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

Recognition of the complexity of estrogen and estrogen receptor (ER) signal ing 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 supe rfamily of ligand-regulated transcription factors. However, estrogens also exert non-genomic effects that occur independently of gene transcription. T ypically, these relatively rapid events are initiated at the plasma membran e, and result in the activation of intracellular signaling pathways. Regula tion of ER transcriptional activity is also complex. Not only do ligands re gulate ER-dependent gene expression, but this receptor in the apparent abse nce of its estrogenic ligand can also be transcriptionally activated by a v ariety of intracellular signaling pathways. Recent evidence also extends th e effects of these signaling pathways to regulating the activity of coactiv ators, proteins which bind to the ER and amplify its transcriptional activi ty. Taken together, it is clear that estrogens, ERs and intracellular signa ling pathways are intimately linked and this review will explore the relati onship between these components of the estrogen-ER signal transduction proc ess.