - Lifetime US7193046B2 (en) 1998-10-20 2002-05-07 Polypeptide encoded by a nucleic acid overexpressed in esophageal and lung tumor, and underexpressesd in kidney tumor and melanoma
US10/063,665 Expired - Lifetime US7427664B2 (en) 1999-03-08 2002-05-07 Antibodies to polypeptides that stimulate TNF-α release
US10/063,714 Abandoned US20030180913A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,726 Abandoned US20030180919A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,692 Abandoned US20030180846A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,744 Abandoned US20030180863A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,686 Abandoned US20030180844A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,712 Abandoned US20030180912A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,709 Expired - Fee Related US7189564B2 (en) 1999-03-08 2002-05-08 PRO1335 nucleic acids
US10/063,720 Abandoned US20030180917A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,698 Abandoned US20030180849A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,728 Abandoned US20030180920A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,721 Abandoned US20030181702A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,736 Abandoned US20030180860A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,727 Abandoned US20030180857A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,682 Abandoned US20030181701A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,707 Abandoned US20030180853A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,715 Abandoned US20030180914A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,713 Abandoned US20030180855A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,732 Abandoned US20030180922A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,685 Abandoned US20030180909A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,716 Abandoned US20030180915A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,724 Abandoned US20030180856A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,703 Expired - Lifetime US7189563B2 (en) 1999-03-08 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,699 Abandoned US20030180850A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,730 Abandoned US20030180858A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,689 Abandoned US20030180845A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,731 Abandoned US20030180921A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,693 Abandoned US20030180847A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,705 Expired - Fee Related US7220850B2 (en) 1999-03-08 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,723 Abandoned US20030181703A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,718 Abandoned US20030190698A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,688 Abandoned US20030186408A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,722 Abandoned US20030180918A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,734 Abandoned US20030180859A1 (en) 1998-10-08 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,694 Abandoned US20030180848A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,735 Abandoned US20030138882A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,711 Abandoned US20030180911A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,702 Expired - Lifetime US7193074B2 (en) 1999-03-08 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,710 Abandoned US20030180910A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,717 Abandoned US20030180916A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,684 Abandoned US20030186407A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,741 Expired - Lifetime US7118887B2 (en) 1999-03-08 2002-05-09 Nucleic acid overexpressed in esophageal tumor, normal stomach and melanoma
US10/063,745 Abandoned US20040058411A1 (en) 1998-12-30 2002-05-09 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,742 Expired - Fee Related US7189532B2 (en) 1999-03-08 2002-05-09 Nucleic acid underexpressed in stomach tumor and lung tumor
US10/063,743 Abandoned US20030180862A1 (en) 1998-12-30 2002-05-09 Secreted and transmembrane polypeptides and nucleic acids encoding the same

Family Applications Before (37)

Application Number Title Priority Date Filing Date
US10/063,517 Expired - Lifetime US7232889B2 (en) 1999-03-08 2002-05-01 PRO300 antibodies
US10/063,518 Expired - Lifetime US7465785B2 (en) 1999-03-08 2002-05-01 Polypeptide encoded by a nucleic acid over-expressed in melanoma
US10/063,510 Expired - Fee Related US7109292B2 (en) 1999-03-08 2002-05-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,520 Abandoned US20030187196A1 (en) 1998-12-30 2002-05-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,521 Abandoned US20030190669A1 (en) 1998-12-30 2002-05-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,519 Granted US20030009013A1 (en) 1998-12-30 2002-05-01 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,564 Abandoned US20030180794A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,545 Expired - Lifetime US7256261B2 (en) 1999-03-08 2002-05-02 Polypeptides encoded by a nucleic acid over expressed in normal stomach normal skin and kidney tumor
US10/063,547 Granted US20020182638A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,565 Abandoned US20030180904A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,561 Expired - Lifetime US7271247B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptide encoded by a nucleic acid differentially expressed in melanoma
US10/063,532 Expired - Lifetime US7202336B2 (en) 1999-03-08 2002-05-02 Polypeptide encoded by a nucleic acid overexpressed in kidney tumor and underexpressed in lung tumor
US10/063,523 Granted US20030181636A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,524 Granted US20030027992A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,544 Abandoned US20030027212A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,525 Abandoned US20030036634A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,530 Expired - Lifetime US7193059B2 (en) 1999-03-08 2002-05-02 Antibodies that recognize a polypeptide overexpressed in rectal tumors
US10/063,569 Granted US20030018168A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,551 Granted US20020183494A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,566 Abandoned US20030073821A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,541 Abandoned US20030060601A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,540 Granted US20030181667A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,538 Expired - Lifetime US7253255B2 (en) 1999-03-08 2002-05-02 Polypeptide encoded by a nucleic acid underexpressed in esophageal tumor and melanoma
US10/063,523 Expired - Fee Related US7220830B2 (en) 1999-03-08 2002-05-02 Polypeptide underexpressed in stomach tumors
US10/063,553 Granted US20030045684A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,551 Expired - Lifetime US7214777B2 (en) 1999-03-08 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,569 Expired - Lifetime US7378491B2 (en) 1999-03-08 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,547 Expired - Lifetime US7294690B2 (en) 1999-03-08 2002-05-02 Polypeptides encoded by a nucleic acid differentially expressed in lung tumor
US10/063,528 Abandoned US20030181666A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,536 Granted US20030181696A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,545 Granted US20020183505A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,567 Abandoned US20030069394A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,563 Abandoned US20030060602A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,549 Expired - Lifetime US7253256B2 (en) 1999-03-08 2002-05-02 Polypeptides encoded by a nucleic acid are expressed in esophageal and kidney tumor
US10/063,554 Expired - Fee Related US7223841B2 (en) 1999-03-08 2002-05-02 PR0994 antibodies
US10/063,548 Granted US20030187228A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,524 Expired - Lifetime US7205391B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptide suppressed in stomach tumors

Family Applications After (121)

Application Number Title Priority Date Filing Date
US10/063,546 Expired - Lifetime US7435798B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptide encoded by a nucleic acid overexpressed in normal stomach, normal skin and kidney tumor
US10/063,526 Abandoned US20030171550A1 (en) 1998-06-02 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,537 Expired - Lifetime US7276586B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptide encoded by a nucleic acid under-expressed in stomach and lung tumor
US10/063,540 Expired - Lifetime US7193061B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptide encoded by a nucleic acid underexpressed in esophageal tumor and melanoma
US10/063,560 Expired - Fee Related US7232882B2 (en) 1999-03-08 2002-05-02 Polypeptide uder-expressed in melanoma
US10/063,527 Abandoned US20030181637A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,562 Abandoned US20030181697A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,555 Abandoned US20030065143A1 (en) 1998-12-30 2002-05-02 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,553 Expired - Lifetime US7235630B2 (en) 1999-03-08 2002-05-02 PRO994 polypeptides
US10/063,536 Expired - Lifetime US7259238B2 (en) 1999-03-08 2002-05-02 Polypeptide encoded by a nucleic acid under-expressed in stomach and lung tumor
US10/063,548 Expired - Lifetime US7232892B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptide encoded by a nucleic acid differentailly expressed in stomach, lung and melanoma tumor
US10/063,534 Expired - Lifetime US7193060B2 (en) 1999-03-08 2002-05-02 Antibodies to a polypeptides encoded by a nucleic acid overexpressed in kidney tumor and underexpressed in lung tumor
US10/063,611 Granted US20030181677A1 (en) 1998-12-30 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,592 Granted US20030181672A1 (en) 1998-10-27 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,589 Abandoned US20030181641A1 (en) 1998-12-30 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,610 Granted US20030180907A1 (en) 1998-12-30 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,610 Expired - Lifetime US7371814B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,597 Expired - Lifetime US7227000B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,577 Expired - Lifetime US7423130B2 (en) 1999-03-08 2002-05-03 PRO1158 polypeptides
US10/063,600 Expired - Fee Related US7230076B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,616 Expired - Lifetime US7358339B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,598 Expired - Fee Related US7223838B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,591 Granted US20030180906A1 (en) 1998-10-27 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,593 Expired - Lifetime US7189805B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,602 Expired - Lifetime US7230082B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,611 Expired - Lifetime US7378501B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,596 Expired - Lifetime US7285624B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,617 Expired - Lifetime US7423119B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,588 Abandoned US20030130483A1 (en) 1998-12-30 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,579 Abandoned US20030181638A1 (en) 1998-12-30 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,591 Expired - Lifetime US7196174B2 (en) 1998-10-27 2002-05-03 PRO1557 polypeptide encoded by a nucleic acid highly expressed in esophageal and kidney tumors
US10/063,583 Expired - Lifetime US7189804B2 (en) 1999-03-08 2002-05-03 PRO1335 polypeptides
US10/063,606 Abandoned US20030181675A1 (en) 1998-12-30 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,578 Expired - Lifetime US7417125B2 (en) 1999-03-08 2002-05-03 Antibodies that bind a PRO1158 polypeptide
US10/063,581 Expired - Lifetime US7189803B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,614 Expired - Lifetime US7393931B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,618 Expired - Lifetime US7468424B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,592 Expired - Lifetime US7220841B2 (en) 1998-10-27 2002-05-03 Antibody to PRO1557 polypeptide encoded by a nucleic acid highly expressed in esophageal and kidney tumors
US10/063,615 Expired - Lifetime US7405269B2 (en) 1998-10-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,607 Expired - Fee Related US7345145B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,582 Expired - Lifetime US7205389B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,604 Expired - Lifetime US7390876B2 (en) 1999-03-08 2002-05-03 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,640 Expired - Lifetime US7354997B2 (en) 1999-03-08 2002-05-07 Polypeptide encoded by a nucleic acid underexpressed in stomach tumor
US10/063,646 Granted US20030181681A1 (en) 1998-10-20 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,648 Expired - Lifetime US7193062B2 (en) 1998-10-20 2002-05-07 Antibodies to a polypeptide encoded by a nucleic acid over expressed in esoprageal and lung tumor, and under expressed in kidney tumor and melanoma
US10/063,650 Expired - Lifetime US7217787B2 (en) 1999-03-08 2002-05-07 Polypeptide encoded by a nucleic acid underexpressed in rectal tumor
US10/063,652 Expired - Lifetime US7230077B2 (en) 1999-03-08 2002-05-07 Polypeptide encoded by a nucleic acid underexpressed in melanoma
US10/063,653 Expired - Lifetime US7238787B2 (en) 1999-03-08 2002-05-07 Antibodies to a polypeptide encoded by a nucleic acid underexpressed in melanoma
US10/063,638 Expired - Fee Related US7101970B2 (en) 1999-03-08 2002-05-07 PRO1570 polypeptides
US10/063,662 Abandoned US20030180795A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,676 Abandoned US20030180843A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,647 Granted US20030187197A1 (en) 1998-10-20 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,642 Abandoned US20030181650A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,646 Expired - Lifetime US7189821B2 (en) 1998-10-20 2002-05-07 Antibodies to a polypeptide encoded by a nucleic acid underexpressed in lung tumor
US10/063,644 Granted US20030181651A1 (en) 1998-10-20 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,664 Expired - Lifetime US7256262B2 (en) 1999-03-08 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,659 Expired - Lifetime US7186801B2 (en) 1999-03-08 2002-05-07 Polypeptide encoded by a nucleic acid underexpressed in stomach tumor and lung tumor
US10/063,672 Abandoned US20030181700A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,669 Abandoned US20030180838A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,666 Expired - Lifetime US7411037B2 (en) 1999-03-08 2002-05-07 Polypeptides encoded by a nucleic acid underexpressed in melanoma
US10/063,671 Abandoned US20030180840A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,660 Expired - Lifetime US7189822B2 (en) 1999-03-08 2002-05-07 Antibodies to a polypeptide encoded by a nucleic acid underexpressed in stomach and lung tumor
US10/063,675 Abandoned US20030180842A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,677 Abandoned US20030187242A1 (en) 1998-06-02 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,670 Abandoned US20030180839A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,668 Abandoned US20030191290A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,657 Expired - Lifetime US7193063B2 (en) 1999-03-08 2002-05-07 Antibodies to a polypeptide encoded by a nucleic acid overexpressed in esophageal tumor, normal stomach and melanoma
US10/063,674 Abandoned US20030180841A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,661 Expired - Lifetime US7193047B2 (en) 1999-03-08 2002-05-07 Polypeptide encoded by a nucleic acid underexpressed in esophageal tumor
US10/063,644 Expired - Lifetime US7196167B2 (en) 1998-10-20 2002-05-07 Polypeptide underexpressed in lung tumor
US10/063,654 Expired - Lifetime US7202337B2 (en) 1999-03-08 2002-05-07 Polypeptide encoded by a nucleic acid overexpressed in esophageal tumor, normal stomach and melanoma
US10/063,673 Abandoned US20030180908A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,643 Abandoned US20030181680A1 (en) 1998-12-30 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,649 Abandoned US20030181652A1 (en) 1998-10-08 2002-05-07 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,639 Expired - Fee Related US7081520B2 (en) 1998-10-08 2002-05-07 Anti-pro 1570 antibodies
US10/063,647 Expired - Lifetime US7193046B2 (en) 1998-10-20 2002-05-07 Polypeptide encoded by a nucleic acid overexpressed in esophageal and lung tumor, and underexpressesd in kidney tumor and melanoma
US10/063,665 Expired - Lifetime US7427664B2 (en) 1999-03-08 2002-05-07 Antibodies to polypeptides that stimulate TNF-α release
US10/063,714 Abandoned US20030180913A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,726 Abandoned US20030180919A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,692 Abandoned US20030180846A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,744 Abandoned US20030180863A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,686 Abandoned US20030180844A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,712 Abandoned US20030180912A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,709 Expired - Fee Related US7189564B2 (en) 1999-03-08 2002-05-08 PRO1335 nucleic acids
US10/063,720 Abandoned US20030180917A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,698 Abandoned US20030180849A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,728 Abandoned US20030180920A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,721 Abandoned US20030181702A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,736 Abandoned US20030180860A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,727 Abandoned US20030180857A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,682 Abandoned US20030181701A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,707 Abandoned US20030180853A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,715 Abandoned US20030180914A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,713 Abandoned US20030180855A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,732 Abandoned US20030180922A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,685 Abandoned US20030180909A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,716 Abandoned US20030180915A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,724 Abandoned US20030180856A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,703 Expired - Lifetime US7189563B2 (en) 1999-03-08 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,699 Abandoned US20030180850A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,730 Abandoned US20030180858A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,689 Abandoned US20030180845A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,731 Abandoned US20030180921A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,693 Abandoned US20030180847A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,705 Expired - Fee Related US7220850B2 (en) 1999-03-08 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,723 Abandoned US20030181703A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,718 Abandoned US20030190698A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,688 Abandoned US20030186408A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,722 Abandoned US20030180918A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,734 Abandoned US20030180859A1 (en) 1998-10-08 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,694 Abandoned US20030180848A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,735 Abandoned US20030138882A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,711 Abandoned US20030180911A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,702 Expired - Lifetime US7193074B2 (en) 1999-03-08 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,710 Abandoned US20030180910A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,717 Abandoned US20030180916A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,684 Abandoned US20030186407A1 (en) 1998-12-30 2002-05-08 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,741 Expired - Lifetime US7118887B2 (en) 1999-03-08 2002-05-09 Nucleic acid overexpressed in esophageal tumor, normal stomach and melanoma
US10/063,745 Abandoned US20040058411A1 (en) 1998-12-30 2002-05-09 Secreted and transmembrane polypeptides and nucleic acids encoding the same
US10/063,742 Expired - Fee Related US7189532B2 (en) 1999-03-08 2002-05-09 Nucleic acid underexpressed in stomach tumor and lung tumor
US10/063,743 Abandoned US20030180862A1 (en) 1998-12-30 2002-05-09 Secreted and transmembrane polypeptides and nucleic acids encoding the same

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