Nuclear CDKs Drive Smad Transcriptional Activation and Turnover in BMP and TGF-β Pathways

Claudio Alarcón, Alexia Ileana Zaromytidou, Qiaoran Xi, Sheng Gao, Jianzhong Yu, Sho Fujisawa, Afsar Barlas, Alexandria N. Miller, Katia Manova-Todorova, Maria J. Macias, Gopal Sapkota, Duojia Pan, Joan Massagué

Research output: Contribution to journalArticle

444 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)757-769
Number of pages13
JournalCell
Volume139
Issue number4
DOIs
StatePublished - Nov 13 2009

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Phosphorylation
Transcriptional Activation
Chemical activation
Mediator Complex
Bone Morphogenetic Protein Receptors
Smad Proteins
Organ Size
Proteasome Endopeptidase Complex
Transcription
Ligases
Ubiquitin
Stem cells
Elongation
Transcription Factors
Phosphotransferases

Keywords

  • PROTEINS
  • SIGNALING

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Alarcón, C., Zaromytidou, A. I., Xi, Q., Gao, S., Yu, J., Fujisawa, S., ... Massagué, J. (2009). Nuclear CDKs Drive Smad Transcriptional Activation and Turnover in BMP and TGF-β Pathways. Cell, 139(4), 757-769. https://doi.org/10.1016/j.cell.2009.09.035

Nuclear CDKs Drive Smad Transcriptional Activation and Turnover in BMP and TGF-β Pathways. / Alarcón, Claudio; Zaromytidou, Alexia Ileana; Xi, Qiaoran; Gao, Sheng; Yu, Jianzhong; Fujisawa, Sho; Barlas, Afsar; Miller, Alexandria N.; Manova-Todorova, Katia; Macias, Maria J.; Sapkota, Gopal; Pan, Duojia; Massagué, Joan.

In: Cell, Vol. 139, No. 4, 13.11.2009, p. 757-769.

Research output: Contribution to journalArticle

Alarcón, C, Zaromytidou, AI, Xi, Q, Gao, S, Yu, J, Fujisawa, S, Barlas, A, Miller, AN, Manova-Todorova, K, Macias, MJ, Sapkota, G, Pan, D & Massagué, J 2009, 'Nuclear CDKs Drive Smad Transcriptional Activation and Turnover in BMP and TGF-β Pathways', Cell, vol. 139, no. 4, pp. 757-769. https://doi.org/10.1016/j.cell.2009.09.035
Alarcón C, Zaromytidou AI, Xi Q, Gao S, Yu J, Fujisawa S et al. Nuclear CDKs Drive Smad Transcriptional Activation and Turnover in BMP and TGF-β Pathways. Cell. 2009 Nov 13;139(4):757-769. https://doi.org/10.1016/j.cell.2009.09.035
Alarcón, Claudio ; Zaromytidou, Alexia Ileana ; Xi, Qiaoran ; Gao, Sheng ; Yu, Jianzhong ; Fujisawa, Sho ; Barlas, Afsar ; Miller, Alexandria N. ; Manova-Todorova, Katia ; Macias, Maria J. ; Sapkota, Gopal ; Pan, Duojia ; Massagué, Joan. / Nuclear CDKs Drive Smad Transcriptional Activation and Turnover in BMP and TGF-β Pathways. In: Cell. 2009 ; Vol. 139, No. 4. pp. 757-769.
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AU - Barlas, Afsar

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