Diverse post-translational modifications of estrogen receptor α cross-talk in the coordination of 17 β-estradiol-dependent cell proliferation

""The sex hormone 17-estradiol (E2) exerts its pleiotropic effects through the binding to the ligand-activated transcription factor estrogen receptor alpha (ERThe E2:ER complex regulates several physiological processes including cell survival and proliferation through transcriptional [i.e., estrogen responsive element (ERE)-based gene transcription] and non-transcriptional membrane-initiated effects (i.e., activation of signalling cascades).. Many post-translational modifications occur on ER and are regulated by E2. Indeed, E2 induces ER phosphorylation that facilitates ER-dependent gene transcription while the hormone reduces ER palmitoylation, thus modulating the amount of the receptor located at the plasma membrane and the E2 signalling to cell proliferation. The ER is also an ubiquitinated protein: ER polyubiquitination (polyUbq) increases upon E2 binding and E2-dependent ER degradation occurs in parallel to the appearance of the E2-evoked physiological effects.. However, the role of ER post-translational modifications in the regulation of the E2-dependent cell proliferation is poorly appreciated. Therefore, we analyzed here how ER phosphorylation, palmitoylation and ubiquitination influence E2-induced cell proliferation in an integrated manner.. Our results demonstrate that the polyUbq-based ER degradation cross-talks with receptor phosphorylation and palmitoylation and is required for the E2-dependent control of cell proliferation. Furthermore, the lack of ER palmitoylation fastens E2-induced polyUbq-dependent ER degradation and prevents both receptor phosphorylation and E2-dependent cell proliferation. Therefore, these data demonstrate that a code of diverse post-translational modifications occurs on ER and uncover a new model of E2:ER cellular signalling in which the E2-dependent control of ER post-translational modifications finely coordinates the E2 ability to regulate cell proliferation.. "