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Vol. 12, Issue 5, 1431-1443, May 2001
and
*Department of Biochemistry, the Cancer Institute of
Japanese Foundation for Cancer Research, and Research for the Future
Program, the Japan Society for the Promotion of Science, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Smads are signal mediators for the members of the transforming
growth factor-The
Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome,
Bunkyo-ku, Tokyo 113-8613, Japan; and §Department of
Molecular Pathology, Graduate School of Medicine, University of Tokyo,
Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
(TGF-) superfamily. Upon phosphorylation by the
TGF- receptors, Smad3 translocates into the nucleus, recruits transcriptional coactivators and corepressors, and regulates
transcription of target genes. Here, we show that Smad3 activated by
TGF- is degraded by the ubiquitin-proteasome pathway. Smad3
interacts with a RING finger protein, ROC1, through its
C-terminal MH2 domain in a ligand-dependent manner. An E3 ubiquitin
ligase complex ROC1-SCFFbw1a consisting of ROC1, Skp1,
Cullin1, and Fbw1a (also termed TrCP1) induces ubiquitination of
Smad3. Recruitment of a transcriptional coactivator, p300, to nuclear
Smad3 facilitates the interaction with the E3 ligase complex and
triggers the degradation process of Smad3. Smad3 bound to
ROC1-SCFFbw1a is then exported from the nucleus to the
cytoplasm for proteasomal degradation. TGF-/Smad3 signaling is thus
irreversibly terminated by the ubiquitin-proteasome pathway.
These authors contributed equally to this work.
Corresponding author. E-mail address:
miyazono-ind{at}umin.ac.jp
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