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J. Biol. Chem., Vol. 278, Issue 23, 20574-20581, June 6, 2003

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Inhibitory Role of the Somatostatin Receptor SST2 on the Intracrine-regulated Cell Proliferation Induced by the 210-Amino Acid Fibroblast Growth Factor-2 Isoform

IMPLICATION OF JAK2^*

Marylis Hortala , Geraldine Ferjoux , Agnes Estival , Claudine Bertrand , Stefan Schulz , Lucien Pradayrol , Christiane Susini  and François Clemente  ¶

From the INSERM U 531, Institut Louis Bugnard, CHU Rangueil, Toulouse, Cédex 4, France and Department of Pharmacology and Toxicology, Otto-von-Guericke University, 39120 Magdeburg, Germany

The fibroblast growth factor (FGF)-2 isoform of 210 amino acids (HMW FGF-2) contains a nuclear localization sequence (NLS) and is targeted to the nucleus. This FGF-2 isoform allows cells to grow in low serum concentrations through still unknown mechanisms called intracrine regulations. Different peptide hormones and cytokines have been found to be nuclearized through NLS and to induce cell proliferation. The existence of molecules acting as negative regulators of the intracrine-induced cell growth has not been explored. Pancreatic cells AR4-2J were stably transfected to express selectively the HMW FGF-2. We demonstrated that activation of the somatostatin receptor subtype SST2 by the somatostatin analogue RC-160 in serum-deprived medium inhibits the mitogenic effect of the HMW FGF-2, without affecting growth of control cells. The signaling pathway implicates G_i/JAK2/SHP-1. The G_i inhibitor pertussis toxin and the JAK2 inhibitor AG490 abrogate the inhibitory effect of RC-160 on HMW FGF-2-induced cell growth. Co-immunoprecipitation studies demonstrate the constitutive association of JAK2 and SHP-1, and RC-160 induces a rapid activation of both proteins followed by the dissociation of the complex. AG490 prevents the RC-160 induced SHP-1 activation indicating the implication of JAK2 in this process. JAK2 and SHP-1 are immunoprecipitated with SST2 in basal conditions indicating the existence of a functional signaling complex at the receptor level. In summary, these data provide the following evidence: 1) the intracrine-induced proliferation can be reversed by extracellular acting polypeptides; 2) SST2 inhibitory signaling may involve the JAK2/SHP-1 pathway.

Received for publication, October 22, 2002 , and in revised form, March 24, 2003.

^* This work was supported by the Association pour la Recherche sur le Cancer Grant 5860-AE and the Ligue 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.

^¶ To whom correspondence should be addressed: INSERM U 531, Institut Louis Bugnard, CHU Rangueil, Bat L3, Av Jean Poulhès, 31403 Toulouse Cédex 4, France. Tel.: 33-05-61-32-24-04; Fax: 33-05-61-32-24-03; E-mail: Francois.Clemente{at}toulouse.inserm.fr.

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