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  • Review Article
  • Published:

Tetraspanins: push and pull in suppressing and promoting metastasis

Nature Reviews Cancer volume 9, pages 40–55 (2009)Cite this article

Key Points

  • The tetraspanins are a family of proteins that cross the membrane four times and have a short amino- and carboxy-terminal tail, a small intracellular loop between transmembrane region 2 (TM2) and TM3, a small extracellular loop (ECL1) between TM1 and TM2 and a large extracellular loop (ECL2) between TM3 and TM4. Palmitoylation of intracellular, juxtamembrane cysteines is thought to be required for initiating tetraspanin–tetraspanin web formation.

  • Tetraspanins form complexes by interacting between themselves and with a variety of transmembrane and cytosolic proteins that are required for their function, including integrins, growth factor receptors, G-protein-coupled receptors and their intracellular associated heterotrimeric G-proteins, several peptidases, transmembrane proteins associated with tumour progression, immunoglobulin superfamily members and cytosolic signal transduction molecules.

  • Tetraspanins also associate with cholesterol and gangliosides, enabling higher order tetraspanin complexes to form in microdomains, termed tetraspanin-enriched membrane microdomains (TEMs), which provide a signalling platform. Although TEMs share several features with lipid rafts, they are independent and different from these structures.

  • Tetraspanins are abundant in membranes of various types of endocytic organelles and in exosomes — 30–100 nm vesicles that are released by many cells. Exosomes are thought to constitute a potent mode of intercellular communication that is also important in tumour progression.

  • Tetraspanins function by modulating, stabilizing or preventing the activities of their associated molecules, which vary depending on the composition of the TEM. Thus, tetraspanins can promote spreading and migration, which mostly rely on compartmentalization of integrins or integrin internalization and recycling or on modulating integrin signalling. However, tetraspanins can also be important in cell adhesion by regulating the trafficking and biosynthesis of associating integrins.

  • The tetraspanins CD82 and CD9 mostly suppress tumour progression. By their interactions with a variety of proteins including integrins, signalling proteins and immunoglobulin superfamily members they suppress motility and promote adherance to the surrounding matrix. Their expression is often reduced in late-stage human tumours.

  • Two tetraspanins, CD151 and tetraspanin 8 (D6.1A in rats), are overexpressed in several human tumours and seem to support tumour progression. CD151 regulates cell migration, mostly through its association with α3β1, α6β4 and matrix metalloproteinases. Additional transmembrane and cytosolic proteins in multimolecular complexes in TEM, contribute. Tetraspanin 8 regulates cell motility and survival and is involved in the promotion of angiogenesis.

  • The opposing effects of CD82 and CD9 versus CD15 and tetraspanin 8 on metastasis suppression and promotion cannot be fully explained by differences in the composition of the TEM. Indeed, there are strong hints that, by their enrichment in exosomes, tetraspanins and associated molecules become engaged in intercellular communication, where their involvement in membrane fusion facilitates message, including mRNA and microRNA, delivery.

  • A more comprehensive picture of the dynamics of TEM and the contribution of tetraspanins to exosome-meditated intercellular communication might allow us to therapeutically dictate the push and pull of tetraspanins in metastasis suppression.

Abstract

Tumours progress through a cascade of events that enable the formation of metastases. Some of the components that are required for this fatal process are well established. Tetraspanins, however, have only recently received attention as both metastasis suppressors and metastasis promoters. This late appreciation is probably due to their capacity to associate with various molecules, which they recruit into special membrane microdomains, and their abundant presence in tumour-derived small vesicles that aid intercellular communication. It is reasonable to assume that differences in the membrane and vesicular web components that associate with individual tetraspanins account for their differing abilities to promote and suppress metastasis.

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Figure 1: Tetraspanins and associated molecules.
Figure 2: The generation and composition of exosomes.
Figure 3: Modes of CD82-mediated metastasis inhibition: CD82 impairs cell motility through several routes.
Figure 4: The multiple routes of CD9-mediated metastasis suppression.
Figure 5: CD151, matrix metalloproteinses (MMPs) and integrin-promoted cell motility.
Figure 6: Tetraspanins in intercellular communication exemplified for D6.1A.

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Acknowledgements

am most grateful to S. Levy for her suggestions and help during preparation of this article. I thank the (former) people of my laboratory, particularly Christoph Claas, for helpful comments. The work in the author's laboratory described in this article is supported by the German Research Foundation (grant ZO 40/12-1) and the Tumourzentrum Heidelberg/Mannheim.

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Authors and Affiliations

  1. Department of Tumour Cell Biology, and Department of Tumour Progression and Immune Defense, University Hospital of Surgery, German Cancer Research Center, Heidelberg

    Margot Zöller

  2. Department of Applied Genetics, University of Karlsruhe, Karlsruhe, Germany

    Margot Zöller

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Diagnostic and prognostic relevance of CD9, CD151 and CO-029 expression in human cancer (PDF 206 kb)

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Glossary

Palmitoylation

S-Acylation of proteins with palmitate.

Gangliosides

Anionic glycosphingolipids characterized by sialic acid residues. Non-transformed cells mostly express gangliosides with complex oligosaccharides like GM1 and GD1a; tumour cells mostly express GM3 and GM2, which are characterized by a loss of complex oligosaccharides.

Type II phosphatidylinositol 4-kinase

(PI4KII). PI4KIIs generate phosphatidylinositol 4-phosphates, which are precursors of important regulatory phosphoinosites. PI4KIIs regulate a diverse array of signalling events, as well as vesicular trafficking and lipid transport.

EWI

A new class of transmembrane immunoglobulin G superfamily molecules that contain a conserved glutamic acid – phenyalanine–isoleucine (EWI) motif. Two members, EWI-F and EWI-2, can associate with tetraspanins directly.

Cable formation

Some cells grow on gelatinous matrices such as Matrigel along lines of mechanical tension, forming a pattern of intersecting cellular cables.

Ezrin–radixin–moesin proteins

(ERM proteins). ERM proteins mediate actin–membrane linkage and regulate signalling molecules. In the dormant state the N-terminal domain is masked by interactions with the C-terminal domain. Only phosphorylated ERM proteins link membrane proteins to the actin cytoskeleton.

ADAM

(A disintegrin and metalloprotease). A family of multidomain membrane proteins that combine a cytokine-rich disintegrin and a zinc metalloprotease domain in their ectodomain.

GRB2

(Growth factor receptor-bound protein 2). GRB2 is a key molecule in intracellular signal transduction, linking activated cell surface receptors to downstream targets by binding to specific phosphotyrosine-containing and proline-rich sequence motifs. GRB2 signalling is crucial for cell cycle progression and actin-based cell motility, and more complex processes such as epithelial morphogenesis, angiogenesis and vasculogenesis.

Endosomal sorting complexes required for transport

(ESCRT). ESCRT complexes deform the endosome-limiting membrane by specific protein–protein and protein–lipid interactions, thereby orchestrating the inward budding of vesicles.

CD13 or CD26

CD13 is a zinc-dependent metalloprotease. Along with CD26, a serine exopeptidase, it cleaves neutral amino acids from the amino-termini of proteins. CD13 is frequently deregulated in cancer.

FAKp–130CAS–CRKII complex

The recruitment of SRC into a focal adhesion kinase (FAK)–SRC signalling complex facilitates the phosphorylation of FAK-associated proteins. SRC recruits the docking protein p130CAS to focal adhesions in association with CRKII. Together, these proteins stimulate cell migration and invasion.

GAB1

(GRB2 associated binder 1). A member of an adaptor/scaffolding protein family. Gab adaptors are involved in multiple signalling pathways that are mediated by receptor and non-receptor protein tyrosine kinases and become phosphorylated upon stimulation.

TBX2

(T-box 2). A member of a family of genes encoding developmental transcription factors, characterized by a 200 amino acid DNA binding domain (a T-box). TBX2 has been implicated in development of a number of different tissues and in tumour development through downregulation of the tumour suppressor ARF and an associated bypass of senescence.

AP2

A transcription factor originally described as involved in the transcription of NRAS, PKC and TGFα.

NCOR1–TAB2–HDAC3 complex

A complex containing the nuclear receptor co-repressor NCOR1 and the TAK1-binding adaptor protein TAB2, which physically interacts with histone deacetylase 3 (HDAC3).

CSK

(C-terminal Src kinase). An endogenous inhibitor of the Src family protein tyrosine kinases.

WAVE2

Member of the WASP (Wiskott–Aldrich syndrome protein) family of proteins that regulate cortical actin filament reorganization in response to extracellular stimuli.

ARP2 and ARP3

(Actin-related proteins 2 and 3). ARP2 and ARP3 act as multifunctional organizers of actin filaments in all eukaryotes.

CLEC2

(C-type lectin-like receptor 2). CLEC2 is expressed on the surface of platelets and functions as a receptor for the snake venom protein rhodocytin. It displays a single carbohydrate recognition domain and a cytoplasmic tyrosine-based motif. CLEC2 signals through a single YXXL motif that requires the tandem SH2 domains of SYK.

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Zöller, M. Tetraspanins: push and pull in suppressing and promoting metastasis. Nat Rev Cancer 9, 40–55 (2009). https://doi.org/10.1038/nrc2543

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