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A more recent version of this article appeared on July 1, 2003
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Submitted on July 30, 2002
Revised on January 24, 2003
Accepted on March 4, 2003
1 Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; and Department of Orthopedic Surgery, Shinshu University, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
2 Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
3 Department of Orthopedic Surgery, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan
4 Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; and Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
5 Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan
* Corresponding author. E-mail address: miyazono-ind{at}umin.ac.jp.
Smad ubiquitin regulatory factor (Smurf) 1 binds to receptor-regulated Smads (R-Smads) for bone morphogenetic proteins (BMPs), Smad1/5, and promotes their degradation. In addition, Smurf1 associates with transforming growth factor (TGF)-
type I receptor through the inhibitory Smad (I-Smad), Smad7, and induces their degradation. Here we examined whether Smurf1 negatively regulates BMP signaling together with the I-Smads, Smad6/7. Smurf1 and Smad6 cooperatively induced secondary axes in Xenopus embryos. Using a BMP-responsive promoter-reporter construct in mammalian cells, we found that Smurf1 cooperated with I-Smad in inhibiting BMP signaling, and that the inhibitory activity of Smurf1 was not necessarily correlated with its ability to bind to Smad1/5 directly. Smurf1 bound to BMP type I receptors via I-Smads, and induced ubiquitination and degradation of these receptors. Moreover, Smurf1 associated with Smad1/5 indirectly through I-Smads, and induced their ubiquitination and degradation. Smurf1 thus controls BMP signaling with and without I-Smads through multiple mechanisms.
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