title: Specific control of BMP signaling and mesenchymal differentiation by cytoplasmic phosphatase PPM1H.
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.
authors.affiliation: 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.
authors.forename: Tao
authors.initials: T
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Chuang
authors.initials: C
authors.lastname: Sun
authors.affiliation: Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Zhengmao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Ningyi
authors.initials: N
authors.lastname: Xu
authors.affiliation: Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Duan
authors.affiliation: 1] Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China [2] Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA [3] Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA [4] Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
authors.affiliation: Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Lin
mesh_terms: D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D051898:Smad1 Protein / Q000737:chemistry / Q000378:metabolism; D051902:Smad5 Protein / Q000737:chemistry / Q000378:metabolism; D051904:Smad8 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D034741:RNA, Small Interfering; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; D016212:Transforming Growth Factor beta; C521058:PPM1H protein, human; D010749:Phosphoprotein Phosphatases
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