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

Abstract

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-β receptor (PDGFβ-R). We report here, in agreement with previous data, that AngII and PDGF-B-chain homodimer (PDGF-BB) stimulate tyrosine phosphorylation of the PDGFβ-R. Both AngII and PDGF-BB stimulated the phosphorylation of PDGFβ-R via the binding of tyrosine-phosphorylated Shc to PDGFβ-R. Both PDGF-BB-and AngII-induced phosphorylation of the Shc-PDGFβ-R complex was inhibited by antioxidants such as N-acetylcysteine and Tiron, but not by calcium chelation. However, transactivation of PDGFβ-R by AngII (measured by PDGFβ- R tyrosine phosphorylation) differed significantly from PDGF-BB. Evidence to support different mechanisms of PDGFβ-R phosphorylation includes differences in the time course of PDGFβ-R phosphorylation, differing effects of inhibitors of the endogenous PDGFβ-R tyrosine kinase and Src family tyrosine kinases, differing results when the PDGFβ-R was directly immunoprecipitated (PDGFβ-R-antibody) versus coimmunoprecipitated (Shc-antibody), and cell fractionation studies that suggested that the Shc·PDGFβ-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.