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Molecular and Cellular Biology, June 2009, p. 3204-3218, Vol. 29, No. 11
0270-7306/09/$08.00+0     doi:10.1128/MCB.01128-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase Signaling Initiates a Dynamic Interplay between Sumoylation and Ubiquitination To Regulate the Activity of the Transcriptional Activator PEA3{triangledown}

Baoqiang Guo and Andrew D. Sharrocks*

Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom

Received 17 July 2008/ Returned for modification 3 October 2008/ Accepted 17 March 2009

Many transcription factors are controlled through SUMO modification, and in the majority of cases this modification results in enhancements in their repressive properties. In some instances, SUMO modification and its associated repressive activities can be reversed by the action of intracellular signaling pathways, leading to enhanced transcriptional capacities of transcription factors. Here we have investigated sumoylation of the ETS domain transcription factor PEA3 and its interplay with the extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase signaling pathway. PEA3 is modified by SUMO in vitro and in vivo on multiple sites in its N-terminal region. Activation of the ERK MAP kinase pathway promotes sumoylation of PEA3. Importantly, sumoylation of PEA3 is required for maximal activation of target gene promoters, including MMP-1 and COX-2. Molecularly, sumoylation is selectively required for synergistic activation of target gene expression with the coactivator CBP. Moreover, sumoylation of PEA3 is required for ubiquitination of PEA3 and promotes its degradation, suggesting that SUMO-mediated recycling of PEA3 plays a role in PEA3-mediated promoter activation. Thus, in contrast to the majority of other transcription factors studied, sumoylation of PEA3 plays a positive role in PEA3-mediated transcriptional activation and the ERK MAP kinase pathway cooperates with rather than antagonizes this process.

* Corresponding author. Mailing address: Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom. Phone: 44-161 275 5979. Fax: 44-161 275 5082. E-mail: a.d.sharrocks{at}manchester.ac.uk

{triangledown} Published ahead of print on 23 March 2008.

Molecular and Cellular Biology, June 2009, p. 3204-3218, Vol. 29, No. 11
0270-7306/09/$08.00+0     doi:10.1128/MCB.01128-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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