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J. Biol. Chem., Vol. 279, Issue 38, 39366-39373, September 17, 2004

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The DIX Domain Protein Coiled-coil-DIX1 Inhibits c-Jun N-terminal Kinase Activation by Axin and Dishevelled through Distinct Mechanisms^*

Chung Kai Wong, Wen Luo¶, Ying Deng¶, Haiying Zou¶, Zhiyun Ye¶, and Sheng-Cai Lin¶||

From the Department of Biochemistry, Hong Kong University of Science and Technology, Kowloon, Hong Kong, and the ^¶State Key Laboratory of Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Fujian 361005, China

Axin, Ccd1 (coiled-coil-DIX1), and dishevelled (Dvl or Dsh) are three known DIX domain proteins that play important roles in Wnt signaling. In addition, Dvl and Axin can activate the mitogen-activated protein kinase JNK via distinct mechanisms, through interaction with MEKK1/4 and Rac GTPase, respectively. Axin utilizes two distinct domains for interaction with MEKK1 and MEKK4. JNK activation by Axin is regulated by several factors in the Wnt pathway, whereas little is known about cross-regulation of Dvl-mediated JNK activation. In the present study, we have investigated whether Ccd1 could play a regulatory role in Axin- and Dvl-mediated JNK activation. Here we show that Ccd1 drastically inhibited JNK activation both by Axin and by Dvl. Although DIX domains are sufficient for dimer formation between Dvl and Ccd1, Ccd1 also required its coiled-coil domain for inhibition of JNK activation by Dvl. Interestingly, Rac remained associated with Dvl heterodimerized with Ccd1. How Ccd1 blocks Rac/Dvl signaling to JNK is unclear. In contrast, Axin, when complexed with Ccd1, did not bind to MEKK1. Furthermore, Ccd1 physically interacted with MEKK4 in their physiological concentrations and prevented MEKK4 from binding to Axin. Reduction of Ccd1 protein by small interfering RNA could elevate JNK signaling as assayed with an AP1-dependent transcriptional reporter. We have therefore demonstrated that Ccd1 inhibits Axin-mediated JNK activation by simultaneously adopting two distinct mechanisms, one through conformational changes that disallow MEKK1 binding and the other via direct sequestration of MEKK4.

Received for publication, April 26, 2004 , and in revised form, June 22, 2004.

^* This work was supported in part by Grants HKUST 6122/02M and 6141/03M from the Research Grants Council of Hong Kong (to S.-C. L.) and by Grant 2002F002 from the Fujian Council of Science and Technology (to S.-C. L.). 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.

These authors contributed equally to this work.

^|| Recipient of National Outstanding Young Investigator Award 30125012. To whom correspondence should be addressed: Dept. of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. Tel.: 852-2358-7294; Fax: 852-2358-1552; E-mail: linsc{at}ust.hk.

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