Lysophosphatidic acid induces alpha1B-adrenergic receptor phosphorylation through G beta gamma, phosphoinositide 3-kinase, protein kinase C and epidermal growth factor receptor transactivation.
Lysophosphatidic acid (LPA) induces alpha(1B)-adrenoceptor phosphorylation through pertussis toxin-sensitive G proteins, phosphoinositide 3-kinase (PI3K) and protein kinase C (PKC). Here we showed that transfection of the carboxyl terminus of the beta-adrenergic receptor kinase (betaARK) or the Deltap85 mutant of PI3K markedly decreased the alpha(1B)-adrenoceptor phosphorylation induced by LPA without decreasing the receptor phosphorylations induced by active phorbol esters or noradrenaline. In addition, it was observed that inhibitors of epidermal growth factor (EGF) receptor kinase and of metalloproteinases and an anti-heparin binding-EGF antibody also diminish LPA-induced phosphorylation; such partial inhibitions were not additive, indicating that they occur through a common process. Our data indicate that stimulation of LPA receptors activates pertussis-toxin-sensitive G proteins. Dissociated Gbetagamma subunits initiate two processes: one of them involving activation of metalloproteinases, heparin binding-EGF shedding and transactivation of EGF receptors and another independent of these events. Both processes triggered PI3K activity, which lead to activation of PKC and this to alpha(1B)-adrenoceptor phosphorylation. This is the first demonstration of a role of EGF receptor transactivation in the phosphorylation of a G protein-coupled receptor.
Casas-González
Patricia
P
Departamento de Biología Celular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Apartado postal 70-248, México, D.F., 04510, Mexico.
Ruiz-Martínez
Alejandro
A
García-Sáinz
J Adolfo
JA
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000502:physiology*; D008956:Models, Chemical; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D015533:Transcriptional Activation; D020032:Tyrphostins / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D020962:Heterotrimeric GTP-Binding Proteins; D008246:Lysophospholipids; D010649:Phenylalanine; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011480:Protease Inhibitors; D020033:Protein Isoforms; D011493:Protein Kinase C; D018340:Receptors, Adrenergic, alpha-1; D019311:Staurosporine; D013876:Thiophenes; D020032:Tyrphostins; D000077191:Wortmannin; C106250:6,7-dimethoxy-3-phenylquinoxaline; C080985:batimastat