Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads.
Smad ubiquitin regulatory factor (Smurf) 1 binds to receptor-regulated Smads for bone morphogenetic proteins (BMPs) Smad1/5 and promotes their degradation. In addition, Smurf1 associates with transforming growth factor-beta type I receptor through the inhibitory Smad (I-Smad) Smad7 and induces their degradation. Herein, 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.
Murakami
Gyo
G
Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo 170-8455, Japan.
Watabe
Tetsuro
T
Takaoka
Kunio
K
Miyazono
Kohei
K
Imamura
Takeshi
T
D030201:Activin Receptors, Type I / Q000378:metabolism*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D019556:COS Cells; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004625:Embryo, Nonmammalian; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D011994:Recombinant Proteins; D015398:Signal Transduction; D051905:Smad6 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014981:Xenopus; D029867:Xenopus Proteins
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D051905:Smad6 Protein; C497805:Smad6 protein, Xenopus; D051906:Smad7 Protein; C497809:Smad7 protein, Xenopus; D015534:Trans-Activators; D029867:Xenopus Proteins; C120925:SMURF1 protein, Xenopus; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I