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

doi:10.1016/j.cell.2009.09.035

Back

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

Journal article

Open access

Peer reviewed

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, …

Cell, Vol.139(4), pp.757-769

11/13/2009

DOI: 10.1016/j.cell.2009.09.035

PMCID: 2818353

PMID: 19914168

Files and links (1)

url

https://doi.org/10.1016/j.cell.2009.09.035View

Published (Version of record) Open Access

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.

PROTEINS

SIGNALING

Details

Title: Subtitle: Nuclear CDKs Drive Smad Transcriptional Activation and Turnover in BMP and TGF-β Pathways
Creators: Claudio Alarcón - Memorial Sloan Kettering Cancer Center
Alexia-Ileana Zaromytidou - Memorial Sloan Kettering Cancer Center
Qiaoran Xi - Memorial Sloan Kettering Cancer Center
Sheng Gao - Memorial Sloan Kettering Cancer Center
Jianzhong Yu - Johns Hopkins University
Sho Fujisawa - Memorial Sloan Kettering Cancer Center
Afsar Barlas - Memorial Sloan Kettering Cancer Center
Alexandria N. Miller - Memorial Sloan Kettering Cancer Center
Katia Manova-Todorova - Memorial Sloan Kettering Cancer Center
Maria J. Macias - Structural and Computational Biology Programme, Institute for Research in Biomedicine, Barcelona 08028, Spain
Gopal Sapkota - Memorial Sloan Kettering Cancer Center
Duojia Pan - Johns Hopkins Medicine
Joan Massagué - Memorial Sloan Kettering Cancer Center
Resource Type: Journal article
Publication Details: Cell, Vol.139(4), pp.757-769
Publisher: Elsevier Inc
DOI: 10.1016/j.cell.2009.09.035
PMID: 19914168
PMCID: 2818353
ISSN: 0092-8674
eISSN: 1097-4172
Language: English
Date published: 11/13/2009
Academic Unit: Molecular Physiology and Biophysics
Record Identifier: 9984446426902771

Metrics

5 Record Views

605 Times Cited - Web of Science

See more details