Angiotensin II induces transactivation of two different populations of the platelet-derived growth factor β receptor -: Key role for the p66 adaptor protein Shc

Several signal transduction events induced by angiotensin II (AngII) binding to the angiotensin II type 1 receptor resemble those evoked by platelet-derived growth factor (PDGF) binding to the PDGF-beta receptor (PDGF beta-R), We report here, in agreement with previous data, that AngII and PDGF-B-chain homodimer (PDGF-BB) stimulate tyrosine phosphorylation of the PDGF beta-R. Both AngII and PDGF-BB stimulated the phosphorylation of PDGF beta-R via the binding of tyrosine-phosphorylated Shc to PDGF beta-R, Both PDGF-BB and AngII-induced phosphorylation of the Shc PDGF beta-R complex was inhibited by antioxidants such as N-acetylcysteine and Tiron, but not by calcium chelation, However, transactivation of PDGF beta-R by AngII (measured by PDGF beta-R tyrosine phosphorylation) differed significantly from PDGF-BB. Evidence to support different mechanisms of PDGF beta-R phosphorylation includes differences in the time course of PDGFP-R phosphorylation, differing effects of inhibitors of the endogenous PDGF beta-R tyrosine kinase and Src family tyrosine kinases, differing results when the PDGFP-R was directly immunoprecipitated (PDGF beta-R-antibody) versus coimmunoprecipitated (Shc-antibody), and cell fractionation studies that suggested that the Shc PDGF beta-R complexes phosphorylated by AngII and PDGF-BB were located in separate subcellular compartments. These studies are the first to suggest that transactivation of tyrosine kinase receptors by G protein-coupled receptors involves a unique pathway that regulates a population of tyrosine kinase receptors different from the endogenous tyrosine kinase ligand.