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...

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Bibliographic Details
Published in:Molecular biology of the cell 2003-07, Vol.14 (7), p.2809-2817
Main Authors: Murakami, Gyo, Watabe, Tetsuro, Takaoka, Kunio, Miyazono, Kohei, Imamura, Takeshi
Format: Article
Language:English
Subjects:
Activin Receptors, Type I - metabolism
Animals
Bone Morphogenetic Proteins - metabolism
Cells, Cultured
COS Cells
DNA-Binding Proteins - metabolism
Embryo, Nonmammalian
Models, Molecular
Phosphorylation
Protein Binding
Protein-Serine-Threonine Kinases
Receptors, Transforming Growth Factor beta - metabolism
Recombinant Proteins
Signal Transduction
Smad6 Protein
Smad7 Protein
Trans-Activators - metabolism
Ubiquitin-Protein Ligases - metabolism
Xenopus
Xenopus Proteins
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Summary: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.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.e02-07-0441