Stimulation of the α_1A adrenergic receptor inhibits PDGF-induced PDGF β receptor Tyr751 phosphorylation and PI 3-kinase activation

Several reports indicate that some G_αq-coupled receptors antagonize the activation of phosphatidylinositol (PI) 3-kinase by receptor tyrosine kinases. We used Rat-1 fibroblasts expressing the α_1A adrenergic receptor to study how this G_αq-coupled receptor inhibits platelet-derived growth factor (PDGF) activation of PI 3-kinase. Phenylephrine (PE) stimulation of the α_1A 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 G_αq. These results suggest that the α_1A adrenergic receptor, and perhaps other G_αq-coupled receptors, uses tyrosine dephosphorylation to block PI 3-kinase activation by PDGF.