Tetraspanins in Cancer

  • Andries Zijlstra


The Tetraspanins comprise a distinct family of small transmembrane proteins capable of molecular organization of its non-tetraspanin partners. The 33 family members are characterized by a recurrent structural theme and conserved cysteines. While catalytic domains and ligands have not been identified, tetraspanins appear to function as molecular organizers by recruiting non-tetraspanin partners into organized membrane structures known as tetraspanin-enriched microdomains (TERM). These interactions allow tetraspanins to regulate adhesion, cytoskeletal interactions, molecular signaling, and protein trafficking. Tetraspanins are involved in a multitude of biological processes ranging from synaptic contacts at neuromuscular junctions to epithelial integrity and T-cell activation. In recent years, their role in several malignancies has become particularly apparent. Some tetraspanins appear capable of limiting cancer progression while others promote tumor growth, invasion, and metastasis. This chapter focuses on reviewing the current understanding of tetraspanins in tumorigenesis.


Tetraspanin Cancer Migration Tetraspanin Enriched Microdomain (TERM) TSPAN TM4SF Scaffold 



This work was supported, in part, by -5K01 CA120711-02 (NIH/NCI).


  1. Abe M, Sugiura T, Takahashi M, Ishii K, Shimoda M, Shirasuna K (2008) A novel function of CD82/KAI-1 on E-cadherin-mediated homophilic cellular adhesion of cancer cells. Cancer Lett 266(2):163–170PubMedGoogle Scholar
  2. Andre F, Schartz NE et al (2002) Malignant effusions and immunogenic tumour-derived exosomes. Lancet 360(9329):295–305PubMedGoogle Scholar
  3. André M, Le Caer JP, Greco C, Planchon S, El Nemer W, Boucheix C, Rubinstein E, Chamot-Rooke J, Le Naour F (2006) Proteomic analysis of the tetraspanin web using LC-ESI-MS/MS and MALDI-FTICR-MS. Proteomics 6(5):1437–1449PubMedGoogle Scholar
  4. Ang J, Lijovic M, Ashman LK, Kan K, Frauman AG (2004) 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(11 Pt 1):1717–1721PubMedGoogle Scholar
  5. Arduise C, Abache T et al (2008) Tetraspanins regulate ADAM10-mediated cleavage of TNF-alpha and epidermal growth factor. J Immunol 181(10):7002–7013PubMedGoogle Scholar
  6. Baleato RM, Guthrie PL, Gubler MC, Ashman LK, Roselli S (2008) Deletion of CD151 results in a strain-dependent glomerular disease due to severe alterations of the glomerular basement membrane. Am J Pathol 173(4):927–937PubMedGoogle Scholar
  7. Berditchevski F (2001) Complexes of tetraspanins with integrins: More than meets the eye. J Cell Sci 114(Pt 23):4143–4151PubMedGoogle Scholar
  8. Berditchevski F, Odintsova E (1999) Characterization of integrin-tetraspanin adhesion complexes: Role of tetraspanins in integrin signaling. J Cell Biol 146(2):477–492PubMedGoogle Scholar
  9. Berditchevski F, Odintsova E (2007) Tetraspanins as regulators of protein trafficking. Traffic 8(2):89–96PubMedGoogle Scholar
  10. Berditchevski F, Zutter MM, Hemler ME (1996) Characterization of novel complexes on the cell surface between integrins and proteins with 4 transmembrane domains (TM4 proteins). Mol Biol Cell 7(2):193–207PubMedGoogle Scholar
  11. Berditchevski F, Gilbert E, Griffiths MR, Fitter S, Ashman L, Jenner SJ (2001) Analysis of the CD151-alpha3beta1 integrin and CD151-tetraspanin interactions by mutagenesis. J Biol Chem 276(44):41165–41174PubMedGoogle Scholar
  12. Berditchevski F, Odintsova E, Sawada S, Gilbert E (2002) Expression of the palmitoylation-deficient CD151 weakens the association of alpha 3 beta 1 integrin with the tetraspanin-enriched microdomains and affects integrin-dependent signaling. J Biol Chem 277(40):36991–37000PubMedGoogle Scholar
  13. Bienstock RJ, Barrett JC (2001) KAI1, a prostate metastasis suppressor: Prediction of solvated structure and interactions with binding partners; integrins, cadherins, and cell-surface receptor proteins. Mol Carcinog 32(3):139–153PubMedGoogle Scholar
  14. Caby MP, Lankar D, Vincendeau-Scherrer C, Raposo G, Bonnerot C (2005) Exosomal-like vesicles are present in human blood plasma. Int Immunol 17(7):879–887PubMedGoogle Scholar
  15. Carloni V, Mazzocca A, Ravichandran KS (2004) Tetraspanin CD81 is linked to ERK/MAPKinase signaling by Shc in liver tumor cells. Oncogene 23(8):1566–1574PubMedGoogle Scholar
  16. Charrin S, Manié S, Billard M, Ashman L, Gerlier D, Boucheix C, Rubinstein E (2003) Multiple levels of interactions within the tetraspanin web. Biochem Biophys Res Commun 304(1):107–112PubMedGoogle Scholar
  17. Chattopadhyay N, Wang Z, Ashman LK, Brady-Kalnay SM, Kreidberg JA (2003) alpha3beta1 integrin-CD151, a component of the cadherin-catenin complex, regulates PTPmu expression and cell–cell adhesion. J Cell Biol 163(6):1351–1362PubMedGoogle Scholar
  18. Chen Z, Mustafa T et al (2004) CD82, and CD63 in thyroid cancer. Int J Mol Med 14(4):517–527PubMedGoogle Scholar
  19. Chen L, Wang Z, Zhan X, Li DC, Zhu YY, Zhu J (2007) Association of NET-1 gene expression with human hepatocellular carcinoma. Int J Surg Pathol 15(4):346–353PubMedGoogle Scholar
  20. Chen L, Li X, Wang GL, Wang Y, Zhu YY, Zhu J (2008) Clinicopathological significance of overexpression of TSPAN1, Ki67 and CD34 in gastric carcinoma. Tumori 94(4):531–538PubMedGoogle Scholar
  21. Claas C, Seiter S, Claas A, Savelyeva L, Schwab M, Zöller M (1998) Association between the rat homologue of CO-029, a metastasis-associated tetraspanin molecule and consumption coagulopathy. J Cell Biol 141(1):267–280PubMedGoogle Scholar
  22. Deng J, Yeung VP, Tsitoura D, DeKruyff RH, Umetsu DT, Levy S (2000) Allergen-induced airway hyperreactivity is diminished in CD81-deficient mice. J Immunol 165(9):5054–5061PubMedGoogle Scholar
  23. Dong JT, Lamb PW, Rinker-Schaeffer CW, Vukanovic J, Ichikawa T, Isaacs JT, Barrett JC (1995) KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science 268(5212):884–886PubMedGoogle Scholar
  24. Escola JM, Kleijmeer MJ, Stoorvogel W, Griffith JM, Yoshie O, Geuze HJ (1998) Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. J Biol Chem 273(32):20121–20127PubMedGoogle Scholar
  25. Feigelson SW, Grabovsky V, Shamri R, Levy S, Alon R (2003) 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(51):51203–51212PubMedGoogle Scholar
  26. Funakoshi T, Tachibana I et al (2003) Expression of tetraspanins in human lung cancer cells: Frequent downregulation of CD9 and its contribution to cell motility in small cell lung cancer. Oncogene 22(5):674–687PubMedGoogle Scholar
  27. Garcia-España A, Chung PJ, Sarkar IN, Stiner E, Sun TT, Desalle R (2008) Appearance of new tetraspanin genes during vertebrate evolution. Genomics 91(4):326–334PubMedGoogle Scholar
  28. Geary SM, Cambareri AC, Sincock PM, Fitter S, Ashman LK (2001) Differential tissue expression of epitopes of the tetraspanin CD151 recognised by monoclonal antibodies. Tissue Antigens 58(3):141–153PubMedGoogle Scholar
  29. Gesierich S, Paret C et al (2005) Colocalization of the tetraspanins, CO-029 and CD151, with integrins in human pancreatic adenocarcinoma: Impact on cell motility. Clin Cancer Res 11(8):2840–2852PubMedGoogle Scholar
  30. Gesierich S, Berezovskiy I, Ryschich E, Zöller M (2006) Systemic induction of the angiogenesis switch by the tetraspanin D6.1A/CO-029. Cancer Res 66(14):7083–7094PubMedGoogle Scholar
  31. Griffith L, Slupsky J, Seehafer J, Boshkov L, Shaw AR (1991) Platelet activation by immobilized monoclonal antibody: Evidence for a CD9 proximal signal. Blood 78(7):1753–1759PubMedGoogle Scholar
  32. Guindon S, Gascuel O (2003) A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood. Syst Biol 52(5):696–704PubMedGoogle Scholar
  33. Guo X, Friess H, Graber HU, Kashiwagi M, Zimmermann A, Korc M, Büchler MW (1996) KAI1 expression is up-regulated in early pancreatic cancer and decreased in the presence of metastases. Cancer Res 56(21):4876–4880PubMedGoogle Scholar
  34. Guo XZ, Friess H et al (1998) KAI1 is unchanged in metastatic and nonmetastatic esophageal and gastric cancers. Cancer Res 58(4):753–758PubMedGoogle Scholar
  35. Hadjiargyrou M, Patterson PH (1995) An anti-CD9 monoclonal antibody promotes adhesion and induces proliferation of Schwann cells in vitro. J Neurosci 15(1 Pt 2):574–583PubMedGoogle Scholar
  36. Hashida H, Takabayashi A et al (2003) Clinical significance of transmembrane 4 superfamily in colon cancer. Br J Cancer 89(1):158–167PubMedGoogle Scholar
  37. Hemler ME (2005) Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol 6(10):801–811PubMedGoogle Scholar
  38. Hemler ME (2008) Targeting of tetraspanin proteins – potential benefits and strategies. Nat Rev Drug Discov 7(9):747–758PubMedGoogle Scholar
  39. Higashiyama M, Taki T, Ieki Y, Adachi M, Huang CL, Koh T, Kodama K, Doi O, Miyake M (1995a) Reduced motility related protein-1 (MRP-1/CD9) gene expression as a factor of poor prognosis in non-small cell lung cancer. Cancer Res 55(24):6040–6044PubMedGoogle Scholar
  40. Higashiyama S, Iwamoto R, Goishi K, Raab G, Taniguchi N, Klagsbrun M, Mekada E (1995b) The membrane protein CD9/DRAP 27 potentiates the juxtacrine growth factor activity of the membrane-anchored heparin-binding EGF-like growth factor. J Cell Biol 128(5):929–938PubMedGoogle Scholar
  41. Hinoda Y, Adachi Y, Takaoka A, Mitsuuchi H, Satoh Y, Itoh F, Kondoh Y, Imai K (1998) Decreased expression of the metastasis suppressor gene KAI1 in gastric cancer. Cancer Lett 129(2):229–234PubMedGoogle Scholar
  42. Hirano T, Higuchi T et al (1999) CD9 is involved in invasion of human trophoblast-like choriocarcinoma cell line, BeWo cells. Mol Hum Reprod 5(2):168–174PubMedGoogle Scholar
  43. Hood JD, Cheresh DA (2002) Role of integrins in cell invasion and migration. Nat Rev Cancer 2(2):91–100PubMedGoogle Scholar
  44. Hori H, Yano S, Koufuji K, Takeda J, Shirouzu K (2004) CD9 expression in gastric cancer and its significance. J Surg Res 117(2):208–215PubMedGoogle Scholar
  45. Hotta H, Takahashi N, Homma M (1989) Transcriptional enhancement of the human gene encoding for a melanoma-associated antigen (ME491) in association with malignant transformation. Jpn J Cancer Res 80(12):1186–1191PubMedGoogle Scholar
  46. Hotta H, Hara I, Miyamoto H, Homma M (1991) Overexpression of the human melanoma-associated antigen ME491 partially suppresses in vivo malignant phenotypes of H-ras-transformed NIH3T3 cells in athymic nude mice. Melanoma Res 1(2):125–132PubMedGoogle Scholar
  47. Huang CI, Kohno N, Ogawa E, Adachi M, Taki T, Miyake M (1998) Correlation of reduction in MRP-1/CD9 and KAI1/CD82 expression with recurrences in breast cancer patients. Am J Pathol 153(3):973–983PubMedGoogle Scholar
  48. Huang S, Yuan S et al (2005a) The phylogenetic analysis of tetraspanins projects the evolution of cell–cell interactions from unicellular to multicellular organisms. Genomics 86(6):674–684PubMedGoogle Scholar
  49. Huang H, Groth J, Sossey-Alaoui K, Hawthorn L, Beall S, Geradts J (2005b) Aberrant expression of novel and previously described cell membrane markers in human breast cancer cell lines and tumors. Clin Cancer Res 11(12):4357–4364PubMedGoogle Scholar
  50. Huang H, Sossey-Alaoui K, Beachy SH, Geradts J (2007) The tetraspanin superfamily member NET-6 is a new tumor suppressor gene. J Cancer Res Clin Oncol 133(10):761–769PubMedGoogle Scholar
  51. Ikeyama S, Koyama M, Yamaoko M, Sasada R, Miyake M (1993) Suppression of cell motility and metastasis by transfection with human motility-related protein (MRP-1/CD9) DNA. J Exp Med 177(5):1231–1237PubMedGoogle Scholar
  52. Ito E, Honma R et al (2003) A tetraspanin-family protein, T-cell acute lymphoblastic leukemia-associated antigen 1, is induced by the Ewing’s sarcoma-Wilms’ tumor 1 fusion protein of desmoplastic small round-cell tumor. Am J Pathol 163(6):2165–2172PubMedGoogle Scholar
  53. Jackson P, Kingsley EA, Russell PJ (2000) Inverse correlation between KAI1 mRNA levels and invasive behaviour in bladder cancer cell lines. Cancer Lett 156(1):9–17PubMedGoogle Scholar
  54. Jackson P, Marreiros A, Russell PJ (2005) KAI1 tetraspanin and metastasis suppressor. Int J Biochem Cell Biol 37(3):530–534PubMedGoogle Scholar
  55. Jankowski SA, Mitchell DS, Smith SH, Trent JM, Meltzer PS (1994) SAS, a gene amplified in human sarcomas, encodes a new member of the transmembrane 4 superfamily of proteins. Oncogene 9(4):1205–1211PubMedGoogle Scholar
  56. Janowska-Wieczorek A, Wysoczynski M, Kijowski J, Marquez-Curtis L, Machalinski B, Ratajczak J, Ratajczak MZ (2005) Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer 113(5):752–760PubMedGoogle Scholar
  57. Jee BK, Lee JY, Lim Y, Lee KH, Jo YH (2007) Effect of KAI1/CD82 on the beta1 integrin maturation in highly migratory carcinoma cells. Biochem Biophys Res Commun 359(3):703–708PubMedGoogle Scholar
  58. Kanetaka K, Sakamoto M, Yamamoto Y, Yamasaki S, Lanza F, Kanematsu T, Hirohashi S (2001) Overexpression of tetraspanin CO-029 in hepatocellular carcinoma. J Hepatol 35(5):637–642PubMedGoogle Scholar
  59. Kanetaka K, Sakamoto M, Yamamoto Y, Takamura M, Kanematsu T, Hirohashi S (2003) Possible involvement of tetraspanin CO-029 in hematogenous intrahepatic metastasis of liver cancer cells. J Gastroenterol Hepatol 18(11):1309–1314PubMedGoogle Scholar
  60. Karamatic Crew V, Burton N, Kagan A, Green CA, Levene C, Flinter F, Brady RL, Daniels G, Anstee DJ (2004) 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(8):2217–2223PubMedGoogle Scholar
  61. Karamatic Crew V, Poole J et al (2008) Two MER2-negative individuals with the same novel CD151 mutation and evidence for clinical significance of anti-MER2. Transfusion 48(9):1912–1916PubMedGoogle Scholar
  62. Kazarov AR, Yang X, Stipp CS, Sehgal B, Hemler ME (2002) An extracellular site on tetraspanin CD151 determines alpha 3 and alpha 6 integrin-dependent cellular morphology. J Cell Biol 158(7):1299–1309PubMedGoogle Scholar
  63. Klosek SK, Nakashiro K, Hara S, Shintani S, Hasegawa H, Hamakawa H (2005) CD151 forms a functional complex with c-Met in human salivary gland cancer cells. Biochem Biophys Res Commun 336(2):408–416PubMedGoogle Scholar
  64. Kobayashi T, Vischer UM, Rosnoblet C, Lebrand C, Lindsay M, Parton RG, Kruithof EK, Gruenberg J (2000) The tetraspanin CD63/lamp3 cycles between endocytic and secretory compartments in human endothelial cells. Mol Biol Cell 11(5):1829–1843PubMedGoogle Scholar
  65. Koenig-Hoffmann K, Bonin-Debs AL et al (2005) High throughput functional genomics: Identification of novel genes with tumor suppressor phenotypes. Int J Cancer 113(3):434–439PubMedGoogle Scholar
  66. Kohl S, Giddings I, Besch D, Apfelstedt-Sylla E, Zrenner E, Wissinger B (1998) The role of the peripherin/RDS gene in retinal dystrophies. Acta Anat (Basel) 162(2–3):75–84Google Scholar
  67. Kohno M, Hasegawa H, Miyake M, Yamamoto T, Fujita S (2002) CD151 enhances cell motility and metastasis of cancer cells in the presence of focal adhesion kinase. Int J Cancer 97(3):336–343PubMedGoogle Scholar
  68. Kolesnikova TV, Kazarov AR, Lemieux ME, Lafleur MA, Kesari S, Kung AL, Hemler ME (2009) Glioblastoma inhibition by cell surface immunoglobulin protein EWI-2, in vitro and in vivo. Neoplasia 11(1):77–86 74p following 86PubMedGoogle Scholar
  69. Kondoh M, Ueda M, Ichihashi M, Mishima Y (1993) Decreased expression of human melanoma-associated antigen ME491 along the progression of melanoma pre-canceroses to invasive and metastatic melanomas. Melanoma Res 3(4):241–245PubMedGoogle Scholar
  70. Kovalenko OV, Yang XH, Hemler ME (2007) A novel cysteine cross-linking method reveals a direct association between claudin-1 and tetraspanin CD9. Mol Cell Proteomics 6(11):1855–1867PubMedGoogle Scholar
  71. Kubista B, Erovic BM, Klinger H, Sulzbacher I, Trieb K (2004) CD9 expression is not a prognostic factor in human osteosarcoma. Cancer Lett 209(1):105–110PubMedGoogle Scholar
  72. Kuhn S, Koch M, Nubel T, Ladwein M, Antolovic D (2007a) A Complex of EpCAM, Claudin-7, CD44 variant isoforms, and tetraspanins promotes colorectal cancer. Mol Cancer Res 5(6):553–567PubMedGoogle Scholar
  73. Kuhn S, Koch M et al (2007b) A complex of EpCAM, claudin-7, CD44 variant isoforms, and tetraspanins promotes colorectal cancer progression. Mol Cancer Res 5(6):553–567PubMedGoogle Scholar
  74. Kwon MS, Shin SH, Yim SH, Lee KY, Kang HM, Kim TM, Chung YJ (2007) CD63 as a biomarker for predicting the clinical outcomes in adenocarcinoma of lung. Lung Cancer 57(1):46–53PubMedGoogle Scholar
  75. Lafleur MA, Xu D, Hemler ME (2009) Tetraspanin proteins regulate membrane type-1 matrix metalloproteinase (MT1-MMP)-dependent pericellular proteolysis. Mol Biol Cell 20:2030–2040PubMedGoogle Scholar
  76. Lammerding J, Kazarov AR, Huang H, Lee RT, Hemler ME (2003) Tetraspanin CD151 regulates alpha6beta1 integrin adhesion strengthening. Proc Natl Acad Sci USA 100(13):7616–7621PubMedGoogle Scholar
  77. Lazo PA (2007) Functional implications of tetraspanin proteins in cancer biology. Cancer Sci 98(11):1666–1677PubMedGoogle Scholar
  78. Le Naour F, Zoller M (2008) The tumor antigen EpCAM: Tetraspanins and the tight junction protein claudin-7, new partners, new functions. Front Biosci 13:5847–5865PubMedGoogle Scholar
  79. Le Naour F, Rubinstein E, Jasmin C, Prenant M, Boucheix C (2000) Severely reduced female fertility in CD9-deficient mice. Science 287(5451):319–321PubMedGoogle Scholar
  80. Le Naour F, André M, Greco C, Billard M, Sordat B, Emile JF, Lanza F, Boucheix C, Rubinstein E (2006) Profiling of the tetraspanin web of human colon cancer cells. Mol Cell Proteomics 5(5):845–857PubMedGoogle Scholar
  81. Lekishvili T, Fromm E, Mujoomdar M, Berditchevski F (2008) The tumour-associated antigen L6 (L6-Ag) is recruited to the tetraspanin-enriched microdomains: Implication for tumour cell motility. J Cell Sci 121(5):685PubMedGoogle Scholar
  82. Levy S, Shoham T (2005) The tetraspanin web modulates immune-signalling complexes. Nat Rev Immunol 5(2):136–148PubMedGoogle Scholar
  83. Ley K, Zhang H (2008) Dances with leukocytes: How tetraspanin-enriched microdomains assemble to form endothelial adhesive platforms. J Cell Biol 183(3):375–376PubMedGoogle Scholar
  84. Li J, Li W et al (2003) Recombinant CD63/ME491/neuroglandular/NKI/C-3 antigen inhibits growth of established tumors in transgenic mice. J Immunol 171(6):2922–2929PubMedGoogle Scholar
  85. Liu WM, Zhang XA (2006) KAI1/CD82, a tumor metastasis suppressor. Cancer Lett 240(2):183–194PubMedGoogle Scholar
  86. Liu FS, Chen JT, Dong JT, Hsieh YT, Lin AJ, Ho ES, Hung MJ, Lu CH (2001) KAI1 metastasis suppressor gene is frequently down-regulated in cervical carcinoma. Am J Pathol 159(5):1629–1634PubMedGoogle Scholar
  87. Liu L, He B, Liu WM, Zhou D, Cox JV, Zhang XA (2007) Tetraspanin CD151 Promotes Cell Migration by Regulating Integrin Trafficking. J Biol Chem 282(43):31631–31642PubMedGoogle Scholar
  88. Lombardi DP, Geradts J, Foley JF, Chiao C, Lamb PW, Barrett JC (1999) Loss of KAI1 expression in the progression of colorectal cancer. Cancer Res 59(22):5724–5731PubMedGoogle Scholar
  89. Maecker HT, Todd SC, Levy S (1997) The tetraspanin superfamily: Molecular facilitators. FASEB J 11(6):428–442PubMedGoogle Scholar
  90. Mantegazza AR, Barrio MM, Moutel S, Bover L, Weck M, Brossart P, Teillaud JL, Mordoh J (2004) CD63 tetraspanin slows down cell migration and translocates to the endosomal-lysosomal-MIICs route after extracellular stimuli in human immature dendritic cells. Blood 104(4):1183–1190PubMedGoogle Scholar
  91. Masellis-Smith A, Shaw AR (1994) CD9-regulated adhesion. Anti-CD9 monoclonal antibody induce pre-B cell adhesion to bone marrow fibroblasts through de novo recognition of fibronectin. J Immunol 152(6):2768–2777PubMedGoogle Scholar
  92. Mazzocca A, Liotta F, Carloni V (2008) Tetraspanin CD81-regulated cell motility plays a critical role in intrahepatic metastasis of hepatocellular carcinoma. Gastroenterology 135(1):244–256.e241PubMedGoogle Scholar
  93. Mhawech P, Herrmann F, Coassin M, Guillou L, Iselin CE (2003) Motility-related protein 1 (MRP-1/CD9) expression in urothelial bladder carcinoma and its relation to tumor recurrence and progression. Cancer 98(8):1649–1657PubMedGoogle Scholar
  94. Mhawech P, Dulguerov P, Tschanz E, Verdan C, Ares C, Allal AS (2004) Motility-related protein-1 (MRP-1/CD9) expression can predict disease-free survival in patients with squamous cell carcinoma of the head and neck. Br J Cancer 90(2):471–475PubMedGoogle Scholar
  95. Miranti CK (2009) Controlling cell surface dynamics and signaling: How CD82/KAI1 suppresses metastasis. Cell Signal 21(2):196–211PubMedGoogle Scholar
  96. Miyado K, Mekada E, Kobayashi K (2000) A crucial role of tetraspanin, CD9 in fertilization. Tanpakushitsu Kakusan Koso 45(10):1728–1734PubMedGoogle Scholar
  97. Miyake M, Koyama M, Seno M, Ikeyama S (1991) Identification of the motility-related protein (MRP-1), recognized by monoclonal antibody M31–15, which inhibits cell motility. J Exp Med 174(6):1347–1354PubMedGoogle Scholar
  98. Miyake M, Nakano K, Ieki Y, Adachi M, Huang CL, Itoi S, Koh T, Taki T (1995) Motility related protein 1 (MRP-1/CD9) expression: Inverse correlation with metastases in breast cancer. Cancer Res 55(18):4127–4131PubMedGoogle Scholar
  99. Miyake M, Nakano K, Itoi SI, Koh T, Taki T (1996) Motility-related protein-1 (MRP-1/CD9) reduction as a factor of poor prognosis in breast cancer. Cancer Res 56(6):1244–1249PubMedGoogle Scholar
  100. Miyamoto S, Maruyama A, Okugawa K, Akazawa K, Baba H, Maehara Y, Mekada E (2001) Loss of motility-related protein 1 (MRP1/CD9) and integrin alpha3 expression in endometrial cancers. Cancer 92(3):542–548PubMedGoogle Scholar
  101. Miyazaki T, Müller U, Campbell KS (1997) Normal development but differentially altered proliferative responses of lymphocytes in mice lacking CD81. EMBO J 16(14):4217–4225PubMedGoogle Scholar
  102. Miyazaki T, Kato H et al (2000) Mutation and expression of the metastasis suppressor gene KAI1 in esophageal squamous cell carcinoma. Cancer 89(5):955–962PubMedGoogle Scholar
  103. Miyazaki T, Kato H et al (2005) Evaluation of tumor malignancy in esophageal squamous cell carcinoma using different characteristic factors. Anticancer Res 25(6B):4005–4011PubMedGoogle Scholar
  104. Murayama Y, Miyagawa J et al (2004) CD9-mediated activation of the p46 Shc isoform leads to apoptosis in cancer cells. J Cell Sci 117(Pt 15):3379–3388PubMedGoogle Scholar
  105. Murayama Y, Shinomura Y et al (2008) The tetraspanin CD9 modulates epidermal growth factor receptor signaling in cancer cells. J Cell Physiol 216(1):135–143PubMedGoogle Scholar
  106. Nishiuchi R, Sanzen N, Nada S, Sumida Y, Wada Y, Okada M, Takagi J, Hasegawa H, Sekiguchi K (2005) Potentiation of the ligand-binding activity of integrin alpha3beta1 via association with tetraspanin CD151. Proc Natl Acad Sci USA 102(6):1939–1944PubMedGoogle Scholar
  107. Odintsova E, Sugiura T, Berditchevski F (2000) Attenuation of EGF receptor signaling by a metastasis suppressor, the tetraspanin CD82/KAI-1. Curr Biol 10(16):1009–1012PubMedGoogle Scholar
  108. Odintsova E, Voortman J, Gilbert E, Berditchevski F (2003) Tetraspanin CD82 regulates compartmentalisation and ligand-induced dimerization of EGFR. J Cell Sci 116(Pt 22):4557–4566PubMedGoogle Scholar
  109. Oren R, Takahashi S, Doss C, Levy R, Levy S (1990) TAPA-1, the target of an antiproliferative antibody, defines a new family of transmembrane proteins. Mol Cell Biol 10(8):4007–4015PubMedGoogle Scholar
  110. Puls KL, Ni J, Liu D, Morahan G, Wright MD (1999) The molecular characterisation of a novel tetraspanin protein, TM4-B(1). Biochim Biophys Acta 1447(1):93–99PubMedGoogle Scholar
  111. Radford KJ, Mallesch J, Hersey P (1995) Suppression of human melanoma cell growth and metastasis by the melanoma-associated antigen CD63 (ME491). Int J Cancer 62(5):631–635PubMedGoogle Scholar
  112. Radford KJ, Thorne RF, Hersey P (1996) CD63 associates with transmembrane 4 superfamily members, CD9 and CD81, and with beta 1 integrins in human melanoma. Biochem Biophys Res Commun 222(1):13–18PubMedGoogle Scholar
  113. Radford KJ, Thorne RF, Hersey P (1997) Regulation of tumor cell motility and migration by CD63 in a human melanoma cell line. J Immunol 158(7):3353–3358PubMedGoogle Scholar
  114. Regina Todeschini A, Hakomori SI (2008) Functional role of glycosphingolipids and gangliosides in control of cell adhesion, motility, and growth, through glycosynaptic microdomains. Biochim Biophys Acta 1780(3):421–433PubMedGoogle Scholar
  115. Rous BA, Reaves BJ, Ihrke G, Briggs JA, Gray SR, Stephens DJ, Banting G, Luzio JP (2002) Role of adaptor complex AP-3 in targeting wild-type and mutated CD63 to lysosomes. Mol Biol Cell 13(3):1071–1082PubMedGoogle Scholar
  116. Rubinstein E, Boucheix C (1999) “Tetraspans.” InGuidebook to the Extracellular Matrix, Anchor, and Adhesion Proteins. Oxford University Press, Oxford, pp 321–324
  117. Ryu F, Takahashi T, Nakamura K, Takahashi Y, Kobayashi T, Shida S, Kameyama T, Mekada E (2000) Domain analysis of the tetraspanins: Studies of CD9/CD63 chimeric molecules on subcellular localization and upregulation activity for diphtheria toxin binding. Cell Struct Funct 25(5):317–327PubMedGoogle Scholar
  118. Sachs N, Kreft M, van den Bergh Weerman MA, Beynon AJ, Peters TA, Weening JJ, Sonnenberg A (2006) Kidney failure in mice lacking the tetraspanin CD151. J Cell Biol 175(1):33–39PubMedGoogle Scholar
  119. Sala-Valdés M, Ursa A, Charrin S, Rubinstein E, Hemler ME, Sánchez-Madrid F, Yáñez-Mó M (2006) 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(28):19665–19675PubMedGoogle Scholar
  120. Sanyal S, De Ruiter A, Hawkins RK (1980) Development and degeneration of retina in rds mutant mice: Light microscopy. J Comp Neurol 194(1):193–207PubMedGoogle Scholar
  121. Sawada S, Yoshimoto M, Odintsova E, Hotchin NA, Berditchevski F (2003) The tetraspanin CD151 functions as a negative regulator in the adhesion-dependent activation of Ras. J Biol Chem 278(29):26323–26326PubMedGoogle Scholar
  122. Schöniger-Hekele M, Hänel S, Wrba F, Müller C (2005) Hepatocellular carcinoma-survival and clinical characteristics in relation to various histologic molecular markers in Western patients. Liver Int 25(1):62–69PubMedGoogle Scholar
  123. Schorey JS, Bhatnagar S (2008) Exosome function: From tumor immunology to pathogen biology. Traffic 9(6):871–881PubMedGoogle Scholar
  124. Serru V, Dessen P, Boucheix C, Rubinstein E (2000) Sequence and expression of seven new tetraspans. Biochim Biophys Acta 1478(1):159–163PubMedGoogle Scholar
  125. Sharma C, Yang XH, Hemler ME (2008) DHHC2 Affects palmitoylation, stability, and functions of tetraspanins CD9 and CD151. Mol Biol Cell 19:3415–3425PubMedGoogle Scholar
  126. Shen SQ, Li K, Zhu N, Nakao A (2008) Expression and clinical significance of NET-1 and PCNA in hepatocellular carcinoma. Med Oncol 25(3):341–345PubMedGoogle Scholar
  127. Shigeta M, Sanzen N, Ozawa M, Gu J, Hasegawa H, Sekiguchi K (2003) CD151 regulates epithelial cell–cell adhesion through PKC- and Cdc42-dependent actin cytoskeletal reorganization. J Cell Biol 163(1):165–176PubMedGoogle Scholar
  128. Shinohara T, Nishimura N, Hanibuchi M, Nokihara H, Miki T, Hamada H, Sone S (2001) Transduction of KAI1/CD82 cDNA promotes hematogenous spread of human lung-cancer cells in natural killer cell-depleted SCID mice. Int J Cancer 94(1):16–23PubMedGoogle Scholar
  129. Si Z, Hersey P (1993) Expression of the neuroglandular antigen and analogues in melanoma. CD9 expression appears inversely related to metastatic potential of melanoma. Int J Cancer 54(1):37–43PubMedGoogle Scholar
  130. Silvie O, Charrin S et al (2006) Cholesterol contributes to the organization of tetraspanin-enriched microdomains and to CD81-dependent infection by malaria sporozoites. J Cell Sci 119(Pt 10):1992–2002PubMedGoogle Scholar
  131. Sincock PM, Mayrhofer G, Ashman LK (1997) Localization of the transmembrane 4 superfamily (TM4SF) member PETA-3 (CD151) in normal human tissues: Comparison with CD9, CD63, and alpha5beta1 integrin. J Histochem Cytochem 45(4):515–525PubMedGoogle Scholar
  132. Sridhar SC, Miranti CK (2006) Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases. Oncogene 25(16):2367–2378PubMedGoogle Scholar
  133. Sterk LM, Geuijen CA, van den Berg JG, Claessen N, Weening JJ, Sonnenberg A (2002) Association of the tetraspanin CD151 with the laminin-binding integrins alpha3beta1, alpha6beta1, alpha6beta4 and alpha7beta1 in cells in culture and in vivo. J Cell Sci 115(Pt 6):1161–1173PubMedGoogle Scholar
  134. Sun TT, Zhao H, Provet J, Aebi U, Wu XR (1996) Formation of asymmetric unit membrane during urothelial differentiation. Mol Biol Rep 23(1):3–11PubMedGoogle Scholar
  135. Szala S, Kasai Y, Steplewski Z, Rodeck U, Koprowski H, Linnenbach AJ (1990) Molecular cloning of cDNA for the human tumor-associated antigen CO-029 and identification of related transmembrane antigens. Proc Natl Acad Sci USA 87(17):6833–6837PubMedGoogle Scholar
  136. Takagi S, Fujikawa K et al (1995) Identification of a highly specific surface marker of T-cell acute lymphoblastic leukemia and neuroblastoma as a new member of the transmembrane 4 superfamily. Int J Cancer 61(5):706–715PubMedGoogle Scholar
  137. Takaoka A, Hinoda Y, Sato S, Itoh F, Adachi M, Hareyama M, Imai K (1998a) Reduced invasive and metastatic potentials of KAI1-transfected melanoma cells. Jpn J Cancer Res 89(4):397–404PubMedGoogle Scholar
  138. Takaoka A, Hinoda Y, Satoh S, Adachi Y, Itoh F, Adachi M, Imai K (1998b) Suppression of invasive properties of colon cancer cells by a metastasis suppressor KAI1 gene. Oncogene 16(11):1443–1453PubMedGoogle Scholar
  139. Takeda Y, Kazarov AR, Butterfield CE, Hopkins BD, Benjamin LE, Kaipainen A, Hemler ME (2007) Deletion of tetraspanin Cd151 results in decreased pathologic angiogenesis in vivo and in vitro. Blood 109(4):1524–1532PubMedGoogle Scholar
  140. Todd SC, Doctor VS, Levy S (1998) Sequences and expression of six new members of the tetraspanin/TM4SF family. Biochim Biophys Acta 1399(1):101–104PubMedGoogle Scholar
  141. Todeschini AR, Dos Santos JN, Handa K, Hakomori SI (2007) Ganglioside GM2-tetraspanin CD82 complex inhibits met and its cross-talk with integrins, providing a basis for control of cell motility through glycosynapse. J Biol Chem 282(11):8123–8133PubMedGoogle Scholar
  142. Todeschini AR, Dos Santos JN, Handa K, Hakomori SI (2008) Ganglioside GM2/GM3 complex affixed on silica nanospheres strongly inhibits cell motility through CD82/cMet-mediated pathway. Proc Natl Acad Sci USA 105(6):1925–1930PubMedGoogle Scholar
  143. Tokuhara T, Hasegawa H, Hattori N, Ishida H, Taki T, Tachibana S, Sasaki S, Miyake M (2001) Clinical significance of CD151 gene expression in non-small cell lung cancer. Clin Cancer Res 7(12):4109–4114PubMedGoogle Scholar
  144. Tsitsikov EN, Gutierrez-Ramos JC, Geha RS (1997) 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(20):10844–10849PubMedGoogle Scholar
  145. Uchida S, Shimada Y, Watanabe G, Li ZG, Hong T, Miyake M, Imamura M (1999) Motility-related protein (MRP-1/CD9) and KAI1/CD82 expression inversely correlate with lymph node metastasis in oesophageal squamous cell carcinoma. Br J Cancer 79(7–8):1168–1173PubMedGoogle Scholar
  146. van Soest S, Westerveld A, de Jong PT, Bleeker-Wagemakers EM, Bergen AA (1999) Retinitis pigmentosa: Defined from a molecular point of view. Surv Ophthalmol 43(4):321–334PubMedGoogle Scholar
  147. van Spriel AB, Puls KL, Sofi M, Pouniotis D, Hochrein H, Orinska Z, Knobeloch KP, Plebanski M, Wright MD (2004) A regulatory role for CD37 in T cell proliferation. J Immunol 172(5):2953–2961PubMedGoogle Scholar
  148. VanCompernolle SE, Levy S, Todd SC (2001) Anti-CD81 activates LFA-1 on T cells and promotes T cell-B cell collaboration. Eur J Immunol 31(3):823–831PubMedGoogle Scholar
  149. Wang XQ, Yan Q, Sun P, Liu JW, Go L, McDaniel SM, Paller AS (2007) Suppression of epidermal growth factor receptor signaling by protein kinase C-alpha activation requires CD82, caveolin-1, and ganglioside. Cancer Res 67(20):9986–9995PubMedGoogle Scholar
  150. Winterwood NE, Varzavand A, Meland MN, Ashman LK, Stipp CS (2006) A critical role for tetraspanin CD151 in {alpha}3{beta}1 and {alpha}6{beta}4 integrin-dependent tumor cell functions on laminin-5. Mol Biol Cell 17(6):2707–2721PubMedGoogle Scholar
  151. Wright MD, Tomlinson MG (1994) The ins and outs of the transmembrane 4 superfamily. Immunol Today 15(12):588–594PubMedGoogle Scholar
  152. Wright MD, Geary SM et al (2004) Characterization of mice lacking the tetraspanin superfamily member CD151. Mol Cell Biol 24(13):5978–5988PubMedGoogle Scholar
  153. Xu L, Hynes RO (2007) GPR56 and TG2: Possible roles in suppression of tumor growth by the microenvironment. Cell Cycle 6(2):160–165PubMedGoogle Scholar
  154. Xu L, Begum S, Hearn JD, Hynes RO (2006) GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis. Proc Natl Acad Sci USA 103(24):9023–9028PubMedGoogle Scholar
  155. Yamada M, Tamura Y et al (2008) Probing the interaction of tetraspanin CD151 with integrin alpha3beta1 using a panel of monoclonal antibodies with distinct reactivities toward the CD151-integrin alpha3beta1 complex. Biochem J 415(3):417–427PubMedGoogle Scholar
  156. Yanez-Mo M, Barreiro O et al (2008) MT1-MMP collagenolytic activity is regulated through association with tetraspanin CD151 in primary endothelial cells. Blood 112:3217–3226PubMedGoogle Scholar
  157. Yang XH, Welch DR, Phillips KK, Weissman BE, Wei LL (1997) KAI1, a putative marker for metastatic potential in human breast cancer. Cancer Lett 119(2):149–155PubMedGoogle Scholar
  158. Yang X, Kovalenko OV, Tang W, Claas C, Stipp CS, Hemler ME (2004) Palmitoylation supports assembly and function of integrin-tetraspanin complexes. J Cell Biol 167(6):1231–1240PubMedGoogle Scholar
  159. Yang XH, Kovalenko OV, Kolesnikova TV, Andzelm MM, Rubinstein E, Strominger JL, Hemler ME (2006) Contrasting effects of EWI proteins, integrins, and protein palmitoylation on cell surface CD9 organization. J Biol Chem 281(18):12976–12985PubMedGoogle Scholar
  160. Yang JM, Peng ZH, Si SH, Liu WW, Luo YH, Ye ZY (2008) KAI1 gene suppresses invasion and metastasis of hepatocellular carcinoma MHCC97-H cells in vitro and in animal models. Liver Int 28(1):132–139PubMedGoogle Scholar
  161. Yauch RL, Hemler ME (2000) Specific interactions among transmembrane 4 superfamily (TM4SF) proteins and phosphoinositide 4-kinase. Biochem J 351(Pt 3):629–637PubMedGoogle Scholar
  162. Zemni R, Bienvenu T et al (2000) A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation. Nat Genet 24(2):167–170PubMedGoogle Scholar
  163. Zhang XA, Bontrager AL, Hemler ME (2001a) Transmembrane-4 superfamily proteins associate with activated protein kinase C (PKC) and link PKC to specific beta(1) integrins. J Biol Chem 276(27):25005–25013PubMedGoogle Scholar
  164. Zhang XA, Bontrager AL, Hemler ME (2001b) Transmembrane-4 superfamily proteins associate with activated protein kinase C (PKC) and link PKC to specific beta(1) integrins. J Biol Chem 276(27):25005–25013PubMedGoogle Scholar
  165. Zhang XA, Kazarov AR, Yang X, Bontrager AL, Stipp CS, Hemler ME (2002) Function of the tetraspanin CD151-alpha6beta1 integrin complex during cellular morphogenesis. Mol Biol Cell 13(1):1–11PubMedGoogle Scholar
  166. Zheng R, Yano S, Zhang H, Nakataki E, Tachibana I, Kawase I, Hayashi S, Sone S (2005) CD9 overexpression suppressed the liver metastasis and malignant ascites via inhibition of proliferation and motility of small-cell lung cancer cells in NK cell-depleted SCID mice. Oncol Res 15(7–8):365–372PubMedGoogle Scholar
  167. Zhou B, Liu L, Reddivari M, Zhang XA (2004) The palmitoylation of metastasis suppressor KAI1/CD82 is important for its motility- and invasiveness-inhibitory activity. Cancer Res 64(20):7455–7463PubMedGoogle Scholar
  168. Zijlstra A, Lewis J, Degryse B, Stuhlmann H, Quigley JP (2008) The inhibition of tumor cell intravasation and subsequent metastasis via regulation of in vivo tumor cell motility by the tetraspanin CD151. Cancer Cell 13(3):221–234PubMedGoogle Scholar
  169. Zöller M (2006) Gastrointestinal tumors: Metastasis and tetraspanins. Zeitschrift für Gastroenterologie 44(7):573–586PubMedGoogle Scholar
  170. Zöller M (2009) Tetraspanins: Push and pull in suppressing and promoting metastasis. Nat Rev Cancer 9(1):40–55PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Departments of Pathology and Cancer BiologyVanderbilt UniversityNashvilleUSA

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