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Submitted on January 12, 2007
Accepted on May 21, 2007
Department of Molecular and Cellular Biology (C.M.W., H-Y. F., J.S.R.) Baylor College of Medicine, Houston, TX 77030, Department of Pharmacology and Toxicology (X.C.) School of Medicine, University of Texas Medical Branch, Galveston, TX 77555
* To whom correspondence should be addressed. E-mail: joanner{at}bcm.tmc.edu.
Follicle stimulating hormone (FSH) regulates ovarian granulosa cell differentiation not only by activating adenylyl cyclase (AC) and protein kinase A (PKA) but also by other complex mechanisms. Using primary rat granulosa cell cultures, we provide novel evidence that FSH rapidly activates two small GTP binding proteins RAP1 and RAS. FSH activation of RAP1 requires cAMP-mediated activation of EPAC (exchange factor activated by cAMP)/RAPGEF3 whereas FSH activation of RAS and downstream signaling cascades involves multiple factors. Specifically, FSH activation of RAS required SRC family tyrosine kinase (SFK) and EGF receptor tyrosine kinase activities but not PKA. FSH induced phosphorylation of ERK1/2 was blocked by dominant-negative RAS as well as by inhibitors of EGF receptor tyrosine kinase, metalloproteinases involved in growth factor shedding and SRC family tyrosine kinases (SFKs). In contrast, FSH-induced phosphorylation of protein kinase B (PKB/AKT) and the Forkhead transcription factor, FOXO1a occurred by SFK dependent but RAS independent mechanisms. The SFKs, c-SRC and FYN and the SRC-related tyrosine kinase ABL were present and phosphorylated rapidly in response to FSH. Lastly, the EGF-like factor amphiregulin (AREG) activated RAS and ERK1/2 phosphorylation in granulosa cells by mechanisms that were selectively blocked an EGF receptor antagonist but not by an SFK antagonist. However, AREG mediated phosphorylation of PKB and FOXO1a required both EGF receptor and SFK activation. Moreover, we show that FSH induces AREG and that activation of the EGF receptor impacts granulosa cell differentiation and the expression of genes characteristic of the luteal cell phenotype. Thus, FSH orchestrates the coordinate activation of three diverse membrane-associated signaling cascades (AC, RAS and SFKs) that converge downstream to activate specific kinases (PKA, ERK1/2 and PKB/FOXO1a) that control granulosa cell function and differentiation.
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