Dephosphorylation of the linker regions of Smad1 and Smad2/3 by small C-terminal domain phosphatases has distinct outcomes for bone morphogenetic protein and transforming growth factor-β pathways Journal Article

  

Authors:	Sapkota, G.; Knockaert, M.; Alarcón, C.; Montalvo, E.; Brivanlou, A. H.; Massague, J.
Article Title:	Dephosphorylation of the linker regions of Smad1 and Smad2/3 by small C-terminal domain phosphatases has distinct outcomes for bone morphogenetic protein and transforming growth factor-β pathways
Abstract:	Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-β (TGFβ) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases. The activity of Smad1 in the BMP pathway and Smad2/3 in the TGFβ pathway is restricted by pathway cross-talk and feedback through protein kinases, including MAPK, CDK2/4, p38MAPK, JNK, and others. These kinases phosphorylate Smads 1-3 at the region that links the N-terminal DNA-binding domain and the C-terminal transcriptional domain. Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. Here we provide evidence that SCP1-3 also dephosphorylate the linker regions of Smad1 and Smad2/3 in vitro, in mammalian cells and in Xenopus embryos. Overexpression of SCP 1, 2, or 3 decreased linker phosphorylation of Smads 1, 2 and 3. Moreover, RNA interference-mediated knockdown of SCP1/2 increased the BMP-dependent phosphorylation of the Smad1 linker region as well as the C terminus. In contrast, SCP1/2 knockdown increased the TGFβ-dependent linker phosphorylation of Smad2/3 but not the C-terminal phosphorylation. Consequently, SCP1/2 knockdown inhibited TGFβ transcriptional responses, but it enhanced BMP transcriptional responses. Thus, by dephosphorylating Smad2/3 at the linker (inhibitory) but not the C-terminal (activating) site, the SCPs enhance TGFβ signaling, and by dephosphorylating Smad1 at both sites, the SCPs reset Smad1 to the basal unphosphorylated state. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
Keywords:	signal transduction; controlled study; protein expression; unclassified drug; human cell; nonhuman; proteins; mammalia; animals; protein kinases; bone morphogenetic protein; phosphatase; smad1 protein; smad2 protein; smad3 protein; transforming growth factor beta; carboxy terminal sequence; embryo; cell line; genetic transcription; cell line, tumor; phosphorylation; nuclear proteins; dna; carrier proteins; peptide fragments; bone; transforming growth factor beta1; protein structure, tertiary; binding energy; protein dephosphorylation; enzyme kinetics; biochemistry; phosphoprotein phosphatase; xenopus; xenopus laevis; bone morphogenetic proteins; bone morphogenetic protein (bmp); dna-binding domains; small c terminal domain phosphatase 1; small c terminal domain phosphatase 2; small c terminal domain phosphatase 3
Journal Title:	Journal of Biological Chemistry
Volume:	281
Issue:	52
ISSN:	0021-9258
Publisher:	American Society for Biochemistry and Molecular Biology
Date Published:	2006-12-29
Start Page:	40412
End Page:	40419
Language:	English
DOI:	10.1074/jbc.M610172200
PUBMED:	17085434
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-33845970267&partnerID=40&md5=5ebecfdae9c5af0a1d6b66d33f6b4b72
Notes:	--- - "Cited By (since 1996): 45" - "Export Date: 4 June 2012" - "CODEN: JBCHA" - "Source: Scopus"

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