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Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways.

Cell | 2009

TGF-beta 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-beta pathways.

Pubmed ID: 19914168 RIS Download

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Associated grants

  • Agency: Howard Hughes Medical Institute, United States
  • Agency: PHS HHS, United States
    Id: BFU2008-02795
  • Agency: NCI NIH HHS, United States
    Id: R01 CA034610
  • Agency: NEI NIH HHS, United States
    Id: R01 EY015708
  • Agency: NCI NIH HHS, United States
    Id: R37 CA034610-27
  • Agency: NCI NIH HHS, United States
    Id: P30 CA008748
  • Agency: NEI NIH HHS, United States
    Id: EY015708
  • Agency: NCI NIH HHS, United States
    Id: R37 CA034610
  • Agency: NCI NIH HHS, United States
    Id: CA34610

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LSM Image Examiner (tool)

RRID:SCR_014344

Software used to compile images obtained from the Zeiss LSM 510 confocal microscope. The browser can be used for general image archiving and handling and interactive measurement in labs and workgroups. Features include orthogonal sectioning, 3D cut function, 3D view with calculation of single projections, and interactive measurement functions in the overlay dialog, such as scale bar, distance, and area.

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