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J. Biol. Chem., Vol. 283, Issue 31, 21334-21346, August 1, 2008

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Elongin B/C Recruitment Regulates Substrate Binding by CIS^*

From the Department of Medical Protein Research, Flanders Institute for Biotechnology (VIB), and the Department of Biochemistry, Faculty of Medicine and Health Sciences, Ghent University, A. Baertsoenkaai 3, 9000 Ghent, Belgium

SOCS proteins play a major role in the regulation of cytokine signaling. They are recruited to activated receptors and can suppress signaling by different mechanisms including targeting of the receptor complex for proteasomal degradation. The activity of SOCS proteins is regulated at different levels including transcriptional control and posttranslational modification. We describe here a novel regulatory mechanism for CIS, one of the members of this protein family. A CIS mutant deficient in recruitment of the Elongin B/C complex completely failed to suppress STAT5 activation. This deficiency was not caused by altered turnover of CIS but by loss of cytokine receptor interaction. Intriguingly, no such effect was seen for binding to MyD88. The interaction between CIS and the Elongin B/C complex, which depends on the levels of uncomplexed Elongin B/C, was easily disrupted. This regulatory mechanism may be unique for CIS, as similar mutations in SOCS1, -2, -3, -6, and -7 had no functional impact. Our findings indicate that the SOCS box not only plays a role in the formation of E3 ligase complexes but, at least for CIS, can also regulate the binding modus of SOCS box-containing proteins.

Received for publication, May 15, 2008

^* This work was supported by Grant 1.5.446.98 from the Fund for Scientific Research-Flanders (FWO-V) (to J. P.), Grant GOA 12051401 from Ghent University, and Grant P6:28 from the Interuniversity Attraction Poles. 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 To whom correspondence should be addressed. Tel.: 32-9-2649302; Fax: 32-9-2649492; E-mail: Jan.Tavernier{at}Ugent.be.

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