Cancer and Metastasis Reviews

, Volume 24, Issue 3, pp 395–402 | Cite as

Integrin-mediated activation of latent transforming growth factor β

  • Dean Sheppard


Members of the integrin family recognize a variety of spatially-restricted extracellular ligands. Classically, ligation of integrins activates cytoplasmic signals in the integrin-expressing cell and contributes to cell adhesion, migration, proliferation and survival. At least two members of this family, αvβ6 and αvβ8 perform an additional function, activation of latent complexes of transforming growth factor β. In effect, this process allows integrins on one cell to activate signals on adjacent (in the case of αvβ6) or nearby cells (in the case of αvβ8). Integrin-mediated TGFβ activation has been shown to play important roles in modulating tissue fibrosis, acute lung injury and pulmonary emphysema. Given the important roles that TGFβ plays in modulating epithelial cell growth, epithelial-to-mesenchymal transformation and tumor invasion and metastasis, integrin-mediated TGFβ activation is likely to play important roles in tumor growth ad metastasis.


transforming growth factor β activation αv integrins pulmonary fibrosis 


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  1. 1.
    Hynes RO: Integrins: A family of cell surface receptors. Cell 48: 549–554, 1987CrossRefPubMedGoogle Scholar
  2. 2.
    Ruoslahti E, MD Pierschbacher: New perspectives in cell adhesion: RGD and integrins. Science 238: 491–497, 1987PubMedGoogle Scholar
  3. 3.
    Clark EA, Brugge JS: Integrins and signal transduction pathways: The road taken. Science 268: 233–239, 1995PubMedGoogle Scholar
  4. 4.
    Constantin G, Majeed M, Giagulli C, Piccio L, Kim JY, Butcher EC, Laudanna C: Chemokines trigger immediate beta2 integrin affinity and mobility changes: Differential regulation and roles in lymphocyte arrest under flow. Immunity 13: 759–769, 2000PubMedGoogle Scholar
  5. 5.
    Barnard, JA, RM Lyons, and HL Moses: The cell biology of transforming growth factor beta. Biochim Biophys Acta 1032: 79–87, 1990PubMedGoogle Scholar
  6. 6.
    Munger JS, Harpel JG, Gleizes P, Mazzieri R, Nunes I, Rifkin DB: Latent transforming growth factor-beta: Structural features and mechanisms of activation. Kidney International 51: 1376–1382, 1997PubMedGoogle Scholar
  7. 7.
    Taipale J, Miyazono K, Heldin CH, Keski-Oja J: Latent transforming growth factor-beta 1 associates to fibroblast extracellular matrix via latent TGF-beta binding protein. J Cell Biol 124: 171–181, 1994CrossRefPubMedGoogle Scholar
  8. 8.
    Nunes I, Gleizes PE, Metz CN, Rifkin DB: Latent transforming growth factor-beta binding protein domains involved in activation and transglutaminase-dependent cross-linking of latent transforming growth factor-beta. J Cell Biol 136: 1151–1163, 1997CrossRefPubMedGoogle Scholar
  9. 9.
    Schultz-Cherry S, Murphy-Ullrich JE: Thrombospondin causes activation of latent transforming growth factor-beta secreted by endothelial cells by a novel mechanism. J Cell Biol 122: 923–932, 1993CrossRefPubMedGoogle Scholar
  10. 10.
    Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes RO, Boivin GP, Bouck N: Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell 93: 1159–1170, 1998CrossRefPubMedGoogle Scholar
  11. 11.
    Munger JS, Huang XZ, Kawakatsu H, Griffiths MJD, Dalton SL, Wu JF, Pittet JF, Kaminisk N, Garat C, Matthay MA, Rifkin DB, Sheppard D: The integrin α vβ 6 binds and activates latent TGFβ 1: A mechanism for regulating pulmonary inflammation and fibrosis. Cell 96: 319–328, 1999CrossRefPubMedGoogle Scholar
  12. 12.
    Busk M, Pytela R, Sheppard D: Characterization of the integrin α vβ 6 as a fibronectin-binding protein. J Biol Chem 267: 5790–5796, 1992PubMedGoogle Scholar
  13. 13.
    Breuss JM, Gillett N, Lu L, Sheppard D, Pytela R: Restricted distribution of integrin beta 6 mRNA in primate epithelial tissues. J Histochem Cytochem 41: 1521–1527, 1993PubMedGoogle Scholar
  14. 14.
    Breuss JM, Gallo J, DeLisser HM, Klimanskaya IV, Folkesson HG, Pittet JF, Nishimura SL, Aldape K, Landers DV, Carpenter W, Gillett N, Sheppard D, Matthay M, Albelda SM, Kramer RH, Pytela R: Expression of the β 6 integrin in development, neoplasia, and tissue repair suggests a role in epithelial remodeling. J. Cell Sci. 108: 2241–2251, 1995PubMedGoogle Scholar
  15. 15.
    Huang XZ, Wu JF, Cass D, Erle DJ, Corry D, Young SG, Farese RVJ, Sheppard D: Inactivation of the integrin beta 6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin. J Cell Biol 133: 921–928, 1996CrossRefPubMedGoogle Scholar
  16. 16.
    Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359: 693–699, 1992CrossRefPubMedGoogle Scholar
  17. 17.
    Border WA, Noble NA, Yamamoto T, Harper JR, Yamaguchi Y, Pierschbacher MD, Ruoslahti E: Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease. Nature 360: 361–364, 1992CrossRefPubMedGoogle Scholar
  18. 18.
    Giri S, Hyde DM, Hollinger MA: Effect of antibody to transforming growth factor-beta on bleomycin induced accumulation of lung collagen in mice. Thorax 48: 959–966, 1993PubMedGoogle Scholar
  19. 19.
    Abe M, Harpel JG, Metz CN, Nunes I, Loskutoff DJ, Rifkin DB: An assay for transforming growth factor-beta using cells transfected with a plasminogen activator inhibitor-1 promoter-luciferase construct. Anal Biochem 216: 276–284, 1994CrossRefPubMedGoogle Scholar
  20. 20.
    Annes JP, Rifkin DB, Munger JS: The integrin alphaVbeta6 binds and activates latent TGFbeta3. FEBS Lett 511: 65–68, 2002CrossRefPubMedGoogle Scholar
  21. 21.
    Annes JP, Chen JS, Munger JS, Rifkin DB: Integrin α vβ 6-mediated activation of latent TGF-β requires the latent TGF-β binding protein-1. J Cell Biol 165: 723–731, 2004CrossRefPubMedGoogle Scholar
  22. 22.
    Ludbrook SB, Barry ST, Delves CJ, Horgan CM: The integrin alphavbeta3 is a receptor for the latency-associated peptides of transforming growth factors beta1 and beta3. Biochem J 369: 311–318, 2003CrossRefPubMedGoogle Scholar
  23. 23.
    Lu M, Munger JS, Steadele M, Busald C, Tellier M, Schnapp LM: Integrin alpha8beta1 mediates adhesion to LAP-TGFbeta1. J Cell Sci 115: 4641–4648, 2002CrossRefPubMedGoogle Scholar
  24. 24.
    Mu D, Cambier S, Fjellbirkeland L, Baron JL, Munger JS, Kawakatsu H, Sheppard D, Broaddus VC, Nishimura SL: The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1. J Cell Biol 157: 493–507, 2002CrossRefPubMedGoogle Scholar
  25. 25.
    Munger JS, Harpel JG, Giancotti FG, Rifkin DB: Interac- tions between growth factors and integrins: Latent forms of transforming growth factor-beta are ligands for the integrin alphavbeta1. Mol Biol Cell 9: 2627–2638, 1998PubMedGoogle Scholar
  26. 26.
    Zhu J, Motejlek K, Wang D, Zang K, Schmidt A, Reichardt LF: beta8 integrins are required for vascular morphogenesis in mouse embryos. Development 129: 2891–2903, 2002PubMedGoogle Scholar
  27. 27.
    Proetzel G, Pawlowski SA, Wiles MV, Yin M, Boivin GP, Howles PN, Ding J, Ferguson MW, Doetschman T: Transforming growth factor-beta 3 is required for secondary palate fusion. Nat Genet 11: 409–414, 1995CrossRefGoogle Scholar
  28. 28.
    Bader BL, Rayburn H, Crowley D, Hynes RO: Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins. Cell 95: 507–519, 1998CrossRefPubMedGoogle Scholar
  29. 29.
    Ma LJ, Yang H, Gaspert A, Carlesso G, Barty MM, Davidson JM, Sheppard D, Fogo AB: Transforming growth factor-beta-dependent and -independent pathways of induction of tubulointerstitial fibrosis in beta6(-/-) mice. Am J Pathol 163: 1261–1273, 2003PubMedGoogle Scholar
  30. 30.
    Kaminski N, Allard JD, Pittet JF, Zuo F, Griffiths MJ, Morris D, Huang X, Sheppard D, Heller RA: Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis. Proc Natl Acad Sci USA 97: 1778–1783, 2000CrossRefPubMedGoogle Scholar
  31. 31.
    Morris DG, Huang X, Kaminski N, Wang Y, Shapiro SD, Dolganov G, Glick A, Sheppard D: Loss of integrin alphavbeta6-mediated TGF-beta activation causes Mmp12-dependent emphysema. Nature 422: 169–173, 2003CrossRefPubMedGoogle Scholar
  32. 32.
    Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD: Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 277: 2002–2004, 1997CrossRefPubMedGoogle Scholar
  33. 33.
    Huang XZ, Wu JF, Zhu W, Pytela R, Sheppard D: Expression of the Human Integrin beta6 Subunit in Alveolar Type II Cells and Bronchiolar Epithelial Cells Reverses Lung Inflammation in beta6 Knockout Mice. Am J Respir Cell Mol Biol 19: 636–642, 1998PubMedGoogle Scholar
  34. 34.
    Pittet JF, Griffiths MJ, Geiser T, Kaminski N, Dalton SL, Huang X, Brown LA, Gotwals PJ, Koteliansky VE, Matthay MA, Sheppard D: TGF-beta is a critical mediator of acute lung injury. J Clin Invest 107: 1537–1544, 2001PubMedGoogle Scholar
  35. 35.
    Derynck R, Akhurst RJ, Balmain A: TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 29: 117–129, 2001CrossRefPubMedGoogle Scholar
  36. 36.
    Akhurst RJ, R Derynck: TGF-beta signaling in cancer–a double-edged sword. Trends Cell Biol 11: S44–S51, 2001PubMedGoogle Scholar
  37. 37.
    Cui W, Fowlis DJ, Bryson S, Duffie E, Ireland H, Balmain A, Akhurst RJ: TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 86: 531–542, 1996CrossRefPubMedGoogle Scholar
  38. 38.
    Oft M, Heider KH, Beug H: TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 8: 1243–1252, 1998CrossRefPubMedGoogle Scholar
  39. 39.
    Portella G, Cumming SA, Liddell J, Cui W, Ireland H, Akhurst RJ, Balmain A: Transforming growth factor beta is essential for spindle cell conversion of mouse skin carcinoma in vivo: Implications for tumor invasion. Cell Growth Differ 9: 393–404, 1998PubMedGoogle Scholar
  40. 40.
    Agrez M, Chen A, Cone R, Pytela R, Sheppard D: The alpha v beta 6 integrin promotes proliferation of colon carcinoma cells through a unique region of the beta 6 cytoplasmic domain. J Cell Biol 127: 547–56, 1994CrossRefPubMedGoogle Scholar
  41. 41.
    Xue H, Atakilit A, Zhu W, Li X, Ramos DM, Pytela R: Role of the alpha(v)beta6 integrin in human oral squamous cell carcinoma growth in vivo and in vitro. Biochem Biophys Res Commun 288: 610–618, 2001CrossRefPubMedGoogle Scholar
  42. 42.
    Dixit RB, Chen A, Chen J, Sheppard D: Identification of a sequence within the integrin beta6 subunit cytoplasmic domain that is required to support the specific effect of alphavbeta6 on proliferation in three-dimensional culture. J. Biol. Chem. 271: 25976–25980, 1996CrossRefPubMedGoogle Scholar
  43. 43.
    Morgan MR, Thomas GJ, Russell A, Hart IR, Marshall JF: The integrin cytoplasmic-tail motif EKQKVDLSTDC is sufficient to promote MMP-2 or MMP-9-mediated tumour cell invasion. J Biol Chem 2004Google Scholar
  44. 44.
    Thomas GJ, Lewis MP, Whawell SA, Russell A, Sheppard D, Hart IR, Speight PM, Marshall JF: Expression of the alphavbeta6 integrin promotes migration and invasion in squamous carcinoma cells. J Invest Dermatol 117: 67–73, 2001CrossRefPubMedGoogle Scholar
  45. 45.
    Niu J, Gu X, Turton J, Meldrum C, Howard EW, Agrez M: Integrin-mediated signalling of gelatinase B secretion in colon cancer cells. Biochem Biophys Res Commun 249: 287–291, 1998.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  1. 1.Lung Biology CenterUniversity of California San FranciscoSan Francisco

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