Role of Smad phosphatases in BMP-Smad signaling axis-induced osteoblast differentiation

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Abstract

Bone morphogenetic proteins (BMPs) are members of the transforming growth factorβ-b (TGFβ-b) superfamily and stimulate the osteoblast differentiation of various types of cells. Smads play central roles downstream of BMP signaling. Receptor-regulated Smads (R-Smads) are phosphorylated by BMP receptors on 2 serine residues in the Ser-X-Ser (SXS) motif at the C terminus. Phosphorylated R-Smads form heteromeric complexes with Smad4 and directly activate the transcription of BMP-responsive genes such as Id1. In contrast, the phosphorylation of a linker region of R-Smads by mitogen-activated protein kinases suppresses their translocation to the nucleus and thus represses their transcriptional activity. Recently, distinct types of phosphatases, i.e., small C-terminal domain phosphatases (SCPs) and protein phosphatase magnesium-dependent 1A (PPM1A), have been identified as enzymes that suppress BMP activity by dephosphorylating the C-terminal SXS motifs in Smads. In this review, we focus on these Smad phosphatases and the role of the phosphorylation and dephosphorylation of Smad by introducing our own studies. To determine the role of the phosphorylation and dephosphorylation of Smad1, we used a constitutively active Smad1 mutant expression plasmid, Smad1 (DVD), in which the C-terminal serine residues have been substituted by aspartic acids. PPM1A and SCP1 suppressed the activity of Smad1 (DVD). PPM1A suppressed the osteoblast differentiation induced by BMPs by decreasing Smad protein levels. In contrast, SCP1 did not reduce Smad protein levels but suppressed osteoblast differentiation to target the downstream effectors of Smad, especially Runx2. In conclusion, SCP1 and PPM1A suppress the osteoblast differentiation induced by BMPs independent of Smad dephosphorylation. © 2012 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.

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Kokabua, S., Katagiria, T., Yodab, T., & Rosenc, V. (2012). Role of Smad phosphatases in BMP-Smad signaling axis-induced osteoblast differentiation. Journal of Oral Biosciences. Japanese Association for Oral Biology. https://doi.org/10.1016/j.job.2012.02.003

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