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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 for publication 20 September 2001.
Revision received 13 November 2001.
Accepted for publication 1 February 2002.
Abstract:
Axam has been identified as a novel Axin-binding protein thatinhibits the Wnt signaling pathway. We studied the molecularmechanism by which Axam stimulates the downregulation of ß-catenin.The C-terminal region of Axam has an amino acid sequence similarto that of the catalytic region of SENP1, a SUMO-specific protease(desumoylation enzyme). Indeed, Axam exhibited activity to removeSUMO from sumoylated proteins in vitro and in intact cells.The Axin-binding domain is located in the central region ofAxam, which is different from the catalytic domain. Neitherthe Axin-binding domain nor the catalytic domain alone was sufficientfor the downregulation of ß-catenin. An Axam fragmentwhich contains both domains was able to decrease the level ofß-catenin. On substitution of Ser for Cys547 in thecatalytic domain, Axam lost its desumoylation activity. Further,this Axam mutant decreased the activity to downregulate ß-catenin.Although Axam strongly inhibited axis formation and expressionof siamois, a Wnt-response gene, in Xenopus embryos, AxamC547Sshowed weak activities. These results demonstrate that Axamfunctions as a desumoylation enzyme to downregulate ß-cateninand suggest that sumoylation is involved in the regulation ofthe 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.
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