The extra-nuclear interactome of the estrogen receptors: implications for physiological functions

Over the last decades, a great body of evidence has defined a novel view of the cellular mechanism of action ofthe steroid hormone 17β-estradiol (E2) through its estrogen receptors (i.e., ERα and ERβ). It is now clear that theE2-activated ERs work both as transcription factors and extra-nuclear plasma membrane-localized receptors. Theactivation of a plethora of signal transduction cascades follows the E2-dependent engagement of plasmamembrane-localized ERs and is required for the coordination of gene expression, which ultimately controls theoccurrence of the pleiotropic effects of E2. The definition of the molecular mechanisms by which the ERs locateat the cell surface (i.e., palmitoylation and protein association) determined the quest for understanding thespecificity of the extra-nuclear E2 signaling. The use of mice models lacking the plasma membrane ERα localizationunveiled that the extra-nuclear E2 signaling is operational in vivo but tissue-specific. However, the underlyingmolecular details for such ERs signaling diversity in the perspective of the E2 physiological functions inthe different cellular contexts are still not understood. Therefore, to gain insights into the tissue specificity of theextra-nuclear E2 signaling to physiological functions, here we reviewed the known ERs extra-nuclear interactorsand tried to extrapolate from available databases the ERα and ERβ extra-nuclear interactomes. Based on literaturedata, it is possible to conclude that by specifically binding to extra-nuclear localized proteins in differentsub-cellular compartments, the ERs fine-tune their molecular activities. Moreover, we report that the contextdependentdiversity of the ERs-mediated extra-nuclear E2 actions can be ascribed to the great flexibility ofthe physical structures of ERs and the spatial-temporal organization of the logistics of the cells (i.e., the endocyticcompartments). Finally, we provide lists of proteins belonging to the potential ERα and ERβ extra-nuclearinteractomes and propose that the systematic experimental definition of the ERs extra-nuclear interactomes indifferent tissues represents the next step for the research in the ERs field. Such characterization will be fundamentalfor the identification of novel druggable targets for the innovative treatment of ERs-related diseases.