αvβ3 integrin associates with activated insulin and PDGFβ receptors and potentiates the biological activity of PDGF

factor responses may be either pathways shared by many Maximilian Schneller, Kristiina Vuori and integrins, or they may be specific for a few integrins. In Erkki Ruoslahti1 some cases, a signal appears to be specific for one La Jolla Cancer Research Center, The Burnham Institute, particular integrin. Activation of the focal adhesion kinase 10901 North Torrey Pines Road, La Jolla, CA 92037, (FAK) is a pathway shared by several integrins. It seems USA to be particularly important in anchorage dependence 1Corresponding author (Frisch et al., 1996; Xu et al., 1996). Moreover, several growth factor receptors have been shown to be present in Integrin-mediated cell attachment modulates growth isolated focal adhesion complexes and in other membrane responses and growth factors regulate cell attachment. structures containing aggregated integrins (Plopper et al., Moreover, both cell attachment to extracellular matrix 1995; Miyamoto et al., 1996). and mitogenic signaling by growth factors are necessary The pathways that are known to be restricted to indifor the proliferation of most types of normal cells, vidual integrins include up-regulation of the anti-apoptosis suggesting that integrin and growth factor receptor protein Bcl-2 by the α5β1 integrin (Zhang et al., 1995), signaling pathways meet at some downstream point. activation of the adaptor protein Shc by α6β4 (Mainiero We report here that a small, highly tyrosine-phoset al., 1995) and, presumably by an unrelated process, by phorylated fraction of PDGFβ and insulin receptors certain other integrins (Wary et al., 1996). Moreover, the co-immunoprecipitates with the αvβ3 integrin from αvβ3 integrin interacts with the PDGF and insulin receptor cells. The integrin association requires growth factor signaling pathways (Bartfeld et al., 1993; Vuori and stimulation of the receptors. Several signaling moleRuoslahti, 1994). cules that are known to be associated with activated That the αvβ3 integrin is somehow linked to PDGF growth factor receptors were present in the αvβ3 signaling was first suggested by the finding of Bartfeld integrin complexes. Mitogenicity and chemotaxis et al. (1993) that a 190 kDa tyrosine-phosphorylated induced by PDGF-BB were enhanced in cells plated protein could be immunoprecipitated together with αvβ3 on the αvβ3 ligand vitronectin compared with cells from PDGF-BB-stimulated cells. The identity of the 190 plated on the β1 integrin ligand collagen. Thus, the kDa protein is not known. An involvement of αvβ3 in engagement of the αvβ3 integrin in cell–matrix interinsulin signaling was discovered when IRS-1, a cytoactions appears to coordinate an intense response to growth factors, helping to explain the importance of plasmic signal transduction mediator of the insulin (and this integrin for tissue regeneration, angiogenesis and insulin-like growth factor, IGF) receptors, was found to tumor metastasis. co-immunoprecipitate with αvβ3 (Vuori and Ruoslahti,