Activation of TRAP/mediator subunit TRAP220/Med1 is regulated by mitogen-activated protein kinase-dependent phosphorylation.
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 G(2)/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.
Pandey
Pradeep K
PK
Department of Physiology and Biophysics, Robert Wood Johnson Medical School, UMDNJ, Piscataway, NJ 08854, USA.
Udayakumar
T S
TS
Lin
Xinjie
X
Sharma
Dipali
D
Shapiro
Paul S
PS
Fondell
Joseph D
JD
D000818:Animals; D002453:Cell Cycle; D002466:Cell Nucleolus / Q000737:chemistry / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D056913:Mediator Complex Subunit 1; D009154:Mutation; D010766:Phosphorylation; D021122:Protein Subunits / Q000378:metabolism; D034622:RNA Interference; D017384:Sequence Deletion; D013912:Threonine / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
C538855:MED1 protein, human; D056913:Mediator Complex Subunit 1; D021122:Protein Subunits; D014157:Transcription Factors; D013912:Threonine; D048049:Extracellular Signal-Regulated MAP Kinases