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Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.

Niculescu-Duvaz D ,

Cancer Genome Project

Affiliations

1. Section of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK.
Authors
Wan PT¹
(1 author)

ORCIDs linked to this article

Cell, 01 Mar 2004, 116(6):855-867
https://doi.org/10.1016/s0092-8674(04)00215-6 PMID: 15035987

A comment on this article appears in "Oncogenic mutations in B-Raf: some losses yield gains." Cell. 2004 Mar 19;116(6):764-6.

Abstract

Over 30 mutations of the B-RAF gene associated with human cancers have been identified, the majority of which are located within the kinase domain. Here we show that of 22 B-RAF mutants analyzed, 18 have elevated kinase activity and signal to ERK in vivo. Surprisingly, three mutants have reduced kinase activity towards MEK in vitro but, by activating C-RAF in vivo, signal to ERK in cells. The structures of wild type and oncogenic V599EB-RAF kinase domains in complex with the RAF inhibitor BAY43-9006 show that the activation segment is held in an inactive conformation by association with the P loop. The clustering of most mutations to these two regions suggests that disruption of this interaction converts B-RAF into its active conformation. The high activity mutants signal to ERK by directly phosphorylating MEK, whereas the impaired activity mutants stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or transphosphorylation mechanism.

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Read article at publisher's site: https://doi.org/10.1016/s0092-8674(04)00215-6

Read article for free, from open access legal sources, via Unpaywall: http://www.cell.com/article/S0092867404002156/pdf

References

Articles referenced by this article (48)

Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade.
Avruch J, Khokhlatchev A, Kyriakis JM, Luo Z, Tzivion G, Vavvas D, Zhang XF
Recent Prog Horm Res, 127-155 2001
MED: 11237210
Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL.
Azam M, Latek RR, Daley GQ
Cell, (6):831-843 2003
MED: 12654249
A scaleable Synthesis of BAY 43–9006
Bankston
Organic Process Res. & Dev. 2002
Hsp-90-associated oncoproteins: multiple targets of geldanamycin and its analogs.
Blagosklonny MV
Leukemia, (4):455-462 2002
MED: 11960322
BRAF and RAS mutations in human lung cancer and melanoma.
Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, Einhorn E, Herlyn M, Minna J, Nicholson A, Roth JA, Albelda SM, Davies H, Cox C, Brignell G, Stephens P, Futreal PA, Wooster R, Stratton MR, Weber BL
Cancer Res, (23):6997-7000 2002
MED: 12460918
Crystallography & NMR system: A new software suite for macromolecular structure determination.
Brunger AT, Adams PD, Clore GM, DeLano WL, Gros P, Grosse-Kunstleve RW, Jiang JS, Kuszewski J, Nilges M, Pannu NS, Read RJ, Rice LM, Simonson T, Warren GL
Acta Crystallogr D Biol Crystallogr, (Pt 5):905-921 1998
MED: 9757107
The CCP4 (Collaborative Computational Project Number 4) Suite
CCP4
Acta Cryst D 1991
Positive and negative regulation of Raf kinase activity and function by phosphorylation.
Chong H, Lee J, Guan KL
EMBO J, (14):3716-3727 2001
MED: 11447113
Lack of BRAF mutation in primary uveal melanoma.
Cohen Y, Goldenberg-Cohen N, Parrella P, Chowers I, Merbs SL, Pe'er J, Sidransky D
Invest Ophthalmol Vis Sci, (7):2876-2878 2003
MED: 12824225
Mutations of the BRAF gene in human cancer.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, [...] Futreal PA
Nature, (6892):949-954 2002
MED: 12068308

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Wikipedia (4)

Data

Data that cites the article

This data has been provided by curated databases and other sources that have cited the article.

Diseases in OMIM

V-RAF MURINE SARCOMA VIRAL ONCOGENE HOMOLOG B1; BRAF(OMIM - 164757)

Proteins in UniProt (Showing 5 of 51)

Fibrinogen gamma chain(UniProt - P02679)
Fibronectin(UniProt - P02751)
RAF proto-oncogene serine/threonine-protein kinase(UniProt - P04049)
Fibrinogen beta chain(UniProt - P02675)
Fibrinogen alpha chain(UniProt - P02671)

Go to all (51) records in UniProt

GlyGen is an international glycobioinformatics knowledgebase funded by The National Institutes of Health to facilitate glycoscience research by integrating diverse kinds of information, including glycomics, genomics, proteomics (and glycoproteomics), cell biology, developmental biology and biochemistry.

https://www.glygen.org/publication/MED/15035987

Protein structures in PDBe (2)

the complex of mutant v599e b-raf and bay439006.(PDB - 1uwj)
View structure
the complex of wild type b-raf and bay439006.(PDB - 1uwh)
View structure

The Rat Genome Database (RGD) was established in 1999 and rapidly became the premier site for genetic, genomic, phenotype, and disease-related data generated from rat research. In addition, RGD has expanded to include a large body of structured and standardized data for eight species (rat, mouse, human, chinchilla, bonobo, 13-lined ground squirrel, dog and pig). Much of this data is the result of manual curation work by RGD curators. In other instances, it has been imported into RGD from other databases through custom ELT (Extract, Load and Transform) pipelines giving RGD users integrated access to a wide variety of data to support their research efforts. RGD also offers a growing suite of innovative tools for querying, analyzing and visualizing this data making it a valuable resource for researchers worldwide.

https://rgd.mcw.edu/rgdweb/report/reference/main.html?id=11068352

Reactome (3)

Xenbase is a model organism database, providing bioinformatics resources, as well as genomic and biological data on Xenopus laevis and Xenopus tropicalis frogs.

https://www.xenbase.org/literature/article.do?method=display&articleId=34648

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