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J. Biol. Chem., Vol. 281, Issue 44, 32953-32966, November 3, 2006

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Functional Cross-modulation between SOCS Proteins Can Stimulate Cytokine Signaling^*

Julie Piessevaux¹, Delphine Lavens¹, Tony Montoye, Joris Wauman, Dominiek Catteeuw, Joël Vandekerckhove, Denise Belsham, Frank Peelman, and Jan Tavernier²

From the Flanders Interuniversity Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, Baertsoenkaai 3, B-9000 Ghent, Belgium and the Department of Physiology, University of Toronto, Ontario M5S 1A8, Canada

SOCS (suppressors of cytokine signaling) proteins are negative regulators of cytokine signaling that function primarily at the receptor level. Remarkably, in vitro and in vivo observations revealed both inhibitory and stimulatory effects of SOCS2 on growth hormone signaling, suggesting an additional regulatory level. In this study, we examined the possibility of direct cross-modulation between SOCS proteins and found that SOCS2 could interfere with the inhibitory actions of other SOCS proteins in growth hormone, interferon, and leptin signaling. This SOCS2 effect was SOCS box-dependent, required recruitment of the elongin BC complex, and coincided with degradation of target SOCS proteins. Detailed mammalian protein-protein interaction trap (MAPPIT) analysis indicated that SOCS2 can interact with all members of the SOCS family. SOCS2 may thus function as a molecular bridge between a ubiquitin-protein isopeptide ligase complex and SOCS proteins, targeting them for proteasomal turnover. We furthermore extended these observations to SOCS6 and SOCS7. Our findings point to a unique regulatory role for SOCS2, SOCS6, and SOCS7 within the SOCS family and provide an explanation for the unexpected phenotypes observed in SOCS2 and SOCS6 transgenic mice.

Received for publication, January 25, 2006 , and in revised form, August 31, 2006.

Note Added in Proof—After submission of this manuscript, a paper was published by Ouyang et al. (58) demonstrating positive effects of SOCS2 upon ectopic expression in C2C12 myoblasts.

^* This work was supported by Flanders Institute of Science and Technology Grant GBOU 010090, Fund for Scientific Research-Flanders Grant FWO-V 1.5.446.98 [EC] (to J. P. and D. L.), and Ghent University Grant GOA 12051401. 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.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 32-9-264-9302; Fax: 32-9-264-9492; E-mail: jan.tavernier{at}ugent.be.

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