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J. Biol. Chem., Vol. 283, Issue 19, 13132-13139, May 9, 2008

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Protein Encoded by the Axin^Fu Allele Effectively Down-regulates Wnt Signaling but Exerts a Dominant Negative Effect on c-Jun N-terminal Kinase Signaling^*

Zailian Lu¹, Wei Liu¹, Huizhe Huang¹, Ying He, Ying Han, Yanning Rui, Yanhai Wang, Qinxi Li, Ka Ruan, Zhiyun Ye, Boon Chuan Low^¶, Anming Meng^||, and Sheng-Cai Lin²

From the Key Laboratory of Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China, the Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China, the ^||Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China, and the ^¶Department of Biological Sciences, National University of Singapore, Singapore 117609, Republic of Singapore

Axin plays an architectural role in many important signaling pathways that control various aspects of development and tumorigenesis, including the Wnt, transforming growth factor-β, MAP kinase pathways, as well as p53 activation cascades. It is encoded by the mouse Fused (Fu) locus; the Axin^Fu allele is caused by insertion of an IAP transposon. Axin^Fu/Fu mice display varying phenotypes ranging from embryonic lethality to relatively normal adulthood with kinky tails. However, the protein product(s) has not been identified or characterized. In the present study, we conducted immunoprecipitation using brain extracts from the Axin^Fu mice with specific antibodies against different regions of Axin and found that a truncated Axin containing amino acids 1–596 (designated as Axin^Fu-NT) and the full-length complement of Axin (Axin^WT) can both be generated from the Axin^Fu allele. When tested for functionality changes, Axin^Fu-NT was found to abolish Axin-mediated activation of JNK, which plays a critical role in dorsoventral patterning. Together with a proteomics approach, we found that Axin^Fu-NT contains a previously uncharacterized dimerization domain and can form a heterodimeric interaction with Axin^WT. The Axin^Fu-NT/Axin^WT is not conducive to JNK activation, providing a molecular explanation for the dominant negative effect of Axin^Fu-NT on JNK activation by wild-type Axin. Importantly, Axin^Fu-NT exhibits no difference in the inhibition of Wnt signaling compared with Axin^WT as determined by reporter gene assays, interaction with key Wnt regulators, and expression of Wnt marker genes in zebrafish embryos, suggesting that altered JNK signaling contributes, at least in part, to the developmental defects seen in Axin^Fu mice.

Received for publication, December 31, 2007 , and in revised form, March 3, 2008.

^* This work was supported in part by grants from the Ministry of Science and Technology (863 Program, 2006AA02A303; 973 Program, 2007CB914602), Project 111 sponsored by the State Bureau of Foreign Experts and Ministry of Education (B06016), the National Science Foundation of China (30528014, 30730025, 30500273), the Ministry of Education (705030), and the National Foundation for Fostering Talents of Basic Science (J0630649). 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 These authors contributed equally to this work.

² To whom correspondence should be addressed: School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China. Tel.: 86-592-218-2993; Fax: 86-592-2184687; E-mail: linsc{at}xmu.edu.cn.

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