Aim: 

The estrogen receptor alpha (ERalpha) is a palmitoylated protein and the palmitoylation is required for its localization to the plasma membrane. In addition ERalpha palmitoylation is negatively regulated by 17beta-estradiol (E2) and is critical for the E2-induced PI3K/AKT and ERK/MAPK activation in different cell lines. A well recognized effect of E2 in target cells is the hormone ability to reduce the ERalpha cellular content by inducing the proteasome-mediated receptor degradation.

Methods and Results: 

Here, we evaluated the influence of membrane bound ERalpha upon receptor degradation in MCF-7 cells. Data shows that also in MCF-7 cells ERalpha is enzymatically palmitoylated, E2 reduces the level of ERalpha palmitoylation and that the rapid E2-evoked activation of the ERK/MAPK and PI3K/AKT signal trasduction pathways are dependent on ERalpha palmitoylation. Remarkably, lack of ERalpha palmitoylation fastens the E2-induced ERalpha breakdown. Moreover, different natural or synthetic ERalpha ligands differentially impact on ERalpha turnover and activation of signal kinases.

Conclusions: 

Thus, the E2-induced membrane starting signals protect ERalpha from E2-induced degradation and receptor palmitoylation stabilizes ERalpha. These data strongly imply membrane bound ERalpha in the regulation of receptor turnover and steady state.