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J Bone Miner Res. 2011 Jul;26(7):1411-24. doi: 10.1002/jbmr.348.

Phospho-Smad1 modulation by nedd4 E3 ligase in BMP/TGF-β signaling.

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Department of Biochemistry, School of Dentistry, Kyungpook National University, and Second BK21 Program, Daegu 700-422, Korea.

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  • J Bone Miner Res. 2012 Jun;27(6):1437.


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.

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