Key Points
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Tetraspanins do not protrude far above the plasma membrane, and do not typically bind external ligands. Nonetheless, this large family of molecules (for example, there are 32 in mammals) has considerable functional importance. By organizing multimolecular membrane complexes, tetraspanins regulate cell migration, fusion and signalling events.
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Mammalian genetics has yielded new insights into tetraspanin functions. For example, CD151 contributes to normal kidney, skin and platelet function; peripherin/RDS and ROM-1 support retinal integrity; and TALLA-1/A15 is important for brain function. Other tetraspanins enable sperm–egg fusion (CD9), support nervous system development (CD9, CD81), regulate monocyte fusion (CD9, CD81) and contribute to T-cell proliferation (CD151, CD37, Tssc6, CD81).
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Additional definitive insights come from genetic analyses in other species. Drosophila melanogaster tetraspanins are linked to light-induced retinal degeneration and haemocyte proliferation. The first reported Caenorhabditis elegans tetraspanin mutation leads to a disrupted epidermis, and several fungal tetraspanins are linked to host leaf penetration. These results from non-mammalian species provide important clues regarding the functions of tetraspanins in mammals.
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Although the tetraspanins CD81 and CD151 do not affect integrin-dependent ligand binding and cell adhesion, they do markedly influence integrin-dependent adhesion strengthening. Such results strongly suggest that tetraspanins can modulate the cytoskeleton, but specific connections remain to be established.
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Antibodies to the tetraspanins CD9 and CD81 can reduce cell proliferation. In both cases, recruitment of phosphatidylinositol 4-kinase, activation of Shc, and activation of the extracellular signal-regulated kinase (ERK)–mitogen-activated protein kinase (MAPK) pathway might underlie effects on proliferation. These same pathways might also link CD9 to apoptosis. CD151 and CD82 have also been linked to various signalling events, which could help to explain their effects on cell morphology, motility and tumour progression.
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Understanding the organization of tetraspanin-enriched microdomains (TEMs) is essential for understanding tetraspanin functions. At the core of TEMs are various direct protein–protein partnerships, both homophilic and heterophilic. These primary building blocks are then assembled into a larger network of secondary interactions, with protein palmitoylation having an important supporting role. TEMs are distinct from lipid rafts in terms of the identity of components, and sensitivity to temperature, cholesterol, detergents and protein palmitoylation.
Abstract
Cell-surface proteins of the tetraspanin family are small, and often hidden by a canopy of tall glycoprotein neighbours in the cell membrane. Consequently, tetraspanins have been understudied and underappreciated, despite their presence on nearly all cell and tissue types. Important new genetic evidence has now emerged, and is bolstered by new insights into the cell biology, signalling and biochemistry of tetraspanins. These new findings provide a framework for better understanding of these mysterious molecules in the regulation of cellular processes, from signalling to motility.
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References
Tarrant, J. M., Robb, L., van Spriel, A. B. & Wright, M. D. Tetraspanins: molecular organisers of the leukocyte surface. Trends Immunol. 24, 610–617 (2003).
Hemler, M. E. Tetraspanin proteins mediate cellular penetration, invasion and fusion events, and define a novel type of membrane microdomain. Ann. Rev. Cell Dev. Biol. 19, 397–422 (2003).
Boucheix, C. & Rubinstein, E. Tetraspanins. Cell Mol. Life Sci. 58, 1189–1205 (2001).
Boucheix, C., Thien Duc, G. H., Jasmin, C. & Rubinstein, E. Tetraspanins and malignancy. Expert Rev. Mol. Med. [online], http://www-ermm.cbcu.cam.ac.uk/01002381h.htm (2001).
Levy, S., Todd, S. C. & Maecker, H. T. CD81 (TAPA-1): a molecule involved in signal transduction and cell adhesion in the immune system. Annu. Rev. Immunol. 16, 89–109 (1998).
Maecker, H. T., Todd, S. C. & Levy, S. The tetraspanin superfamily: molecular facilitators. FASEB J. 11, 428–442 (1997).
Todres, E., Nardi, J. B. & Robertson, H. M. The tetraspanin superfamily in insects. Insect Mol. Biol. 9, 581–590 (2000).
Kitadokoro, K. et al. CD81 extracellular domain 3D structure: insight into the tetraspanin superfamily structural motifs. EMBO J. 20, 12–18 (2001). Provides the first detailed structural information for a tetraspanin.
Seigneuret, M., Delaguillaumie, A., Lagaudriere-Gesbert, C. & Conjeaud, H. Structure of the tetraspanin main extracellular domain. A partially conserved fold with a structurally variable domain insertion. J. Biol. Chem. 276, 40055–40064 (2001).
Berditchevski, F. Complexes of tetraspanins with integrins: more than meets the eye. J. Cell Sci. 114, 4143–4151 (2001).
Zemni, R. et al. A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation. Nature Genet. 24, 167–170 (2000).
Abidi, F. E. et al. A novel 2 bp deletion in the TM4SF2 gene is associated with MRX58. J. Med. Genet. 39, 430–433 (2002).
Kohl, S. et al. The role of the peripherin/RDS gene in retinal dystrophies. Acta Anat. (Basel) 162, 75–84 (1998).
Karamatic Crew, V. et al. CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin. Blood 104, 2217–2223 (2004). Human genetic information shows functions for CD151, and validates the importance of CD151–integrin complexes.
Yánez-Mó, M . et al. Regulation of endothelial cell motility by complexes of tetraspan molecules CD81/TAPA-1 and CD151/PETA-3 with α3β1 integrin localized at endothelial lateral junctions. J. Cell Biol. 141, 791–804 (1998).
Yauch, R. L., Berditchevski, F., Harler, M. B., Reichner, J. & Hemler, M. E. Highly stoichiometric, stable and specific association of integrin α3β1 with CD151 provides a major link to phosphatidylinositol 4-kinase and may regulate cell migration. Mol. Biol. Cell 9, 2751–2765 (1998).
Sincock, P. M. et al. PETA-3/CD151, a member of the transmembrane 4 superfamily, is localised to the plasma membrane and endocytic system of endothelial cells, associates with multiple integrins and modulates cell function. J. Cell Sci. 112, 833–844 (1999).
Kazarov, A. R., Yang, X., Stipp, C. S., Sehgal, B. & Hemler, M. E. An extracellular site on tetraspanin CD151 determines α3 and α6 integrin-dependent cellular morphology. J Cell. Biol. 158, 1299–1309 (2002).
Sterk, L. M. et al. Association of the tetraspanin CD151 with the laminin-binding integrins α3β1, α6β1, α6β4 and α7β1 in cells in culture and in vivo. J. Cell Sci. 115, 1161–1173 (2002).
Sterk, L. M. et al. The tetraspan molecule CD151, a novel constituent of hemidesmosomes, associates with the integrin alphaα6β4 and may regulate the spatial organization of hemidesmosomes. J. Cell Biol. 149, 969–982 (2000).
Ruzzi, L. et al. A homozygous mutation in the integrin α6 gene in junctional epidermolysis bullosa with pyloric atresia. J. Clin. Invest. 99, 2826–2831 (1997).
Gil, S. G., Brown, T. A., Ryan, M. C. & Carter, W. G. Junctional epidermolysis bullosis: defects in expression of epiligrin/nicein/kalinin and integrin β4 that inhibit hemidesmosome formation. J. Invest. Derm. 103, 31S–38S (1994).
Kreidberg, J. A. et al. α3β1 integrin has a crucial role in kidney and lung organogenesis. Development 122, 3537–3547 (1996).
Dipersio, C. M., Hodivala-Dilke, K. M., Jaenisch, R. & Kreidberg, J. A. α3β1 integrin is required for normal development of the epidermal basement membrane. J. Cell Biol. 137, 729–742 (1997).
Kagan, A., Feld, S., Chemke, J. & Bar-Khayim, Y. Occurrence of hereditary nephritis, pretibial epidermolysis bullosa and βthalassemia minor in two siblings with end-stage renal disease. Nephron 49, 331–332 (1988).
Connell, G. et al. Photoreceptor peripherin is the normal product of the gene responsible for retinal degeneration in the rds mouse. Proc. Natl Acad. Sci. USA 88, 723–726 (1991).
Clarke, G. et al. Rom-1 is required for rod photoreceptor viability and the regulation of disk morphogenesis. Nature Genet. 25, 67–73 (2000).
Lau, L. M. et al. The tetraspanin superfamily member, CD151 regulates outside-in integrin αIIbβ3 signalling and platelet function. Blood 104, 2368–2375 (2004).
Wright, M. D. et al. Characterization of mice lacking the tetraspanin superfamily member CD151. Mol. Cell. Biol. 24, 5978–5988 (2004).
Lammerding, J., Kazarov, A. R., Huang, H., Lee, R. T. & Hemler, M. E. Tetraspanin CD151 regulates alpha6beta1 integrin adhesion strengthening. Proc. Natl Acad. Sci. USA 100, 7616–7621 (2003).
Fitter, S., Sincock, P. M., Jolliffe, C. N. & Ashman, L. K. Transmembrane 4 superfamily protein CD151 (PETA-3) associates with β1 and αIIbβ3 integrins in haemopoietic cell lines and modulates cell-cell adhesion. Biochem. J. 338, 61–70 (1999).
Miyazaki, T., Muller, U. & Campbell, K. S. Normal development but differentially altered proliferative responses of lymphocytes in mice lacking CD81. EMBO J. 16, 4217–4225 (1997).
van Spriel, A. B. et al. A regulatory role for CD37 in T cell proliferation. J. Immunol. 172, 2953–2961 (2004).
Tarrant, J. M. et al. The absence of Tssc6, a member of the tetraspanin superfamily, does not affect lymphoid development but enhances in vitro T-cell proliferative responses. Mol. Cell. Biol. 22, 5006–5018 (2002).
Maecker, H. T. & Levy, S. Normal lymphocyte development but delayed humoral immune response in CD81-null mice. J. Exp. Med. 185, 1505–1510 (1997).
Knobeloch, K. P. et al. Targeted inactivation of the tetraspanin CD37 impairs T-cell-dependent B-cell response under suboptimal costimulatory conditions. Mol. Cell. Biol. 20, 5363–5369 (2000).
Wright, M. D., Moseley, G. W. & van Spriel, A. B. Tetraspanin microdomains in immune cell signalling and malignant disease. Tissue Antigens 64, 533–542 (2004).
Levy, S. & Shoham, T. The tetraspanin web modulates immune-signalling complexes. Nature Rev. Immunol. 5, 136–148 (2005).
Kaji, K. et al. The gamete fusion process is defective in eggs of Cd9-deficient mice. Nature Genet. 24, 279–282 (2000).
Le Naour, F., Rubinstein, E., Jasmin, C., Prenant, M. & Boucheix, C. Severely reduced female fertility in CD9-deficient mice. Science 287, 319–321 (2000).
Miyado, K. et al. Requirement of CD9 on the egg plasma membrane for fertilization. Science 287, 321–324 (2000). Papers 39–41 provide the first evidence for a protein on oocyte plasma membranes being needed for fertilization.
Deng, J. et al. Allergen-induced airway hyperreactivity is diminished in CD81-deficient mice. J. Immunol. 165, 5054–5061 (2000).
Takeda, Y. et al. Tetraspanins CD9 and CD81 function to prevent the fusion of mononuclear phagocytes. J. Cell Biol. 161, 945–956 (2003). Definitive genetic evidence shows that tetraspanins can sometimes inhibit cell fusion, in contrast to other papers emphasizing the promotion of cell fusion.
Ishibashi, T. et al. Tetraspanin protein CD9 is a novel paranodal component regulating paranodal junctional formation. J. Neurosci. 24, 96–102 (2004).
Cha, J. H., Brooke, J. S., Ivey, K. N. & Eidels, L. Cell surface monkey CD9 antigen is a coreceptor that increases diphtheria toxin sensitivity and diphtheria toxin receptor affinity. J. Biol. Chem. 275, 6901–6907 (2000).
Moribe, H. et al. Tetraspanin protein (TSP-15) is required for epidermal integrity in Caenorhabditis elegans. J. Cell Sci. 117, 5209–5220 (2004).Provides the first definitive evidence that a C. elegans tetraspanin is functionally important.
Kopczynski, C. C., Davis, G. W. & Goodman, C. S. A neural tetraspanin, encoded by late bloomer, that facilitates synapse formation. Science 271, 1867–1870 (1996).
Fradkin, L. G., Kamphorst, J. T., DiAntonio, A., Goodman, C. S. & Noordermeer, J. N. Genomewide analysis of the Drosophila tetraspanins reveals a subset with similar function in the formation of the embryonic synapse. Proc. Natl Acad. Sci. USA 99, 13663–13668 (2002).
Xu, H. et al. A lysosomal tetraspanin associated with retinal degeneration identified via a genome-wide screen. EMBO J. 23, 811–822 (2004). The power of genetic screening in Drosophila melanogaster is applied in the discovery of novel tetraspanin function.
Sinenko, S. A. et al. Yantar, a conserved arginine-rich protein is involved in Drosophila hemocyte development. Dev. Biol. 273, 48–62 (2004).
Sinenko, S. A. & Mathey-Prevot, B. Increased expression of Drosophila tetraspanin, Tsp68C, suppresses the abnormal proliferation of ytr-deficient and Ras/Raf-activated hemocytes. Oncogene 23, 9120–9128 (2004). A gain-of-function Drosophila melanogaster mutant provides in vivo evidence in support of tetraspanin control of haemocyte proliferation.
Clergeot, P. H. et al. PLS1, a gene encoding a tetraspanin-like protein, is required for penetration of rice leaf by the fungal pathogen Magnaporthe grisea. Proc. Natl Acad. Sci. USA 98, 6963–6968 (2001). This paper, involving tetraspanin-dependent fungal penetration into rice leaves, could have relevance to tetraspanin-dependent invasion by mammalian tumour cells.
Gourgues, M., Brunet-Simon, A., Lebrun, M. H. & Levis, C. The tetraspanin BcPls1 is required for appressorium-mediated penetration of Botrytis cinerea into host plant leaves. Mol. Microbiol. 51, 619–629 (2004).
Gourgues, M. et al. A new class of tetraspanins in fungi. Biochem. Biophys. Res. Commun. 297, 1197–1204 (2002).
Hemler, M. E., Mannion, B. A. & Berditchevski, F. Association of TM4SF proteins with integrins: relevance to cancer. Biochim. Biophys. Acta 1287, 67–71 (1996).
Hemler, M. E. Integrin-associated proteins. Curr. Opin. Cell Biol. 10, 578–585 (1998).
Zhang, X. A. et al. Function of the tetraspanin CD151-α6β1 integrin complex during cellular morphogenesis. Mol. Biol. Cell 13, 1–11 (2002).
Feigelson, S. W., Grabovsky, V., Shamri, R., Levy, S. & Alon, R. The CD81 tetraspanin facilitates instantaneous leukocyte VLA-4 adhesion strengthening to vascular cell adhesion molecule 1 (VCAM-1) under shear flow. J. Biol. Chem. 278, 51203–51212 (2003).
Mannion, B. A., Berditchevski, F., Kraeft, S.-K., Chen, L. B. & Hemler, M. E. TM4SF proteins CD81 (TAPA-1), CD82, CD63 and CD53 specifically associate with α4β1 integrin. J. Immunol. 157, 2039–2047 (1996).
Serru, V. et al. Selective tetraspan-integrin complexes (CD81/α4β1, CD151/α3β1, CD151/α6β1) under conditions disrupting tetraspan interactions. Biochem. J. 340, 103–111 (1999).
Berditchevski, F. & Odintsova, E. Characterization of integrin-tetraspanin adhesion complexes: role of tetraspanins in integrin signaling. J. Cell Biol. 146, 477–492 (1999).
Delaguillaumie, A. et al. Tetraspanin CD82 controls the association of cholesterol-dependent microdomains with the actin cytoskeleton in T lymphocytes: relevance to co-stimulation. J. Cell Sci. 117, 5269–5282 (2004).
Zhang, X. A., Bontrager, A. L. & Hemler, M. E. TM4SF proteins associate with activated PKC and Link PKC to specific β1 integrins. J. Biol. Chem. 276, 25005–25013 (2001).
Keenan, C. & Kelleher, D. Protein kinase C and the cytoskeleton. Cell Signal. 10, 225–232 (1998).
Hung, A. Y. & Sheng, M. PDZ domains: structural modules for protein complex assembly. J. Biol. Chem. 277, 5699–5702 (2002).
Stipp, C. S., Kolesnikova, T. V. & Hemler, M. E. EWI-2 is a major CD9 and CD81 partner, and member of a novel Ig protein subfamily. J. Biol. Chem. 276, 40545–40554 (2001).
Stipp, C. S., Kolesnikova, T. V. & Hemler, M. E. EWI-2 regulates α3β1 integrin-dependent cell functions on laminin-5. J. Cell Biol. 163, 1167–1177 (2003).
Kolesnikova, T. V. et al. EWI-2 modulates lymphocyte integrin α4β1 functions. Blood 103, 3013–3019 (2004).
He, B. et al. Tetraspanin CD82 attenuates cellular morphogenesis through down-regulating integrin α6-mediated cell adhesion. J. Biol. Chem. (2004).
Barreiro, O. et al. Endothelial tetraspanin microdomains regulate leukocyte firm adhesion during extravasation. Blood 105, 2852–2862 (2004).
Oren, R., Takahashi, S., Doss, C., Levy, R. & Levy, S. TAPA-1, the target of an antiproliferative antibody, defines a new family of transmembrane proteins. Mol. Cell. Biol. 10, 4007–4015 (1990).
Inui, S. et al. Possible role of coexpression of CD9 with membrane-anchored heparin-binding EGF-like growth factor and amphiregulin in cultured human keratinocyte growth. J. Cell. Physiol. 171, 291–298 (1997).
Murayama, Y. et al. CD9-mediated activation of the p46 Shc isoform leads to apoptosis in cancer cells. J. Cell Sci. 117, 3379–3388 (2004).
Carloni, V., Mazzocca, A. & Ravichandran, K. S. Tetraspanin CD81 is linked to ERK/MAPKinase signaling by Shc in liver tumor cells. Oncogene 23, 1566–1574 (2004).
Berditchevski, F., Tolias, K. F., Wong, K., Carpenter, C. L. & Hemler, M. E. A novel link between integrins, TM4SF proteins (CD63, CD81) and phosphatidylinositol 4-kinase. J. Biol. Chem. 272, 2595–2598 (1997).
Yauch, R. L. & Hemler, M. E. Specific interactions among transmembrane 4 superfamily (TM4SF) proteins and phosphatidylinositol 4-kinase. Biochem. J. 351, 629–637 (2000).
Kolch, W. et al. Protein kinase Cα activates RAF-1 by direct phosphorylation. Nature 364, 249–252 (1993).
Cai, H. et al. Role of diacylglycerol-regulated protein kinase C isotypes in growth factor activation of the Raf-1 protein kinase. Mol. Cell. Biol. 17, 732–741 (1997).
Tachibana, I. & Hemler, M. E. Role of transmembrane-4 superfamily (TM4SF) proteins CD9 and CD81 in muscle cell fusion and myotube maintenance. J. Cell Biol. 146, 893–904 (1999).
Ono, M., Handa, K., Withers, D. A. & Hakomori, S. Motility inhibition and apoptosis are induced by metastasis-suppressing gene product CD82 and its analogue CD9, with concurrent glycosylation. Cancer Res. 59, 2335–2339 (1999).
Gu, J., Sumida, Y., Sanzen, N. & Sekiguchi, K. Laminin-10/11 and fibronectin differentially regulate integrin-dependent Rho and Rac activation via p130(Cas)-CrkII-DOCK180 pathway. J. Biol. Chem. 276, 27090–27097 (2001).
Shigeta, M. et al. CD151 regulates epithelial cell-cell adhesion through PKC- and Cdc42-dependent actin cytoskeletal reorganization. J. Cell Biol. 163, 165–176 (2003).
Sawada, S., Yoshimoto, M., Odintsova, E., Hotchin, N. A. & Berditchevski, F. The tetraspanin CD151 functions as a negative regulator in the adhesion-dependent activation of Ras. J. Biol. Chem. 278, 26323–26326 (2003).
Dong, J.-T. et al. KAI 1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science 268, 884–886 (1995).
Gu, J. et al. Shc and FAK differentially regulate cell motility and directionality modulated by PTEN. J. Cell Biol. 146, 389–403 (1999).
Klemke, R. L. et al. CAS/Crk coupling serves as a 'molecular switch' for induction of cell migration. J. Cell Biol. 140, 961–972 (1998).
Zhang, X. A., He, B., Zhou, B. & Liu, L. Requirement of the p130CAS-Crk coupling for metastasis suppressor KAI1/CD82-mediated inhibition of cell migration. J. Biol. Chem. 278, 27319–27328 (2003).
Zhang, X. A., Lane, W. S., Charrin, S., Rubinstein, E. & Liu, L. EWI2/PGRL associates with the metastasis suppressor KAI1/CD82 and inhibits the migration of prostate cancer cells. Cancer Res. 63, 2665–2674 (2003).
Charrin, S. et al. EWI-2 is a new component of the tetraspanin web in hepatocytes and lymphoid cells. Biochem. J. 373, 409–421 (2003).
Odintsova, E., Sugiura, T. & Berditchevski, F. Attenuation of EGF receptor signaling by a metastasis suppressor, the tetraspanin CD82/KAI-1. Curr. Biol. 10, 1009–1012 (2000).
Odintsova, E., Voortman, J., Gilbert, E. & Berditchevski, F. Tetraspanin CD82 regulates compartmentalisation and ligand-induced dimerization of EGFR. J. Cell Sci. 116, 4557–4566 (2003).
Kovalenko, O. V., Yang, X., Kolesnikova, T. V. & Hemler, M. E. Evidence for specific tetraspanin homodimers: inhibition of palmitoylation makes cysteine residues available for cross-linking. Biochem. J. 377, 407–417 (2004).
Oostergetel, G. T., Keegstra, W. & Brisson, A. Structure of the major membrane protein complex from urinary bladder epithelial cells by cryo-electron crystallography. J. Mol. Biol. 314, 245–252 (2001).
Yang, X. et al. Palmitoylation of tetraspanin proteins: modulation of CD151 lateral interactions, subcellular distribution, and integrin-dependent cell morphology. Mol. Biol. Cell 13, 767–781 (2002).
Berditchevski, F., Odintsova, E., Sawada, S. & Gilbert, E. Expression of the palmitoylation-deficient CD151 weakens the association of α3β1 integrin with the tetraspanin-enriched microdomains and affects integrin-dependent signalling. J. Biol. Chem. 277, 36991–37000 (2002).
Zhou, B., Liu, L., Reddivari, M. & Zhang, X. A. The palmitoylation of metastasis suppressor KAI1/CD82 is important for its motility- and invasiveness-inhibitory activity. Cancer Res. 64, 7455–7463 (2004).
Clark, K. L. et al. CD81 associates with 14–3-3 in a redox-regulated palmitoylation-dependent manner. J. Biol. Chem. 279, 19401–19406 (2004).
Charrin, S. et al. Differential stability of tetraspanin/tetraspanin interactions: role of palmitoylation. FEBS Lett. 516, 139–144 (2002).
Yang, X. et al. Palmitoylation supports assembly and function of integrin-tetraspanin complexes. J. Cell Biol. 167, 1231–1240 (2004).
Gagnoux-Palacios, L. et al. Compartmentalization of integrin α6β4 signaling in lipid rafts. J. Cell Biol. 162, 1189–1196 (2003).
Smotrys, J. E. & Linder, M. E. Palmitoylation of intracellular signaling proteins: regulation and function. Annu. Rev. Biochem. 73, 559–587 (2004).
Shogomori, H. et al. Palmitoylation and intracellular-domain interactions both contribute to raft targeting of linker for activation of T cells (LAT). J. Biol. Chem. 280,18931–18942(2005).
Charrin, S. et al. A physical and functional link between cholesterol and tetraspanins. Eur. J. Immunol. 33, 2479–2489 (2003).
Miura, Y. et al. Reversion of the Jun-induced oncogenic phenotype by enhanced synthesis of sialosyllactosylceramide (GM3 ganglioside). Proc. Natl Acad. Sci. USA 101, 16204–16209 (2004).
Cherukuri, A. et al. The tetraspanin CD81 is necessary for partitioning of coligated CD19/CD21-B cell antigen receptor complexes into signaling-active lipid rafts. J. Immunol. 172, 370–380 (2004).
Cherukuri, A. et al. B cell signaling is regulated by induced palmitoylation of CD81. J. Biol. Chem. 279, 31973–31982 (2004).
Claas, C., Stipp, C. S. & Hemler, M. E. Evaluation of prototype TM4SF protein complexes and their relation to lipid rafts. J. Biol. Chem. 276, 7974–7984 (2001).
Brown, D. A. & London, E. Functions of lipid rafts in biological membranes. Annu. Rev. Cell Dev. Biol. 14, 111–136 (1998).
Kropshofer, H. et al. Tetraspan microdomains distinct from lipid rafts enrich select peptide-MHC class II complexes. Nature Immunol. 3, 61–68 (2002). Provides evidence for a clear functional difference between tetraspanin-enriched microdomains (TEMs) and lipid rafts.
Escola, J. M. et al. Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B- lymphocytes. J. Biol. Chem. 273, 20121–20127 (1998).
Foster, L. J., De Hoog, C. L. & Mann, M. Unbiased quantitative proteomics of lipid rafts reveals high specificity for signaling factors. Proc. Natl Acad. Sci. USA 100, 5813–5818 (2003).
Stipp, C. S., Kolesnikova, T. V. & Hemler, M. E. Functional domains in tetraspanin proteins. Trends Biochem. Sci. 28, 106–112 (2003).
Hemler, M. E. Specific tetraspanin functions. J. Cell Biol. 155, 1103–1107 (2001).
Higashiyama, S. et al. The membrane protein CD9/DRAP27 potentiates the juxtacrine growth factor activity of the membrane-anchored heparin-binding EGF-like growth factor. J. Cell Biol. 128, 929–938 (1995).
Shi, W., Fan, H., Shum, L. & Derynck, R. The tetraspanin CD9 associates with transmembrane TGFα and regulates TGFαinduced EGF receptor activation and cell proliferation. J. Cell Biol. 148, 591–602 (2000).
Dryja, T. P., Hahn, L. B., Kajiwara, K. & Berson, E. L. Dominant and digenic mutations in the peripherin/RDS and ROM1 genes in retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 38, 1972–1982 (1997).
Kajiwara, K., Berson, E. L. & Dryja, T. P. Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. Science 264, 1604–1608 (1994).
Tsitsikov, E. N., Gutierrez-Ramos, J. C. & Geha, R. S. Impaired CD19 expression and signaling, enhanced antibody response to type II T independent antigen and reduction of B-1 cells in CD81-deficient mice. Proc. Natl Acad. Sci. USA 94, 10844–10849 (1997).
Geisert, E. E. et al. Increased brain size and glial cell number in CD81-null mice. J. Comp. Neurol. 453, 22–32 (2002).
Silvie, O. et al. Hepatocyte CD81 is required for Plasmodium falciparum and Plasmodium yoelii sporozoite infectivity. Nature Med. 9, 93–96 (2003).
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Glossary
- ROD OUTER SEGMENTS
-
The portion of the rod photoreceptor cell between the inner segment and the pigment epithelial layer of the retina.
- INTEGRINS
-
A large family of heterodimeric transmembrane proteins that function as receptors for cell-adhesion molecules.
- GANGLIOSIDES
-
Anionic glycosphingolipids that carry, in addition to other sugar residues, one or more sialic acid residues.
- PALMITOYLATION
-
The post-translational S-acylation of proteins with palmitate.
- ERYTHROID PROGENITORS
-
The precursors to erythrocytes (red blood cells).
- ERYTHROPOIETIN
-
A glycoprotein hormone that stimulates stem cells in the bone marrow to transform into erythrocytes (red blood cells).
- PLATELETS
-
The smallest blood cells, which are important in haemostasis and blood coagulation.
- KERATINOCYTES
-
Epithelial cells of the skin that have differentiated to produce keratin. Keratinocytes are the predominant cell type in the epidermis of the skin.
- HUMORAL IMMUNE SYSTEM
-
Mediates immunity in the body through antibodies present in the blood plasma, tissue fluid and lymph.
- MONOCYTE
-
A large leukocyte with a horseshoe-shaped nucleus. Monocytes derive from pluripotent stem cells and become phagocytic macrophages when they enter tissues.
- GIANT CELL
-
A large, multinucleate cell that is thought to result from the fusion of several macrophages.
- MYELINATION
-
The process by which myelin — a protein produced by Schwann cells or oligodendrocytes — is ensheathed around the axons of vertebrate nerves.
- AXOGLIAL PARANODAL JUNCTIONS
-
Specialized adhesion sites between the axolemma (the outer membrane covering an axon) and myelinating glial cells.
- HYPODERMIS
-
A thin layer of cells — often syncytial — that underlie the cuticle in nematodes.
- RNA INTERFERENCE
-
(RNAi). A form of post-transcriptional gene silencing in which expression or transfection of dsRNA induces degradation, by nucleases, of the homologous endogenous transcripts. This mimics the effect of the reduction, or loss, of gene activity.
- NEUROMUSCULAR JUNCTION
-
(NMJ). The place of contact between the terminal of a motor neuron and the membrane of a muscle fibre. Nerve impulses are transmitted across the gap by diffusion of a transmitter.
- G-PROTEIN-COUPLED RECEPTOR
-
(GPCR). A seven-helix transmembrane-spanning cell-surface receptor that signals through heterotrimeric GTP-binding and -hydrolysing G-proteins to stimulate or inhibit the activity of a downstream enzyme.
- HAEMOCYTES
-
Blood cells, particularly of insects and crustacea. They are similar in many respects to leukocytes, as they are phagocytic and are not involved in oxygen transport.
- EXTRACELLULAR MATRIX
-
(ECM). The complex, multi-molecular material that surrounds cells. The ECM comprises a scaffold on which tissues are organized, it provides cellular microenvironments and it regulates various cellular functions.
- CABLE FORMATION
-
When dispersed on the surface of Matrigel or other gelatinous substrate, cells exert force onto the substrate and subsequently migrate along lines of mechanical tension to form a pattern of intersecting cellular cables.
- MATRIGEL
-
The extracellular matrix secreted by the Engelbrecht–Holm–Swarm mouse sarcoma cell line. It contains laminin, collagen IV, nidogen/entactin and proteoglycans, and therefore resembles the basement membrane.
- COSTAMERE
-
A myofibril attachment site that contains the protein vinculin and that forms one of the main linkage sites of the skeletal muscle cell.
- SHEAR FLOW
-
When fluid flows through a tube or channel, velocity is zero at the wall, and maximal at the centre. This has a shearing effect on the fluid (and in the case of blood, any cells within the fluid or attached to the wall).
- PDZ DOMAIN
-
A protein-interaction domain that often occurs in scaffolding proteins, and is named after the founding members of this protein family (PSD95, Discs large and ZO1).
- RUFFLING
-
A process that is formed by the movement of lamellipodia that are in the dynamic process of folding back onto the cell body from which they previously extended.
- RHO-FAMILY GTPASES
-
A subfamily of small (∼21 kDa) GTP-binding proteins that are related to Ras, and that regulate the cytoskeleton.
- GUANINE NUCLEOTIDE-EXCHANGE FACTOR
-
(GEF). A protein that activates a specific small GTPase by catalysing the exchange of bound GDP for GTP.
- HAPTOTACTIC CELL MIGRATION
-
The directed migration of cells along surfaces with gradients of immobilized factors.
- IMMUNOGLOBULIN SUPERFAMILY
-
A large family of proteins that includes antibodies and adhesive transmembrane proteins. Their structure is characterized by 'immunoglobulin loops' that are formed by disulphide bonds.
- COMPLEMENT
-
Nine interacting serum proteins (C1–C9) — mostly enzymes — that are activated in a coordinated way and participate in bacterial lysis and macrophage chemotaxis.
- GLYCOSYLPHOSPHATIDYL-INOSITOL (GPI) ANCHOR
-
The function of this post-translational modification is to attach proteins to the exoplasmic leaflet of membranes, possibly to specific domains therein. The anchor is composed of one molecule of phosphatidylinositol to which a carbohydrate chain is linked through the C-6 hydroxyl of the inositol and is linked to the protein through an ethanolamine phosphate moiety.
- MAJOR HISTOCOMPATIBILITY COMPLEX
-
(MHC). A complex of genetic loci in higher vertebrates that encodes a family of cellular antigens that allow the immune system to recognize self from non-self.
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Hemler, M. Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol 6, 801–811 (2005). https://doi.org/10.1038/nrm1736
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DOI: https://doi.org/10.1038/nrm1736
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