Endocrine Abstracts

The sex hormone 17β-estradiol (E2) exerts its pleiotropic effects through the binding to the ligand-activated transcription factor estrogen receptor alpha (ERa). The E2:ERa 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 ERa and are regulated by E2. Indeed, E2 induces ERa phosphorylation that facilitates ERa-dependent gene transcription while the hormone reduces ERa palmitoylation, thus modulating the amount of the receptor located at the plasma membrane and the E2 signalling to cell proliferation. The ERa is also an ubiquitinated protein: ERa polyubiquitination (polyUbq) increases upon E2 binding and E2-dependent ERa degradation occurs in parallel to the appearance of the E2-evoked physiological effects.

However, the role of ERa post-translational modifications in the regulation of the E2-dependent cell proliferation is poorly appreciated. Therefore, we analyzed here how ERa phosphorylation, palmitoylation and ubiquitination influence E2-induced cell proliferation in an integrated manner.

Our results demonstrate that the polyUbq-based ERa degradation cross-talks with receptor phosphorylation and palmitoylation and is required for the E2-dependent control of cell proliferation. Furthermore, the lack of ERa palmitoylation fastens E2-induced polyUbq-dependent ERa 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 ERa and uncover a new model of E2: ERa cellular signalling in which the E2-dependent control of ERa post-translational modifications finely coordinates the E2 ability to regulate cell proliferation.