Several reports indicate that some Gαq-coupled receptors antagonize the activation of phosphatidylinositol (PI) 3-kinase by receptor tyrosine kinases. We used Rat-1 fibroblasts expressing the α1A adrenergic receptor to study how this Gαq-coupled receptor inhibits platelet-derived growth factor (PDGF) activation of PI 3-kinase. Phenylephrine (PE) stimulation of the α1A adrenergic receptor inhibited PDGF-induced binding of PI 3-kinase to the PDGF receptor (PDGFR) and phosphorylation of the PDGFR at Tyr751, which forms a docking site for PI 3-kinase. By contrast, activation of phospholipase Cγ by PDGF and phosphorylation of the PDGFR at Tyr716 and Tyr771 were not inhibited by PE. The protein tyrosine phosphatase SHP-2, which dephosphorylates Tyr751 on the PDGFR, was more active in cells treated with PDGF plus PE than in cells treated with either agent alone. PDGF-induced PI 3-kinase signaling was also inhibited by treatment of cells with Pasteurella multocida toxin to activate Gαq. These results suggest that the α1A adrenergic receptor, and perhaps other Gαq-coupled receptors, uses tyrosine dephosphorylation to block PI 3-kinase activation by PDGF.
