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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Acknowledgements
We thank Dr Di Chen and Dr Peter ten Dijke for essential reagents. We are grateful to Ana María Rodríguez for editing of the manuscript. This research was supported by grants from MOST (2012CB966600), NSFC (31090360), NIH (R01DK073932, R01AR053591, R01GM063773, and R01CA108454), DoD-BCRP Idea Award (W81XWH-08-1-0745), NSFZ (Z2110591), Project 985, and the Fundamental Research Funds for the Central Universities.
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Shen, T., Sun, C., Zhang, Z. et al. Specific control of BMP signaling and mesenchymal differentiation by cytoplasmic phosphatase PPM1H. Cell Res 24, 727–741 (2014). https://doi.org/10.1038/cr.2014.48
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DOI: https://doi.org/10.1038/cr.2014.48
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