Cellular and Molecular Life Sciences

, Volume 68, Issue 20, pp 3323–3335 | Cite as

Functional interplay between tetraspanins and proteases

  • María Yáñez-MóEmail author
  • Maria Dolores Gutiérrez-LópezEmail author
  • Carlos CabañasEmail author


Several recent publications have described examples of physical and functional interations between tetraspanins and specific membrane proteases belonging to the TM-MMP and α-(ADAMs) and γ-secretases families. Collectively, these examples constitute an emerging body of evidence supporting the notion that tetraspanin-enriched microdomains (TEMs) represent functional platforms for the regulation of key cellular processes including the release of surface protein ectodomains ("shedding"), regulated intramembrane proteolysis ("RIPing") and matrix degradation and assembly. These cellular processes in turn play a crucial role in an array of physiological and pathological phenomena. Thus, TEMs may represent new therapeutical targets that may simultaneously affect the proteolytic activity of different enzymes and their substrates. Agonistic or antagonistic antibodies and blocking soluble peptides corresponding to tetraspanin functional regions may offer new opportunities in the treatment of pathologies such as chronic inflammation, cancer, or Alzheimer's disease. In this review article, we will discuss all these aspects of functional regulation of protease activities by tetraspanins.


Tetraspanins MMP ADAMS α-secretases Shedding RIP 



Alzheimer's disease


A disintegrin and metalloprotease domain


Amyloid precursor protein


Epidermal growth factor


Epidermal growth factor receptor


G protein-coupled receptors


Heparin-binding epidermal growth factor


Intercellular adhesion molecule-1


Monoclonal antibodies


Membrane-type-1-matrix metalloprotease




Regulated intramembrane proteolysis


Tetraspanin-enriched microdomains


Triple membrane-passing signaling


Tumor necrosis factor-α



This work was supported by grants BFU2007-66443/BMC and BFU2010-19144/BMC from Ministerio de Ciencia e Innovación, a grant from Fundación de Investigación Médica Mutua Madrileña and by the RETICS Program RD08/0075-RIER (Red de Inflamación y Enfermedades Reumáticas) from Instituto de Salud Carlos III (to C.C.), a grant from Fundación de Investigación Médica Mutua Madrileña (to M.D.G.L.), and the grant PI080794 from Instituto de Salud Carlos III (to M.Y-M).


  1. 1.
    Charrin S, le Naour F, Silvie O, Milhiet PE, Boucheix C, Rubinstein E (2009) Lateral organization of membrane proteins: tetraspanins spin their web. Biochem J 420:133–154PubMedGoogle Scholar
  2. 2.
    Zoller M (2009) Tetraspanins: push and pull in suppressing and promoting metastasis. Nat Rev Cancer 9:40–55PubMedGoogle Scholar
  3. 3.
    Yanez-Mo M, Barreiro O, Gordon-Alonso M, Sala-Valdes M, Sanchez-Madrid F (2009) Tetraspanin-enriched microdomains: a functional unit in cell plasma membranes. Trends Cell Biol 19:434–446PubMedGoogle Scholar
  4. 4.
    Hemler ME (2005) Tetraspanin functions and associated microdomains. Nature Rev 6:801–811Google Scholar
  5. 5.
    Edwards DR, Handsley MM, Pennington CJ (2008) The ADAM metalloproteinases. Mol Aspects Med 29:258–289PubMedGoogle Scholar
  6. 6.
    Blobel CP (2005) ADAMs: key components in EGFR signalling and development. Nature Rev 6:32–43Google Scholar
  7. 7.
    Reiss K, Saftig P (2009) The "a disintegrin and metalloprotease" (ADAM) family of sheddases: physiological and cellular functions. Semin Cell Dev Biol 20:126–137PubMedGoogle Scholar
  8. 8.
    Murphy G (2008) The ADAMs: signalling scissors in the tumour microenvironment. Nat Rev Cancer 8:929–941PubMedGoogle Scholar
  9. 9.
    Pruessmeyer J, Ludwig A (2009) The good, the bad and the ugly substrates for ADAM10 and ADAM17 in brain pathology, inflammation and cancer. Semin Cell Dev Biol 20:164–174PubMedGoogle Scholar
  10. 10.
    Jackson LF, Qiu TH, Sunnarborg SW, Chang A, Zhang C, Patterson C, Lee DC (2003) Defective valvulogenesis in HB-EGF and TACE-null mice is associated with aberrant BMP signaling. EMBO J 22:2704–2716PubMedGoogle Scholar
  11. 11.
    Sternlicht MD, Sunnarborg SW (2008) The ADAM17-amphiregulin-EGFR axis in mammary development and cancer. J Mammary Gland Biol Neoplasia 13:181–194PubMedGoogle Scholar
  12. 12.
    Fischer OM, Hart S, Gschwind A, Ullrich A (2003) EGFR signal transactivation in cancer cells. Biochem Soc Trans 31:1203–1208PubMedGoogle Scholar
  13. 13.
    Liebmann C (2010) EGF receptor activation by GPCRs: an universal pathway reveals different versions. Mol Cell Endocrinol 331:222–231PubMedGoogle Scholar
  14. 14.
    Ohtsu H, Dempsey PJ, Eguchi S (2006) ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors. Am J Physiol 291:C1–C10Google Scholar
  15. 15.
    Yan Y, Shirakabe K, Werb Z (2002) The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G protein-coupled receptors. J Cell Biol 158:221–226PubMedGoogle Scholar
  16. 16.
    Horiuchi K, Le Gall S, Schulte M, Yamaguchi T, Reiss K, Murphy G, Toyama Y, Hartmann D, Saftig P, Blobel CP (2007) Substrate selectivity of epidermal growth factor-receptor ligand sheddases and their regulation by phorbol esters and calcium influx. Mol Biol Cell 18:176–188PubMedGoogle Scholar
  17. 17.
    Diaz-Rodriguez E, Montero JC, Esparis-Ogando A, Yuste L, Pandiella A (2002) Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated shedding. Mol Biol Cell 13:2031–2044PubMedGoogle Scholar
  18. 18.
    Fan H, Turck CW, Derynck R (2003) Characterization of growth factor-induced serine phosphorylation of tumor necrosis factor-alpha converting enzyme and of an alternatively translated polypeptide. J Biol Chem 278:18617–18627PubMedGoogle Scholar
  19. 19.
    Soond SM, Everson B, Riches DW, Murphy G (2005) ERK-mediated phosphorylation of Thr735 in TNFalpha-converting enzyme and its potential role in TACE protein trafficking. J Cell Sci 118:2371–2380PubMedGoogle Scholar
  20. 20.
    Nagano O, Murakami D, Hartmann D, De Strooper B, Saftig P, Iwatsubo T, Nakajima M, Shinohara M, Saya H (2004) Cell-matrix interaction via CD44 is independently regulated by different metalloproteinases activated in response to extracellular Ca(2+) influx and PKC activation. J Cell Biol 165:893–902PubMedGoogle Scholar
  21. 21.
    Murphy G (2009) Regulation of the proteolytic disintegrin metalloproteinases, the ‘Sheddases’. Semin Cell Dev Biol 20:138–145PubMedGoogle Scholar
  22. 22.
    Arduise C, Abache T, Li L, Billard M, Chabanon A, Ludwig A, Mauduit P, Boucheix C, Rubinstein E, Le Naour F (2008) Tetraspanins regulate ADAM10-mediated cleavage of TNF-alpha and epidermal growth factor. J Immunol 181:7002–7013PubMedGoogle Scholar
  23. 23.
    Xu D, Sharma C, Hemler ME (2009) Tetraspanin12 regulates ADAM10-dependent cleavage of amyloid precursor protein. Faseb J 23:3674–3681Google Scholar
  24. 24.
    Gutiérrez-López M, Gilsanz A, Yánez-Mó M, Ovalle S, Lafuente M, Domínguez C, Monk P, González-Alvaro I, Sánchez-Madrid F, Cabañas C (2011) The sheddase activity of ADAM17/TACE is regulated by the tetraspanin CD9. Cell Mol Life Sci. doi: 10.1007/s00018-011-0639-0
  25. 25.
    Gutwein P, Mechtersheimer S, Riedle S, Stoeck A, Gast D, Joumaa S, Zentgraf H, Fogel M, Altevogt DP (2003) ADAM10-mediated cleavage of L1 adhesion molecule at the cell surface and in released membrane vesicles. Faseb J 17:292–294PubMedGoogle Scholar
  26. 26.
    Stoeck A, Keller S, Riedle S, Sanderson MP, Runz S, Le Naour F, Gutwein P, Ludwig A, Rubinstein E, Altevogt P (2006) A role for exosomes in the constitutive and stimulus-induced ectodomain cleavage of L1 and CD44. Biochem J 393:609–618PubMedGoogle Scholar
  27. 27.
    Keller S, Konig AK, Marme F, Runz S, Wolterink S, Koensgen D, Mustea A, Sehouli J, Altevogt P (2009) Systemic presence and tumor-growth promoting effect of ovarian carcinoma released exosomes. Cancer Lett 278:73–81PubMedGoogle Scholar
  28. 28.
    Soderberg A, Barral AM, Soderstrom M, Sander B, Rosen A (2007) Redox-signaling transmitted in trans to neighboring cells by melanoma-derived TNF-containing exosomes. Free Radic Biol Med 43:90–99PubMedGoogle Scholar
  29. 29.
    Thery C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9:581–593PubMedGoogle Scholar
  30. 30.
    Simons M, Raposo G (2009) Exosomes–vesicular carriers for intercellular communication. Curr Opin Cell Biol 21:575–581PubMedGoogle Scholar
  31. 31.
    Zoller M (2006) Gastrointestinal tumors: metastasis and tetraspanins. Z Gastroenterol 44:573–586PubMedGoogle Scholar
  32. 32.
    Chen MS, Tung KS, Coonrod SA, Takahashi Y, Bigler D, Chang A, Yamashita Y, Kincade PW, Herr JC, White JM (1999) Role of the integrin-associated protein CD9 in binding between sperm ADAM 2 and the egg integrin alpha6beta1: implications for murine fertilization. Proc Natl Acad Sci USA 96:11830–11835PubMedGoogle Scholar
  33. 33.
    Ziyyat A, Rubinstein E, Monier-Gavelle F, Barraud V, Kulski O, Prenant M, Boucheix C, Bomsel M, Wolf JP (2006) CD9 controls the formation of clusters that contain tetraspanins and the integrin alpha 6 beta 1, which are involved in human and mouse gamete fusion. J Cell Sci 119:416–424PubMedGoogle Scholar
  34. 34.
    Takahashi Y, Bigler D, Ito Y, White JM (2001) Sequence-specific interaction between the disintegrin domain of mouse ADAM 3 and murine eggs: role of beta1 integrin-associated proteins CD9, CD81, and CD98. Mol Biol Cell 12:809–820PubMedGoogle Scholar
  35. 35.
    Miller BJ, Georges-Labouesse E, Primakoff P, Myles DG (2000) Normal fertilization occurs with eggs lacking the integrin alpha6beta1 and is CD9-dependent. J Cell Biol 149:1289–1296PubMedGoogle Scholar
  36. 36.
    Le Naour F, Rubinstein E, Jasmin C, Prenant M, Boucheix C (2000) Severely reduced female fertility in CD9-deficient mice. Science 287:319–321PubMedGoogle Scholar
  37. 37.
    Kaji K, Oda S, Shikano T, Ohnuki T, Uematsu Y, Sakagami J, Tada N, Miyazaki S, Kudo A (2000) The gamete fusion process is defective in eggs of Cd9-deficient mice. Nat Genet 24:279–282PubMedGoogle Scholar
  38. 38.
    Miyado K, Yamada G, Yamada S, Hasuwa H, Nakamura Y, Ryu F, Suzuki K, Kosai K, Inoue K, Ogura A, Okabe M, Mekada E (2000) Requirement of CD9 on the egg plasma membrane for fertilization. Science 287:321–324PubMedGoogle Scholar
  39. 39.
    Rubinstein E, Ziyyat A, Prenant M, Wrobel E, Wolf JP, Levy S, Le Naour F, Boucheix C (2006) Reduced fertility of female mice lacking CD81. Dev Biol 290:351–358PubMedGoogle Scholar
  40. 40.
    Kaji K, Oda S, Miyazaki S, Kudo A (2002) Infertility of CD9-deficient mouse eggs is reversed by mouse CD9, human CD9, or mouse CD81; polyadenylated mRNA injection developed for molecular analysis of sperm-egg fusion. Dev Biol 247:327–334PubMedGoogle Scholar
  41. 41.
    Zhou GB, Liu GS, Meng QG, Liu Y, Hou YP, Wang XX, Li N, Zhu SE (2009) Tetraspanin CD9 in bovine oocytes and its role in fertilization. J Reprod Dev 55:305–308PubMedGoogle Scholar
  42. 42.
    Waterhouse R, Ha C, Dveksler GS (2002) Murine CD9 is the receptor for pregnancy-specific glycoprotein 17. J Exp Med 195:277–282PubMedGoogle Scholar
  43. 43.
    Ellerman DA, Ha C, Primakoff P, Myles DG, Dveksler GS (2003) Direct binding of the ligand PSG17 to CD9 requires a CD9 site essential for sperm–egg fusion. Mol Biol Cell 14:5098–5103PubMedGoogle Scholar
  44. 44.
    Miyado K, Yoshida K, Yamagata K, Sakakibara K, Okabe M, Wang X, Miyamoto K, Akutsu H, Kondo T, Takahashi Y, Ban T, Ito C, Toshimori K, Nakamura A, Ito M, Miyado M, Mekada E, Umezawa A (2008) The fusing ability of sperm is bestowed by CD9-containing vesicles released from eggs in mice. Proc Natl Acad Sci USA 105:12921–12926PubMedGoogle Scholar
  45. 45.
    Gupta S, Primakoff P, Myles DG (2009) Can the presence of wild-type oocytes during insemination rescue the fusion defect of CD9 null oocytes? Mol Reprod Dev 76:602PubMedGoogle Scholar
  46. 46.
    Woo HN, Baik SH, Park JS, Gwon AR, Yang S, Yun YK, Jo DG (2011) Secretases as therapeutic targets for Alzheimer’s disease. Biochem Biophys Res Commun 404:10–15PubMedGoogle Scholar
  47. 47.
    Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P, Black RA, Israel A (2000) A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Molecular cell 5:207–216PubMedGoogle Scholar
  48. 48.
    Mumm JS, Schroeter EH, Saxena MT, Griesemer A, Tian X, Pan DJ, Ray WJ, Kopan R (2000) A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Molecular cell 5:197–206PubMedGoogle Scholar
  49. 49.
    Hartmann D, de Strooper B, Serneels L, Craessaerts K, Herreman A, Annaert W, Umans L, Lubke T, Lena Illert A, von Figura K, Saftig P (2002) The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts. Hum Mol Genet 11:2615–2624PubMedGoogle Scholar
  50. 50.
    Srinivasan B, Wang Z, Brun-Zinkernagel AM, Collier RJ, Black RA, Frank SJ, Barker PA, Roque RS (2007) Photic injury promotes cleavage of p75NTR by TACE and nuclear trafficking of the p75 intracellular domain. Mol Cell Neurosci 36:449–461PubMedGoogle Scholar
  51. 51.
    Spasic D, Annaert W (2008) Building gamma-secretase: the bits and pieces. J Cell Sci 121:413–420PubMedGoogle Scholar
  52. 52.
    Wakabayashi T, Craessaerts K, Bammens L, Bentahir M, Borgions F, Herdewijn P, Staes A, Timmerman E, Vandekerckhove J, Rubinstein E, Boucheix C, Gevaert K, De Strooper B (2009) Analysis of the gamma-secretase interactome and validation of its association with tetraspanin-enriched microdomains. Nat Cell Biol 11:1340–1346PubMedGoogle Scholar
  53. 53.
    Ovalle S, Gutierrez-Lopez MD, Olmo N, Turnay J, Lizarbe MA, Majano P, Molina-Jimenez F, Lopez-Cabrera M, Yanez-Mo M, Sanchez-Madrid F, Cabanas C (2007) The tetraspanin CD9 inhibits the proliferation and tumorigenicity of human colon carcinoma cells. Int J Cancer 121:2140–2152PubMedGoogle Scholar
  54. 54.
    Sestan N, Artavanis-Tsakonas S, Rakic P (1999) Contact-dependent inhibition of cortical neurite growth mediated by notch signaling. Science 286:741–746PubMedGoogle Scholar
  55. 55.
    Hitoshi S, Alexson T, Tropepe V, Donoviel D, Elia AJ, Nye JS, Conlon RA, Mak TW, Bernstein A, van der Kooy D (2002) Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells. Genes Dev 16:846–858PubMedGoogle Scholar
  56. 56.
    Poirazi P, Mel BW (2001) Impact of active dendrites and structural plasticity on the memory capacity of neural tissue. Neuron 29:779–796PubMedGoogle Scholar
  57. 57.
    Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410:372–376PubMedGoogle Scholar
  58. 58.
    Berezovska O, Xia MQ, Hyman BT (1998) Notch is expressed in adult brain, is coexpressed with presenilin-1, and is altered in Alzheimer disease. J Neuropathol Exp Neurol 57:738–745PubMedGoogle Scholar
  59. 59.
    Dunn CD, Sulis ML, Ferrando AA, Greenwald I (2010) A conserved tetraspanin subfamily promotes Notch signaling in Caenorhabditis elegans and in human cells. Proc Natl Acad Sci USA 107:5907–5912PubMedGoogle Scholar
  60. 60.
    Hemler ME (2008) Targeting of tetraspanin proteins–potential benefits and strategies. Nat Rev Drug Discov 7:747–758PubMedGoogle Scholar
  61. 61.
    Lazo PA (2007) Functional implications of tetraspanin proteins in cancer biology. Cancer Sci 98:1666–1677PubMedGoogle Scholar
  62. 62.
    Cook GA, Wilkinson DA, Crossno J T Jr, Raghow R, Jennings LK (1999) The tetraspanin CD9 influences the adhesion, spreading, and pericellular fibronectin matrix assembly of Chinese hamster ovary cells on human plasma fibronectin. Exp Cell Res 251:356–371PubMedGoogle Scholar
  63. 63.
    Sachs N, Kreft M, h Weerman MA, Beynon AJ, Peters TA, Weening JJ, Sonnenberg A (2006) Kidney failure in mice lacking the tetraspanin CD151. J Cell Biol 175:33–39PubMedGoogle Scholar
  64. 64.
    Cowin AJ, Adams D, Geary SM, Wright MD, Jones JC, Ashman LK (2006) Wound healing is defective in mice lacking tetraspanin CD151. J Invest Dermatol 126:680–689PubMedGoogle Scholar
  65. 65.
    Sugiura T, Berditchevski F (1999) Function of alpha3beta1-tetraspanin protein complexes in tumor cell invasion. Evidence for the role of the complexes in production of matrix metalloproteinase 2 (MMP-2). J Cell Biol 146:1375–1389PubMedGoogle Scholar
  66. 66.
    Mazzocca A, Sciammetta SC, Carloni V, Cosmi L, Annunziato F, Harada T, Abrignani S, Pinzani M (2005) Binding of hepatitis C virus envelope protein E2 to CD81 up-regulates matrix metalloproteinase-2 in human hepatic stellate cells. J Biol Chem 280:11329–11339PubMedGoogle Scholar
  67. 67.
    Hong IK, Jin YJ, Byun HJ, Jeoung DI, Kim YM, Lee H (2006) Homophilic interactions of Tetraspanin CD151 up-regulate motility and matrix metalloproteinase-9 expression of human melanoma cells through adhesion-dependent c-Jun activation signaling pathways. J Biol Chem 281:24279–24292PubMedGoogle Scholar
  68. 68.
    Shi GM, Ke AW, Zhou J, Wang XY, Xu Y, Ding ZB, Devbhandari RP, Huang XY, Qiu SJ, Shi YH, Dai Z, Yang XR, Yang GH, Fan J (2010) CD151 modulates expression of matrix metalloproteinase 9 and promotes neoangiogenesis and progression of hepatocellular carcinoma. Hepatology (Baltimore, MD) 52:183–196Google Scholar
  69. 69.
    Hong IK, Kim YM, Jeoung DI, Kim KC, Lee H (2005) Tetraspanin CD9 induces MMP-2 expression by activating p38 MAPK, JNK and c-Jun pathways in human melanoma cells. Exp Mol Med 37:230–239PubMedGoogle Scholar
  70. 70.
    Saito Y, Tachibana I, Takeda Y, Yamane H, He P, Suzuki M, Minami S, Kijima T, Yoshida M, Kumagai T, Osaki T, Kawase I (2006) Absence of CD9 enhances adhesion-dependent morphologic differentiation, survival, and matrix metalloproteinase-2 production in small cell lung cancer cells. Cancer Res 66:9557–9565PubMedGoogle Scholar
  71. 71.
    Liu WM, Cao YJ, Yang YJ, Li J, Hu Z, Duan EK (2006) Tetraspanin CD9 regulates invasion during mouse embryo implantation. J Mol Endocrinol 36:121–130PubMedGoogle Scholar
  72. 72.
    Tohami T, Drucker L, Shapiro H, Radnay J, Lishner M (2007) Overexpression of tetraspanins affects multiple myeloma cell survival and invasive potential. FASEB J 21:691–699PubMedGoogle Scholar
  73. 73.
    Shiomi T, Inoki I, Kataoka F, Ohtsuka T, Hashimoto G, Nemori R, Okada Y (2005) Pericellular activation of proMMP-7 (promatrilysin-1) through interaction with CD151. Lab Investig J Tech Methods Pathol 85:1489–1506Google Scholar
  74. 74.
    Jung K, Liu X, Chirco R, Fridman R, Kim H (2006) Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein. EMBO J 25:3934–3942PubMedGoogle Scholar
  75. 75.
    Lafleur MA, Xu D, Hemler ME (2009) Tetraspanin proteins regulate membrane type-1 matrix metalloproteinase-dependent pericellular proteolysis. Mol Biol Cell 20:2030–2040PubMedGoogle Scholar
  76. 76.
    Takino T, Miyamori H, Kawaguchi N, Uekita T, Seiki M, Sato H (2003) Tetraspanin CD63 promotes targeting and lysosomal proteolysis of membrane-type 1 matrix metalloproteinase. Biochem Biophys Res Commun 304:160–166PubMedGoogle Scholar
  77. 77.
    Yanez-Mo M, Barreiro O, Gonzalo P, Batista A, Megias D, Genis L, Sachs N, Sala-Valdes M, Alonso MA, Montoya MC, Sonnenberg A, Arroyo AG, Sanchez-Madrid F (2008) MT1-MMP collagenolytic activity is regulated through association with tetraspanin CD151 in primary endothelial cells. Blood 112:3217–3226PubMedGoogle Scholar
  78. 78.
    Sato H, Takino T (2010) Coordinate action of membrane-type matrix metalloproteinase-1 (MT1-MMP) and MMP-2 enhances pericellular proteolysis and invasion. Cancer Sci 101:843–847PubMedGoogle Scholar
  79. 79.
    Holmbeck K, Bianco P, Caterina J, Yamada S, Kromer M, Kuznetsov SA, Mankani M, Robey PG, Poole AR, Pidoux I, Ward JM, Birkedal-Hansen H (1999) MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99:81–92PubMedGoogle Scholar
  80. 80.
    Itoh T, Tanioka M, Yoshida H, Yoshioka T, Nishimoto H, Itohara S (1998) Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res 58:1048–1051PubMedGoogle Scholar
  81. 81.
    Oh J, Takahashi R, Adachi E, Kondo S, Kuratomi S, Noma A, Alexander DB, Motoda H, Okada A, Seiki M, Itoh T, Itohara S, Takahashi C, Noda M (2004) Mutations in two matrix metalloproteinase genes, MMP-2 and MT1-MMP, are synthetic lethal in mice. Oncogene 23:5041–5048PubMedGoogle Scholar
  82. 82.
    Galvez BG, Matias-Roman S, Yanez-Mo M, Vicente-Manzanares M, Sanchez-Madrid F, Arroyo AG (2004) Caveolae are a novel pathway for membrane-type 1 matrix metalloproteinase traffic in human endothelial cells. Mol Biol Cell 15:678–687PubMedGoogle Scholar
  83. 83.
    Gingras D, Beliveau R (2010) Emerging concepts in the regulation of membrane-type 1 matrix metalloproteinase activity. Biochim Biophys Acta 1803:142–150PubMedGoogle Scholar
  84. 84.
    Bravo-Cordero JJ, Marrero-Diaz R, Megias D, Genis L, Garcia-Grande A, Garcia MA, Arroyo AG, Montoya MC (2007) MT1-MMP proinvasive activity is regulated by a novel Rab8-dependent exocytic pathway. EMBO J 26:1499–1510PubMedGoogle Scholar
  85. 85.
    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 11:77–86PubMedGoogle Scholar
  86. 86.
    Bass R, Werner F, Odintsova E, Sugiura T, Berditchevski F, Ellis V (2005) Regulation of urokinase receptor proteolytic function by the tetraspanin CD82. J Biol Chem 280:14811–14818PubMedGoogle Scholar
  87. 87.
    Kallquist L, Hansson M, Persson AM, Janssen H, Calafat J, Tapper H, Olsson I (2008) The tetraspanin CD63 is involved in granule targeting of neutrophil elastase. Blood 112:3444–3454PubMedGoogle Scholar
  88. 88.
    Le Naour F, Andre M, Boucheix C, Rubinstein E (2006) Membrane microdomains and proteomics: lessons from tetraspanin microdomains and comparison with lipid rafts. Proteomics 6:6447–6454PubMedGoogle Scholar
  89. 89.
    Shi W, Fan H, Shum L, Derynck R (2000) The tetraspanin CD9 associates with transmembrane TGF-alpha and regulates TGF-alpha-induced EGF receptor activation and cell proliferation. J Cell Biol 148:591–602PubMedGoogle Scholar
  90. 90.
    Higashiyama S, Iwamoto R, Goishi K, Raab G, Taniguchi N, Klagsbrun M, Mekada E (1995) 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 128:929–938PubMedGoogle Scholar
  91. 91.
    Barreiro O, Yanez-Mo M, Sala-Valdes M, Gutierrez-Lopez MD, Ovalle S, Higginbottom A, Monk PN, Cabanas C, Sanchez-Madrid F (2005) Endothelial tetraspanin microdomains regulate leukocyte firm adhesion during extravasation. Blood 105:2852–2861PubMedGoogle Scholar
  92. 92.
    Garton KJ, Gough PJ, Raines EW (2006) Emerging roles for ectodomain shedding in the regulation of inflammatory responses. J Leukoc Biol 79:1105–1116PubMedGoogle Scholar
  93. 93.
    Tsakadze NL, Sithu SD, Sen U, English WR, Murphy G, D’Souza SE (2006) Tumor necrosis factor-alpha-converting enzyme (TACE/ADAM-17) mediates the ectodomain cleavage of intercellular adhesion molecule-1 (ICAM-1). J Biol Chem 281:3157–3164PubMedGoogle Scholar
  94. 94.
    Gearing AJ, Newman W (1993) Circulating adhesion molecules in disease. Immunol Today 14:506–512PubMedGoogle Scholar
  95. 95.
    van Kilsdonk JW, van Kempen LC, van Muijen GN, Ruiter DJ, Swart GW (2010) Soluble adhesion molecules in human cancers: sources and fates. Eur J Cell Biol 89:415–427PubMedGoogle Scholar
  96. 96.
    Barreiro O, Zamai M, Yanez-Mo M, Tejera E, Lopez-Romero P, Monk PN, Gratton E, Caiolfa VR, Sanchez-Madrid F (2008) Endothelial adhesion receptors are recruited to adherent leukocytes by inclusion in preformed tetraspanin nanoplatforms. J Cell Biol 183:527–542PubMedGoogle Scholar
  97. 97.
    Mori H, Tomari T, Koshikawa N, Kajita M, Itoh Y, Sato H, Tojo H, Yana I, Seiki M (2002) CD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domain. EMBO J 21:3949–3959PubMedGoogle Scholar
  98. 98.
    Marrero-Diaz R, Bravo-Cordero JJ, Megias D, Garcia MA, Bartolome RA, Teixido J, Montoya MC (2009) Polarized MT1-MMP-CD44 interaction and CD44 cleavage during cell retraction reveal an essential role for MT1-MMP in CD44-mediated invasion. Cell Motil Cytoskeleton 66:48–61PubMedGoogle Scholar
  99. 99.
    Stipp CS (2010) Laminin-binding integrins and their tetraspanin partners as potential antimetastatic targets. Expert Rev Mol Med 12:e3PubMedGoogle Scholar
  100. 100.
    Dijkstra S, Kooij G, Verbeek R, van der Pol SM, Amor S, Geisert E E Jr, Dijkstra CD, van Noort JM, Vries HE (2008) Targeting the tetraspanin CD81 blocks monocyte transmigration and ameliorates EAE. Neurobiol Dis 31:413–421PubMedGoogle Scholar
  101. 101.
    Nakamoto T, Murayama Y, Oritani K, Boucheix C, Rubinstein E, Nishida M, Katsube F, Watabe K, Kiso S, Tsutsui S, Tamura S, Shinomura Y, Hayashi N (2009) A novel therapeutic strategy with anti-CD9 antibody in gastric cancers. J Gastroenterol 44:889–896PubMedGoogle Scholar
  102. 102.
    Robak T, Robak P, Smolewski P (2009) TRU-016, a humanized anti-CD37 IgG fusion protein for the potential treatment of B-cell malignancies. Curr Opin Investig Drugs 10:1383–1390PubMedGoogle Scholar
  103. 103.
    Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, Prinzen C, Endres K, Hiemke C, Blessing M, Flamez P, Dequenne A, Godaux E, van Leuven F, Fahrenholz F (2004) A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest 113:1456–1464PubMedGoogle Scholar
  104. 104.
    Tachida Y, Nakagawa K, Saito T, Saido TC, Honda T, Saito Y, Murayama S, Endo T, Sakaguchi G, Kato A, Kitazume S, Hashimoto Y (2008) Interleukin-1 beta up-regulates TACE to enhance alpha-cleavage of APP in neurons: resulting decrease in Abeta production. J Neurochem 104:1387–1393PubMedGoogle Scholar
  105. 105.
    Kim ML, Zhang B, Mills IP, Milla ME, Brunden KR, Lee VM (2008) Effects of TNFalpha-converting enzyme inhibition on amyloid beta production and APP processing in vitro and in vivo. J Neurosci 28:12052–12061PubMedGoogle Scholar
  106. 106.
    Chow VW, Mattson MP, Wong PC, Gleichmann M (2009) An overview of APP processing enzymes and products. Neuromolecular Med 12:1–12Google Scholar
  107. 107.
    Woo HN, Park JS, Gwon AR, Arumugam TV, Jo DG (2009) Alzheimer’s disease and Notch signaling. Biochem Biophys Res Commun 390:1093–1097PubMedGoogle Scholar
  108. 108.
    Moss ML, Stoeck A, Yan W, Dempsey PJ (2008) ADAM10 as a target for anti-cancer therapy. Curr Pharm Biotechnol 9:2–8PubMedGoogle Scholar
  109. 109.
    Arribas J, Bech-Serra JJ, Santiago-Josefat B (2006) ADAMs, cell migration and cancer. Cancer Metastasis Rev 25:57–68PubMedGoogle Scholar
  110. 110.
    Klein-Soyer C, Azorsa DO, Cazenave JP, Lanza F (2000) CD9 participates in endothelial cell migration during in vitro wound repair. Arterioscler Thromb Vasc Biol 20:360–369PubMedGoogle Scholar
  111. 111.
    Sincock PM, Fitter S, Parton RG, Berndt MC, Gamble JR, Ashman LK (1999) 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 112:833–844PubMedGoogle Scholar
  112. 112.
    Deissler H, Kuhn EM, Lang GE, Deissler H (2007) Tetraspanin CD9 is involved in the migration of retinal microvascular endothelial cells. Int J Mol Med 20:643–652PubMedGoogle Scholar
  113. 113.
    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 13:1–11PubMedGoogle Scholar
  114. 114.
    Yanez-Mo M, Alfranca A, Cabanas C, Marazuela M, Tejedor R, Ursa MA, Ashman LK, de Landazuri MO, Sanchez-Madrid F (1998) Regulation of endothelial cell motility by complexes of tetraspan molecules CD81/TAPA-1 and CD151/PETA-3 with alpha3 beta1 integrin localized at endothelial lateral junctions. J Cell Biol 141:791–804PubMedGoogle Scholar
  115. 115.
    Dominguez-Jimenez C, Yanez-Mo M, Carreira A, Tejedor R, Gonzalez-Amaro R, Alvarez V, Sanchez-Madrid F (2001) Involvement of alpha3 integrin/tetraspanin complexes in the angiogenic response induced by angiotensin II. FASEB J 15:1457–1459PubMedGoogle Scholar
  116. 116.
    Junge HJ, Yang S, Burton JB, Paes K, Shu X, French DM, Costa M, Rice DS, Ye W (2009) TSPAN12 regulates retinal vascular development by promoting Norrin-but not Wnt-induced FZD4/beta-catenin signaling. Cell 139:299–311PubMedGoogle Scholar
  117. 117.
    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 109:1524–1532PubMedGoogle Scholar
  118. 118.
    Zuo H, Liu Z, Liu X, Yang J, Liu T, Wen S, Zhang XA, Cianflone K, Wang D (2009) CD151 gene delivery after myocardial infarction promotes functional neovascularization and activates FAK signaling. Molecular Med (Cambridge, Mass) 15:307–315Google Scholar

Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  1. 1.Servicio de Inmunología, Hospital de la PrincesaInstituto de Investigación Sanitaria PrincesaMadridSpain
  2. 2.Facultad de Medicina, Departamento de FarmacologíaUCMMadridSpain
  3. 3.Centro de Biología Molecular Severo Ochoa (CSIC-UAM)MadridSpain
  4. 4.Facultad de Medicina, Departamento de Microbiología I (Inmunología)UCMMadridSpain

Personalised recommendations