[HTML][HTML] Specific control of BMP signaling and mesenchymal differentiation by cytoplasmic phosphatase PPM1H

T Shen, C Sun, Z Zhang, N Xu, X Duan, XH Feng, X Lin - Cell research, 2014 - nature.com
T Shen, C Sun, Z Zhang, N Xu, X Duan, XH Feng, X Lin
Cell research, 2014nature.com
Bone morphogenetic proteins (BMPs) belong to the TGF-β superfamily of structurally related
signaling proteins that regulate a wide array of cellular functions. The key step in BMP signal
transduction is the BMP receptor-mediated phosphorylation of transcription factors Smad1,
5, and 8 (collectively Smad1/5/8), which leads to the subsequent activation of BMP-induced
gene transcription in the nucleus. In this study, we describe the identification and
characterization of PPM1H as a novel cytoplasm-localized Smad1/5/8-specific phosphatase …
Abstract
Bone morphogenetic proteins (BMPs) belong to the TGF-β superfamily of structurally related signaling proteins that regulate a wide array of cellular functions. The key step in BMP signal transduction is the BMP receptor-mediated phosphorylation of transcription factors Smad1, 5, and 8 (collectively Smad1/5/8), which leads to the subsequent activation of BMP-induced gene transcription in the nucleus. In this study, we describe the identification and characterization of PPM1H as a novel cytoplasm-localized Smad1/5/8-specific phosphatase. PPM1H directly interacts with Smad1/5/8 through its Smad-binding domain, and dephosphorylates phospho-Smad1/5/8 (P-Smad1/5/8) in the cytoplasm. Ectopic expression of PPM1H attenuates BMP signaling, whereas loss of PPM1H activity or expression greatly enhances BMP-dependent gene regulation and mesenchymal differentiation. In conclusion, this study suggests that PPM1H acts as a gatekeeper to prevent excessive BMP signaling through dephosphorylation and subsequent nuclear exclusion of P-Smad1/5/8 proteins.
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