INSULIN-INDUCED ACTIVATION OF PHOSPHATIDYLINOSITOL (PI)3-KINASE - INSULIN-INDUCED PHOSPHORYLATION OF INSULIN-RECEPTORS AND INSULIN-RECEPTORSUBSTRATE-1 DISPLACES PHOSPHORYLATED PLATELET-DERIVED GROWTH-FACTOR RECEPTORS FROM BINDING-SITES ON PI-3-KINASE

Phosphatidylinositol (PI) 3-kinase is an enzyme that functions in the signaling pathways downstream from multiple cell surface receptors, Th e p85 regulatory subunit of PI 3-kinase binds to phosphotyrosine resid ues of various phosphoproteins including the platelet-derived growth f actor (PDGF) receptor, the insulin receptor, and insulin receptor subs trate-1 (IRS-1). Using NIH-3T3 cells overexpressing the human insulin receptor, we demonstrate that the p85 regulatory subunit of PI 3-kinas e binds to phosphorylated PDGF receptor in cells incubated in the abse nce of insulin. When insulin is added, p85 is released from phosphoryl ated PDGF receptors and binds to phosphorylated insulin receptors and insulin receptor substrate-1. Moreover, insulin-induced dissociation o f PDGF receptors from binding sites on PI 3-kinase requires a function al insulin receptor and is not prevented by vanadate treatment. In con trast, insulin activation does not displace PDGF receptors from bindin g sites on Ras GTPase-activating protein. This competition for binding to PI 3-kinase provides a mechanism for cross-talk among signaling pa thways initiated by distinct peptide hormones and growth factors such as insulin and PDGF.