1] Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA [2] Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA [3] Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.
1] Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA [2] Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Cell Res. 2014 Jun;24(6):727-41. doi: 10.1038/cr.2014.48. Epub 2014 Apr 15.
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.
骨形态发生蛋白（BMPs）属于 TGF-β超家族的结构相关信号蛋白，可调节广泛的细胞功能。BMP 信号转导的关键步骤是 BMP 受体介导的转录因子 Smad1、5 和 8（统称为 Smad1/5/8）的磷酸化，这导致随后在核内激活 BMP 诱导的基因转录。在这项研究中，我们描述了 PPM1H 作为一种新型细胞质定位的 Smad1/5/8 特异性磷酸酶的鉴定和特性。PPM1H 通过其 Smad 结合结构域直接与 Smad1/5/8 相互作用，并在细胞质中去磷酸化磷酸化 Smad1/5/8（P-Smad1/5/8）。PPM1H 的异位表达减弱了 BMP 信号，而 PPM1H 活性或表达的丧失则极大地增强了 BMP 依赖性基因调控和间充质分化。总之，本研究表明 PPM1H 通过去磷酸化和随后 P-Smad1/5/8 蛋白的核外排除，作为防止过度 BMP 信号的守门员。
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