Ppm1a Functions As a Smad Phosphatase to Terminate Tgfbeta Signaling.
From: Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA. xialin@bcm.edu
Cell
- Publish Date: Jun 2006
- ISSN: 0092-8674
- Volume: 125
- Issue: 5
- Pages: 915-28
- Medium: Print
- Language: English
- Citation (JAMA): Lin Xia, Duan Xueyan, Liang Yao-Yun, et al. Ppm1a Functions As a Smad Phosphatase to Terminate Tgfbeta Signaling.. Cell Jun 2006;125:915-28
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.
Mesh Headings (Keywords): Active Transport, Cell Nucleus, Activin Receptors, Type I, Animals, Cell Line, Cell Line, Tumor, Embryo, Nonmammalian, Humans, Phosphoprotein Phosphatases, Phosphorylation, Protein-Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Signal Transduction, Smad2 Protein, Smad3 Protein, Transforming Growth Factor beta, Up-Regulation, Zebrafish
Check for Full Text / PubMed Unique Identifier (PMID): 16751101
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