Cancer and Metastasis Reviews

, Volume 14, Issue 3, pp 165–172 | Cite as

Integrin mediated signal transduction in oncogenesis: An overview

  • Shoukat Dedhar

Key words

integrins anchorage dependent growth kinases signal transduction apoptosis metastasis 


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  1. 1.
    Hynes RO: Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69: 11–25, 1992Google Scholar
  2. 2.
    Giancotti, FG, Mainiero F: Integrin-mediated adhesion and signalling in tumorigenesis. Biochim Biophys Acta 1198: 47–64, 1994Google Scholar
  3. 3.
    Clark EA, Brugge JS: Integrins and signal transduction pathways: the road taken. Science 268: 233–239, 1995Google Scholar
  4. 4.
    Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L, Bell JC, Dedhar S: A novel, ankyrin repeat-containing serine/threonine protein kinase interacts with the β1 integrin cytoplasmic domain. Submitted: 1995Google Scholar
  5. 5.
    Leung-Hagesteijn C, Milankov K, Michalak M, Wilkins J, Dedhar S: Cell attachment to extracellular matrix substrates is inhibited upon downregulation of expression of calreticulin, an intracellular integrin α-subunit-binding protein. J Cell Sci 107: 589–600, 1994Google Scholar
  6. 6.
    Dedhar S: Novel functions for calreticulin: interaction with integrins and modulation of gene expression? Trends Biochem Sci 19: 269–271, 1994Google Scholar
  7. 7.
    Miyamoto S, Akiyama SK, Yamada KM: Synergeistic roles for receptor occupancy and aggregation in integrin transmembrane function. Science 267: 883–885, 1995Google Scholar
  8. 8.
    Adams J, Watt F: Fibronectin inhibits the terminal differentiation of human keratinocytes. Nature 340: 307–309, 1989Google Scholar
  9. 9.
    Menko AS, Boettiger D: Occupation of the extracellular matrix receptor, integrin, is a control point for myogenic differentiation. Cell 51: 51–57, 1987Google Scholar
  10. 10.
    Dedhar S: Signal transduction via the β integrins is a required intermediate in interleukin-1 induced phenotypic differentiation of human osteosarcoma cells. Exp Cell Res 183: 207–214, 1989Google Scholar
  11. 11.
    Dedhar S, Mitchell MD, Pierschbacher MD: The osteoblastlike differentiated phenotype of a variant of human MG-63 osteosarcoma cell line correlated with altred adhesive properties. Connective Tissue Res 20: 49–61, 1989Google Scholar
  12. 12.
    Dedhar S, Gray V, Roberston K, Haqq C: Differential regulation of expression of specific integrin receptors by nerve growth factor and transforming growth factor β during differentiation of human neuroblastoma cells. Mol Cell Diff 1: 1–20, 1993Google Scholar
  13. 13.
    Werb Z, Tremble PM, Behrendtsen O, Crowley F, Damsky CH: Signal transduction through the fibronectin receptor induces collagenase and stromeysin gene expression. J Cell Biol 109: 877–889, 1989Google Scholar
  14. 14.
    Bates RC, Buret A, Van Holden DF, Horton M, Burns CF: Apoptosis induced by inhibition of intercellular contact. J Cell Biol 125: 403–415, 1994Google Scholar
  15. 15.
    Frisch SM, Francis H: Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 124: 619–626, 1994Google Scholar
  16. 16.
    Boudreau N, Sympson CJ, Werb Z, Bissell MJ: Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix. Science 267: 891–893, 1995Google Scholar
  17. 17.
    Meredith J, Bazeli B, Schwartz M: The extracellular matrix as a survival factor. Mol Biol Cell 4: 953–961, 1993Google Scholar
  18. 18.
    Guadagno TM, Ohtsubo M, Roberts JM, Assoian RK: A link between cyclin A expression and adhesion-dependent cell cycle progression. Science 262: 1572–1575, 1993Google Scholar
  19. 19.
    George EL, Georges-Labouerse EN, Patel-King RS, Rayburn H, Hynes RO: Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Devel 119: 1079–1091, 1993Google Scholar
  20. 20.
    Yang JT, Rayburn H, Hynes RO: Cell adhesion events mediated by α4 integrins are essential in placental and cardiac development. Devel 121: 549–560, 1995Google Scholar
  21. 21.
    Yang JT, Rayburn H, Hynes RO: Embryonic mesodermal defects in α5 integrin-deficient mice. Devel 119: 1093–1105, 1993Google Scholar
  22. 22.
    Shimizu Y, van Seventer G, Horgan K, Shaw S: Costimulation of proliferative responses of resting CD4 and T cells by interaction of VLA4 and VLA5 with fibronectin or VLA6 with laminin. J Immunol 145: 59–67, 1990Google Scholar
  23. 23.
    Nojima Y, Humphries M, Mould A, Komoriya A, Yamada K, Schlorsman S, Morimoto C: VLA-4 mediates CD3-dependent CD4+ T-cells activation via the CSI alternatively spliced domain of fibronectin. J Exp Med 172: 1185–1192, 1990Google Scholar
  24. 24.
    van Seventer GA, Newman W, Shimizu Y, Nutman TB, Tanaka Y, Horgan KJ, Gopal T, Ennis E, O'Sullivan D, Grey H, Shaw S: Analysis of T cell stimulation by superantigen plus major histocompatibility complex class II molecules or by CD3 monoclonal antibody: costimulation by purified adhesion ligands VCAM-1, but not ELAM-1. J Exp Med 174: 901–913, 1991Google Scholar
  25. 25.
    van Seventer G, Shimizu Y, Shaw S: Roles of multiple accessing molecules in T-cell activation. Curr Opin Immunol 3: 294–303, 1991Google Scholar
  26. 26.
    Yurochko A, Liu D, Eierman D, Haskill S: Integrins as a primary signal transduction molecule regulating monocyte immediate-early gene induction. Proc Natl Acad Sci USA 89: 9034–9038, 1992Google Scholar
  27. 27.
    Schwartz MA, Lechene C, Ingber DE: Insoluble fibronectin activates the Na+/H+ antiporter by clustering and immobilizing integrin α5β1, independent of cell shape. Proc Natl Acad Sci USA 88: 7849–7853, 1991Google Scholar
  28. 28.
    Juliano R, Haskill S: Signal transduction from the extracellular matrix. J Cell Biol 120: 577–585, 1993Google Scholar
  29. 29.
    Guan J, Trevethick J, Hynes R: Fibronectin/integrin interaction induces tyrosine phosphorylation of a 120 kDa protein. Cell Regul 2: 951–964, 1991Google Scholar
  30. 30.
    Kornberg L, Earp H, Turner C, Prockon C, Juliano R: Signal transduction by integrins: increased protein tyrosine phosphorylation caused by clustering of beta 1 integrins. Proc Natl Acad Sci USA 88: 8392–8396, 1991Google Scholar
  31. 31.
    Kapron-Bras C, Fitz-Gibbon L, Jeevaratnam P, Wilkins J, Dedhar S: Stimulation of tyrosine phosphorylation and accumulation of GTP-bound p21ras upon antibody-mediated α2β1 integrin activation in T-lymphoblastic cells. J Biol Chem 268: 20701–20704, 1993Google Scholar
  32. 32.
    Burridge K, Turner C, Romer L: Tyrosine phosphorylation of paxillin and pp125FAK accompanies cell adhesion to extracellular matrix: a role in cytoskeletal assembly. J Cell Biol 119: 893–904, 1992Google Scholar
  33. 33.
    Schaller MD, Borgman CA, Cobb BS, Vines RR, Reynolds AB, Parsons JT: pp125FAK, as structurally distinctive proteintyrosine kinase associated with focal adhesions. Proc Natl Acad Sci USA 89: 5192–5196, 1992Google Scholar
  34. 34.
    Kornberg L, Earp H, Parsons T, Schaller M, Juliano R: Cell adhesion or integrin clustering increases phosphorylation of a focal adhesion associated tyrosine kinase. J Biol Chem 267: 23439–23442, 1992Google Scholar
  35. 35.
    Guan JL, Shalloway D: Regulation of focal adhesion associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation. Nature 358: 390–392, 1992Google Scholar
  36. 36.
    Jewell K, Kapron-Bras C, Jeevaratnam P, Dedhar S: Stimulation of tyrosine phosphorylation of distinct proteins in response to antibody-mediated ligation and clustering of α3 and α6 integrins. J Cell Sci 108: 1165–1174, 1995Google Scholar
  37. 37.
    Chen Q, Kinch MS, Lin TH, Burridge K, Juliano R: Integrinmediated cell adhesion activates mitogen-activated protein kinases. J Biol Chem 269: 26602–26605, 1994Google Scholar
  38. 38.
    Schaepjer DD, Hanks SK, Hunter T, van der Geer P: Integrin-mediated signal transduction linked toras pathway by GRB-2 binding to focal adhesion kinase. Nature 372: 786–791, 1994Google Scholar
  39. 39.
    Rozakis-Adcock M, McGlade J, Mbanolu G, Pelicci G, Daly R, Li W, Batzen A, Thomas S, Brugge J, Pelicci PG, Schlesinger J, Pawson T: Association of the Shc and Grb2/sems SH2 containing proteins is implicated in activation of the Ras pathway by tyrosine kinases. Nature 360: 689–692, 1992Google Scholar
  40. 40.
    Calalb MB, Polte TR, Hanks SK: Tyrosine phosphorylation of FAK at sites within the catalytic domain regulates kinase activity: a role for Src-family kinases. Mol Cell Biol. In press: 1995Google Scholar
  41. 41.
    Lin TH, Ywochko A, Kornberg L, Morris J, Walker JJ, Haskill S, Juliano RL: The role of protein tyrosine phosphorylation in integrin-mediated gene induction in monocytes. J Cell Biol 126: 1585–1593, 1994Google Scholar
  42. 42.
    Ridley AJ, Hall A: The small GTP-binding protein rho regulates the asembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70: 389–399, 1992Google Scholar
  43. 43.
    McGlade J, Brunkhorst B, Anderson D, Mbamalu G, Settleman J, Dedhar S, Rozakis-Adcock M, Chen LB, Pawson T: The amino terminal region of GAP regulates cytoskeletal structure and cell adhesion. EMBO J 12: 3073–3081, 1993Google Scholar
  44. 44.
    Zachary I, Sinnet-Smith J, Rozengurt E: Bombesin, vasopresin, and endothelin stimulation of tyrosine phosphorylation in Swiss 3T3 cells. Identification of a novel tyrosine kinase as a major substrate. J Biol Chem 267: 19031–19034, 1992Google Scholar
  45. 45.
    Kumagai N, Morii N, Fugisawa K, Nemoto Y, Narunyia S: ADP-ribosylation of Rho p21 inhibits lysophosphatidic acid-induced protein tyrosine phosphorylation and phosphatidylinositol 3-kinase activation in Swiss 3T3 cells. J Biol Chem 268: 24545–24538, 1993Google Scholar
  46. 46.
    Vouri K, Ruoshalti E: Association of insulin receptor substrate-1 with integrins. Science, 266: 1576–1578, 1994Google Scholar
  47. 47.
    Rojiani M, Finlay BB, Gray V, Dedhar S:In vitro interaction of a polypeptide homologous to human Ro/SS-A antigen (Calreticulin) with a highly conserved amino acid sequence in the cytoplasmic domain of integrin α subunits. Biochemistry 30: 9859–9866, 1991Google Scholar
  48. 48.
    Dedhar S, Rennie PS, Shago M, Leung-Hagesteijn C, Yang H, Filmus J, Hawley RG, Bruchovsky N, Cheng H, Matusik RJ, Giguere V: Inhibition of nuclear hormone receptor activity by calreticulin. Nature 367: 480–483, 1994Google Scholar
  49. 49.
    Dedhar S: Integrins and tumor invasion. BioEssays 12: 583–590, 1990Google Scholar
  50. 50.
    Dedhar S, Saulnier R: Alterations in integrin receptor expression on chemically transformed human cells: specific enhancement of laminin and collagen receptor complexes. J Cell Biol 110: 481–489, 1990Google Scholar
  51. 51.
    Chan BM, Matsaura N, Takada Y, Zetter BR, Hemler ME:In vitro andin vivo consequences of VLA-2 expression on rhabdamyosarcoma cells. Science 251: 1600–1602, 1991Google Scholar
  52. 52.
    Albeida SM, Mette SA, Elder DE, Stewart R, Danjanovich K, Herlyn M, Buck CA: Integrin distribution in malignant melanomas: association of the β3 subunit with tumor progression. Cancer Res 50: 6757–6764, 1990Google Scholar
  53. 53.
    Felding-Habermann B, Mueller BM, Romerdahl CA, Cheresh D: Involvement of αv gene expression in human melanoma tumorigenesis. J Clin Invest 89: 2018, 1992Google Scholar
  54. 54.
    Montgomery AMP, Reisfeld RA, Cheresh DA: Integrin αvβ3 rescues melanoma cells from apoptosis in three-dimensional dermal collagen. Proc Natl Acad Sci USA 91: 8856–8860, 1994Google Scholar
  55. 55.
    Brooks PC, Montgomery AMP, Rosenfeld M, Reisfeld RA, Hu T, Klier G, Cheresh DA: Integrin αvβ3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79: 1157–1164, 1994Google Scholar
  56. 56.
    Weiner TM, Liu ET, Craven RJ, Cance WG: Expression of focal adhesion kinase gene and invasive cancer. Lancet 342: 1024–1025, 1993Google Scholar
  57. 57.
    Ridley AJ, Hall A: Signal transduction pathways regulating Rho-mediated stress fibre formation: requirement for a tyrosine kinase. EMBO J 13: 2600–2610, 1994Google Scholar
  58. 58.
    Jimenez B, Averds M, Esteve P, Pevona R, Sandez R, Cajal S, Wyllie A, Lacal JC: Induction of apoptosis in NIH3T3 cells after serum deprivation by overexpression of rho-p21, a GTPase protein of the ras family. Oncogene 10: 811–816, 1995Google Scholar
  59. 59.
    Habets GGM, Scholtes EHM, Zuydgeest D, van der Kannman RA, Stam JC, Berns A, Collard JG: Identification of an invasion-inducing gene Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins. Cell 77: 537–549, 1994Google Scholar

Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • Shoukat Dedhar
    • 1
  1. 1.Cancer Biology Program, Department of Medical BiophysicsUniversity of Toronto, Sunnybrook Health Science CentreToronto, OntarioCanada

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