title: C-terminal domain (CTD) small phosphatase-like 2 modulates the canonical bone morphogenetic protein (BMP) signaling and mesenchymal differentiation via Smad dephosphorylation.
abstract: The bone morphogenetic protein (BMP) signaling pathway regulates a wide range of cellular responses in metazoans. A key step in the canonical BMP signaling is the phosphorylation and activation of transcription factors Smad1, Smad5, and Smad8 (collectively Smad1/5/8) by the type I BMP receptors. We previously identified PPM1A as a phosphatase toward dephosphorylation of all receptor-regulated Smads (R-Smads), including Smad1/5/8. Here we report another nuclear phosphatase named SCP4/CTDSPL2, belonging to the FCP/SCP family, as a novel Smad phosphatase in the nucleus. SCP4 physically interacts with and specifically dephosphorylates Smad1/5/8, and as a result attenuates BMP-induced transcriptional responses. Knockdown of SCP4 in multipotent mesenchymal C2C12 cells leads to increased expression of BMP target genes and consequently promotes BMP-induced osteogenic differentiation. Collectively, our results demonstrate that SCP4, as a Smad phosphatase, plays a critical role in BMP-induced signaling and cellular functions.
authors.affiliation: Life Sciences Institute, and Innovation Center for Cell Biology, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Life Sciences Institute, and Innovation Center for Cell Biology, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Mu
authors.initials: M
authors.lastname: Xiao
authors.affiliation: Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030; Department of Molecular Physiology and Biophysics, and Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Baoguo
authors.initials: B
authors.lastname: Sun
authors.affiliation: Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Zhengmao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030; Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, and.
authors.forename: Tao
authors.initials: T
authors.lastname: Shen
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Duan
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114.
authors.forename: Paul Borchyung
authors.initials: PB
authors.lastname: Yu
authors.affiliation: Life Sciences Institute, and Innovation Center for Cell Biology, Zhejiang University, Hangzhou, Zhejiang 310058, China,; Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030; Department of Molecular Physiology and Biophysics, and Baylor College of Medicine, Houston, Texas 77030; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030,. Electronic address: xhfeng@zju.edu.cn.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
authors.affiliation: Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030. Electronic address: xialin@bcm.edu.
authors.forename: Xia
authors.initials: X
authors.lastname: Lin
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D020134:Catalytic Domain; D002454:Cell Differentiation; D002460:Cell Line; D015870:Gene Expression; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D010006:Osteoblasts / Q000502:physiology; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D012319:RNA Polymerase II / Q000378:metabolism; D015398:Signal Transduction; D051898:Smad1 Protein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D012319:RNA Polymerase II; C000594849:CTDSPL2 protein, mouse; D010749:Phosphoprotein Phosphatases
keywords: Bone Morphogenetic Protein (BMP); Osteoblast; Phosphatase; Phosphorylation; SMAD Transcription Factor; Transforming Growth Factor Beta (TGF-β)
references.citation: Genes Dev. 2006 Mar 15;20(6):648-53
references.pmid: 16510868
references.citation: Cell. 2003 Jun 13;113(6):685-700
references.pmid: 12809600
references.citation: Blood. 2010 Jun 10;115(23):4689-98
references.pmid: 20371744
references.citation: Mol Cell. 2002 Aug;10(2):283-94
references.pmid: 12191474
references.citation: Cell. 2006 Jun 2;125(5):915-28
references.pmid: 16751101
references.citation: Mol Cell. 2006 Dec 8;24(5):759-770
references.pmid: 17157258
references.citation: Dev Cell. 2009 Mar;16(3):329-43
references.pmid: 19289080
references.citation: J Biol Chem. 2006 Dec 15;281(50):38365-75
references.pmid: 17035229
references.citation: J Cell Biol. 1994 Dec;127(6 Pt 1):1755-66
references.pmid: 7798324
references.citation: Nat Rev Genet. 2003 Oct;4(10):763-73
references.pmid: 14526373
references.citation: Nature. 2003 Oct 9;425(6958):577-84
references.pmid: 14534577
references.citation: Annu Rev Cell Dev Biol. 2005;21:659-93
references.pmid: 16212511
references.citation: Nat Chem Biol. 2008 Jan;4(1):33-41
references.pmid: 18026094
references.citation: Genes Dev. 2003 Dec 15;17(24):2993-7
references.pmid: 14701870
references.citation: J Biol Chem. 2013 Jan 4;288(1):79-88
references.pmid: 23150675
references.citation: Cell Res. 2014 Jun;24(6):727-41
references.pmid: 24732009
references.citation: Nat Rev Mol Cell Biol. 2004 Mar;5(3):209-19
references.pmid: 14991001
references.citation: Mol Cell. 2002 Aug;10(2):271-82
references.pmid: 12191473
references.citation: Cell Res. 2009 Jan;19(1):8-20
references.pmid: 19114991
references.citation: Cell Cycle. 2005 Jan;4(1):63-6
references.pmid: 15611645
references.citation: Dev Cell. 2009 Mar;16(3):345-57
references.pmid: 19289081
references.citation: J Biol Chem. 2006 Dec 1;281(48):36526-32
references.pmid: 16931515
references.citation: J Biol Chem. 2006 Dec 29;281(52):40412-9
references.pmid: 17085434
references.citation: Nature. 2008 May 22;453(7194):519-23
references.pmid: 18497825
references.citation: Cell. 2003 Oct 31;115(3):281-92
references.pmid: 14636556
references.citation: J Biol Chem. 2002 Feb 15;277(7):4883-91
references.pmid: 11729207
references.citation: Development. 2010 Jul;137(13):2095-105
references.pmid: 20504958
references.citation: Biochem Pharmacol. 2013 Apr 1;85(7):857-64
references.pmid: 23333766
references.citation: Trends Cell Biol. 2003 May;13(5):216-20
references.pmid: 12742164
references.citation: Cold Spring Harb Perspect Biol. 2016 May 02;8(5):
references.pmid: 27141051
references.citation: Clin Orthop Relat Res. 1990 Mar;(252):276-93
references.pmid: 2154350
references.citation: Ann N Y Acad Sci. 2007 Nov;1116:29-49
references.pmid: 18083919
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):11940-5
references.pmid: 16882717