title: PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling.
abstract: TGFbeta signaling controls diverse normal developmental processes and pathogenesis of diseases including cancer and autoimmune and fibrotic diseases. TGFbeta responses are generally mediated through transcriptional functions of Smads. A key step in TGFbeta signaling is ligand-induced phosphorylation of receptor-activated Smads (R-Smads) catalyzed by the TGFbeta type I receptor kinase. However, the potential of Smad dephosphorylation as a regulatory mechanism of TGFbeta signaling and the identity of Smad-specific phosphatases remain elusive. Using a functional genomic approach, we have identified PPM1A/PP2Calpha as a bona fide Smad phosphatase. PPM1A dephosphorylates and promotes nuclear export of TGFbeta-activated Smad2/3. Ectopic expression of PPM1A abolishes TGFbeta-induced antiproliferative and transcriptional responses, whereas depletion of PPM1A enhances TGFbeta signaling in mammalian cells. Smad-antagonizing activity of PPM1A is also observed during Nodal-dependent early embryogenesis in zebrafish. This work demonstrates that PPM1A/PP2Calpha, through dephosphorylation of Smad2/3, plays a critical role in terminating TGFbeta signaling.
authors.affiliation: Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA. xialin@bcm.edu
authors.forename: Xia
authors.initials: X
authors.lastname: Lin
authors.forename: Xueyan
authors.initials: X
authors.lastname: Duan
authors.forename: Yao-Yun
authors.initials: YY
authors.lastname: Liang
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.forename: Katharine H
authors.initials: KH
authors.lastname: Wrighton
authors.forename: Jianyin
authors.initials: J
authors.lastname: Long
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.forename: Candi M
authors.initials: CM
authors.lastname: Davis
authors.forename: Jinrong
authors.initials: J
authors.lastname: Wang
authors.forename: F Charles
authors.initials: FC
authors.lastname: Brunicardi
authors.forename: Yigong
authors.initials: Y
authors.lastname: Shi
authors.forename: Ye-Guang
authors.initials: YG
authors.lastname: Chen
authors.forename: Anming
authors.initials: A
authors.lastname: Meng
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D030201:Activin Receptors, Type I / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004625:Embryo, Nonmammalian; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology; D015027:Zebrafish
chemical_list: D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000607456:PPM1A protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C