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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, Paul S. Shapiro,³ and Joseph D. Fondell^1*

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.

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

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