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J. Biol. Chem., Vol. 278, Issue 35, 32618-32630, August 29, 2003

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c-Src Is Activated by the Epidermal Growth Factor Receptor in a Pathway That Mediates JNK and ERK Activation by Gonadotropin-releasing Hormone in COS7 Cells^*

Sarah Kraus  , Outhiriaradjou Benard  , Zvi Naor ¶ and Rony Seger  ||

From the Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel and the ^¶Department of Biochemistry, Tel Aviv University, Ramat Aviv 69978, Israel

Key participants in G protein-coupled receptor (GPCR) signaling are the mitogen-activated protein kinase (MAPK) signaling cascades. The mechanisms involved in the activation of the above cascades by GPCRs are not fully elucidated. A prototypic GPCR that has been widely used to study these signaling mechanisms is the receptor for gonadotropin-releasing hormone (GnRHR), which serves as a key regulator of the reproductive system. Here we expressed GnRHR in COS7 cells and found that GnRHR transmits its signals to MAPKs mainly via G_i, EGF receptor without the involvement of Hb-EGF, and c-Src, but independently of PKCs. The main pathway that leads to JNK activation downstream of the EGF receptor involves a sequential activation of c-Src and phosphatidylinositol 3-kinase (PI3K). ERK activation by GnRHR is mediated by the EGF receptor, which activates Ras either directly or via c-Src. Besides the main pathway, the dissociated G and -arrestin may initiate additional, albeit minor, pathways that lead to MAPK activation in the transfected COS7 cells. The pathways detected are significantly different from those in other cell lines bearing GnRHR, indicating that GnRH can utilize various signaling mechanisms for the activation of MAPK cascades. The unique pathway elucidated here in which c-Src and PI3K are sequentially activated downstream of the EGF receptor may serve as a prototype of signaling mechanisms by GnRHR and by additional GPCRs in various cell types.

Received for publication, April 14, 2003

^* This work was supported by grants from the Estate of Siegmund Landau, the Benozyio Institute for Molecular Medicine at The Weizmann Institute of Science, the Moross Institute for Cancer Research at the Weizmann Institute of Science, and the Israel Academy of Sciences and Humanities. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^|| To whom correspondence should be addressed: Dept. of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel. Tel.: 972-8-9343602; Fax: 972-8-9344116; E-mail: rony.seger{at}weizmann.ac.il.

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