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Molecular and Cellular Biology, December 2005, p. 10695-10710, Vol. 25, No. 24
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.24.10695-10710.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Activation of TRAP/Mediator Subunit TRAP220/Med1 Is Regulated by Mitogen-Activated Protein Kinase-Dependent Phosphorylation

Pradeep K. Pandey,1 T. S. Udayakumar,1 Xinjie Lin,1 Dipali Sharma,2,{dagger} Paul S. Shapiro,3 and Joseph D. Fondell1*

Department of Physiology and Biophysics, Robert Wood Johnson Medical School, UMDNJ, Piscataway, New Jersey 08854,1 Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201,2 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 212013

Received 16 June 2005/ Returned for modification 15 July 2005/ Accepted 29 August 2005

The TRAP/Mediator coactivator complex serves as a molecular bridge between gene-specific activators and RNA polymerase II. TRAP220/Med1 is a key component of TRAP/Mediator that targets the complex to nuclear hormone receptors and other types of activators. We show here that human TRAP220/Med1 is a specific substrate for extracellular signal-regulated kinase (ERK) of the mitogen-activated protein kinase (MAPK) family. We demonstrate that ERK phosphorylates TRAP220/Med1 in vivo at two specific sites: threonine 1032 and threonine 1457. Importantly, we found that ERK phosphorylation significantly increases the stability and half-life of TRAP220/Med1 in vivo and correlates with increased thyroid hormone receptor-dependent transcription. Furthermore, ERK phosphorylates TRAP220/Med1 in a cell cycle-dependent manner, resulting in peak levels of expression during the G2/M phase of the cell cycle. ERK phosphorylation of ectopic TRAP220/Med1 also triggered shuttling into the nucleolus, thus suggesting that ERK may regulate TRAP220/Med1 subnuclear localization. Finally, we observed that ERK phosphorylation of TRAP220/Med1 stimulates its intrinsic transcriptional coactivation activity. We propose that ERK-mediated phosphorylation is a regulatory mechanism that controls TRAP220/Med1 expression levels and modulates its functional activity.

* Corresponding author. Mailing address: Robert Wood Johnson Medical School, UMDNJ, 683 Hoes Lane, Piscataway, NJ 08854. Phone: (732) 235-3348. Fax: (732) 235-5823. E-mail: fondeljd{at}umdnj.edu.

{dagger} Present address: Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322.

Molecular and Cellular Biology, December 2005, p. 10695-10710, Vol. 25, No. 24
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.24.10695-10710.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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