Epidermal Growth Factor-Induced Heterologous Desensitization of the Luteinizing Hormone/Choriogonadotopin Receptor in a Cell-Free Membrane Preparation Is Associated with the Tyrosine Phosphorylation of the Epidermal Growth Factor Receptor
Epidermal growth factor (EGF) attenuated hCG-stimulated ad- enylyl cyclase activity in rat luteal and follicular membranes. H7, an equipotent serine/threonine protein kinase inhibitor of cAMP-depen- dent protein kinases, cGMP-dependent protein kinases, and lipid- dependent protein kinase C, did not effect the ability of EGF to decrease hCG-responsive adenylyl cyclase activity, suggesting that a serine/threonine phosphorylation event catalyzed by these kinases was not critically involved in EGF-induced desensitization. Likewise, pertussis toxin-catalyzed ADP-ribosylation of a 40-kDa luteal mem- brane protein, which exhibited immunoreactivity with an antibody against Gia, did not hinder the ability of EGF to attenuate hCG- stimulated adenylyl cyclase activity, indicating that Gi did not me- diate EGF-induced desensitization. Rather, EGF-induced heterolo- gous desensitization of LH/CG receptor in ovarian membranes was closely associated with the specific and prominent tyrosine phosphor- ylation of the 170-kDa EGF receptor. Both EGF-stimulated auto- phosphorylation of EGF receptor and EGF-induced LH/CG receptor desensitization were attenuated by genistein, a tyrosine kinase in- hibitor. These results suggest that tyrosine phosphorylation of the 170-kDa EGF receptor is a necessary component of the signaling pathway in EGF-induced heterologous desensitization of the LH/CG receptor. (Endocrinology 140: 29 -36, 1999)