Skip to main content

Advertisement

Log in

Integrin signaling in malignant melanoma

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Cell adhesion and migration are essential for embryonic development, tissue regeneration, but also for tumor development. The physical link between the extracellular matrix (ECM) and the actin cytoskeleton is mainly mediated by receptors of the integrin family. Through signals transduced upon integrin ligation to ECM proteins, this family of proteins plays key roles in regulating tumor growth and metastasis as well as tumor angiogenesis. During melanoma development, changes in integrin expression, intracellular control of integrin functions and signals perceived from integrin ligand binding impact upon the ability of tumor cells to interact with their environment and enable melanoma cells to convert from a sessile, stationary to a migratory and invasive phenotype. Antagonists of several integrins are now under evaluation in clinical trials to determine their potential as therapeutics for malignant melanoma and other kinds of cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Pfarrer C, Hirsch P, Guillomot M, Leiser R: Interaction of integrin receptors with extracellular matrix is involved in trophoblast giant cell migration in bovine placentomes. Placenta 24: 588–597, 2003

    Google Scholar 

  2. Schmitt DM, Brower DL: Intron dynamics and the evolution of integrin beta-subunit genes: Maintenance of an ancestral gene structure in the coral, Acropora millepora. J Mol Evol 53: 703–710, 2001

    Google Scholar 

  3. van der FA, Sonnenberg A: Function and interactions of integrins. Cell Tissue Res 305: 285–298, 2001

    Google Scholar 

  4. Trikha M, Timar J, Lundy SK, Szekeres K, Cai Y, Porter AT, Honn KV: The high affinity alphaIIb beta3 integrin is involved in invasion of human melanoma cells. Cancer Res 57: 2522–2528, 1997

    Google Scholar 

  5. Aplin JD, Hey NA, Graham RA: Human endometrial MUC1 carries keratan sulfate: Characteristic glycoforms in the luminal epithelium at receptivity. Glycobiology 8: 269–276, 1998

    Google Scholar 

  6. Stupack DG, Puente XS, Boutsaboualoy S, Storgard CM, Cheresh DA: Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. J Cell Biol 155: 459–470, 2001

    Google Scholar 

  7. Pankov R, Cukierman E, Clark K, Matsumoto K, Hahn C, Poulin B, Yamada KM: Specific beta1 integrin site selectively regulates Akt/protein kinase B signaling via local activation of protein phosphatase 2A. J Biol Chem 278: 18671–18681, 2003

    Google Scholar 

  8. Kim S, Harris M, Varner JA: Regulation of integrin alpha vbeta 3-mediated endothelial cell migration and angiogenesis by integrin alpha5beta1 and protein kinase A. J Biol Chem 275: 33920–33928, 2000

    Google Scholar 

  9. Mehta RJ, Diefenbach B, Brown A, Cullen E, Jonczyk A, Gussow D, Luckenbach GA, Goodman SL: Transmembrane-truncated alphavbeta3 integrin retains high affinity for ligand binding: Evidence for an ‘inside-out’ suppressor? Biochem J 330(Pt~2): 861–869, 1998

    Google Scholar 

  10. Brakebusch C, Fassler R: The integrin-actin connection, an eternal love affair. EMBO J 22: 2324–2333, 2003

    Google Scholar 

  11. Hynes RO: Integrins: bidirectional, allosteric signaling machines. Cell 110: 673–687, 2002

    Google Scholar 

  12. Karpusas M, Ferrant J, Weinreb PH, Carmillo A, Taylor FR, Garber EA: Crystal structure of the alpha1beta1 integrin I domain in complex with an antibody Fab fragment. J Mol Biol 327: 1031–1041, 2003

    Google Scholar 

  13. LaFlamme SE, Thomas LA, Yamada SS, Yamada KM: Single subunit chimeric integrins as mimics and inhibitors of endogenous integrin functions in receptor localization, cell spreading and migration, and matrix assembly. J Cell Biol 126: 1287–1298, 1994

    Google Scholar 

  14. Marshall JF, Rutherford DC, Happerfield L, Hanby A, McCartney AC, Newton-Bishop J, Hart IR: Comparative analysis of integrins in vitro and in vivo in uveal and cutaneous melanomas. Br J Cancer 77: 522–529, 1998

    Google Scholar 

  15. Moretti S, Martini L, Berti E, Pinzi C, Giannotti B: Adhesion molecule profile and malignancy of melanocytic lesions. Melanoma Res 3: 235–239, 1993

    Google Scholar 

  16. Hartstein ME, Grove AS, Jr., Woog JJ: The role of the integrin family of adhesion molecules in the development of tumors metastatic to the orbit. Ophthal Plast Reconstr Surg 13: 227–238, 1997

    Google Scholar 

  17. Nikkola J, Vihinen P, Vlaykova T, Hahka-Kemppinen M, Heino J, Pyrhonen S: Integrin chains beta1 and alphav as prognostic factors in human metastatic melanoma. Melanoma Res 14: 29–37, 2004

    Google Scholar 

  18. Yoshinaga IG, Vink J, Dekker SK, Mihm MC, Jr., Byers HR: Role of alpha 3 beta 1 and alpha 2 beta 1 integrins in melanoma cell migration. Melanoma Res 3: 435–441, 1993

    Google Scholar 

  19. Danen EH, Ten Berge PJ, Van Muijen GN, Van ‘t Hof-Grootenboer AE, Brocker EB, Ruiter DJ: Emergence of alpha 5 beta 1 fibronectin- and alpha v beta 3 vitronectin-receptor expression in melanocytic tumour progression. Histopathology 24: 249–256, 1994

    Google Scholar 

  20. Holzmann B, Gosslar U, Bittner M: Alpha 4 integrins and tumor metastasis. Curr Top Microbiol Immunol 231: 125–141, 1998

    Google Scholar 

  21. Ziober BL, Chen YQ, Ramos DM, Waleh N, Kramer RH: Expression of the alpha7beta1 laminin receptor suppresses melanoma growth and metastatic potential. Cell Growth Differ 10: 479–490, 1999

    Google Scholar 

  22. Zhu N, Eves PC, Katerinaki E, Szabo M, Morandini R, Ghanem G, Lorigan P, MacNeil S, Haycock JW: Melanoma cell attachment, invasion, and integrin expression is upregulated by tumor necrosis factor alpha and suppressed by alpha melanocyte stimulating hormone. J Invest Dermatol 119: 1165–1171, 2002

    Google Scholar 

  23. Van Belle PA, Elenitsas R, Satyamoorthy K, Wolfe JT, Guerry D, Schuchter L, Van Belle TJ, Albelda S, Tahin P, Herlyn M, Elder DE: Progression-related expression of beta3 integrin in melanomas and nevi. Hum Pathol 30: 562–567, 1999

    Google Scholar 

  24. Friedl P, Zanker KS, Brocker EB: Cell migration strategies in 3-D extracellular matrix: Differences in morphology, cell matrix interactions, and integrin function. Microsc Res Tech 43: 369–378, 1998

    Google Scholar 

  25. Meier F, Caroli U, Satyamoorthy K, Schittek B, Bauer J, Berking C, Moller H, Maczey E, Rassner G, Herlyn M, Garbe C: Fibroblast growth factor-2 but not Mel-CAM and/or beta3 integrin promotes progression of melanocytes to melanoma. Exp Dermatol 12: 296–306, 2003

    Google Scholar 

  26. Natali PG, Nicotra MR, Bartolazzi A, Cavaliere R, Bigotti A: Integrin expression in cutaneous malignant melanoma: Association of the alpha 3/beta 1 heterodimer with tumor progression. Int J Cancer 54: 68–72, 1993

    Google Scholar 

  27. Schadendorf D, Gawlik C, Haney U, Ostmeier H, Suter L, Czarnetzki BM: Tumour progression and metastatic behaviour in vivo correlates with integrin expression on melanocytic tumours. J Pathol 170: 429–434, 1993

    Google Scholar 

  28. Johnson JP: Cell adhesion molecules in the development and progression of malignant melanoma. Cancer Metastasis Rev 18: 345–357, 1999

    Google Scholar 

  29. Hangan D, Morris VL, Boeters L, von Ballestrem C, Uniyal S, Chan BM: An epitope on VLA-6 (alpha6beta1) integrin involved in migration but not adhesion is required for extravasation of murine melanoma B16F1 cells in liver. Cancer Res 57: 3812–3817, 1997

    Google Scholar 

  30. Pochec E, Litynska A, Amoresano A, Casbarra A: Glycosylation profile of integrin alpha 3 beta 1 changes with melanoma progression. Biochim Biophys Acta 1643: 113–123, 2003

    Google Scholar 

  31. Garofalo A, Chirivi RG, Foglieni C, Pigott R, Mortarini R, Martin-Padura I, Anichini A, Gearing AJ, Sanchez-Madrid F, Dejana E: Involvement of the very late antigen 4 integrin on melanoma in interleukin 1-augmented experimental metastases. Cancer Res 55: 414–419, 1995

    Google Scholar 

  32. Danen EH, Jansen KF, van Kraats AA, Cornelissen IM, Ruiter DJ, Van Muijen GN: Alpha v-integrins in human melanoma: gain of alpha v beta 3 and loss of alpha v beta 5 are related to tumor progression in situ but not to metastatic capacity of cell lines in nude mice. Int J Cancer 61: 491–496, 1995

    Google Scholar 

  33. Kramer RH, Vu M, Cheng YF, Ramos DM: Integrin expression in malignant melanoma. Cancer Metastasis Rev 10: 49–59, 1991

    Google Scholar 

  34. Zambruno G, Marchisio PC, Melchiori A, Bondanza S, Cancedda R, De Luca M: Expression of integrin receptors and their role in adhesion, spreading and migration of normal human melanocytes. J Cell Sci 105(Pt~1): 179–190, 1993

    Google Scholar 

  35. Elshaw SR, Sisley K, Cross N, Murray AK, MacNeil SM, Wagner M, Nichols CE, Rennie IG: A comparison of ocular melanocyte and uveal melanoma cell invasion and the implication of alpha1beta1, alpha4beta1 and alpha6beta1 integrins. Br J Ophthalmol 85: 732–738, 2001

    Google Scholar 

  36. Bogenrieder T and Herlyn M: Axis of evil: Molecular mechanisms of cancer metastasis. Oncogene 22: 6524–6536, 2003

    Google Scholar 

  37. Bogenrieder T and Herlyn M: Cell-surface proteolysis, growth factor activation and intercellular communication in the progression of melanoma. Crit Rev Oncol Hematol 44: 1–15, 2002

    Google Scholar 

  38. Ballestrem C, Wehrle-Haller B, Imhof BA: Actin dynamics in living mammalian cells. J Cell Sci 111: 1649–1658, 1998

    Google Scholar 

  39. Wehrle-Haller B and Imhof BA: Integrin-dependent pathologies. J Pathol 200: 481–487, 2003

    Google Scholar 

  40. Miranti CK and Brugge JS: Sensing the environment: A historical perspective on integrin signal transduction. Nat Cell Biol 4: E83–E90, 2002

    Google Scholar 

  41. Takagi J and Springer TA: Integrin activation and structural rearrangement. Immunol Rev 186:141–163, 2002

    Google Scholar 

  42. Takagi J, Erickson HP, Springer TA: C-terminal opening mimics ‘inside-out’ activation of integrin alpha5beta1. Nat Struct Biol 8: 412–416, 2001

    Google Scholar 

  43. Shattil SJ, Kashiwagi H, Pampori N: Integrin signaling: The platelet paradigm. Blood 91: 2645–2657, 1998

    Google Scholar 

  44. Miyamoto S, Teramoto H, Coso OA, Gutkind JS, Burbelo PD, Akiyama SK, Yamada KM: Integrin function: Molecular hierarchies of cytoskeletal and signaling molecules. J Cell Biol 131: 791–805, 1995

    Google Scholar 

  45. Gille J and Swerlick RA: Integrins: Role in cell adhesion and communication. Ann N Y Acad Sci 797: 93–106, 1996

    Google Scholar 

  46. Ruoslahti E and Pierschbacher MD: New perspectives in cell adhesion: RGD and integrins. Science 238: 491–497, 1987

    Google Scholar 

  47. Loftus JC, Smith JW, Ginsberg MH: Integrin-mediated cell adhesion: The extracellular face. J Biol Chem 269: 25235–25238, 1994

    Google Scholar 

  48. Hynes RO: Integrins: A family of cell surface receptors. Cell 48: 549–554, 1987

    Google Scholar 

  49. Rawlings NG, Simko E, Bebchuk T, Caldwell SJ, Singh B: Localization of integrin alpha(v)beta3 and vascular endothelial growth factor receptor-2 (KDR/Flk-1) in cutaneous and oral melanomas of dog. Histol Histopathol 18: 819–826, 2003

    Google Scholar 

  50. Popova SN, Rodriguez-Sanchez B, Liden A, Betsholtz C, Van Den BT, Gullberg D: The mesenchymal alpha11beta1 integrin attenuates PDGF-BB-stimulated chemotaxis of embryonic fibroblasts on collagens. Dev Biol 270: 427–442, 2004

    Google Scholar 

  51. Kagami S, Urushihara M, Kitamura A, Kondo S, Hisayama T, Kitamura M, Loster K, Reutter W, Kuroda Y: PDGF-BB enhances alpha1beta1 integrin-mediated activation of the ERK/AP-1 pathway involved in collagen matrix remodeling by rat mesangial cells. J Cell Physiol 198: 470–478, 2004

    Google Scholar 

  52. Ahlen K, Ring P, Tomasini-Johansson B, Holmqvist K, Magnusson KE, Rubin K: Platelet-derived growth factor-BB modulates membrane mobility of beta1 integrins. Biochem Biophys Res Commun 314: 89–96, 2004

    Google Scholar 

  53. Gailit J, Xu J, Bueller H, Clark RA: Platelet-derived growth factor and inflammatory cytokines have differential effects on the expression of integrins alpha 1 beta 1 and alpha 5 beta 1 by human dermal fibroblasts in vitro. J Cell Physiol 169: 281–289, 1996

    Google Scholar 

  54. Brooks PC, Klemke RL, Schon S, Lewis JM, Schwartz MA, Cheresh DA: Insulin-like growth factor receptor cooperates with integrin alpha v beta 5 to promote tumor cell dissemination in vivo. J Clin Invest 99: 1390–1398, 1997

    Google Scholar 

  55. Janji B, Melchior C, Vallar L, Kieffer N: Cloning of an isoform of integrin-linked kinase (ILK) that is upregulated in HT-144 melanoma cells following TGF-beta1 stimulation. Oncogene 19: 3069–3077, 2000

    Google Scholar 

  56. Tai YT, Podar K, Catley L, Tseng YH, Akiyama M, Shringarpure R, Burger R, Hideshima T, Chauhan D, Mitsiades N, Richardson P, Munshi NC, Kahn CR, Mitsiades C, Anderson KC: Insulin-like growth factor-1 induces adhesion and migration in human multiple myeloma cells via activation of beta1-integrin and phosphatidylinositol 3′-kinase/AKT signaling. Cancer Res 63: 5850–5858, 2003

    Google Scholar 

  57. Lehmann JM, Riethmuller G, Johnson JP: MUC18, a marker of tumor progression in human melanoma, shows sequence similarity to the neural cell adhesion molecules of the immunoglobulin superfamily. Proc Natl Acad Sci USA 86: 9891–9895, 1989

    Google Scholar 

  58. Lehmann JM, Holzmann B, Breitbart EW, Schmiegelow P, Riethmuller G, Johnson JP: Discrimination between benign and malignant cells of melanocytic lineage by two novel antigens, a glycoprotein with a molecular weight of 113,000 and a protein with a molecular weight of 76,000. Cancer Res 47: 841–845, 1987

    Google Scholar 

  59. Sers C, Riethmuller G, Johnson JP: MUC18, a melanoma-progression associated molecule, and its potential role in tumor vascularization and hematogenous spread. Cancer Res 54: 5689–5694, 1994

    Google Scholar 

  60. Shih IM, Elder DE, Hsu MY, Herlyn M: Regulation of Mel-CAM/MUC18 expression on melanocytes of different stages of tumor progression by normal keratinocytes. Am J Pathol 145: 837–845, 1994

    Google Scholar 

  61. Shih IM, Speicher D, Hsu MY, Levine E, Herlyn M: Melanoma cell-cell interactions are mediated through heterophilic Mel-CAM/ligand adhesion. Cancer Res 57: 3835–3840, 1997

    Google Scholar 

  62. Seftor RE, Seftor EA, Hendrix MJ: Molecular role(s) for integrins in human melanoma invasion. Cancer Metastasis Rev 18: 359–375, 1999

    Google Scholar 

  63. Meredith JE, Jr., Fazeli B, Schwartz MA: The extracellular matrix as a cell survival factor. Mol Biol Cell 4: 953–961, 1993

    Google Scholar 

  64. Frisch SM and Ruoslahti E: Integrins and anoikis. Curr Opin Cell Biol 9: 701–706, 1997

    Google Scholar 

  65. Felding-Habermann B, O’Toole TE, Smith JW, Fransvea E, Ruggeri ZM, Ginsberg MH, Hughes PE, Pampori N, Shattil SJ, Saven A, Mueller BM: Integrin activation controls metastasis in human breast cancer. Proc Natl Acad Sci USA 98: 1853–1858, 2001

    Google Scholar 

  66. Albelda SM and Buck CA: Integrins and other cell adhesion molecules. FASEB J 4: 2868–2880, 1990

    Google Scholar 

  67. Filardo EJ, Brooks PC, Deming SL, Damsky C, Cheresh DA: Requirement of the NPXY motif in the integrin beta 3 subunit cytoplasmic tail for melanoma cell migration in vitro and in vivo. J Cell Biol 130: 441–450, 1995

    Google Scholar 

  68. Natali PG, Nicotra MR, Di Filippo F, Bigotti A: Expression of fibronectin, fibronectin isoforms and integrin receptors in melanocytic lesions. Br J Cancer 71: 1243–1247, 1995

    Google Scholar 

  69. Hsu MY, Shih DT, Meier FE, Van Belle P, Hsu JY, Elder DE, Buck CA, Herlyn M: Adenoviral gene transfer of beta3 integrin subunit induces conversion from radial to vertical growth phase in primary human melanoma. Am J Pathol 153: 1435–1442, 1998

    Google Scholar 

  70. Brooks PC, Stromblad S, Sanders LC, von Schalscha TL, Aimes RT, Stetler-Stevenson WG, Quigley JP, Cheresh DA: Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell 85: 683–693, 1996

    Google Scholar 

  71. Hofmann UB, Westphal JR, Waas ET, Becker JC, Ruiter DJ, Van Muijen GN: Coexpression of integrin alpha(v)beta3 and matrix metalloproteinase-2 (MMP-2) coincides with MMP-2 activation: Correlation with melanoma progression. J Invest Dermatol 115: 625-632, 2000

    Google Scholar 

  72. Felding-Habermann B, Fransvea E, O’Toole TE, Manzuk L, Faha B, Hensler M: Involvement of tumor cell integrin alpha v beta 3 in hematogenous metastasis of human melanoma cells. Clin Exp Metastasis 19: 427–436, 2002

    Google Scholar 

  73. Geissinger E, Weisser C, Fischer P, Schartl M, Wellbrock C: Autocrine stimulation by osteopontin contributes to antiapoptotic signalling of melanocytes in dermal collagen. Cancer Res 62: 4820–4828, 2002

    Google Scholar 

  74. Ntayi C, Lorimier S, Berthier-Vergnes O, Hornebeck W, Bernard P: Cumulative influence of matrix metalloproteinase-1 and -2 in the migration of melanoma cells within three-dimensional type I collagen lattices. Exp Cell Res 270: 110–118, 2001

    Google Scholar 

  75. Kurschat P, Zigrino P, Nischt R, Breitkopf K, Steurer P, Klein CE, Krieg T, Mauch C: Tissue inhibitor of matrix metalloproteinase-2 regulates matrix metalloproteinase-2 activation by modulation of membrane-type 1 matrix metalloproteinase activity in high and low invasive melanoma cell lines. J Biol Chem 274: 21056–21062, 1999

    Google Scholar 

  76. Kanemoto T, Reich R, Royce L, Greatorex D, Adler SH, Shiraishi N, Martin GR, Yamada Y, Kleinman HK: Identification of an amino acid sequence from the laminin A chain that stimulates metastasis and collagenase IV production. Proc Natl Acad Sci USA 87: 2279–2283, 1990

    Google Scholar 

  77. Nomizu M, Kuratomi Y, Malinda KM, Song SY, Miyoshi K, Otaka A, Powell SK, Hoffman MP, Kleinman HK, Yamada Y: Cell binding sequences in mouse laminin alpha1 chain. J Biol Chem 273: 32491–32499, 1998

    Google Scholar 

  78. Kuratomi Y, Nomizu M, Nielsen PK, Tanaka K, Song SY, Kleinman HK, Yamada Y: Identification of metastasis-promoting sequences in the mouse laminin alpha 1 chain. Exp Cell Res 249: 386–395, 1999

    Google Scholar 

  79. Nakahara H, Nomizu M, Akiyama SK, Yamada Y, Yeh Y, Chen WT: A mechanism for regulation of melanoma invasion. Ligation of alpha6beta1 integrin by laminin G peptides. J Biol Chem 271: 27221–27224, 1996

    Google Scholar 

  80. Mitra A, Chakrabarti J, Chatterjee A: Binding of alpha5 monoclonal antibody to cell surface alpha5beta1 integrin modulates MMP-2 and MMP-7 activity in B16F10 melanoma cells. J Environ Pathol Toxicol Oncol 22: 167–178, 2003

    Google Scholar 

  81. Dekker SK, Vink J, Vermeer BJ, Bruijn JA, Mihm MC, Jr., Byers HR: Differential effects of interleukin 1-alpha (IL-1 alpha) or tumor necrosis factor-alpha (TNF-alpha) on motility of human melanoma cell lines on fibronectin. J Invest Dermatol 102: 898–905, 1994

    Google Scholar 

  82. Frisch SM, Vuori K, Ruoslahti E, Chan-Hui PY: Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol 134: 793–799, 1996

    Google Scholar 

  83. Xu F, Zhao ZJ: Cell density regulates tyrosine phosphorylation and localization of focal adhesion kinase. Exp Cell Res 262: 49–58, 2001

    Google Scholar 

  84. Schlaepfer DD, Hanks SK, Hunter T, van der GP: Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature 372: 786–791, 1994

    Google Scholar 

  85. Calalb MB, Polte TR, Hanks SK: Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: A role for Src family kinases. Mol Cell Biol 15: 954–963, 1995

    Google Scholar 

  86. Schaller MD: Biochemical signals and biological responses elicited by the focal adhesion kinase. Biochim Biophys Acta 1540: 1–21, 2001

    Google Scholar 

  87. Schlaepfer DD, Hauck CR, Sieg DJ: Signaling through focal adhesion kinase. Prog Biophys Mol Biol 71: 435–478, 1999

    Google Scholar 

  88. Ilic D, Furuta Y, Kanazawa S, Takeda N, Sobue K, Nakatsuji N, Nomura S, Fujimoto J, Okada M, Yamamoto T: Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 377: 539–544, 1995

    Google Scholar 

  89. Cobb BS, Schaller MD, Leu TH, Parsons JT: Stable association of pp60src and pp59fyn with the focal adhesion-associated protein tyrosine kinase, pp125FAK. Mol Cell Biol 14: 147–155, 1994

    Google Scholar 

  90. Guinebault C, Payrastre B, Racaud-Sultan C, Mazarguil H, Breton M, Mauco G, Plantavid M, Chap H: Integrin-dependent translocation of phosphoinositide 3-kinase to the cytoskeleton of thrombin-activated platelets involves specific interactions of p85 alpha with actin filaments and focal adhesion kinase. J Cell Biol 129: 831–842, 1995

    Google Scholar 

  91. Sabe H, Hata A, Okada M, Nakagawa H, Hanafusa H: Analysis of the binding of the Src homology 2 domain of Csk to tyrosine-phosphorylated proteins in the suppression and mitotic activation of c-Src. Proc Natl Acad Sci USA 91: 3984–3988, 1994

    Google Scholar 

  92. Schlaepfer DD and Hunter T: Focal adhesion kinase overexpression enhances ras-dependent integrin signaling to ERK2/mitogen-activated protein kinase through interactions with and activation of c-Src. J Biol Chem 272: 13189–13195, 1997

    Google Scholar 

  93. Khwaja A, Rodriguez-Viciana P, Wennstrom S, Warne PH, Downward J: Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J 16: 2783–2793, 1997

    Google Scholar 

  94. Chen HC, Guan JL: Stimulation of phosphatidylinositol 3′-kinase association with foca adhesion kinase by platelet-derived growth factor. J Biol Chem 269: 31229–31233, 1994

    Google Scholar 

  95. Schaller MD, Parsons JT: pp125FAK-dependent tyrosine phosphorylation of paxillin creates a high-affinity binding site for Crk. Mol Cell Biol 15: 2635–2645, 1995

    Google Scholar 

  96. Sieg DJ, Hauck CR, Ilic D, Klingbeil CK, Schaefer E, Damsky CH, Schlaepfer DD: FAK integrates growth-factor and integrin signals to promote cell migration. Nat Cell Biol 2: 249–256, 2000

    Google Scholar 

  97. Golubovskaya V, Beviglia L, Xu LH, Earp HS, III, Craven R, Cance W: Dual inhibition of focal adhesion kinase and epidermal growth factor receptor pathways cooperatively induces death receptor-mediated apoptosis in human breast cancer cells. J Biol Chem 277: 38978–38987, 2002

    Google Scholar 

  98. Chen R, Kim O, Li M, Xiong X, Guan JL, Kung HJ, Chen H, Shimizu Y, Qiu Y: Regulation of the PH-domain-containing tyrosine kinase Etk by focal adhesion kinase through the FERM domain. Nat Cell Biol 3: 439–444, 2001

    Google Scholar 

  99. Poullet P, Gautreau A, Kadare G, Girault JA, Louvard D, Arpin M: Ezrin interacts with focal adhesion kinase and induces its activation independently of cell-matrix adhesion. J Biol Chem 276: 37686–37691, 2001

    Google Scholar 

  100. Neill F, Sear JW, French G, Lam H, Kemp M, Hooper RJ, Foex P: Increases in serum concentrations of cardiac proteins and the prediction of early postoperative cardiovascular complications in noncardiac surgery patients. Anaesthesia 55: 641–647, 2000

    Google Scholar 

  101. Kahana O, Micksche M, Witz IP, Yron I: The focal adhesion kinase (P125FAK) is constitutively active in human malignant melanoma. Oncogene 21: 3969–3977, 2002

    Google Scholar 

  102. Maung K, Easty DJ, Hill SP, Bennett DC: Requirement for focal adhesion kinase in tumor cell adhesion. Oncogene 18: 6824–6828, 1999

    Google Scholar 

  103. Miyazaki T, Kato H, Nakajima M, Sohda M, Fukai Y, Masuda N, Manda R, Fukuchi M, Tsukada K, Kuwano H: FAK overexpression is correlated with tumour invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma. Br J Cancer 89: 140–145, 2003

    Google Scholar 

  104. Clark EA, Golub TR, Lander ES, Hynes RO: Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406: 532–535, 2000

    Google Scholar 

  105. Hendrix MJ, Seftor EA, Hess AR, Seftor RE: Molecular plasticity of human melanoma cells. Oncogene 22: 3070–3075, 2003

    Google Scholar 

  106. Li X, Chen B, Blystone SD, McHugh KP, Ross FP, Ramos DM: Differential expression of alphav integrins in K1735 melanoma cells. Invasion Metastasis 18: 1–14, 1998

    Google Scholar 

  107. Gabarra-Niecko V, Schaller MD, Dunty JM: FAK regulates biological processes important for the pathogenesis of cancer. Cancer Metastasis Rev 22: 359–374, 2003

    Google Scholar 

  108. Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L, Coppolino MG, Radeva G, Filmus J, Bell JC, Dedhar S: Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase. Nature 379: 91–96, 1996

    Google Scholar 

  109. Pasquet JM, Noury M, Nurden AT: Evidence that the platelet integrin alphaIIb beta3 is regulated by the integrin-linked kinase, ILK, in a PI3-kinase dependent pathway. Thromb Haemost 88: 115–122, 2002

    Google Scholar 

  110. Wu C: ILK interactions. J Cell Sci 114: 2549–2550, 2001

    Google Scholar 

  111. Wu C, Dedhar S: Integrin-linked kinase (ILK) and its interactors: A new paradigm for the coupling of extracellular matrix to actin cytoskeleton and signaling complexes. J Cell Biol 155: 505–510, 2001

    Google Scholar 

  112. Tu Y, Huang Y, Zhang Y, Hua Y, Wu C: A new focal adhesion protein that interacts with integrin-linked kinase and regulates cell adhesion and spreading. J Cell Biol 153: 585–598, 2001

    Google Scholar 

  113. Yamaji S, Suzuki A, Sugiyama Y, Koide Y, Yoshida M, Kanamori H, Mohri H, Ohno S, Ishigatsubo Y: A novel integrin-linked kinase-binding protein, affixin, is involved in the early stage of cell-substrate interaction. J Cell Biol 153: 1251–1264, 2001

    Google Scholar 

  114. Nikolopoulos SN, Turner CE: Integrin-linked kinase (ILK) binding to paxillin LD1 motif regulates ILK localization to focal adhesions. J Biol Chem 276: 23499–23505, 2001

    Google Scholar 

  115. Persad S, Dedhar S: The role of integrin-linked kinase (ILK) in cancer progression. Cancer Metastasis Rev 22: 375–384, 2003

    Google Scholar 

  116. Dedhar S: Cell-substrate interactions and signaling through ILK. Curr Opin Cell Biol 12: 250–256, 2000

    Google Scholar 

  117. Troussard AA, Tan C, Yoganathan TN, Dedhar S: Cell-extracellular matrix interactions stimulate the AP-1 transcription factor in an integrin-linked kinase- and glycogen synthase kinase 3-dependent manner. Mol Cell Biol 19: 7420–7427, 1999

    Google Scholar 

  118. Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S: Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci USA 95: 11211–11216, 1998

    Google Scholar 

  119. Persad S, Attwell S, Gray V, Delcommenne M, Troussard A, Sanghera J, Dedhar S: Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells. Proc Natl Acad Sci USA 97: 3207–3212, 2000

    Google Scholar 

  120. Radeva G, Petrocelli T, Behrend E, Leung-Hagesteijn C, Filmus J, Slingerland J, Dedhar S: Overexpression of the integrin-linked kinase promotes anchorage-independent cell cycle progression. J Biol Chem 272: 13937–13944, 1997

    Google Scholar 

  121. Graff JR, Deddens JA, Konicek BW, Colligan BM, Hurst BM, Carter HW, Carter JH: Integrin-linked kinase expression increases with prostate tumor grade. Clin Cancer Res 7: 1987–1991, 2001

    Google Scholar 

  122. Chung DH, Lee JI, Kook MC, Kim JR, Kim SH, Choi EY, Park SH, Song HG: ILK (beta1-integrin-linked protein kinase): A novel immunohistochemical marker for Ewing’s sarcoma and primitive neuroectodermal tumour. Virchows Arch 433: 113–117, 1998

    Google Scholar 

  123. Marotta A, Tan C, Gray V, Malik S, Gallinger S, Sanghera J, Dupuis B, Owen D, Dedhar S, Salh B: Dysregulation of integrin-linked kinase (ILK) signaling in colonic polyposis. Oncogene 20: 6250–6257, 2001

    Google Scholar 

  124. Dai DL, Makretsov N, Campos EI, Huang C, Zhou Y, Huntsman D, Martinka M, Li G: Increased expression of integrin-linked kinase is correlated with melanoma progression and poor patient survival. Clin Cancer Res 9: 4409–4414, 2003

    Google Scholar 

  125. Somasiri A, Howarth A, Goswami D, Dedhar S, Roskelley CD: Overexpression of the integrin-linked kinase mesenchymally transforms mammary epithelial cells. J Cell Sci 114: 1125–1136, 2001

    Google Scholar 

  126. Tan C, Costello P, Sanghera J, Dominguez D, Baulida J, de Herreros AG, Dedhar S: Inhibition of integrin linked kinase (ILK) suppresses beta-catenin-Lef/Tcf-dependent transcription and expression of the E-cadherin repressor, snail, in APC−/− human colon carcinoma cells. Oncogene 20: 133–140, 2001

    Google Scholar 

  127. Guaita S, Puig I, Franci C, Garrido M, Dominguez D, Batlle E, Sancho E, Dedhar S, de Herreros AG, Baulida J: Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression. J Biol Chem 277: 39209–39216, 2002

    Google Scholar 

  128. Poser I, Dominguez D, de Herreros AG, Varnai A, Buettner R, Bosserhoff AK: Loss of E-cadherin expression in melanoma cells involves up-regulation of the transcriptional repressor Snail. J Biol Chem 276: 24661–24666, 2001

    Google Scholar 

  129. Troussard AA, Costello P, Yoganathan TN, Kumagai S, Roskelley CD, Dedhar S: The integrin linked kinase (ILK) induces an invasive phenotype via AP-1 transcription factor-dependent upregulation of matrix metalloproteinase 9 (MMP-9). Oncogene 19: 5444–5452, 2000

    Google Scholar 

  130. Fang W, Li H, Kong L, Niu G, Gao Q, Zhou K, Zheng J, Wu B: [Role of matrix metalloproteinases (MMPs) in tumor invasion and metastasis: Serial studies on MMPs and TIMPs]. Beijing Da Xue Xue Bao 35: 441–443, 2003

    Google Scholar 

  131. Luzi L, Confalonieri S, Di Fiore PP, Pelicci PG: Evolution of Shc functions from nematode to human. Curr Opin Genet Dev 10: 668–674, 2000

    Google Scholar 

  132. Pelicci G, Dente L, De Giuseppe A, Verducci-Galletti B, Giuli S, Mele S, Vetriani C, Giorgio M, Pandolfi PP, Cesareni G, Pelicci PG: A family of Shc related proteins with conserved PTB, CH1 and SH2 regions. Oncogene 13: 633–641, 1996

    Google Scholar 

  133. Mainiero F, Pepe A, Wary KK, Spinardi L, Mohammadi M, Schlessinger J, Giancotti FG: Signal transduction by the alpha 6 beta 4 integrin: Distinct beta 4 subunit sites mediate recruitment of Shc/Grb2 and association with the cytoskeleton of hemidesmosomes. EMBO J 14: 4470–4481, 1995

    Google Scholar 

  134. Wary KK, Mariotti A, Zurzolo C, Giancotti FG: A requirement for caveolin-1 and associated kinase Fyn in integrin signaling and anchorage-dependent cell growth. Cell 94: 625–634, 1998

    Google Scholar 

  135. Wary KK, Mainiero F, Isakoff SJ, Marcantonio EE, Giancotti FG: The adaptor protein Shc couples a class of integrins to the control of cell cycle progression. Cell 87: 733–743, 1996

    Google Scholar 

  136. Gotoh N, Toyoda M, Shibuya M: Tyrosine phosphorylation sites at amino acids 239 and 240 of Shc are involved in epidermal growth factor-induced mitogenic signaling that is distinct from Ras/mitogen-activated protein kinase activation. Mol Cell Biol 17: 1824–1831, 1997

    Google Scholar 

  137. Sakai R, Henderson JT, O’Bryan JP, Elia AJ, Saxton TM, Pawson T: The mammalian ShcB and ShcC phosphotyrosine docking proteins function in the maturation of sensory and sympathetic neurons. Neuron 28: 819–833, 2000

    Google Scholar 

  138. Friedmann MC, Migone TS, Russell SM, Leonard WJ: Different interleukin 2 receptor beta-chain tyrosines couple to at least two signaling pathways and synergistically mediate interleukin 2-induced proliferation. Proc Natl Acad Sci USA 93: 2077–2082, 1996

    Google Scholar 

  139. Barberis L, Wary KK, Fiucci G, Liu F, Hirsch E, Brancaccio M, Altruda F, Tarone G, Giancotti FG: Distinct roles of the adaptor protein Shc and focal adhesion kinase in integrin signaling to ERK. J Biol Chem 275: 36532–36540, 2000

    Google Scholar 

  140. Ravichandran KS, Lorenz U, Shoelson SE, Burakoff SJ: Interaction of Shc with Grb2 regulates the Grb2 association with mSOS. Ann N Y Acad Sci 766: 202–203, 1995

    Google Scholar 

  141. Reddy KB, Nabha SM, Atanaskova N: Role of MAP kinase in tumor progression and invasion. Cancer Metastasis Rev 22: 395–403, 2003

    Google Scholar 

  142. Howe AK, Aplin AE, Juliano RL: Anchorage-dependent ERK signaling–mechanisms and consequences. Curr Opin Genet Dev 12: 30–35, 2002

    Google Scholar 

  143. Renshaw MW, Price LS, Schwartz MA: Focal adhesion kinase mediates the integrin signaling requirement for growth factor activation of MAP kinase. J Cell Biol 147: 611–618, 1999

    Google Scholar 

  144. Hauck CR, Hsia DA, Schlaepfer DD: Focal adhesion kinase facilitates platelet-derived growth factor-BB-stimulated ERK2 activation required for chemotaxis migration of vascular smooth muscle cells. J Biol Chem 275: 41092–41099, 2000

    Google Scholar 

  145. Qi JH, Ito N, Claesson-Welsh L: Tyrosine phosphatase SHP-2 is involved in regulation of platelet-derived growth factor-induced migration. J Biol Chem 274: 14455–14463, 1999

    Google Scholar 

  146. Gu J, Tamura M, Yamada KM: Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways. J Cell Biol 143: 1375–1383, 1998

    Google Scholar 

  147. Tsao H, Mihm MC, Jr., Sheehan C: PTEN expression in normal skin, acquired melanocytic nevi, and cutaneous melanoma. J Am Acad Dermatol 49: 865–872, 2003

    Google Scholar 

  148. Satyamoorthy K, Li G, Gerrero MR, Brose MS, Volpe P, Weber BL, Van Belle P, Elder DE, Herlyn M: Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res 63: 756–759, 2003

    Google Scholar 

  149. Smalley KS: A pivotal role for ERK in the oncogenic behaviour of malignant melanoma? Int J Cancer 104: 527–532, 2003

    Google Scholar 

  150. van Elsas A, Zerp S, van der FS, Kruse-Wolters M, Vacca A, Ruiter DJ, Schrier P: Analysis of N-ras mutations in human cutaneous melanoma: Tumor heterogeneity detected by polymerase chain reaction/single-stranded conformation polymorphism analysis. Recent Results Cancer Res 139: 57–67, 1995

    Google Scholar 

  151. Herlyn M, Satyamoorthy K: Activated ras. Yet another player in melanoma? Am J Pathol 149: 739–744, 1996

    Google Scholar 

  152. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA: Mutations of the BRAF gene in human cancer. Nature 417: 949–954, 2002

    Google Scholar 

  153. Mattei S, Colombo MP, Melani C, Silvani A, Parmiani G, Herlyn M: Expression of cytokine/growth factors and their receptors in human melanoma and melanocytes. Int J Cancer 56: 853–857, 1994

    Google Scholar 

  154. Lazar-Molnar E, Hegyesi H, Toth S, Falus A: Autocrine and paracrine regulation by cytokines and growth factors in melanoma. Cytokine 12: 547–554, 2000

    Google Scholar 

  155. Satyamoorthy K, Li G, Vaidya B, Patel D, Herlyn M: Insulin-like growth factor-1 induces survival and growth of biologically early melanoma cells through both the mitogen-activated protein kinase and beta-catenin pathways. Cancer Res 61: 7318–7324, 2001

    Google Scholar 

  156. Englaro W, Bertolotto C, Busca R, Brunet A, Pages G, Ortonne JP, Ballotti R: Inhibition of the mitogen-activated protein kinase pathway triggers B16 melanoma cell differentiation. J Biol Chem 273: 9966–9970, 1998

    Google Scholar 

  157. Kim DS, Kim SY, Chung JH, Kim KH, Eun HC, Park KC: Delayed ERK activation by ceramide reduces melanin synthesis in human melanocytes. Cell Signal 14: 779–785, 2002

    Google Scholar 

  158. McGill GG, Horstmann M, Widlund HR, Du J, Motyckova G, Nishimura EK, Lin YL, Ramaswamy S, Avery W, Ding HF, Jordan SA, Jackson IJ, Korsmeyer SJ, Golub TR, Fisher DE: Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell 109: 707–718, 2002

    Google Scholar 

  159. Lin JJ, Jiang H, Fisher PB: Melanoma differentiation associated gene-9, mda-9, is a human gamma interferon responsive gene. Gene 207: 105–110, 1998

    Google Scholar 

  160. FitzGerald MG, Harkin DP, Silva-Arrieta S, MacDonald DJ, Lucchina LC, Unsal H, O’Neill E, Koh J, Finkelstein DM, Isselbacher KJ, Sober AJ, Haber DA: Prevalence of germ-line mutations in p16, p19ARF, and CDK4 in familial melanoma: Analysis of a clinic-based population. Proc Natl Acad Sci USA 93: 8541–8545, 1996

    Google Scholar 

  161. MacDougall JR, Bani MR, Lin Y, Muschel RJ, Kerbel RS: ‘Proteolytic switching’: Opposite patterns of regulation of gelatinase B and its inhibitor TIMP-1 during human melanoma progression and consequences of gelatinase B overexpression. Br J Cancer 80: 504–512, 1999

    Google Scholar 

  162. Genersch E, Hayess K, Neuenfeld Y, Haller H: Sustained ERK phosphorylation is necessary but not sufficient for MMP-9 regulation in endothelial cells: Involvement of Ras-dependent and -independent pathways. J Cell Sci 113 (Pt~23): 4319–4330, 2000

    Google Scholar 

  163. Danen EH, de Vries TJ, Morandini R, Ghanem GG, Ruiter DJ, Van Muijen GN: E-cadherin expression in human melanoma. Melanoma Res 6: 127–131, 1996

    Google Scholar 

  164. Li G, Schaider H, Satyamoorthy K, Hanakawa Y, Hashimoto K, Herlyn M: Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development. Oncogene 20: 8125–8135, 2001

    Google Scholar 

  165. Woods D, Cherwinski H, Venetsanakos E, Bhat A, Gysin S, Humbert M, Bray PF, Saylor VL, McMahon M: Induction of beta3-integrin gene expression by sustained activation of the Ras-regulated Raf-MEK-extracellular signal-regulated kinase signaling pathway. Mol Cell Biol 21: 3192–3205, 2001

    Google Scholar 

  166. Arteaga CL: Overview of epidermal growth factor receptor biology and its role as a therapeutic target in human neoplasia. Semin Oncol 29: 3–9, 2002

    Google Scholar 

  167. Prenzel N, Zwick E, Leserer M, Ullrich A: Tyrosine kinase signalling in breast cancer. Epidermal growth factor receptor: Convergence point for signal integration and diversification. Breast Cancer Res 2: 184–190, 2000

    Google Scholar 

  168. Carpenter G: The EGF receptor: A nexus for trafficking and signaling. Bioessays 22: 697–707, 2000

    Google Scholar 

  169. Hackel PO, Zwick E, Prenzel N, Ullrich A: Epidermal growth factor receptors: Critical mediators of multiple receptor pathways. Curr Opin Cell Biol 11: 184–189, 1999

    Google Scholar 

  170. Daub H, Weiss FU, Wallasch C, Ullrich A: Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature 379: 557–560, 1996

    Google Scholar 

  171. Dikic I, Tokiwa G, Lev S, Courtneidge SA, Schlessinger J: A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation. Nature 383: 547–550, 1996

    Google Scholar 

  172. Jost M, Huggett TM, Kari C, Boise LH, Rodeck U: Epidermal growth factor receptor-dependent control of keratinocyte survival and Bcl-xL expression through a MEK-dependent pathway. J Biol Chem 276: 6320–6326, 2001

    Google Scholar 

  173. Tan Y, Demeter MR, Ruan H, Comb MJ: BAD Ser-155 phosphorylation regulates BAD/Bcl-XL interaction and cell survival. J Biol Chem 275: 25865–25869, 2000

    Google Scholar 

  174. Reginato MJ, Mills KR, Paulus JK, Lynch DK, Sgroi DC, Debnath J, Muthuswamy SK, Brugge JS: Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis. Nat Cell Biol 5: 733–740, 2003

    Google Scholar 

  175. Marani M, Hancock D, Lopes R, Tenev T, Downward J, Lemoine NR: Role of Bim in the survival pathway induced by Raf in epithelial cells. Oncogene 23: 2431–2441, 2004

    Google Scholar 

  176. Moro L, Venturino M, Bozzo C, Silengo L, Altruda F, Beguinot L, Tarone G, Defilippi P: Integrins induce activation of EGF receptor: Role in MAP kinase induction and adhesion-dependent cell survival. EMBO J 17: 6622–6632, 1998

    Google Scholar 

  177. Cabodi S, Moro L, Bergatto E, Boeri EE, Di Stefano P, Turco E, Tarone G, Defilippi P: Integrin regulation of epidermal growth factor (EGF) receptor and of EGF-dependent responses. Biochem Soc Trans 32: 438–442, 2004

    Google Scholar 

  178. Yu X, Miyamoto S, Mekada E: Integrin alpha 2 beta 1-dependent EGF receptor activation at cell-cell contact sites. J Cell Sci 113 (Pt 12): 2139–2147, 2000

    Google Scholar 

  179. Gordon-Thomson C, Mason RS, Moore GP: Regulation of epidermal growth factor receptor expression in human melanocytes. Exp Dermatol 10: 321–328, 2001

    Google Scholar 

  180. Kraehn GM, Schartl M, Peter RU: Human malignant melanoma. A genetic disease? Cancer 75: 1228–1237, 1995

    Google Scholar 

  181. Kari C, Chan TO, Rocha dQ, Rodeck U: Targeting the epidermal growth factor receptor in cancer: Apoptosis takes center stage. Cancer Res 63: 1–5, 2003

    Google Scholar 

  182. Koprowski H, Herlyn M, Balaban G, Parmiter A, Ross A, Nowell P: Expression of the receptor for epidermal growth factor correlates with increased dosage of chromosome 7 in malignant melanoma. Somat Cell Mol Genet 11: 297–302, 1985

    Google Scholar 

  183. Bodey B, Bodey B, Jr., Groger AM, Luck JV, Siegel SE, Taylor CR, Kaiser HE: Clinical and prognostic significance of the expression of the c-erbB-2 and c-erbB-3 oncoproteins in primary and metastatic malignant melanomas and breast carcinomas. Anticancer Res 17: 1319–1330, 1997

    Google Scholar 

  184. Korabiowska M, Mirecka J, Brinck U, Hoefer K, Marx D, Schauer A: Differential expression of cerbB3 in naevi and malignant melanomas. Anticancer Res 16: 471–474, 1996

    Google Scholar 

  185. Ma D and Niederkorn JY: Role of epidermal growth factor receptor in the metastasis of intraocular melanomas. Invest Ophthalmol Vis Sci 39: 1067–1075, 1998

    Google Scholar 

  186. de Wit PE, Moretti S, Koenders PG, Weterman MA, Van Muijen GN, Gianotti B, Ruiter DJ: Increasing epidermal growth factor receptor expression in human melanocytic tumor progression. J Invest Dermatol 99: 168–173, 1992

    Google Scholar 

  187. Li S, Okamoto T, Chun M, Sargiacomo M, Casanova JE, Hansen SH, Nishimoto I, Lisanti MP: Evidence for a regulated interaction between heterotrimeric G proteins and caveolin. J Biol Chem 270: 15693–15701, 1995

    Google Scholar 

  188. Li S, Couet J, Lisanti MP: Src tyrosine kinases, Galpha subunits, and H-Ras share a common membrane-anchored scaffolding protein, caveolin. Caveolin binding negatively regulates the auto-activation of Src tyrosine kinases. J Biol Chem 271: 29182–29190, 1996

    Google Scholar 

  189. Wei Y, Yang X, Liu Q, Wilkins JA, Chapman HA: A role for caveolin and the urokinase receptor in integrin-mediated adhesion and signaling. J Cell Biol 144: 1285–1294, 1999

    Google Scholar 

  190. Brooks PC, Clark RA, Cheresh DA: Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 264: 569–571, 1994

    Google Scholar 

  191. Marshall JF, Hart IR: The role of alpha v-integrins in tumour progression and metastasis. Semin Cancer Biol 7: 129–138, 1996

    Google Scholar 

  192. Gurrath M, Muller G, Kessler H, Aumailley M, Timpl R: Conformation/activity studies of rationally designed potent anti-adhesive RGD peptides. Eur J Biochem 210: 911–921, 1992

    Google Scholar 

  193. Dechantsreiter MA, Planker E, Matha B, Lohof E, Holzemann G, Jonczyk A, Goodman SL, Kessler H: N-Methylated cyclic RGD peptides as highly active and selective alpha(V)beta(3) integrin antagonists. J Med Chem 42: 3033–3040, 1999

    Google Scholar 

  194. Brooks PC: Role of integrins in angiogenesis. Eur J Cancer 32A: 2423–2429, 1996

    Google Scholar 

  195. Bayless KJ, Salazar R, Davis GE: RGD-dependent vacuolation and lumen formation observed during endothelial cell morphogenesis in three-dimensional fibrin matrices involves the alpha(v)beta(3) and alpha(5)beta(1) integrins. Am J Pathol 156: 1673–1683, 2000

    Google Scholar 

  196. Carron CP, Meyer DM, Pegg JA, Engleman VW, Nickols MA, Settle SL, Westlin WF, Ruminski PG, Nickols GA: A peptidomimetic antagonist of the integrin alpha(v)beta3 inhibits Leydig cell tumor growth and the development of hypercalcemia of malignancy. Cancer Res 58: 1930–1935, 1998

    Google Scholar 

  197. Reinmuth N, Liu W, Ahmad SA, Fan F, Stoeltzing O, Parikh AA, Bucana CD, Gallick GE, Nickols MA, Westlin WF, Ellis LM: Alphavbeta3 integrin antagonist S247 decreases colon cancer metastasis and angiogenesis and improves survival in mice. Cancer Res 63: 2079–2087, 2003

    Google Scholar 

  198. Stoeltzing O, Liu W, Reinmuth N, Fan F, Parry GC, Parikh AA, McCarty MF, Bucana CD, Mazar AP, Ellis LM: Inhibition of integrin alpha5beta1 function with a small peptide (ATN-161) plus continuous 5-FU infusion reduces colorectal liver metastases and improves survival in mice. Int J Cancer %20;104: 496–503, 2003

    Google Scholar 

  199. McLane MA, Marcinkiewicz C, Vijay-Kumar S, Wierzbicka-Patynowski I, Niewiarowski S: Viper venom disintegrins and related molecules. Proc Soc Exp Biol Med 219: 109–119, 1998

    Google Scholar 

  200. Chang HH, Chang CP, Chang JC, Dung SZ, Lo SJ: Application of Recombinant Rhodostomin in Studying Cell Adhesion. J Biomed Sci 4: 235–243, 1997

    Google Scholar 

  201. McLane MA, Kuchar MA, Brando C, Santoli D, Paquette-Straub CA, Miele ME: New insights on disintegrin-receptor interactions: Eristostatin and melanoma cells. Haemostasis 31: 177–182, 2001

    Google Scholar 

  202. Danen EH, Marcinkiewicz C, Cornelissen IM, van Kraats AA, Pachter JA, Ruiter DJ, Niewiarowski S, Van Muijen GN: The disintegrin eristostatin interferes with integrin alpha 4 beta 1 function and with experimental metastasis of human melanoma cells. Exp Cell Res 238: 188–196, 1998

    Google Scholar 

  203. Pytela R, Pierschbacher MD, Argraves S, Suzuki S, Ruoslahti E: Arginine-glycine-aspartic acid adhesion receptors. Methods Enzymol 144:475–89.: 475-489, 1987

    Google Scholar 

  204. Plow EF, Pierschbacher MD, Ruoslahti E, Marguerie G, Ginsberg MH: Arginyl-glycyl-aspartic acid sequences and fibrinogen binding to platelets. Blood 70: 110–115, 1987

    Google Scholar 

  205. Marcinkiewicz C, Calvete JJ, Marcinkiewicz MM, Raida M, Vijay-Kumar S, Huang Z, Lobb RR, Niewiarowski S: EC3, a novel heterodimeric disintegrin from Echis carinatus venom, inhibits alpha4 and alpha5 integrins in an RGD-independent manner. J Biol Chem 274: 12468–12473, 1999

    Google Scholar 

  206. Kang IC, Kim DS, Jang Y, Chung KH: Suppressive mechanism of salmosin, a novel disintegrin in B16 melanoma cell metastasis. Biochem Biophys Res Commun 275: 169–173, 2000

    Google Scholar 

  207. Kang IC, Lee YD, Kim DS: A novel disintegrin salmosin inhibits tumor angiogenesis. Cancer Res 59: 3754–3760, 1999

    Google Scholar 

  208. Correa MC, Jr., Maria DA, Moura-da-Silva AM, Pizzocaro KF, Ruiz IR: Inhibition of melanoma cells tumorigenicity by the snake venom toxin jararhagin. Toxicon 40: 739–748, 2002

    Google Scholar 

  209. Wierzbicka-Patynowski I, Niewiarowski S, Marcinkiewicz C, Calvete JJ, Marcinkiewicz MM, McLane MA: Structural requirements of echistatin for the recognition of alpha(v)beta(3) and alpha(5)beta(1) integrins. J Biol Chem 274: 37809–37814, 1999

    Google Scholar 

  210. Trikha M, De Clerck YA, Markland FS: Contortrostatin, a snake venom disintegrin, inhibits beta 1 integrin-mediated human metastatic melanoma cell adhesion and blocks experimental metastasis. Cancer Res 54: 4993–4998, 1994

    Google Scholar 

  211. Marcinkiewicz C, Weinreb PH, Calvete JJ, Kisiel DG, Mousa SA, Tuszynski GP, Lobb RR: Obtustatin: A potent selective inhibitor of alpha1beta1 integrin in vitro and angiogenesis in vivo. Cancer Res 63: 2020–2023, 2003

    Google Scholar 

  212. Sheu JR, Lin CH, Peng HC, Huang TF: Triflavin, an Arg-Gly-Asp-containing peptide, inhibits the adhesion of tumor cells to matrix proteins via binding to multiple integrin receptors expressed on human hepatoma cells. Proc Soc Exp Biol Med 213: 71–79, 1996

    Google Scholar 

  213. Knudsen KA, Tuszynski GP, Huang TF, Niewiarowski S: Trigramin, an RGD-containing peptide from snake venom, inhibits cell-substratum adhesion of human melanoma cells. Exp Cell Res 179: 42–49, 1988

    Google Scholar 

  214. Soszka T, Knudsen KA, Beviglia L, Rossi C, Poggi A, Niewiarowski S: Inhibition of murine melanoma cell-matrix adhesion and experimental metastasis by albolabrin, an RGD-containing peptide isolated from the venom of Trimeresurus albolabris. Exp Cell Res 196: 6–12, 1991

    Google Scholar 

  215. Trochon-Joseph V, Martel-Renoir D, Mir LM, Thomaidis A, Opolon P, Connault E, Li H, Grenet C, Fauvel-Lafeve F, Soria J, Legrand C, Soria C, Perricaudet M, Lu H: Evidence of antiangiogenic and antimetastatic activities of the recombinant disintegrin domain of metargidin. Cancer Res 64: 2062–2069, 2004

    Google Scholar 

  216. Gutheil JC, Campbell TN, Pierce PR, Watkins JD, Huse WD, Bodkin DJ, Cheresh DA: Targeted antiangiogenic therapy for cancer using Vitaxin: A humanized monoclonal antibody to the integrin alphavbeta3. Clin Cancer Res 6: 3056–3061, 2000

    Google Scholar 

  217. Patel SR, Jenkins J, Papadopolous N, Burgess MA, Plager C, Gutterman J, Benjamin RS: Pilot study of vitaxin–an angiogenesis inhibitor-in patients with advanced leiomyosarcomas. Cancer 92: 1347–1348, 2001

    Google Scholar 

  218. Posey JA, Khazaeli MB, DelGrosso A, Saleh MN, Lin CY, Huse W, LoBuglio AF: A pilot trial of Vitaxin, a humanized anti-vitronectin receptor (anti alpha v beta 3) antibody in patients with metastatic cancer. Cancer Biother Radiopharm 16: 125–132, 2001

    Google Scholar 

  219. Mikecz K: Vitaxin applied molecular evolution. Curr Opin Investig Drugs 1: 199–203, 2000

    Google Scholar 

  220. Trikha M, Zhou Z, Nemeth JA, Chen Q, Sharp C, Emmell E, Giles-Komar J, Nakada MT: CNTO 95, a fully human monoclonal antibody that inhibits alphav integrins, has antitumor and antiangiogenic activity in vivo. Int J Cancer 110: 326–335, 2004

    Google Scholar 

  221. Jin H, Varner J: Integrins: Roles in cancer development and as treatment targets. Br J Cancer 90: 561–565, 2004

    Google Scholar 

  222. Li L, Wartchow CA, Danthi SN, Shen Z, Dechene N, Pease J, Choi HS, Doede T, Chu P, Ning S, Lee DY, Bednarski MD, Knox SJ: A novel antiangiogenesis therapy using an integrin antagonist or anti-Flk-1 antibody coated 90Y-labeled nanoparticles. Int J Radiat Oncol Biol Phys 58: 1215–1227, 2004

    Google Scholar 

  223. Ledezma E, Apitz-Castro R, Cardier J: Apoptotic and anti-adhesion effect of ajoene, a garlic derived compound, on the murine melanoma B16F10 cells: possible role of caspase-3 and the alpha(4)beta(1) integrin. Cancer Lett 206: 35–41, 2004

    Google Scholar 

  224. Hapke S, Gawaz M, Dehne K, Kohler J, Marshall JF, Graeff H, Schmitt M, Reuning U, Lengyel E: beta(3)A-integrin downregulates the urokinase-type plasminogen activator receptor (u-PAR) through a PEA3/ets transcriptional silencing element in the u-PAR promoter. Mol Cell Biol 21: 2118–2132, 2001

    Google Scholar 

  225. Dalvi N, Thomas GJ, Marshall JF, Morgan M, Bass R, Ellis V, Speight PM, Whawell SA: Modulation of the urokinase-type plasminogen activator receptor by the beta6 integrin subunit. Biochem Biophys Res Commun 317: 92–99, 2004

    Google Scholar 

  226. Klekotka PA, Santoro SA, Wang H, Zutter MM: Specific residues within the alpha 2 integrin subunit cytoplasmic domain regulate migration and cell cycle progression via distinct MAPK pathways. J Biol Chem 276: 32353–32361, 2001

    Google Scholar 

  227. Fang F, Orend G, Watanabe N, Hunter T, Ruoslahti E: Dependence of cyclin E-CDK2 kinase activity on cell anchorage. Science 271: 499–502, 1996

    Google Scholar 

  228. Zhu X, Ohtsubo M, Bohmer RM, Roberts JM, Assoian RK: Adhesion-dependent cell cycle progression linked to the expression of cyclin D1, activation of cyclin E-cdk2, and phosphorylation of the retinoblastoma protein. J Cell Biol 133: 391–403, 1996

    Google Scholar 

  229. Roovers K, Davey G, Zhu X, Bottazzi ME, Assoian RK: Alpha5beta1 integrin controls cyclin D1 expression by sustaining mitogen-activated protein kinase activity in growth factor-treated cells. Mol Biol Cell 10: 3197–3204, 1999

    Google Scholar 

  230. Henriet P, Zhong ZD, Brooks PC, Weinberg KI, DeClerck YA: Contact with fibrillar collagen inhibits melanoma cell proliferation by up-regulating p27KIP1. Proc Natl Acad Sci USA 97: 10026–10031, 2000

    Google Scholar 

  231. Petitclerc E, Stromblad S, von Schalscha TL, Mitjans F, Piulats J, Montgomery AM, Cheresh DA, Brooks PC: Integrin alpha(v)beta3 promotes M21 melanoma growth in human skin by regulating tumor cell survival. Cancer Res 59: 2724–2730, 1999

    Google Scholar 

  232. Seftor RE, Seftor EA, Gehlsen KR, Stetler-Stevenson WG, Brown PD, Ruoslahti E, Hendrix MJ: Role of the alpha v beta 3 integrin in human melanoma cell invasion. Proc Natl Acad Sci USA 89: 1557–1561, 1992

    Google Scholar 

  233. Castel S, Pagan R, Garcia R, Casaroli-Marano RP, Reina M, Mitjans F, Piulats J, Vilaro S: Alpha v integrin antagonists induce the disassembly of focal contacts in melanoma cells. Eur J Cell Biol 79: 502–512, 2000

    Google Scholar 

  234. Tsuji T, Kawada Y, Kai-Murozono M, Komatsu S, Han SA, Takeuchi K, Mizushima H, Miyazaki K, Irimura T: Regulation of melanoma cell migration and invasion by laminin-5 and alpha3beta1 integrin (VLA-3). Clin Exp Metastasis 19: 127–134, 2002

    Google Scholar 

  235. Abdel-Ghany M, Cheng HC, Elble RC, Pauli BU: Focal adhesion kinase activated by beta(4) integrin ligation to mCLCA1 mediates early metastatic growth. J Biol Chem 277: 34391–34400, 2002

    Google Scholar 

  236. Van Muijen GN, Jansen KF, Cornelissen IM, Smeets DF, Beck JL, Ruiter DJ: Establishment and characterization of a human melanoma cell line (MV3) which is highly metastatic in nude mice. Int J Cancer 48: 85–91, 1991

    Google Scholar 

  237. Zhu Z, Sanchez-Sweatman O, Huang X, Wiltrout R, Khokha R, Zhao Q, Gorelik E: Anoikis and metastatic potential of cloudman S91 melanoma cells. Cancer Res 61: 1707–1716, 2001

    Google Scholar 

  238. Moyano JV, Maqueda A, Casanova B, Garcia-Pardo A: Alpha4beta1 integrin/ligand interaction inhibits alpha5beta1-induced stress fibers and focal adhesions via down-regulation of RhoA and induces melanoma cell migration. Mol Biol Cell 14: 3699–3715, 2003

    Google Scholar 

  239. Mortarini R, Gismondi A, Santoni A, Parmiani G, Anichini A: Role of the alpha 5 beta 1 integrin receptor in the proliferative response of quiescent human melanoma cells to fibronectin. Cancer Res 52: 4499–4506, 1992

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Anja-Katrin Bosserhoff.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kuphal, S., Bauer, R. & Bosserhoff, AK. Integrin signaling in malignant melanoma. Cancer Metastasis Rev 24, 195–222 (2005). https://doi.org/10.1007/s10555-005-1572-1

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-005-1572-1

Key words

Navigation