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Department of Pharmacology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242
Address all correspondence and requests for reprints to: Dr. Mario Ascoli, Department of Pharmacology, 2-319B BSB, 51 Newton Road, The University of Iowa, Iowa City, Iowa 52242-1109. E-mail: mario-ascoli{at}uiowa.edu.
We show that activation of the recombinant lutropin/choriogonadotropin receptor (LHR) in mouse Leydig tumor cells (MA-10 cells) leads to the tyrosine phosphorylation of Shc (Src homology and collagen homology) and the formation of complexes containing Shc and Sos (Son of sevenless), a guanine nucleotide exchange factor for Ras. Because a dominant-negative mutant of Shc inhibits the LHR-mediated activation of Ras and the phosphorylation of ERK1/2, we conclude that the LHR-mediated phosphorylation of ERK1/2 is mediated, at least partially, by the classical pathway used by growth factor receptors. We also show that the endogenous epidermal growth factor receptor (EGFR) present in MA-10 cells is phosphorylated upon activation of the LHR. The LHR-mediated phosphorylation of the EGFR and Shc, the activation of Ras, and the phosphorylation of ERK1/2 are inhibited by expression of a dominant-negative mutant of Fyn, a member of the Src family kinases (SFKs) expressed in MA-10 cells and by PP2, a pharmacological inhibitor of the SFKs. These are also inhibited, but to a lesser extent, by AG1478, an inhibitor of the EGFR kinase. We conclude that the SFKs are responsible for the LHR-mediated phosphorylation of the EGFR and Shc, the formation of complexes containing Shc and Sos, the activation of Ras, and the phosphorylation of ERK1/2.
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K. Shiraishi and M. Ascoli Lutropin/Choriogonadotropin Stimulate the Proliferation of Primary Cultures of Rat Leydig Cells through a Pathway that Involves Activation of the Extracellularly Regulated Kinase 1/2 Cascade Endocrinology, July 1, 2007; 148(7): 3214 - 3225. [Abstract] [Full Text] [PDF]
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