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Molecular and Cellular Biology, June 2002, p. 3803-3819, Vol. 22, No. 11
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.11.3803-3819.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Desumoylation Activity of Axam, a Novel Axin-Binding Protein, Is Involved in Downregulation of ß-Catenin

Takayuki Kadoya,1,2 Hideki Yamamoto,1 Toshiaki Suzuki,3 Akira Yukita,4 Akimasa Fukui,4 Tatsuo Michiue,5 Toshimasa Asahara,2 Keiji Tanaka,3 Makoto Asashima,4,5 and Akira Kikuchi1*

Department of Biochemistry,1 Second Department of Surgery, Faculty of Medicine, Hiroshima University, Minami-ku, Hiroshima 734-8551,2 The Tokyo Metropolitan Institute of Medical Science and CREST, Japan Science and Technology Corporation, Bunkyo-ku, Tokyo 113-8613,3 Department of Life Science (Biology),4 CREST Project, University of Tokyo, Meguro-ku, Tokyo 153-8902, Japan5

Received 20 September 2001/ Returned for modification 13 November 2001/ Accepted 1 February 2002

Axam has been identified as a novel Axin-binding protein that inhibits the Wnt signaling pathway. We studied the molecular mechanism by which Axam stimulates the downregulation of ß-catenin. The C-terminal region of Axam has an amino acid sequence similar to that of the catalytic region of SENP1, a SUMO-specific protease (desumoylation enzyme). Indeed, Axam exhibited activity to remove SUMO from sumoylated proteins in vitro and in intact cells. The Axin-binding domain is located in the central region of Axam, which is different from the catalytic domain. Neither the Axin-binding domain nor the catalytic domain alone was sufficient for the downregulation of ß-catenin. An Axam fragment which contains both domains was able to decrease the level of ß-catenin. On substitution of Ser for Cys547 in the catalytic domain, Axam lost its desumoylation activity. Further, this Axam mutant decreased the activity to downregulate ß-catenin. Although Axam strongly inhibited axis formation and expression of siamois, a Wnt-response gene, in Xenopus embryos, AxamC547S showed weak activities. These results demonstrate that Axam functions as a desumoylation enzyme to downregulate ß-catenin and suggest that sumoylation is involved in the regulation of the Wnt signaling pathway.

* Corresponding author. Mailing address: Department of Biochemistry, Faculty of Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan. Phone: 81-82-257-5130. Fax: 81-82-257-5134. E-mail: akikuchi{at}hiroshima-u.ac.jp.

Molecular and Cellular Biology, June 2002, p. 3803-3819, Vol. 22, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.11.3803-3819.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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