This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 20/11/2773    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Molina-Muñoz, T. Articles by García-Sáinz, J. A. Search for Related Content PubMed PubMed Citation Articles by Molina-Muñoz, T. Articles by García-Sáinz, J. A.

Insulin-Like Growth Factor-I Induces _1B-Adrenergic Receptor Phosphorylation through Gß and Epidermal Growth Factor Receptor Transactivation

Departamento de Biología Celular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510 México D.F., México

Address all correspondence and requests for reprints to: J. Adolfo García-Sáinz, M.D., Ph.D., Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Apartado Postal 70-248, 04510 México D.F., México. E-mail: agarcia{at}ifc.unam.mx.

IGF-I induces _1B-adrenoceptor (_1B-AR) phosphorylation. The effect of IGF-I was rapid and transient, reaching near-maximal values at 10 min and decreasing after 30 min; it was observed at low IGF-I concentrations (EC₅₀ 10 ng/ml) and was associated to receptor desensitization as evidenced by a decreased _1B-adrenergic effect on intracellular calcium and production of inositol phosphates. The effect of IGF-I was markedly decreased in cells treated with pertussis toxin suggesting involvement of pertussis toxin-sensitive G proteins. Transfection of the carboxyl terminus of the ß-adrenergic receptor kinase or the p85 mutant of phosphoinositide 3-kinase (PI3K) markedly decreased the _1B-AR phosphorylation induced by IGF-I without decreasing the receptor phosphorylation induced by noradrenaline. Inhibitors of PI3K and protein kinase C blocked IGF-I-induced _1B-AR phosphorylation. In addition, it was observed that AG1478, an inhibitor of the epidermal growth factor (EGF) receptor kinase, and BB-94, a metalloproteinase inhibitor, also diminished IGF-I-induced adrenoceptor phosphorylation.

The data clearly show that IGF-I triggers a complex signaling pathway, which leads to the phosphorylation and desensitization of a serpentine G protein-coupled receptor, suggesting the following hypothetical model: 1) stimulation of IGF-I receptors activate pertussis toxin-sensitive G proteins; 2) the growth factor action activates metalloproteinases, which catalyze heparin binding-EGF shedding, and transactivation of EGF receptors, and 3) dissociated Gß subunits and phosphotyrosine residues seem to trigger PI3K activity, which leads to activation of protein kinase C, resulting in _1B-AR phosphorylation and desensitization.