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.
Mesh Terms:
Activin Receptors, Type I, Animals, Bone Morphogenetic Proteins, COS Cells, Cells, Cultured, DNA-Binding Proteins, Embryo, Nonmammalian, Models, Molecular, Phosphorylation, Protein Binding, Protein-Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Recombinant Proteins, Signal Transduction, Smad6 Protein, Smad7 Protein, Trans-Activators, Ubiquitin-Protein Ligases, Xenopus, Xenopus Proteins
Mol. Biol. Cell
Date: Jul. 01, 2003
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