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ZIRC
ZFIN ID: ZDB-PUB-060616-26
PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling
Lin, X., Duan, X., Liang, Y.Y., Su, Y., Wrighton, K.H., Long, J., Hu, M., Davis, C.M., Wang, J., Brunicardi, F.C., Shi, Y., Chen, Y.G., Meng, A., and Feng, X.H.
Date: 2006
Source: Cell   125(5): 915-928 (Journal)
Registered Authors: Meng, Anming, Su, Ying
Keywords: none
MeSH Terms:
  • Active Transport, Cell Nucleus/physiology
  • Activin Receptors, Type I/metabolism
  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Embryo, Nonmammalian
  • Humans
  • Phosphoprotein Phosphatases/genetics
  • Phosphoprotein Phosphatases/metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases/metabolism
  • Receptors, Transforming Growth Factor beta/metabolism
  • Signal Transduction/physiology*
  • Smad2 Protein/metabolism*
  • Smad3 Protein/metabolism*
  • Transforming Growth Factor beta/metabolism*
  • Up-Regulation/physiology
  • Zebrafish
PubMed: 16751101 Full text @ Cell
FIGURES
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.
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