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J. Biol. Chem., Vol. 278, Issue 41, 39356-39371, October 10, 2003

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sst2 Somatostatin Receptor Inhibits Cell Proliferation through Ras-, Rap1-, and B-Raf-dependent ERK2 Activation^*

Hicham Lahlou  , Nathalie Saint-Laurent , Jean-Pierre Estève , Alain Eychène ¶, Lucien Pradayrol , Stéphane Pyronnet  and Christiane Susini  ||

From the INSERM U531, IFR31, Centre Hospitalier Universitaire Rangueil, 1 avenue Jean Poulhès, 31403 Toulouse Cedex and ^¶CNRS Unité Mixte de Recherche 146, Institut Curie, Centre Universitaire, 91405 Orsay Cedex, France

The G protein-coupled sst2 somatostatin receptor is a critical negative regulator of cell proliferation. sstII prevents growth factor-induced cell proliferation through activation of the tyrosine phosphatase SHP-1 leading to induction of the cyclin-dependent kinase inhibitor p27^Kip1. Here, we investigate the signaling molecules linking sst2 to p27^Kip1. In Chinese hamster ovary-DG-44 cells stably expressing sst2 (CHO/sst2), the somatostatin analogue RC-160 transiently stimulates ERK2 activity and potentiates insulin-stimulated ERK2 activity. RC-160 also stimulates ERK2 activity in pancreatic acini isolated from normal mice, which endogenously express sst2, but has no effect in pancreatic acini derived from sst2 knock-out mice. RC-160-induced p27^Kip1 up-regulation and inhibition of insulin-dependent cell proliferation are both prevented by pretreatment of CHO/sst2 cells with the MEK1/2 inhibitor PD98059. In addition, using dominant negative mutants, we show that sst2-mediated ERK2 stimulation is dependent on the pertussis toxin-sensitive G_i/o protein, the tyrosine kinase Src, both small G proteins Ras and Rap1, and the MEK kinase B-Raf but is independent of Raf-1. Phosphatidylinositol 3-kinase (PI3K) and both tyrosine phosphatases, SHP-1 and SHP-2, are required upstream of Ras and Rap1. Taken together, our results identify a novel mechanism whereby a G_i/o protein-coupled receptor inhibits cell proliferation by stimulating ERK signaling via a SHP-1-SHP-2-PI3K/Ras-Rap1/B-Raf/MEK pathway.

Received for publication, April 30, 2003 , and in revised form, July 11, 2003.

^* This work was supported in part by grants from Association pour la Recherche contre le Cancer (4505, ARECA) and Ligue Nationale contre le Cancer. 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.

Supported by a doctoral fellowship from Association pour la Recherche contre le Cancer.

^|| To whom correspondence should be addressed. Tel.: 33-5-61-32-24-07; Fax: 33-5-61-32-24-03; E-mail: susinich{at}toulouse.inserm.fr.

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