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Phospho-Smad1 Modulation by Nedd4 E3 Ligase in BMP/TGF-beta Signaling
Cited 23 time in
Web of Science
Cited 24 time in Scopus
- Authors
- Issue Date
- 2011-07
- Publisher
- WILEY-BLACKWELL
- Citation
- JOURNAL OF BONE AND MINERAL RESEARCH, Vol.26 No.7, pp.1411-1424
- Keywords
- NONOSSEOUS CALCIFICATION ; BMP/TGF beta ; NEDD4 ; SMAD
- Abstract
- 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 beta (TGF-beta) 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-beta 1 signals. In a specific context, both signals regulate the nonclassic Smads pathway reciprocally, BMP-2 to Smad2/3 and TGF-beta 1 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-beta 1 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-beta 1-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 Pi-induced calcification of human vascular smooth muscle cells. These new insights about proteasomal degradation-mediated phosphorylated nonclassic Smad regulation of BMP-2/TGF-beta 1 could, in part, help to unravel the complex mechanisms of abnormal nonosseous calcification by the aberrant activity of BMPTTGF-beta/Smads. (C) 2011 American Society for Bone and Mineral Research.
- ISSN
- 0884-0431
- Language
- English
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