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J. Biol. Chem., Vol. 280, Issue 23, 22115-22123, June 10, 2005

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Degradation of the Tumor Suppressor Smad4 by WW and HECT Domain Ubiquitin Ligases^*

Anita Morén, Takeshi Imamura, Kohei Miyazono¶, Carl-Henrik Heldin, and Aristidis Moustakas||

From the Ludwig Institute for Cancer Research, Box 595, Biomedical Center, Uppsala University, SE-751 24 Uppsala, Sweden, the Department of Biochemistry, The Cancer Institute of Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan, and the ^¶Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Smad4 mediates signaling by the transforming growth factor- (TGF-) superfamily of cytokines. Smad signaling is negatively regulated by inhibitory (I) Smads and ubiquitin-mediated processes. Known mechanisms of proteasomal degradation of Smads depend on the direct interaction of specific E3 ligases with Smads. Alternatively, I-Smads elicit degradation of the TGF- receptor by recruiting the WW and HECT domain E3 ligases, Smurfs, WWP1, or NEDD4–2. We describe an equivalent mechanism of degradation of Smad4 by the above E3 ligases, via formation of ternary complexes between Smad4 and Smurfs, mediated by R-Smads (Smad2) or I-Smads (Smad6/7), acting as adaptors. Smurfs, which otherwise cannot directly bind to Smad4, mediated poly-ubiquitination of Smad4 in the presence of Smad6 or Smad7. Smad4 co-localized with Smad7 and Smurf1 primarily in the cytoplasm and in peripheral cell protrusions. Smad2 or Smad7 mutants defective in Smad4 interaction failed to induce Smurf1-mediated down-regulation of Smad4. A Smad4 mutant defective in Smad2 or Smad7 interaction could not be effectively down-regulated by Smurf1. We propose that Smad4 is targeted for degradation by multiple ubiquitin ligases that can simultaneously act on R-Smads and signaling receptors. Such mechanisms of down-regulation of TGF- signaling may be critical for proper physiological response to this pathway.

Received for publication, December 14, 2004 , and in revised form, March 7, 2005.

^* This work was supported by grants from the Human Frontier Science Program (to A. Moustakas) and the Swedish Foundation for International Cooperation in Research and High Education (to C.-H. H.). 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.

^|| To whom correspondence should be addressed. Tel.: 46-18-160-414; Fax: 46-18-160-420; E-mail: aris.moustakas{at}licr.uu.se.

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