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J. Biol. Chem., Vol. 280, Issue 14, 13817-13823, April 8, 2005

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Suppressor of Cytokine Signaling 7 Inhibits Prolactin, Growth Hormone, and Leptin Signaling by Interacting with STAT5 or STAT3 and Attenuating Their Nuclear Translocation^*

Nele Martens, Galit Uzan, Maxime Wery¶, Robert Hooghe, Elisabeth L. Hooghe-Peters, and Arieh Gertler||

From the Neuroendocrine Immunology, and Pharmacology Department, Medical School, Free University, B-1090 Brussels, Belgium, the Institute of Biochemistry, Food Science, and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel, and the ^¶Laboratory of Molecular Genetics, Facultés Universitaires Notre-Dame de la Paix, B-5000 Namur, Belgium

We report here the role of one of the less studied members of the family of suppressors of cytokine signaling (SOCS), namely SOCS-7, in cytokine signaling. We demonstrate that SOCS-7 inhibits prolactin (PRL), growth hormone (GH), or leptin (LEP) signaling mediated through STAT3 and STAT5 in a dose-dependent manner. SOCS-7 also attenuated STAT3 and STAT5 signaling induced by overexpression of JH1, the catalytic subdomain of JAK2. Since SOCS-7 interacted with phosphorylated STAT3 or STAT5, we assumed that SOCS-7 acts at the level of STAT proteins. Indeed, we showed that SOCS-7 inhibits PRL- and leptin-induced STAT5 and STAT3 phosphorylation and prevented the nuclear translocation of activated STAT3. Taken together, our results indicate that SOCS-7 is a physiological dysregulator of PRL, leptin, and probably also GH signaling and that its mode of action is a novel variation of SOCS protein inhibition of cytokine-inducible STAT-mediated signal transduction.

Received for publication, October 12, 2004 , and in revised form, December 21, 2004.

^* This work was supported by a V.U.B. grant, an FWO-Vlaanderen grant, and Flemish Government Grants GOA 97-02-04 and G.0126.02 (to E. L. H. P.) and by Binational USA-Israel Science Foundation Grant 2000115 (to A. G.). Some of the data published in the present paper were reported at the Annual Meeting of the Belgian Society for Biochemistry and Molecular Biology (12) and the Annual Meeting of the Israeli Endocrine Society (13). 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. Tel.: 972-8-948-9006; Fax: 972-8-948-9006; E-mail: gertler{at}agri.huji.ac.il.

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