Activation of estrogen receptor α by S118 phosphorylation involves a ligand-dependent interaction with TFIIH and participation of CDK7

Phosphorylation of the estrogen receptor alpha (ER alpha) N-terminal transcription activation function AF1 at serine 118 (S118) modulates its activity. We show here that human ER alpha is phosphorylated by the TFIIH cyclin-dependent kinase in a ligand-dependent manner. Furthermore, the efficient phosphorylation of S118 requires a ligand-regulated interaction of TFIIH with AF2, the activation function located in the ligand binding domain (LBD) of ER alpha. This interaction involves (1) the integrity of helix 12 of the LBD/AF2 and (2) p62 and XPD, two subunits of the core TFIIH. These findings are suggestive of a novel mechanism by which nuclear receptor activity can be regulated by ligand-dependent recruitment of modifying activities, such as kinases.