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Targeting of tetraspanin proteins — potential benefits and strategies

Key Points

  • There are 33 mammalian tetraspanin proteins, each with characteristic structural features, including a conserved CCG motif in the large extracellular loop. Genetic evidence in fungi, worms, flies, mice and humans establishes that tetraspanins have key roles in many processes including development, fertilization, invasion and immune-cell function. Tetraspanins, which are expressed on nearly all cell and tissue types, also modulate cell morphology, motility, invasion, fusion, adhesion strengthening, signalling and protein trafficking.

  • Tetraspanins organize laterally, into tetraspanin-enriched microdomains (TEMs). At the core of TEMs are tetraspanins engaging in direct protein–protein interactions with themselves and other proteins, including the immunoglobulin superfamily members EWI-2 and EWI-F, Claudin-1, epidermal growth factor receptor (EGFR) membrane-bound ligands, integrins and Syntenin-1. These primary complexes are then joined into a network of looser secondary interactions involving many additional proteins. Tetraspanins and many of their partner proteins (for example, integrins, EWI proteins and Claudin-1) undergo protein palmitoylation, which helps to stabilize secondary interactions within TEMs.

  • Tetraspanins contribute to a number of normal and pathological processes that could be targeted therapeutically. For example, CD151 may support primary tumour growth as well as metastasis and angiogenesis, whereas tetraspanins CD9 and CD81 are required for oocyte fertilization. In addition, several tetraspanins contribute to the functions of platelets and lymphocytes, thereby enhancing blood clotting and affecting numerous immune functions.

  • Tetraspanins make substantial contributions towards infectious-disease pathologies. For HIV-1, human T-cell lymphotropic virus type 1 and other viruses, tetraspanins affect virus-induced cell fusion events and/or virus assembly and release. In hepatocytes, tetraspanin CD81 is needed for the initial steps in hepatitis C virus binding and infection, and for invasion by sporozoites from malaria-causing parasites.

  • Promising in vivo results suggest that targeting of tetraspanins may be therapeutically useful for injury repair, for cancer models and for combating infectious diseases. Anti-tetraspanin monoclonal antibodies, tetraspanin-derived recombinant soluble extracellular loops and RNAi knockdown strategies have all shown potential for effective modulation of tetraspanin functions.

Abstract

The tetraspanin transmembrane proteins have emerged as key players in malignancy, the immune system, during fertilization and infectious disease processes. Tetraspanins engage in a wide range of specific molecular interactions, occurring through the formation of tetraspanin-enriched microdomains (TEMs). TEMs therefore serve as a starting point for understanding how tetraspanins affect cell signalling, adhesion, morphology, motility, fusion and virus infection. An abundance of recent evidence suggests that targeting tetraspanins, for example, by monoclonal antibodies, soluble large-loop proteins or RNAi technology, should be therapeutically beneficial.

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Figure 1: Tetraspanin structural features.
Figure 2: Strategies for targeting tetraspanins.

References

  1. Huang, S. et al. The phylogenetic analysis of tetraspanins projects the evolution of cell–cell interactions from unicellular to multicellular organisms. Genomics 86, 674–684 (2005).

    CAS  PubMed  Article  Google Scholar 

  2. Garcia-Espana, A. et al. Appearance of new tetraspanin genes during vertebrate evolution. Genomics 91, 326–334 (2008).

    CAS  PubMed  Article  Google Scholar 

  3. Stipp, C. S., Kolesnikova, T. V. & Hemler, M. E. Functional domains in tetraspanin proteins. Trends Biochem. Sci. 28, 106–112 (2003).

    CAS  PubMed  Article  Google Scholar 

  4. 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).

    CAS  PubMed  Article  Google Scholar 

  5. Boucheix, C. & Rubinstein, E. Tetraspanins. Cell. Mol. Life Sci. 58, 1189–1205 (2001).

    CAS  PubMed  Article  Google Scholar 

  6. Maecker, H. T., Todd, S. C. & Levy, S. The tetraspanin superfamily: molecular facilitators. FASEB J. 11, 428–442 (1997).

    CAS  PubMed  Article  Google Scholar 

  7. Kitadokoro, K. et al. CD81 extracellular domain 3D structure: insight into the tetraspanin superfamily structural motifs. EMBO J. 20, 12–18 (2001). The first detailed structural information for a tetraspanin LEL.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Min., G., Wang, H., Sun, T. T. & Kong, X. P. Structural basis for tetraspanin functions as revealed by the cryo-EM structure of uroplakin complexes at 6-Å resolution. J. Cell Biol. 173, 975–983 (2006). The most detailed structural information yet available for a tetraspanin and its partner protein.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Seigneuret, M. Complete predicted three-dimensional structure of the facilitator transmembrane protein and hepatitis C virus receptor CD81: conserved and variable structural domains in the tetraspanin superfamily. Biophys. J. 90, 212–227 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Kovalenko, O. V., Metcalf, D. G., DeGrado, W. F. & Hemler, M. E. Structural organization and interactions of transmembrane domains in tetraspanin proteins. BMC Struct. Biol. 5, 11 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Berditchevski, et al. Analysis of the CD151-α3β1 integrin and CD151-tetraspanin interactions by mutagenesis. J. Biol. Chem. 276, 41165–41174 (2001).

    CAS  PubMed  Article  Google Scholar 

  13. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Kovalenko, O. V., Yang, X. H. & Hemler, M. E. A novel cysteine cross-linking method reveals a direct association between claudin-1 and tetraspanin CD9. Mol. Cell Proteomics 6, 1855–1867 (2007).

    CAS  PubMed  Article  Google Scholar 

  15. 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).

    CAS  PubMed  Article  Google Scholar 

  16. Kishimoto, T. et al. Leukocyte Typing VI 1–1342 (Garland, New York, 1998).

    Google Scholar 

  17. Berditchevski, F. & Odintsova, E. Tetraspanins as regulators of protein trafficking. Traffic 8, 89–96 (2007).

    CAS  PubMed  Article  Google Scholar 

  18. Levy, S. & Shoham, T. The tetraspanin web modulates immune-signalling complexes. Nature Rev. Immunol. 5, 136–148 (2005).

    CAS  Article  Google Scholar 

  19. Hemler, M. E. Tetraspanin proteins mediate cellular penetration, invasion and fusion events, and define a novel type of membrane microdomain. Annu. Rev. Cell Dev. Biol. 19, 397–422 (2003).

    CAS  Article  PubMed  Google Scholar 

  20. Rubinstein, E., Ziyyat, A., Wolf, J. P., Le Naour, F. & Boucheix, C. The molecular players of sperm–egg fusion in mammals. Semin. Cell Dev. Biol. 17, 254–263 (2006).

    CAS  PubMed  Article  Google Scholar 

  21. Lambou, K. et al. Fungi have three tetraspanin families with distinct functions. BMC Genomics 9, 63 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. Todres, E., Nardi, J. B. & Robertson, H. M. The tetraspanin superfamily in insects. Insect Mol. Biol. 9, 581–590 (2000).

    CAS  PubMed  Article  Google Scholar 

  23. Hemler, M. E. Tetraspanin functions and associated microdomains. Nature Rev. Mol. Cell Biol. 6, 801–811 (2005).

    CAS  Article  Google Scholar 

  24. Pileri, P. et al. Binding of hepatitis C virus to CD81. Science 282, 938–941 (1998). First evidence for HCV binding to tetraspanin CD81.

    CAS  PubMed  Article  Google Scholar 

  25. Wu, X. R., Sun, T. T. & Medina, J. J. In vitro binding of type 1-fimbriated Escherichia coli to uroplakins Ia and Ib: relation to urinary tract infections. Proc. Natl Acad. Sci. USA 93, 9630–9635 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. Ellerman, D. A., Ha, C., Primakoff, P., Myles, D. G. & Dveksler, G. S. Direct binding of the ligand PSG17 to CD9 requires a CD9 site essential for sperm–egg fusion. Mol. Biol. Cell 14, 5098–5103 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Odintsova, E. et al. Gangliosides play an important role in the organisation of CD82-enriched microdomains. Biochem. J. 400, 315–325 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Nydegger, S., Khurana, S., Krementsov, D. N., Foti, M. & Thali, M. Mapping of tetraspanin-enriched microdomains that can function as gateways for HIV-1. J. Cell Biol. 173, 795–807 (2006). An excellent characterization of TEMs on the surface of intact cells.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Ono, M. et al. GM3 ganglioside inhibits CD9-facilitated haptotactic cell motility: coexpression of GM3 and CD9 is essential in the downregulation of tumor cell motility and malignancy. Biochemistry 40, 6414–6421 (2001).

    CAS  PubMed  Article  Google Scholar 

  30. Charrin, S. et al. A physical and functional link between cholesterol and tetraspanins. Eur. J. Immunol. 33, 2479–2489 (2003). Definitive crosslinking evidence for cholesterol being a component of TEMs.

    CAS  PubMed  Article  Google Scholar 

  31. 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). First paper to compare and distinguish TEMs and lipid rafts.

    CAS  PubMed  Article  Google Scholar 

  32. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 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).

    CAS  PubMed  Article  Google Scholar 

  34. Charrin, S. et al. Differential stability of tetraspanin/tetraspanin interactions: role of palmitoylation. FEBS Lett. 516, 139–144 (2002).

    CAS  PubMed  Article  Google Scholar 

  35. Kropshofer, H. et al. Tetraspan microdomains distinct from lipid rafts enrich select peptide-MHC class II complexes. Nature Immunol. 3, 61–68 (2002).

    CAS  Article  Google Scholar 

  36. Le Naour, F., Andre, M., Boucheix, C. & Rubinstein, E. Membrane microdomains and proteomics: lessons from tetraspanin microdomains and comparison with lipid rafts. Proteomics 6, 6447–6454 (2006).

    CAS  PubMed  Article  Google Scholar 

  37. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 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).

    CAS  PubMed  Article  Google Scholar 

  39. 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).

    CAS  PubMed  Article  Google Scholar 

  40. Chattopadhyay, N., Wang, Z., Ashman, L. K., Brady-Kalnay, S. M. & Kreidberg, J. A. α3β1 integrin-CD151, a component of the cadherin-catenin complex, regulates PTPmu expression and cell-cell adhesion. J. Cell Biol. 163, 1351–1362 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 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).

    CAS  PubMed  Article  Google Scholar 

  42. Yauch, R. L. & Hemler, M. E. Specific interactions among transmembrane 4 superfamily (TM4SF) proteins and phosphatidylinositol 4-kinase. Biochem. J. 351, 629–637 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Yang, X. et al. Palmitoylation supports assembly and function of integrin–tetraspanin complexes. J. Cell Biol. 167, 1231–1240 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Takeda, Y. et al. Deletion of tetraspanin Cd151 results in decreased pathologic angiogenesis in vivo and in vitro. Blood 109, 1524–1532 (2007). First in vivo evidence for a tetraspanin affecting angiogenesis.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Yang, X. H. et al. CD151 accelerates breast cancer by regulating a6 integrin functions, signaling, and molecular organization. Cancer Res. 68, 3204–3213 (2008). First in vivo evidence for CD151 accelerating progression of breast cancer.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Silvie, O. et al. Cholesterol contributes to the organization of tetraspanin-enriched microdomains and to CD81-dependent infection by malaria sporozoites. J. Cell Sci. 119, 1992–2002 (2006). Use of a novel anti-CD81 mAb to demonstrate a coordinated role for cholesterol and CD81, on hepatocytes, during malaria infection.

    CAS  PubMed  Article  Google Scholar 

  47. 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).

    CAS  PubMed  Article  Google Scholar 

  48. Gesierich, S., Berezovskiy, I., Ryschich, E. & Zoller, M. Systemic induction of the angiogenesis switch by the tetraspanin D6.1A/CO-029. Cancer Res. 66, 7083–7094 (2006).

    CAS  PubMed  Article  Google Scholar 

  49. Ang, J., Lijovic, M., Ashman, L. K., Kan, K. & Frauman, A. G. CD151 protein expression predicts the clinical outcome of low-grade primary prostate cancer better than histologic grading: a new prognostic indicator? Cancer Epidemiol. Biomarkers Prev. 13, 1717–1721 (2004).

    CAS  PubMed  Google Scholar 

  50. Tokuhara, T. et al. Clinical significance of CD151 gene expression in non-small cell lung cancer. Clin. Cancer Res. 7, 4109–4114 (2001).

    CAS  PubMed  Google Scholar 

  51. Kohno, M., Hasegawa, H., Miyake, M., Yamamoto, T. & Fujita, S. CD151 enhances cell motility and metastasis of cancer cells in the presence of focal adhesion kinase. Int. J. Cancer 97, 336–343 (2002).

    CAS  PubMed  Article  Google Scholar 

  52. Testa, J. E., Brooks, P. C., Lin, J. M. & Quigley, J. P. Eukaryotic expression cloning with an antimetastatic monoclonal antibody identifies a tetraspanin (PETA-3/CD151) as an effector of human tumor cell migration and metastasis. Cancer Res. 59, 3812–3820 (1999).

    CAS  PubMed  Google Scholar 

  53. Zijlstra, A., Lewis, J., Degryse, B., Stuhlmann, H. & Quigley, J. P. The inhibition of tumor cell intravasation and subsequent metastasis via regulation of in vivo tumor cell motility by the tetraspanin CD151. Cancer Cell 13, 221–234 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Kreidberg, J. A. et al. α3β1 integrin has a crucial role in kidney and lung organogenesis. Development 122, 3537–3547 (1996).

    CAS  PubMed  Article  Google Scholar 

  55. Georges-Labouesse, E. N. et al. Absence of the α-6 integrin leads to epidermolysis bullosa and neonatal death in mice. Nature Genet. 13, 370–373 (1996).

    CAS  PubMed  Article  Google Scholar 

  56. Feltri, M. L., Arona, M., Scherer, S. S. & Wrabetz, L. Cloning and sequence of the cDNA encoding the β4 integrin subunit in rat peripheral nerve. Gene 186, 299–304 (1997).

    CAS  PubMed  Article  Google Scholar 

  57. Wright, M. D. et al. Characterization of mice lacking the tetraspanin superfamily member CD151. Mol. Cell Biol. 24, 5978–5988 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Sachs, N. et al. Kidney failure in mice lacking the tetraspanin CD151. J. Cell Biol. 175, 33–39 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 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).

    PubMed  Article  CAS  Google Scholar 

  60. Herlevsen, M., Schmidt, D. S., Miyazaki, K. & Zoller, M. The association of the tetraspanin D6.1A with the α6β4 integrin supports cell motility and liver metastasis formation. J. Cell Sci. 116, 4373–4390 (2003).

    CAS  PubMed  Article  Google Scholar 

  61. Claas, C. et al. Association between rat homologue of CO-029, a metastasis-associated tetraspanin molecule and consumption coagulopathy. J. Cell Biol. 141, 267–280 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Kanetaka, K. et al. Overexpression of tetraspanin CO-029 in hepatocellular carcinoma. J. Hepatol. 35, 637–642 (2001).

    CAS  PubMed  Article  Google Scholar 

  63. Zhou, Z. et al. TM4SF3 promotes esophageal carcinoma metastasis via upregulating ADAM12m expression. Clin. Exp.Metastasis 25, 537–548 (2008).

    CAS  PubMed  Article  Google Scholar 

  64. Ikeyama, S., Koyama, M., Yamaoko, M., Sasada, R. & Miyake, M. Suppression of cell motility and metastasis by transfection with human motility-related protein (MRP-1/CD9) DNA. J. Exp. Med. 177, 1231–1237 (1993).

    CAS  PubMed  Article  Google Scholar 

  65. Takeda, T. et al. Adenoviral transduction of MRP-1/CD9 and KAI1/CD82 inhibits lymph node metastasis in orthotopic lung cancer model. Cancer Res. 67, 1744–1749 (2007). In vivo demonstration of potential therapeutic use of tetraspanin tumour suppressor activity.

    CAS  PubMed  Article  Google Scholar 

  66. Saito, Y. et al. Absence of CD9 enhances adhesion-dependent morphologic differentiation, survival, and matrix metalloproteinase-2 production in small cell lung cancer cells. Cancer Res. 66, 9557–9565 (2006).

    CAS  PubMed  Article  Google Scholar 

  67. Ovalle, S. et al. The tetraspanin CD9 inhibits the proliferation and tumorigenicity of human colon carcinoma cells. Int. J. Cancer 121, 2140–2152 (2007).

    CAS  PubMed  Article  Google Scholar 

  68. Huang, H., Sossey-Alaoui, K., Beachy, S. H. & Geradts, J. The tetraspanin superfamily member NET-6 is a new tumor suppressor gene. J. Cancer Res. Clin. Oncol. 133, 761–769 (2007).

    CAS  PubMed  Article  Google Scholar 

  69. Radford, K. J., Mallesch, J. & Hersey, P. Suppression of human melanoma cell growth and metastasis by the melanoma-associated antigen CD63 (ME491). Int. J. Cancer 62, 631–635 (1995).

    CAS  PubMed  Article  Google Scholar 

  70. Moseley, G. W., Elliott, J., Wright, M. D., Partridge, L. J. & Monk, P. N. Interspecies contamination of the KM3 cell line: implications for CD63 function in melanoma metastasis. Int. J. Cancer 105, 613–616 (2003).

    CAS  PubMed  Article  Google Scholar 

  71. Jang, H. I. & Lee, H. A decrease in the expression of CD63 tetraspanin protein elevates invasive potential of human melanoma cells. Exp. Mol. Med. 35, 317–323 (2003).

    CAS  PubMed  Article  Google Scholar 

  72. Liu, W. M. & Zhang, X. A. KAI1/CD82, a tumor metastasis suppressor. Cancer Lett. 240, 183–194 (2006).

    CAS  PubMed  Article  Google Scholar 

  73. Dong, J.-T. et al. KAI 1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science 268, 884–886 (1995).

    CAS  PubMed  Article  Google Scholar 

  74. 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).

    CAS  PubMed  Article  Google Scholar 

  75. Bass, R. et al. Regulation of urokinase receptor proteolytic function by the tetraspanin CD82. J. Biol. Chem. 280, 14811–14818 (2005).

    CAS  PubMed  Article  Google Scholar 

  76. He, B. et al. Tetraspanin CD82 attenuates cellular morphogenesis through down-regulating integrin a6-mediated cell adhesion. J. Biol. Chem. 280, 3346–3354 (2004).

    PubMed  Article  CAS  Google Scholar 

  77. Zheng, Z. Z. & Liu, Z. X. Activation of the phosphatidylinositol 3-kinase/protein kinase Akt pathway mediates CD151-induced endothelial cell proliferation and cell migration. Int. J. Biochem. Cell Biol. 39, 340–348 (2006).

    PubMed  Article  CAS  Google Scholar 

  78. Dorrell, M. I., Aguilar, E. & Friedlander, M. Retinal vascular development is mediated by endothelial filopodia, a preexisting astrocytic template and specific R-cadherin adhesion. Invest. Ophthalmol. Vis. Sci. 43, 3500–3510 (2002).

    PubMed  Google Scholar 

  79. Rubinstein, E. et al. Reduced fertility of female mice lacking CD81. Dev. Biol. 290, 351–358 (2006).

    CAS  PubMed  Article  Google Scholar 

  80. Runge, K. E. et al. Oocyte CD9 is enriched on the microvillar membrane and required for normal microvillar shape and distribution. Dev. Biol. 304, 317–325 (2007).

    CAS  PubMed  Article  Google Scholar 

  81. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Sala-Valdes, M. et al. EWI-2 and EWI-F link the tetraspanin web to the actin cytoskeleton through their direct association with ezrin-radixin-moesin proteins. J. Biol. Chem. 281, 19665–19675 (2006).

    CAS  PubMed  Article  Google Scholar 

  83. Ziyyat, A. et al. CD9 controls the formation of clusters that contain tetraspanins and the integrin α6β1, which are involved in human and mouse gamete fusion. J. Cell Sci. 119, 416–424 (2006).

    CAS  PubMed  Article  Google Scholar 

  84. Primakoff, P. & Myles, D. G. Cell–cell membrane fusion during mammalian fertilization. FEBS Lett. 581, 2174–2180 (2007).

    CAS  PubMed  Article  Google Scholar 

  85. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. van Spriel, A. B. et al. A regulatory role for CD37 in T cell proliferation. J. Immunol. 172, 2953–2961 (2004).

    CAS  PubMed  Article  Google Scholar 

  89. Shoham, T., Rajapaksa, R., Kuo, C. C., Haimovich, J. & Levy, S. Building of the tetraspanin web: distinct structural domains of CD81 function in different cellular compartments. Mol. Cell Biol. 26, 1373–1385 (2006). Comprehensive domain-swapping reveals distinct functions for different domains within CD81.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 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). Strongly supports the concept of tetraspanins as modulators of integrin-dependent adhesion strengthening, rather than initial ligand binding.

    CAS  PubMed  Article  Google Scholar 

  91. Ha, S. A. et al. Regulation of B1 cell migration by signals through Toll-like receptors. J. Exp. Med. 203, 2541–2550 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. Mittelbrunn, M., Yanez-Mo, M., Sancho, D., Ursa, A. & Sanchez-Madrid, F. Cutting Edge: dynamic redistribution of tetraspanin CD81 at the central zone of the immune synapse in both T lymphocytes and APC. J. Immunol. 169, 6691–6695 (2002).

    CAS  PubMed  Article  Google Scholar 

  93. Mazurov, D., Heidecker, G. & Derse, D. HTLV-1 Gag protein associates with CD82 tetraspanin microdomains at the plasma membrane. Virology 346, 194–204 (2006).

    CAS  PubMed  Article  Google Scholar 

  94. Unternaehrer, J. J., Chow, A., Pypaert, M., Inaba, K. & Mellman, I. The tetraspanin CD9 mediates lateral association of MHC class II molecules on the dendritic cell surface. Proc. Natl Acad. Sci. USA 104, 234–239 (2007).

    CAS  PubMed  Article  Google Scholar 

  95. Lau, L. M. et al. The tetraspanin superfamily member, CD151 regulates outside-in integrin αIIbβ3 signalling and platelet function. Blood 104, 2368–2375 (2004).

    CAS  PubMed  Article  Google Scholar 

  96. Goschnick, M. W. et al. Impaired “outside-in” integrin αIIbβ3 signaling and thrombus stability in TSSC6-deficient mice. Blood 108, 1911–1918 (2006).

    CAS  PubMed  Article  Google Scholar 

  97. Israels, S. J. & McMillan-Ward, E. M. CD63 modulates spreading and tyrosine phosphorylation of platelets on immobilized fibrinogen. Thromb. Haemost. 93, 311–318 (2005).

    CAS  PubMed  Article  Google Scholar 

  98. Tricoci, P. & Peterson, E. D. The evolving role of glycoprotein IIb/IIIa inhibitor therapy in contemporary care of acute coronary syndrome patients. J. Interv. Cardiol. 19, 449–455 (2006).

    PubMed  Article  Google Scholar 

  99. Moseley, G. W. Tetraspanin–Fc receptor interactions. Platelets 16, 3–12 (2005).

    CAS  PubMed  Article  Google Scholar 

  100. Cowin, A. J. et al. Wound healing is defective in mice lacking tetraspanin CD151. J. Invest. Dermatol. 126, 680–689 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. Dijkstra, S. et al. Intraspinal administration of an antibody against CD81 enhances functional recovery and tissue sparing after experimental spinal cord injury. Exp. Neurol. 202, 57–66 (2006). One of the few examples of an anti-tetraspanin mAb used successfully in vivo in a disease model.

    CAS  PubMed  Article  Google Scholar 

  102. Garcia, E. et al. HIV-1 trafficking to the dendritic cell–T-cell infectious synapse uses a pathway of tetraspanin sorting to the immunological synapse. Traffic 6, 488–501 (2005).

    CAS  PubMed  Article  Google Scholar 

  103. Wiley, R. D. & Gummuluru, S. Immature dendritic cell-derived exosomes can mediate HIV-1 trans infection. Proc. Natl Acad. Sci. USA 103, 738–743 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  104. Gordon-Alonso, M. et al. Tetraspanins CD9 and CD81 modulate HIV-1-induced membrane fusion. J. Immunol. 177, 5129–5137 (2006).

    CAS  PubMed  Article  Google Scholar 

  105. von Lindern J. J. et al. Potential role for CD63 in CCR5-mediated human immunodeficiency virus type 1 infection of macrophages. J. Virol. 77, 3624–3633 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. Ho, S. H. et al. Recombinant extracellular domains of tetraspanin proteins are potent inhibitors of the infection of macrophages by human immunodeficiency virus type 1. J. Virol. 80, 6487–6496 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. Deneka, M., Pelchen-Matthews, A., Byland, R., Ruiz-Mateos, E. & Marsh, M. In macrophages, HIV-1 assembles into an intracellular plasma membrane domain containing the tetraspanins CD81, CD9, and CD53. J. Cell Biol. 177, 329–341 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. Pelchen-Matthews, A., Kramer, B. & Marsh, M. Infectious HIV-1 assembles in late endosomes in primary macrophages. J. Cell Biol. 162, 443–455 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. Ruiz-Mateos, E., Pelchen-Matthews, A., Deneka, M. & Marsh, M. CD63 is not required for the production of infectious human immunodeficiency virus type 1 in human macrophages. J. Virol. 82, 4751–4761 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. Sato, K. et al. Modulation of human immunodeficiency virus type 1 infectivity through incorporation of tetraspanin proteins. J. Virol. 82, 1021–1033 (2008).

    CAS  PubMed  Article  Google Scholar 

  111. Cocquerel, L., Voisset, C. & Dubuisson, J. Hepatitis C virus entry: potential receptors and their biological functions. J. Gen. Virol. 87, 1075–1084 (2006).

    CAS  PubMed  Article  Google Scholar 

  112. Flint, M. et al. Diverse CD81 proteins support hepatitis C virus infection. J. Virol. 80, 11331–11342 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Bertaux, C. & Dragic, T. Different domains of CD81 mediate distinct stages of hepatitis C virus pseudoparticle entry. J. Virol. 80, 4940–4948 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. Molina, S. et al. Serum-derived hepatitis C virus infection of primary human hepatocytes is tetraspanin CD81 dependent. J. Virol. 82, 569–574 (2008).

    CAS  PubMed  Article  Google Scholar 

  115. Harris, H. J. et al. CD81 and Claudin 1 co-receptor association: a role in hepatitis C virus entry. J. Virol. 82, 5007-5020 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. Evans, M. J. et al. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature 446, 801–805 (2007).

    CAS  PubMed  Article  Google Scholar 

  117. Yang, W. et al. Correlation of the tight junction-like distribution of Claudin-1 to the cellular tropism of hepatitis C virus. J. Biol. Chem. 283, 8643–8653 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. Fukudome, K. et al. Identification of membrane antigen C33 recognized by monoclonal antibodies inhibitory to human T-cell leukemia virus type 1 (HTLV- 1)-induced syncytium formation: altered glycosylation of C33 antigen in HTLV-1-positive T cells. J. Virol. 66, 1394–1401 (1992).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. Pique, C. et al. Interaction of CD82 tetraspanin proteins with HTLV-1 envelope glycoproteins inhibits cell-to-cell fusion and virus transmission. Virology 276, 455–465 (2000).

    CAS  PubMed  Article  Google Scholar 

  120. Mazurov, D., Heidecker, G. & Derse, D. The inner loop of tetraspanins CD82 and CD81 mediates interactions with human T cell lymphotrophic virus type 1 Gag protein. J. Biol. Chem. 282, 3896–3903 (2007).

    CAS  PubMed  Article  Google Scholar 

  121. Loffler, S. et al. CD9, a tetraspan transmembrane protein, renders cells susceptible to canine distemper virus. J. Virol. 71, 42–49 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. Singethan, K. et al. CD9-dependent regulation of Canine distemper virus-induced cell-cell fusion segregates with the extracellular domain of the haemagglutinin. J. Gen. Virol. 87, 1635–1642 (2006).

    CAS  PubMed  Article  Google Scholar 

  123. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. Tanio, Y., Yamazaki, H., Kunisada, T., Miyake, K. & Hayashi, S. I. CD9 molecule expressed on stromal cells is involved in osteoclastogenesis. Exp. Hematol. 27, 853–859 (1999).

    CAS  PubMed  Article  Google Scholar 

  125. Takeda, Y. et al. Tetraspanins CD9 and CD81 function to prevent the fusion of mononuclear phagocytes. J. Cell Biol. 161, 945–956 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. de Parseval, A., Lerner, D. L., Borrow, P., Willett, B. & Elder, J. H. Blocking of feline immunodeficiency virus infection by a monoclonal antibody to CD9 is via inhibition of virus release rather than interference with receptor binding. J. Virol. 71, 5742–5749 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. Silvie, O. et al. Hepatocyte CD81 is required for Plasmodium falciparum and Plasmodium yoelii sporozoite infectivity. Nature Med. 9, 93–96 (2003).

    CAS  PubMed  Article  Google Scholar 

  128. Iwamoto, R. et al. Heparin-binding EGF-like growth factor, which acts as a diphtheria toxin receptor, forms a complex with membrane protein DRAP27/CD9, which upregulates functional receptors and diphtheria toxin sensitivity. EMBO J. 13, 2322–2330 (1994).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. Reichert, J. M. & Valge-Archer, V. E. Development trends for monoclonal antibody cancer therapeutics. Nature Rev. Drug Discov. 6, 349–356 (2007).

    CAS  Article  Google Scholar 

  130. Liu, W. M. et al. Tetraspanin CD9 regulates invasion during mouse embryo implantation. J. Mol. Endocrinol. 36, 121–130 (2006).

    CAS  PubMed  Article  Google Scholar 

  131. Zhao, X. et al. Targeting CD37-positive lymphoid malignancies with a novel engineered small modular immunopharmaceutical. Blood 110, 2569–2577 (2007). One of the few examples of successful tetraspanin targeting in vivo.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 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).

    CAS  PubMed  Article  Google Scholar 

  133. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Boismenu, R., Rhein, M., Fischer, W. H. & Havran, W. L. A role for CD81 in early T cell development. Science 271, 198–200 (1996).

    CAS  PubMed  Article  Google Scholar 

  135. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  136. Geary, S. M., Cambareri, A. C., Sincock, P. M., Fitter, S. & Ashman, L. K. Differential tissue expression of epitopes of the tetraspanin CD151 recognised by monoclonal antibodies. Tissue Antigens 58, 141–153 (2001).

    CAS  PubMed  Article  Google Scholar 

  137. Yauch, R. L., Kazarov, A. R., Desai, B., Lee, R. T. & Hemler, M. E. Direct extracellular contact between integrin α3β1 and TM4SF protein CD151. J. Biol. Chem. 275, 9230–9238 (2000).

    CAS  PubMed  Article  Google Scholar 

  138. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. Kolesnikova, T. V. et al. EWI-2 modulates lymphocyte integrin a4b1 functions. Blood 103, 3013–3019 (2004).

    CAS  PubMed  Article  Google Scholar 

  140. Gutierrez-Lopez, M. D. et al. A functionally relevant conformational epitope on the CD9 tetraspanin depends on the association with activated β1 integrin. J. Biol. Chem. 278, 208–218 (2003).

    CAS  PubMed  Article  Google Scholar 

  141. Yang, X. H. et al. Contrasting Effects of EWI proteins, integrins, and protein palmitoylation on cell surface CD9 organization. J. Biol. Chem. 281, 12976–12985 (2006).

    CAS  PubMed  Article  Google Scholar 

  142. 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).

    CAS  PubMed  Article  Google Scholar 

  143. Press, O. W. et al. Treatment of refractory non-Hodgkin's lymphoma with radiolabeled MB-1 (anti-CD37) antibody. J. Clin. Oncol. 7, 1027–1038 (1989).

    CAS  PubMed  Article  Google Scholar 

  144. Zhu, G. Z. et al. Residues SFQ (173–175) in the large extracellular loop of CD9 are required for gamete fusion. Development 129, 1995–2002 (2002).

    CAS  PubMed  Article  Google Scholar 

  145. Higginbottom, A. et al. Structural requirements for the inhibitory action of the CD9 large extracellular domain in sperm/oocyte binding and fusion. Biochem. Biophys. Res. Commun. 311, 208–214 (2003).

    CAS  PubMed  Article  Google Scholar 

  146. Barreiro, O. et al. Endothelial tetraspanin microdomains regulate leukocyte firm adhesion during extravasation. Blood 105, 2852–2861 (2005).

    CAS  PubMed  Article  Google Scholar 

  147. Winterwood, N. E., Varzavand, A., Meland, M. N., Ashman, L. K. & Stipp, C. S. A critical role for tetraspanin CD151 in α3β1 and α6β4 integrin-dependent tumor cell functions on laminin-5. Mol. Biol. Cell 17, 2707–2721 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. Furuya, M. et al. Down-regulation of CD9 in human ovarian carcinoma cell might contribute to peritoneal dissemination: morphologic alteration and reduced expression of β1 integrin subsets. Cancer Res. 65, 2617–2625 (2005).

    CAS  PubMed  Article  Google Scholar 

  149. Iwai, K., Ishii, M., Ohshima, S., Miyatake, K. & Saeki, Y. Expression and function of transmembrane-4 superfamily (tetraspanin) proteins in osteoclasts: reciprocal roles of Tspan-5 and NET-6 during osteoclastogenesis. Allergol. Int. 56, 457–463 (2007).

    CAS  PubMed  Article  Google Scholar 

  150. Shanmukhappa, K., Kim, J. K. & Kapil, S. Role of CD151, A tetraspanin, in porcine reproductive and respiratory syndrome virus infection. Virol. J. 4, 62 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  151. Bahi, A., Boyer, F., Kolira, M. & Dreyer, J. L. In vivo gene silencing of CD81 by lentiviral expression of small interference RNAs suppresses cocaine-induced behaviour. J. Neurochem. 92, 1243–1255 (2005).

    CAS  PubMed  Article  Google Scholar 

  152. de Fougerolles, A., Vornlocher, H. P., Maraganore, J. & Lieberman, J. Interfering with disease: a progress report on siRNA-based therapeutics. Nature Rev. Drug Discov. 6, 443–453 (2007).

    CAS  Article  Google Scholar 

  153. Peer, D., Park, E. J., Morishita, Y., Carman, C. V. & Shimaoka, M. Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target. Science 319, 627–630 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. Cannon, K. S. & Cresswell, P. Quality control of transmembrane domain assembly in the tetraspanin CD82. EMBO J. 20, 2443–2453 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. Goldberg, A. F. et al. An intramembrane glutamic acid governs peripherin/rds function for photoreceptor disk morphogenesis. Invest. Ophthalmol. Vis. Sci. 48, 2975–2986 (2007).

    PubMed  Article  Google Scholar 

  156. Tarasova, N. I., Rice, W. G. & Michejda, C. J. Inhibition of G-protein-coupled receptor function by disruption of transmembrane domain interactions. J. Biol. Chem. 274, 34911–34915 (1999).

    CAS  PubMed  Article  Google Scholar 

  157. Latysheva, N. et al. Syntenin-1 is a new component of tetraspanin-enriched microdomains: mechanisms and consequences of the interaction of syntenin-1 with CD63. Mol. Cell Biol. 26, 7707–7718 (2006). First demonstration of a specific tetraspanin interaction with a PDZ domain-containing protein.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. Dev., K. K. Making protein interactions druggable: targeting PDZ domains. Nature Rev. Drug Discov. 3, 1047–1056 (2004).

    CAS  Article  Google Scholar 

  159. Holzer, M. et al. Identification of terfenadine as an inhibitor of human CD81-receptor HCV-E2 interaction: synthesis and structure optimization. Molecules 13, 1081–1110 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  160. VanCompernolle, S. E. et al. Small molecule inhibition of hepatitis C virus E2 binding to CD81. Virology 314, 371–380 (2003).

    CAS  PubMed  Article  Google Scholar 

  161. Mitchell, D. A., Vasudevan, A., Linder, M. E. & Deschenes, R. J. Protein palmitoylation by a family of DHHC protein S-acyltransferases. J. Lipid Res. 47, 1118–1127 (2006).

    CAS  PubMed  Article  Google Scholar 

  162. Sharma, C., Yang, X. H. & Hemler, M. E. DHHC2 affects palmitoylation and stability of tetraspanins CD9 and CD151. Mol. Biol. Cell 19, 3415–3425 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. Tsai, Y. C. et al. The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation. Nature Med. 13, 1504–1509 (2007).

    CAS  PubMed  Article  Google Scholar 

  164. Kurzeder, C. et al. CD9 promotes adeno-associated virus type 2 infection of mammary carcinoma cells with low cell surface expression of heparan sulphate proteoglycans. Int. J. Mol. Med. 19, 325–333 (2007).

    CAS  PubMed  Google Scholar 

  165. 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).

    CAS  PubMed  Google Scholar 

  166. Rocha-Perugini, V. et al. The CD81 partner EWI-2wint inhibits hepatitis C virus entry. PLoS ONE 3, e1866 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  167. 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).

    CAS  PubMed  Article  Google Scholar 

  168. 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).

    CAS  PubMed  Article  Google Scholar 

  169. Shi, W., Fan, H., Shum, L. & Derynck, R. The tetraspanin CD9 associates with transmembrane TGF-α and regulates TGF-α-induced EGF receptor activation and cell proliferation. J. Cell Biol. 148, 591–602 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  170. Yan, Y., Shirakabe, K. & Werb, Z. The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G. protein-coupled receptors. J. Cell Biol. 158, 221–226 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  171. Fearon, D. T. & Carter, R. H. The CD19/CR2/TAPA-1 complex of B lymphocytes: linking natural and acquired immunity. Annu. Rev. Immunol. 13, 127–149 (1995).

    CAS  PubMed  Article  Google Scholar 

  172. 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). Excellent use of diagnostic anti-CD151 antibodies to distinguish integrin-associated and non-associated CD151.

    CAS  PubMed  Article  Google Scholar 

  173. 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).

    CAS  PubMed  Article  Google Scholar 

  174. Yanez-Mo, 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  175. Zhang, X. A. et al. Function of the tetraspanin CD151–α6β1 integrin complex during cellular morphogenesis. Mol. Biol. Cell 13, 1–11 (2002).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  176. Lammerding, J., Kazarov, A. R., Huang, H., Lee, R. T. & Hemler, M. E. Tetraspanin CD151 regulates α6β1 integrin adhesion strengthening. Proc. Natl Acad. Sci. USA 100, 7616–7621 (2003). Ligand-coated magnetic beads used to show that CD151 affects ligand detachment rather than attachment.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  177. 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).

    CAS  PubMed  Article  Google Scholar 

  178. Stipp, C. S., Orlicky, D. & Hemler, M. E. FPRP: A major, highly stoichiometric, highly specific CD81 and CD9-associated protein. J. Biol. Chem. 276, 4853–4862 (2001).

    CAS  PubMed  Article  Google Scholar 

  179. Charrin, S. et al. The major CD9 and CD81 molecular partner. Identification and characterization of the complexes. J. Biol. Chem. 276, 14329–14337 (2001).

    CAS  PubMed  Article  Google Scholar 

  180. Clark, K. L., Zeng, Z., Langford, A. L., Bowen, S. M. & Todd, S. C. Pgrl is a major CD81-associated protein on lymphocytes and distinguishes a new family of cell surface proteins. J. Immunol. 167, 5115–5121 (2001).

    CAS  PubMed  Article  Google Scholar 

  181. Horvath, G. et al. CD19 is linked to the integrin-associated tetraspans CD9, CD81, and CD82. J. Biol. Chem. 273, 30537–30543 (1998).

    CAS  PubMed  Article  Google Scholar 

  182. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  183. Miyado, K. et al. Requirement of CD9 on the egg plasma membrane for fertilization. Science 287, 321–324 (2000).

    CAS  PubMed  Article  Google Scholar 

  184. Le Naour, F., Rubinstein, E., Jasmin, C., Prenant, M. & Boucheix, C. Severely reduced female fertility in CD9-deficient mice. Science 287, 319–321 (2000).

    CAS  PubMed  Article  Google Scholar 

  185. Kaji, K. et al. The gamete fusion process is defective in eggs of Cd9-deficient mice. Nature Genet. 24, 279–282 (2000).

    CAS  PubMed  Article  Google Scholar 

  186. Kaminski, M. S. et al. Imaging, dosimetry, and radioimmunotherapy with iodine 131-labeled anti-CD37 antibody in B-cell lymphoma. J. Clin. Oncol. 10, 1696–1711 (1992).

    CAS  PubMed  Article  Google Scholar 

  187. Tanigawa, M. et al. Possible involvement of CD81 in acrosome reaction of sperm in mice. Mol. Reprod. Dev. 75, 150–155 (2008).

    PubMed  Article  CAS  Google Scholar 

  188. Schmid, E. et al. Antibodies to CD9, a tetraspan transmembrane protein, inhibit canine distemper virus-induced cell–cell fusion but not virus–cell fusion. J. Virol. 74, 7554–7561 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  189. Iwamoto, R., Senoh, H., Okada, Y., Uchida, T. & Mekada, E. An antibody that inhibits the binding of diphtheria toxin to cells revealed the association of a 27-kD membrane protein with the diphtheria toxin receptor. J. Biol. Chem. 266, 20463–20469 (1991).

    CAS  PubMed  Article  Google Scholar 

  190. Beatty, W. L. Trafficking from CD63-positive late endocytic multivesicular bodies is essential for intracellular development of Chlamydia trachomatis. J. Cell Sci. 119, 350–359 (2006).

    CAS  PubMed  Article  Google Scholar 

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The author gratefully acknowledges support from the National Institutes of Health grants GM38903 and CA42368.

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FURTHER INFORMATION

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Glossary

Integrins

A family of cell-surface transmembrane proteins (24 mammalian members), with αβ-heterodimeric structures, which function as cell adhesion molecules.

EWI proteins

A family of four cell-surface immunoglobulin superfamily proteins, sharing a conserved glutamine-tryptophan-isoleucine (EWI) motif.

Protein palmitoylation

Post-translational acylation of a protein, typically on an intracellular cysteine residue.

Exosomes

Vesicles of 50–100 nm, enriched 10-fold to 100-fold for tetraspanins, and shed from the multivesicular bodies of cells.

Monoclonal antibody

A specific antibody produced in large quantity by a single hybrid cell clone formed in the laboratory by the fusion of a B cell with a tumour cell.

Angiogenesis

The process by which new blood vessels grow from pre-existing blood vessels.

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, resulting in reduction or loss of gene activity.

DHHC2

A member of a family of enzymes (24 members in mammals) containing a conserved aspartate-histidine-histidine-cysteine (DHHC) motif, responsible for the S-palmitoylation of proteins.

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Hemler, M. Targeting of tetraspanin proteins — potential benefits and strategies. Nat Rev Drug Discov 7, 747–758 (2008). https://doi.org/10.1038/nrd2659

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