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Proc Natl Acad Sci U S A
2006 Aug 08;10332:11940-5. doi: 10.1073/pnas.0605133103.
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Unique players in the BMP pathway: small C-terminal domain phosphatases dephosphorylate Smad1 to attenuate BMP signaling.
Knockaert M
,
Sapkota G
,
Alarcón C
,
Massagué J
,
Brivanlou AH
.
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Smad transcription factors are key signal transducers for the TGF-beta/bone morphogenetic protein (BMP) family of cytokines and morphogens. C-terminal serine phosphorylation by TGF-beta and BMP membrane receptors drives Smads into the nucleus as transcriptional regulators. Dephosphorylation and recycling of activated Smads is an integral part of this process, which is critical for agonist sensing by the cell. However, the nuclear phosphatases involved have remained unknown. Here we provide functional, biochemical, and embryological evidence identifying the SCP (small C-terminal domain phosphatase) family of nuclear phosphatases as mediators of Smad1 dephosphorylation in the BMP signaling pathway in vertebrates. Xenopus SCP2/Os4 inhibits BMP activity in the presumptive ectoderm and leads to neuralization. In Xenopus embryos, SCP2/Os4 and human SCP1, 2, and 3 cause selective dephosphorylation of Smad1 compared with Smad2, inhibiting BMP- and Smad1-dependent transcription and leading to the induction of the secondary dorsal axis. In human cells, RNAi-mediated depletion of SCP1 and SCP2 increases the extent and duration of Smad1 phosphorylation in response to BMP, the transcriptional action of Smad1, and the strength of endogenous BMP gene responses. The present identification of the SCP family as Smad C-terminal phosphatases sheds light on the events that attenuate Smad signaling and reveals unexpected links to the essential phosphatases that control RNA polymerase II in eukaryotes.
Baratte,
Screening for antimitotic compounds using the cdc25 tyrosine phosphatase, an activator of the mitosis-inducing p34cdc2/cyclin Bcdc13 protein kinase.
1992, Pubmed
Baratte,
Screening for antimitotic compounds using the cdc25 tyrosine phosphatase, an activator of the mitosis-inducing p34cdc2/cyclin Bcdc13 protein kinase.
1992,
Pubmed
Barford,
The structure and mechanism of protein phosphatases: insights into catalysis and regulation.
1998,
Pubmed
Bollen,
Signaling by protein phosphatases in the nucleus.
2002,
Pubmed
Brivanlou,
Expression of an engrailed-related protein is induced in the anterior neural ectoderm of early Xenopus embryos.
1989,
Pubmed
,
Xenbase
Chen,
Identification of phosphatases for Smad in the BMP/DPP pathway.
2006,
Pubmed
Demonacos,
A new effector pathway links ATM kinase with the DNA damage response.
2004,
Pubmed
Faure,
Endogenous patterns of TGFbeta superfamily signaling during early Xenopus development.
2000,
Pubmed
,
Xenbase
Feng,
Specificity and versatility in tgf-beta signaling through Smads.
2005,
Pubmed
Hata,
OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-Smad and Olf signaling pathways.
2000,
Pubmed
,
Xenbase
Inman,
Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity.
2002,
Pubmed
James,
TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells.
2005,
Pubmed
Kamenski,
Structure and mechanism of RNA polymerase II CTD phosphatases.
2004,
Pubmed
Kohn,
The protein kinase C inhibitor Gö6976 is a potent inhibitor of DNA damage-induced S and G2 cell cycle checkpoints.
2003,
Pubmed
Korchynskyi,
Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter.
2002,
Pubmed
Lin,
PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling.
2006,
Pubmed
Lo,
Ubiquitin-dependent degradation of TGF-beta-activated smad2.
1999,
Pubmed
Lynch,
PKB-mediated negative feedback tightly regulates mitogenic signalling via Gab2.
2002,
Pubmed
Massagué,
Smad transcription factors.
2005,
Pubmed
Mizuide,
Two short segments of Smad3 are important for specific interaction of Smad3 with c-Ski and SnoN.
2003,
Pubmed
Muñoz-Sanjuán,
Neural induction, the default model and embryonic stem cells.
2002,
Pubmed
Ogata,
Bone morphogenetic protein 2 transiently enhances expression of a gene, Id (inhibitor of differentiation), encoding a helix-loop-helix molecule in osteoblast-like cells.
1993,
Pubmed
Sapkota,
Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell vrowth.
2001,
Pubmed
Schier,
Molecular genetics of axis formation in zebrafish.
2005,
Pubmed
Schmitt,
PKA phosphorylation of Src mediates cAMP's inhibition of cell growth via Rap1.
2002,
Pubmed
Shi,
Mechanisms of TGF-beta signaling from cell membrane to the nucleus.
2003,
Pubmed
Su,
Characterization of a highly conserved gene (OS4) amplified with CDK4 in human sarcomas.
1997,
Pubmed
Suzuki,
Xenopus msx1 mediates epidermal induction and neural inhibition by BMP4.
1997,
Pubmed
,
Xenbase
Takeda,
Interaction with Smad4 is indispensable for suppression of BMP signaling by c-Ski.
2004,
Pubmed
,
Xenbase
Vonica,
TCF is the nuclear effector of the beta-catenin signal that patterns the sea urchin animal-vegetal axis.
2000,
Pubmed
,
Xenbase
Wilson,
Concentration-dependent patterning of the Xenopus ectoderm by BMP4 and its signal transducer Smad1.
1997,
Pubmed
,
Xenbase
Xu,
Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFbeta signaling complexes in the cytoplasm and nucleus.
2002,
Pubmed
Yeo,
A novel RNA polymerase II C-terminal domain phosphatase that preferentially dephosphorylates serine 5.
2003,
Pubmed
Yeo,
Small CTD phosphatases function in silencing neuronal gene expression.
2005,
Pubmed
Zohn,
Expression cloning of Xenopus Os4, an evolutionarily conserved gene, which induces mesoderm and dorsal axis.
2001,
Pubmed
,
Xenbase
