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J. Biol. Chem., Vol. 282, Issue 7, 4728-4737, February 16, 2007

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Ankyrin Repeat and Suppressors of Cytokine Signaling Box Protein Asb-9 Targets Creatine Kinase B for Degradation^*

Marlyse A. Debrincat^¶1, Jian-Guo Zhang, Tracy A. Willson, John Silke^||, Lisa M. Connolly^**, Richard J. Simpson^**, Warren S. Alexander, Nicos A. Nicola, Benjamin T. Kile, and Douglas J. Hilton²

From the Division of Cancer and Haematology and Division of Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia, the ^¶Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia, the ^||Department of Biochemistry, R. L. Reid Building, La Trobe University, Bundoora, Victoria 3086, Australia, and the ^**The Joint Proteomics Laboratory of the Walter and Eliza Hall Institute and Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia

The suppressors of cytokine signaling (SOCS) proteins inhibit cytokine action by direct interaction with Janus kinases or activated cytokine receptors. In addition to the N-terminal and Src homology 2 domains that mediate these interactions, SOCS proteins contain a C-terminal SOCS box. DNA data base searches have identified a number of other protein families that possess a SOCS box, of which the ankyrin repeat and SOCS box-containing (Asb) proteins constitute the largest. Although it is known that the SOCS proteins are involved in the negative regulation of cytokine signaling, the biological and biochemical functions of the Asbs are largely undefined. Using a proteomics approach, we demonstrate that creatine kinase B (CKB) interacts with Asb-9 in a specific, SOCS box-independent manner. This interaction increases the polyubiquitylation of CKB and decreases total CKB levels within the cell. The targeting of CKB for degradation by Asb-9 was primarily SOCS box-dependent and suggests that Asb-9 acts as a specific ubiquitin ligase regulating levels of this evolutionarily conserved enzyme.

Received for publication, September 27, 2006 , and in revised form, November 24, 2006.

^* This work was supported by Australian National Health and Medical Research Council, Canberra, Australia Program Grant 257500; the Anti-Cancer Council of Victoria, Melbourne, Australia; the Australian Federal Government Cooperative Research Centers Program, Australia; and Zenyth Therapeutics Ltd., Melbourne, Australia. 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 Recipient of a Dora Lush Postgraduate Award from the Australian National Health and Medical Research Council.

² To whom correspondence should be addressed. Tel.: 61-3-9345-2555; Fax: 61-3-9347-0852; E-mail: hilton{at}wehi.edu.au.

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