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The serpin PAI-1 inhibits cell migration by blocking integrin αvβ3 binding to vitronectin

Abstract

DURING wound healing, migrating cells increase expression of both the vitronectin receptor (VNR) integrins1 and plasminogen activators2,3. Here we report that vitronectin significantly enhances the migration of smooth muscle cells (SMCs), and that the specific VNR αvβ3 is required for cell motility. We also show that the αvβ3 attachment site on vitronectin overlaps with the binding site for plasminogen activator inhibitor (PAI)-l, and that the active conformation of PAI-1 blocks SMC migration. This effect requires high-affinity binding to vitronectin, and is not dependent on the ability of PAI-1 to inhibit plasminogen activators. Formation of a complex between PAI-1 and plasminogen activators results in loss of PAI-1 affinity for vitronectin and restores cell migration. These data demonstrate a direct link between plasminogen activators and integrin-mediated cell migration, and show that PAI-1 can control cell–matrix interactions by regulating the accessibility of specific cell-attachment sites. This indicates that the localization of plasminogen activators at sites of focal contact does not initiate a proteolytic cascade leading to generalized matrix destruction, but instead is required to expose cryptic cell-attachment sites necessary for SMC migration.

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References

  1. Clark, R. A. F. Tonnesen, M. G., Gailit, J. & Cheresh, D. A. Am. J. Pathol. 148, 1407–1421 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Pepper, M. S. et al. J. Cell Biol. 122, 673–684 (1993).

    Article  CAS  Google Scholar 

  3. Grodahl-Hansen, J., Lund, L. R., Ralfkiaer, E., Ottevanger, V. & Dano, K. J. Invest. Dermatol. 90, 790–795 (1988).

    Article  Google Scholar 

  4. Lauffenburger, D. A. & Horwitz, A. F. Cell 84, 359–369 (1996).

    Article  CAS  Google Scholar 

  5. Clark, E. A. & Brugge, J. S. Science 268, 233–239 (1995).

    Article  ADS  CAS  Google Scholar 

  6. Hannigan, G. E. et al. Nature 379, 91–96 (1996).

    Article  ADS  CAS  Google Scholar 

  7. Brooks, P. C., Clarck, R. A. F. & Cheresh, D. A. Science 264, 569–571 (1994).

    Article  ADS  CAS  Google Scholar 

  8. Brooks, P. C. et al. Cell 79, 1157–1164 (1994).

    Article  CAS  Google Scholar 

  9. More, R. S., Underwood, M. J., Brack, M. J., de Bono, D. P. & Gershlick, A. H. Cardiovasc. Res. 29, 22–26 (1995).

    Article  CAS  Google Scholar 

  10. Ciambrone, G. J. & McKeown-Longo, P. J. J. Biol. Chem. 267, 13617–13622 (1992).

    CAS  PubMed  Google Scholar 

  11. Clyman, R. I., Mauray, F. & Kramer, R. H. Exp. Cell Res. 200, 272–284 (1992).

    Article  CAS  Google Scholar 

  12. Carmeliet, P. et al. Fibrinolysis 10, 194 (1996).

    Article  Google Scholar 

  13. Vassalli, J.-D. & Pepper, M. S. Nature 370, 14–15 (1994).

    Article  ADS  CAS  Google Scholar 

  14. Seiffert, D., Ciambrone, G., Wagner, N. V., Binder, B. R. & Loskutoff, D. J. J. Biol. Chem. 269, 2659–2666 (1994).

    CAS  PubMed  Google Scholar 

  15. Lawrence, D. A., Berkenpas, M. B., Palaniappan, S. & Ginsburg, D. J. Biol. Chem. 269, 15223–15228 (1994).

    CAS  PubMed  Google Scholar 

  16. Shore, J. D. et al. J. Biol. Chem. 270, 5395–5398 (1994).

    Article  Google Scholar 

  17. Lawrence, D. A. et al. J. Biol. Chem. 270, 25309–25312 (1995).

    Article  CAS  Google Scholar 

  18. Declerck, P. J. et al. J. Biol. Chem. 263, 15454–15461 (1988).

    CAS  PubMed  Google Scholar 

  19. Stefansson, S., Lawrence, D. A. & Argraves, W. S. J. Biol. Chem. 271, 8215–8220 (1996).

    Article  CAS  Google Scholar 

  20. Haas, T. A. & Plow, E. F. Curr. Opin. Cell Biol. 6, 656–662 (1994).

    Article  CAS  Google Scholar 

  21. Brown, S. L., Lundgren, C. H., Nordt, T. & Fujii, S. Cardiovasc. Res. 28, 1815–1820 (1994).

    Article  CAS  Google Scholar 

  22. Jones, J. I., Prevette, T., Gockerman, A. & Clemmons, D. R. Proc. Natl Acad. Sci. USA 93, 2482–2487 (1996).

    Article  ADS  CAS  Google Scholar 

  23. Kim, J. P., Zhang, K., Chen, J. D., Kramer, R. H. & Woodley, D. T. J. Biol. Chem. 269, 26926–26932 (1994).

    CAS  PubMed  Google Scholar 

  24. Mimuro, J., Schleef, R. R. & Loskutoff, D. J. Blood 70, 721–728 (1987).

    CAS  PubMed  Google Scholar 

  25. Ehrlich, H. J. et al. J. Biol. Chem. 265, 13029–13035 (1990).

    CAS  PubMed  Google Scholar 

  26. Naski, M. C., Lawrence, D. A., Mosher, D. F., Podor, T. J. & Ginsburg, D. J. Biol. Chem. 268, 12367–12372 (1993).

    CAS  PubMed  Google Scholar 

  27. Pintucci, G. et al. J. Lab. Clin. Med. 122, 69–79 (1993).

    CAS  PubMed  Google Scholar 

  28. Levin, E. G. & Santell, L. J. Cell Biol. 105, 2543–2549 (1987).

    Article  CAS  Google Scholar 

  29. Kvassman, J.-O. & Shore, J. D. Fibrinolysis 9, 215–221 (1995).

    Article  CAS  Google Scholar 

  30. Smith, J. W. & Cheresh, D. A. J. Biol. Chem. 263, 18726–18731 (1988).

    CAS  PubMed  Google Scholar 

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Stefansson, S., Lawrence, D. The serpin PAI-1 inhibits cell migration by blocking integrin αvβ3 binding to vitronectin. Nature 383, 441–443 (1996). https://doi.org/10.1038/383441a0

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