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. 1997 Sep 15;16(18):5600–5607. doi: 10.1093/emboj/16.18.5600

Alphavbeta3 integrin associates with activated insulin and PDGFbeta receptors and potentiates the biological activity of PDGF.

M Schneller 1, K Vuori 1, E Ruoslahti 1
PMCID: PMC1170192  PMID: 9312019

Abstract

Integrin-mediated cell attachment modulates growth responses and growth factors regulate cell attachment. Moreover, both cell attachment to extracellular matrix and mitogenic signaling by growth factors are necessary for the proliferation of most types of normal cells, suggesting that integrin and growth factor receptor signaling pathways meet at some downstream point. We report here that a small, highly tyrosine-phosphorylated fraction of PDGFbeta and insulin receptors co-immunoprecipitates with the alphavbeta3 integrin from cells. The integrin association requires growth factor stimulation of the receptors. Several signaling molecules that are known to be associated with activated growth factor receptors were present in the alphavbeta3 integrin complexes. Mitogenicity and chemotaxis induced by PDGF-BB were enhanced in cells plated on the alphavbeta3 ligand vitronectin compared with cells plated on the beta1 integrin ligand collagen. Thus, the engagement of the alphavbeta3 integrin in cell-matrix interactions appears to coordinate an intense response to growth factors, helping to explain the importance of this integrin for tissue regeneration, angiogenesis and tumor metastasis.

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Selected References

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  1. Bartfeld N. S., Pasquale E. B., Geltosky J. E., Languino L. R. The alpha v beta 3 integrin associates with a 190-kDa protein that is phosphorylated on tyrosine in response to platelet-derived growth factor. J Biol Chem. 1993 Aug 15;268(23):17270–17276. [PubMed] [Google Scholar]
  2. Bhattacharya S., Fu C., Bhattacharya J., Greenberg S. Soluble ligands of the alpha v beta 3 integrin mediate enhanced tyrosine phosphorylation of multiple proteins in adherent bovine pulmonary artery endothelial cells. J Biol Chem. 1995 Jul 14;270(28):16781–16787. doi: 10.1074/jbc.270.28.16781. [DOI] [PubMed] [Google Scholar]
  3. Chen H. C., Guan J. L. The association of focal adhesion kinase with a 200-kDa protein that is tyrosine phosphorylated in response to platelet-derived growth factor. Eur J Biochem. 1996 Feb 1;235(3):495–500. doi: 10.1111/j.1432-1033.1996.00495.x. [DOI] [PubMed] [Google Scholar]
  4. Claesson-Welsh L., Eriksson A., Morén A., Severinsson L., Ek B., Ostman A., Betsholtz C., Heldin C. H. cDNA cloning and expression of a human platelet-derived growth factor (PDGF) receptor specific for B-chain-containing PDGF molecules. Mol Cell Biol. 1988 Aug;8(8):3476–3486. doi: 10.1128/mcb.8.8.3476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Clark E. A., Brugge J. S. Integrins and signal transduction pathways: the road taken. Science. 1995 Apr 14;268(5208):233–239. doi: 10.1126/science.7716514. [DOI] [PubMed] [Google Scholar]
  6. Filardo E. J., Brooks P. C., Deming S. L., Damsky C., Cheresh D. A. 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. 1995 Jul;130(2):441–450. doi: 10.1083/jcb.130.2.441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Friedlander M., Brooks P. C., Shaffer R. W., Kincaid C. M., Varner J. A., Cheresh D. A. Definition of two angiogenic pathways by distinct alpha v integrins. Science. 1995 Dec 1;270(5241):1500–1502. doi: 10.1126/science.270.5241.1500. [DOI] [PubMed] [Google Scholar]
  8. Frisch S. M., Vuori K., Ruoslahti E., Chan-Hui P. Y. Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol. 1996 Aug;134(3):793–799. doi: 10.1083/jcb.134.3.793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gehlsen K. R., Davis G. E., Sriramarao P. Integrin expression in human melanoma cells with differing invasive and metastatic properties. Clin Exp Metastasis. 1992 Mar;10(2):111–120. doi: 10.1007/BF00114587. [DOI] [PubMed] [Google Scholar]
  10. Hayman E. G., Pierschbacher M. D., Suzuki S., Ruoslahti E. Vitronectin--a major cell attachment-promoting protein in fetal bovine serum. Exp Cell Res. 1985 Oct;160(2):245–258. doi: 10.1016/0014-4827(85)90173-9. [DOI] [PubMed] [Google Scholar]
  11. Heldin C. H. Structural and functional studies on platelet-derived growth factor. EMBO J. 1992 Dec;11(12):4251–4259. doi: 10.1002/j.1460-2075.1992.tb05523.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jones J. I., Prevette T., Gockerman A., Clemmons D. R. Ligand occupancy of the alpha-V-beta3 integrin is necessary for smooth muscle cells to migrate in response to insulin-like growth factor. Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2482–2487. doi: 10.1073/pnas.93.6.2482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Klemke R. L., Yebra M., Bayna E. M., Cheresh D. A. Receptor tyrosine kinase signaling required for integrin alpha v beta 5-directed cell motility but not adhesion on vitronectin. J Cell Biol. 1994 Nov;127(3):859–866. doi: 10.1083/jcb.127.3.859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Law D. A., Nannizzi-Alaimo L., Phillips D. R. Outside-in integrin signal transduction. Alpha IIb beta 3-(GP IIb IIIa) tyrosine phosphorylation induced by platelet aggregation. J Biol Chem. 1996 May 3;271(18):10811–10815. doi: 10.1074/jbc.271.18.10811. [DOI] [PubMed] [Google Scholar]
  15. Leavesley D. I., Ferguson G. D., Wayner E. A., Cheresh D. A. Requirement of the integrin beta 3 subunit for carcinoma cell spreading or migration on vitronectin and fibrinogen. J Cell Biol. 1992 Jun;117(5):1101–1107. doi: 10.1083/jcb.117.5.1101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Liaw L., Skinner M. P., Raines E. W., Ross R., Cheresh D. A., Schwartz S. M., Giachelli C. M. The adhesive and migratory effects of osteopontin are mediated via distinct cell surface integrins. Role of alpha v beta 3 in smooth muscle cell migration to osteopontin in vitro. J Clin Invest. 1995 Feb;95(2):713–724. doi: 10.1172/JCI117718. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Liu P., Ying Y., Ko Y. G., Anderson R. G. Localization of platelet-derived growth factor-stimulated phosphorylation cascade to caveolae. J Biol Chem. 1996 Apr 26;271(17):10299–10303. doi: 10.1074/jbc.271.17.10299. [DOI] [PubMed] [Google Scholar]
  18. Mainiero F., Pepe A., Wary K. K., Spinardi L., Mohammadi M., Schlessinger J., Giancotti F. G. 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. 1995 Sep 15;14(18):4470–4481. doi: 10.1002/j.1460-2075.1995.tb00126.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Miyamoto S., Teramoto H., Gutkind J. S., Yamada K. M. Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors. J Cell Biol. 1996 Dec;135(6 Pt 1):1633–1642. doi: 10.1083/jcb.135.6.1633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Montgomery A. M., Reisfeld R. A., Cheresh D. A. Integrin alpha v beta 3 rescues melanoma cells from apoptosis in three-dimensional dermal collagen. Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8856–8860. doi: 10.1073/pnas.91.19.8856. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pierce G. F., Mustoe T. A., Lingelbach J., Masakowski V. R., Griffin G. L., Senior R. M., Deuel T. F. Platelet-derived growth factor and transforming growth factor-beta enhance tissue repair activities by unique mechanisms. J Cell Biol. 1989 Jul;109(1):429–440. doi: 10.1083/jcb.109.1.429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Plopper G. E., McNamee H. P., Dike L. E., Bojanowski K., Ingber D. E. Convergence of integrin and growth factor receptor signaling pathways within the focal adhesion complex. Mol Biol Cell. 1995 Oct;6(10):1349–1365. doi: 10.1091/mbc.6.10.1349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ruoslahti E. RGD and other recognition sequences for integrins. Annu Rev Cell Dev Biol. 1996;12:697–715. doi: 10.1146/annurev.cellbio.12.1.697. [DOI] [PubMed] [Google Scholar]
  24. Schlaepfer D. D., Hanks S. K., Hunter T., van der Geer P. Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature. 1994 Dec 22;372(6508):786–791. doi: 10.1038/372786a0. [DOI] [PubMed] [Google Scholar]
  25. Seiffert D., Schleef R. R. Two functionally distinct pools of vitronectin (Vn) in the blood circulation: identification of a heparin-binding competent population of Vn within platelet alpha-granules. Blood. 1996 Jul 15;88(2):552–560. [PubMed] [Google Scholar]
  26. Settleman J., Narasimhan V., Foster L. C., Weinberg R. A. Molecular cloning of cDNAs encoding the GAP-associated protein p190: implications for a signaling pathway from ras to the nucleus. Cell. 1992 May 1;69(3):539–549. doi: 10.1016/0092-8674(92)90454-k. [DOI] [PubMed] [Google Scholar]
  27. Sonnenberg A., Linders C. J., Modderman P. W., Damsky C. H., Aumailley M., Timpl R. Integrin recognition of different cell-binding fragments of laminin (P1, E3, E8) and evidence that alpha 6 beta 1 but not alpha 6 beta 4 functions as a major receptor for fragment E8. J Cell Biol. 1990 Jun;110(6):2145–2155. doi: 10.1083/jcb.110.6.2145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Suzuki S., Argraves W. S., Pytela R., Arai H., Krusius T., Pierschbacher M. D., Ruoslahti E. cDNA and amino acid sequences of the cell adhesion protein receptor recognizing vitronectin reveal a transmembrane domain and homologies with other adhesion protein receptors. Proc Natl Acad Sci U S A. 1986 Nov;83(22):8614–8618. doi: 10.1073/pnas.83.22.8614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Valius M., Secrist J. P., Kazlauskas A. The GTPase-activating protein of Ras suppresses platelet-derived growth factor beta receptor signaling by silencing phospholipase C-gamma 1. Mol Cell Biol. 1995 Jun;15(6):3058–3071. doi: 10.1128/mcb.15.6.3058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Vuori K., Ruoslahti E. Association of insulin receptor substrate-1 with integrins. Science. 1994 Dec 2;266(5190):1576–1578. doi: 10.1126/science.7527156. [DOI] [PubMed] [Google Scholar]
  31. Wary K. K., Mainiero F., Isakoff S. J., Marcantonio E. E., Giancotti F. G. The adaptor protein Shc couples a class of integrins to the control of cell cycle progression. Cell. 1996 Nov 15;87(4):733–743. doi: 10.1016/s0092-8674(00)81392-6. [DOI] [PubMed] [Google Scholar]
  32. White M. F., Kahn C. R. The insulin signaling system. J Biol Chem. 1994 Jan 7;269(1):1–4. [PubMed] [Google Scholar]
  33. Xu L. H., Owens L. V., Sturge G. C., Yang X., Liu E. T., Craven R. J., Cance W. G. Attenuation of the expression of the focal adhesion kinase induces apoptosis in tumor cells. Cell Growth Differ. 1996 Apr;7(4):413–418. [PubMed] [Google Scholar]
  34. Yatohgo T., Izumi M., Kashiwagi H., Hayashi M. Novel purification of vitronectin from human plasma by heparin affinity chromatography. Cell Struct Funct. 1988 Aug;13(4):281–292. doi: 10.1247/csf.13.281. [DOI] [PubMed] [Google Scholar]
  35. Zhang Z., Vuori K., Reed J. C., Ruoslahti E. The alpha 5 beta 1 integrin supports survival of cells on fibronectin and up-regulates Bcl-2 expression. Proc Natl Acad Sci U S A. 1995 Jun 20;92(13):6161–6165. doi: 10.1073/pnas.92.13.6161. [DOI] [PMC free article] [PubMed] [Google Scholar]

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