Stimulation of the alpha1A adrenergic receptor inhibits PDGF-induced PDGF beta receptor Tyr751 phosphorylation and PI 3-kinase activation.
Several reports indicate that some G(alphaq)-coupled receptors antagonize the activation of phosphatidylinositol (PI) 3-kinase by receptor tyrosine kinases. We used Rat-1 fibroblasts expressing the alpha(1A) adrenergic receptor to study how this G(alphaq)-coupled receptor inhibits platelet-derived growth factor (PDGF) activation of PI 3-kinase. Phenylephrine (PE) stimulation of the alpha(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 C gamma 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(alphaq). These results suggest that the alpha(1A) adrenergic receptor, and perhaps other G(alphaq)-coupled receptors, uses tyrosine dephosphorylation to block PI 3-kinase activation by PDGF.
Lin
Hong-Ying
HY
Institute of Genetics, Roemerstr 164, University of Bonn, 53117 Bonn, Germany.
Ballou
Lisa M
LM
Lin
Richard Z
RZ
D058646:Adrenergic alpha-1 Receptor Agonists; D001426:Bacterial Proteins; D001427:Bacterial Toxins / Q000494:pharmacology; D004789:Enzyme Activation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000737:chemistry / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism*
C547715:Adra1a protein, rat; D058646:Adrenergic alpha-1 Receptor Agonists; D001426:Bacterial Proteins; D001427:Bacterial Toxins; C062258:Pasteurella multocida toxin; D010982:Platelet-Derived Growth Factor; D018340:Receptors, Adrenergic, alpha-1; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta