17beta-estradiol (E2) exerts its pleiotropic effects through the binding to the transcription factor estrogen receptor alpha (ERa). The E2:ERa complex regulates several physiological processes including cell survival and proliferation through transcriptional (gene transcription) and non-transcriptional membrane-initiated effects (activation of signalling cascades).

Many post-translational (PTMs) 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 receptor plasma membrane localization 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 PTMs 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. These data demonstrate that a code of diverse PTMs 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.