Scaffolding proteins mediating membrane-initiated extra-nuclear actions of estrogen receptor

Estrogen mediates biological effects on cell proliferation, differentiation, and homeostasis through estrogen receptor (ER). In addition to functioning as a ligand-activated nuclear transcription factor to directly regulate gene transcription, ER also mediates rapid activation of signaling pathways independent of its transcriptional activity. A subpopulation of ER localized to the cell membrane or cytoplasm has been proposed to mediate ER activation of signaling pathways. This review focuses on recent advances in our understanding of mechanisms responsible for ER cytoplasm/membrane localization, where rapid extra-nuclear signaling is initiated. These mechanisms include lipid modification of the receptor (palmitoylation) and interactions with membrane and cytoplasmic adaptor proteins including caveolins, striatin, p130Cas, Shc, HPIP, MTA-1s, and MNAR/PELP1. While it is clear that ER mediates rapid extra-nuclear signaling resulting in activation of signaling pathways such as Src/MAPK and PI-3 kinase/Akt, how ER extra-nuclear signaling influences overall ER/estrogen physiology is still not well understood. Future studies defining physiological roles of ER extra-nuclear actions and crosstalk with its nuclear counterparts will be important to our overall understanding of estrogen and ER biological functions.