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

在过去的几十年中，大量证据定义了类固醇激素 17β-雌二醇 (E2) 通过其雌激素受体（即 ERα 和 ERβ）的细胞作用机制的新观点。现在很清楚，E2 激活的 ER 既可以作为转录因子，也可以作为核外质膜定位受体。大量信号转导级联的激活遵循 E2 依赖性参与质膜定位的 ER，并且是协调基因表达所必需的，这最终控制了 E2 多效性效应的发生。ER 定位于细胞表面的分子机制（即棕榈酰化和蛋白质结合）的定义决定了对了解核外 E2 信号传导的特异性的探索。体内但组织特异性。然而，从不同细胞环境中的 E2 生理功能的角度来看，此类 ER 信号多样性的潜在分子细节仍不清楚。因此，为了深入了解核外 E2 信号传导对生理功能的组织特异性，我们在此回顾了已知的 ERs 核外相互作用物，并试图从可用的数据库中推断 ERα 和 ERβ 核外相互作用组。根据文献数据，可以得出结论，通过特异性结合不同亚细胞区室中的核外定位蛋白，内质网可以微调其分子活性。而且，我们报告说，ERs 介导的核外 E2 作用的上下文依赖性多样性可归因于 ERs 物理结构的巨大灵活性和细胞后勤的时空组织（即内吞隔室） . 最后，我们提供了属于潜在 ERα 和 ERβ 核外相互作用组的蛋白质列表，并提出不同组织中 ERs 核外相互作用组的系统实验定义代表了 ERs 领域研究的下一步。这种表征对于确定用于创新治疗 ER 相关疾病的新药靶点至关重要。我们提供了属于潜在 ERα 和 ERβ 核外相互作用组的蛋白质列表，并建议对不同组织中 ERs 核外相互作用组的系统实验定义代表了 ERs 领域研究的下一步。这种表征对于确定用于创新治疗 ER 相关疾病的新药靶点至关重要。我们提供了属于潜在 ERα 和 ERβ 核外相互作用组的蛋白质列表，并建议对不同组织中 ERs 核外相互作用组的系统实验定义代表了 ERs 领域研究的下一步。这种表征对于确定用于创新治疗 ER 相关疾病的新药靶点至关重要。