Signaling functions of ubiquitin in the 17β-estradiol (E2):estrogen receptor (ER) α network

Protein posttranslational modifications (PTMs) are signaling alterations that allow coordinating the cellular responses with the changes in the extracellular environment. In this way, the posttranslationally-modified protein becomes a switch node in the transduction network activated by the specific extracellular stimuli. It is now clear that this is the case also for protein ubiquitination: this extremely versatile PTM controls cell physiology through the modulation of protein stability as well as through the modulation of the dynamics of the intracellular signaling cascades. Recent evidence clearly indicates that such a complex scheme appears to be valid also for the 17β-estradiol (E2):estrogen receptor (ER) α signal transduction pathways. Indeed, beside the long standing notion that ERα ubiquitination is required for the regulation of receptor stability, several laboratories, including our own, have clearly indicated that ERα ubiquitination also serves non-degradative functions. This review will reconsider the role of ubiquitination in E2:ERα signaling by particularly highlighting how the functions of the non-degradative ubiquitination impact on ERα activities and contribute to the modulation of E2-dependent physiological processes.

► The ubiquitin- and ERα -based signaling networks merge.
► Ubiquitination of the ERα is not only for the 26S proteasome.
► Proteolytic and non-degradative functions of ubiquitin regulate E2:ERα-mediated cellular processes.