Angiotensin II induces transactivation of two different populations of the platelet-derived growth factor beta 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 (PDGFbeta-R). We report here, in agreement with previous data, that AngII and PDGF-B-chain homodimer (PDGF-BB) stimulate tyrosine phosphorylation of the PDGFbeta-R. Both AngII and PDGF-BB stimulated the phosphorylation of PDGFbeta-R via the binding of tyrosine-phosphorylated Shc to PDGFbeta-R. Both PDGF-BB- and AngII-induced phosphorylation of the Shc.PDGFbeta-R complex was inhibited by antioxidants such as N-acetylcysteine and Tiron, but not by calcium chelation. However, transactivation of PDGFbeta-R by AngII (measured by PDGFbeta-R tyrosine phosphorylation) differed significantly from PDGF-BB. Evidence to support different mechanisms of PDGFbeta-R phosphorylation includes differences in the time course of PDGFbeta-R phosphorylation, differing effects of inhibitors of the endogenous PDGFbeta-R tyrosine kinase and Src family tyrosine kinases, differing results when the PDGFbeta-R was directly immunoprecipitated (PDGFbeta-R-antibody) versus coimmunoprecipitated (Shc-antibody), and cell fractionation studies that suggested that the Shc.PDGFbeta-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.
Heeneman
S
S
Center for Cardiovascular Research, University of Rochester, Rochester, New York 14642, USA.
Haendeler
J
J
Saito
Y
Y
Ishida
M
M
Berk
B C
BC
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000032:analysis; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects*; D020032:Tyrphostins / Q000494:pharmacology; D018909:src Homology Domains
D000975:Antioxidants; D004791:Enzyme Inhibitors; D010982:Platelet-Derived Growth Factor; D020032:Tyrphostins; D000804:Angiotensin II; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta