MED1 phosphorylation promotes its association with Mediator: implications for nuclear receptor signaling

Department of Physiology and Biophysics, Robert Wood Johnson Medical School, UMDNJ, Piscataway, NJ 08854

^* To whom correspondence should be addressed. Email: fondeljd{at}umdnj.edu.

	Abstract

Mediator is a conserved multisubunit complex that acts as a functional interface between regulatory transcription factors and the general RNA polymerase II initiation apparatus. MED1 is a pivotal component of the complex that binds to nuclear receptors and broad array of other gene-specific activators. Paradoxically, MED1 is found in only a fraction of the total cellular Mediator complexes and the mechanisms regulating its binding to the core complex remain unclear. Here we report that phosphorylation of MED1 by MAPK-ERK promotes its association with Mediator. We show that MED1 directly binds to the MED7 subunit and that ERK phosphorylation of MED1 enhances this interaction. Interestingly, we found that both thyroid and steroid hormones stimulate MED1 phosphorylation in vivo, and that MED1 phosphorylation is required for its NR coactivator activity. Finally, we show that MED1 phosphorylation by ERK enhances thyroid hormone receptor-dependent transcription in vitro. Our findings suggest that ERK phosphorylation of MED1 is a regulatory mechanism that promotes MED1 association with Mediator and as such, may facilitate a novel feed-forward action of nuclear hormones.