Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-β pathways Journal Article


Authors: Alarcón, C.; Zaromytidou, A. I.; Xi, Q.; Gao, S.; Yu, J.; Fujisawa, S.; Barlas, A.; Miller, A. N.; Manova-Todorova, K.; Macias, M. J.; Sapkota, G.; Pan, D.; Massague, J.
Article Title: Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-β pathways
Abstract: TGF-β and BMP receptor kinases activate Smad transcription factors by C-terminal phosphorylation. We have identified a subsequent agonist-induced phosphorylation that plays a central dual role in Smad transcriptional activation and turnover. As receptor-activated Smads form transcriptional complexes, they are phosphorylated at an interdomain linker region by CDK8 and CDK9, which are components of transcriptional mediator and elongation complexes. These phosphorylations promote Smad transcriptional action, which in the case of Smad1 is mediated by the recruitment of YAP to the phosphorylated linker sites. An effector of the highly conserved Hippo organ size control pathway, YAP supports Smad1-dependent transcription and is required for BMP suppression of neural differentiation of mouse embryonic stem cells. The phosphorylated linker is ultimately recognized by specific ubiquitin ligases, leading to proteasome-mediated turnover of activated Smad proteins. Thus, nuclear CDK8/9 drive a cycle of Smad utilization and disposal that is an integral part of canonical BMP and TGF-β pathways. © 2009 Elsevier Inc. All rights reserved.
Keywords: signal transduction; controlled study; protein phosphorylation; unclassified drug; human cell; nonhuman; protein function; protein motif; proteins; animal cell; mouse; animal tissue; proteasome; gene expression; signaling; benzyloxycarbonylleucylleucylleucinal; beta iii tubulin; beta tubulin; bone morphogenetic protein; bone morphogenetic protein receptor; cyclin dependent kinase 8; cyclin dependent kinase 9; inhibitor of differentiation 1; mitogen activated protein kinase inhibitor; mitogen activated protein kinase p38; nuclear protein; phosphatase; protein kinase inhibitor; receptor regulated smad protein; serine; smad protein; smad1 protein; smad2 protein; smad3 protein; smad5 protein; smad7 protein; stress activated protein kinase; transforming growth factor beta; ubiquitin protein ligase; yes associated protein; carboxy terminal sequence; embryo; embryonic stem cell; enzyme degradation; germ cell; protein assembly; protein degradation; protein depletion; protein dna binding; protein metabolism; protein protein interaction; protein targeting; transcription initiation
Journal Title: Cell
Volume: 139
Issue: 4
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 2009-11-13
Start Page: 757
End Page: 769
Language: English
DOI: 10.1016/j.cell.2009.09.035
PROVIDER: scopus
PUBMED: 19914168
PMCID: PMC2818353
DOI/URL:
Notes: --- - "Cited By (since 1996): 13" - "Export Date: 30 November 2010" - "CODEN: CELLB" - "Source: Scopus"
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MSK Authors
  1. Sheng Gao
    3 Gao
  2. Joan Massague
    287 Massague
  3. Afsar Barlas
    22 Barlas
  4. Qiaoran Xi
    8 Xi
  5. Alexandria Miller
    8 Miller