Regulation of estrogen rapid signaling through arginine methylation by PRMT1

Evidence is emerging that estrogen receptor alpha (ER alpha) is central to the rapid transduction of estrogen signaling to the downstream kinase cascades; however, the mechanisms underlying this nongenomic function are not fully understood. Here we report a paradigm of ER alpha regulation through arginine methylation by PRMT1, which transiently methylates arginine 260 within the ERa DNA-binding domain. This methylation event is required for mediating the extranuclear function of the receptor by triggering its interaction with the p85 subunit of PI3K and Src. Furthermore, we find that the focal adhesion kinase (FAK), a Src substrate involved in the migration process, is also recruited in this complex. Our data indicate that the methylation of ER alpha is a physiological process occurring in the cytoplasm of normal and malignant epithelial breast cells and that ER alpha is hypermethylated in a subset of breast cancers.