Intracellular signaling pathways: Nongenomic actions of estrogens and ligand-independent activation of estrogen receptors

Recognition of the complexity of estrogen and estrogen receptor (ER) signaling has substantially increased in the last several years. In their genomic role, estrogens enter the cell and bind to ERs which are members of a superfamily of ligand-regulated transcription factors. However, estrogens also exert non-genomic effects that occur independently of gene transcription. Typically, these relatively rapid events are initiated at the plasma membrane, and result in the activation of intracellular signaling pathways. Regulation of ER transcriptional activity is also complex. Not only do ligands regulate ER-dependent gene expression, but this receptor in the apparent absence of its estrogenic ligand can also be transcriptionally activated by a variety of intracellular signaling pathways. Recent evidence also extends the effects of these signaling pathways to regulating the activity of coactivators, proteins which bind to the ER and amplify its transcriptional activity. Taken together, it is clear that estrogens, ERs and intracellular signaling pathways are intimately linked and this review will explore the relationship between these components of the estrogen-ER signal transduction process.