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J. Biol. Chem., Vol. 282, Issue 28, 20492-20501, July 13, 2007

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Arkadia Induces Degradation of SnoN and c-Ski to Enhance Transforming Growth Factor- Signaling^*

Yoshiko Nagano, Konstantinos J. Mavrakis, Kian Leong Lee, Tomoko Fujii, Daizo Koinuma^¶, Hitoshi Sase, Keiko Yuki, Kazunobu Isogaya, Masao Saitoh, Takeshi Imamura^¶, Vasso Episkopou, Kohei Miyazono¹, and Keiji Miyazawa

From the Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan, Mammalian Neurogenesis Medical Research Council, Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom, and the ^¶Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan

Transforming growth factor- (TGF-) signaling is controlled by a variety of regulators that target either signaling receptors or activated Smad complexes. Among the negative regulators, Smad7 antagonizes TGF- signaling mainly through targeting the signaling receptors, whereas SnoN and c-Ski repress signaling at the transcriptional level through inactivation of Smad complexes. We previously found that Arkadia is a positive regulator of TGF- signaling that induces ubiquitin-dependent degradation of Smad7 through its C-terminal RING domain. We report here that Arkadia induces degradation of SnoN and c-Ski in addition to Smad7. Arkadia interacts with SnoN and c-Ski in their free forms as well as in the forms bound to Smad proteins, and constitutively down-regulates levels of their expression. Arkadia thus appears to effectively enhance TGF- signaling through simultaneous down-regulation of two distinct types of negative regulators, Smad7 and SnoN/c-Ski, and may play an important role in determining the intensity of TGF- family signaling in target cells.

Received for publication, February 13, 2007 , and in revised form, May 16, 2007.

^* This work was supported by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Kakenhi). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed. Tel.: 81-3-5841-3345; Fax: 81-3-5841-3354; E-mail: miyazono-ind{at}umin.ac.jp.

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