Phospho-Smad1 modulation by nedd4 E3 ligase in BMP/TGF-β signaling.
A considerable number of studies have focused on the regulation of mothers against decapentaplegic homologue (Smad)-dependent or -independent pathways in the signaling by each transforming growth factor β (TGF-β) superfamily member in diverse biologic contexts. The sophisticated regulation of the actions of these molecules and the underlying molecular mechanisms still ... remain elusive. Here we show new mechanisms of ambilateral R (receptor-regulated)-Smad regulation of bone morphogenetic protein 2 (BMP-2)/TGF-β1 signals. In a specific context, both signals regulate the nonclassic Smads pathway reciprocally, BMP-2 to Smad2/3 and TGF-β1 to Smad1/5/8, as well as their own classic linear Smad pathway. Interestingly, in this study, we found that C-terminal phosphorylated forms of each pathway Smad degraded rapidly 3 hours after stimulation of nonclassic signals but are dramatically restored by treatment with via proteasomal inhibition. Furthermore, an E3 ligase, neural precursor cell expressed, developmentally down-regulated 4 (Nedd4), also was found as one of the important modulators of the p-Smad1 in both BMP-2 and TGF-β1 action. Overexpressed Nedd4 suppressed the BMP-induced osteoblast transdifferentiation process of premyoblast C2C12 cells or alkaline phosphatase (ALP) level of human osteosarcoma cells and promoted TGF-β1-induced degradation of p-Smad1 via physical interaction and polyubiquitination. Conversely, siNedd4 potentiated BMP signals through upregulation of p-Smad1 and ALP activity, the effect of which led to an increased the rate of P(i) -induced calcification of human vascular smooth muscle cells. These new insights about proteasomal degradation-mediated phosphorylated nonclassic Smad regulation of BMP-2/TGF-β1 could, in part, help to unravel the complex mechanisms of abnormal nonosseous calcification by the aberrant activity of BMP/TGF-β/Smads.
Mesh Terms:
Animals, Bone Morphogenetic Protein 2, Calcification, Physiologic, Cell Line, Cell Nucleus, Endosomal Sorting Complexes Required for Transport, Humans, Mice, Models, Biological, Muscle, Smooth, Vascular, Phosphorylation, Polyubiquitin, Proteasome Endopeptidase Complex, Protein Binding, Protein Transport, Signal Transduction, Smad1 Protein, Transforming Growth Factor beta, Ubiquitin-Protein Ligases, Ubiquitination
Animals, Bone Morphogenetic Protein 2, Calcification, Physiologic, Cell Line, Cell Nucleus, Endosomal Sorting Complexes Required for Transport, Humans, Mice, Models, Biological, Muscle, Smooth, Vascular, Phosphorylation, Polyubiquitin, Proteasome Endopeptidase Complex, Protein Binding, Protein Transport, Signal Transduction, Smad1 Protein, Transforming Growth Factor beta, Ubiquitin-Protein Ligases, Ubiquitination
J. Bone Miner. Res.
Date: Jul. 01, 2011
PubMed ID: 21308777
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