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PMID:16751101
| Citation |
Lin, X, Duan, X, Liang, YY, Su, Y, Wrighton, KH, Long, J, Hu, M, Davis, CM, Wang, J, Brunicardi, FC, Shi, Y, Chen, YG, Meng, A and Feng, XH (2006) PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Cell 125:915-28 |
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| 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. |
| Links |
PubMed Online version:10.1016/j.cell.2006.03.044 |
| Keywords |
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 |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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