PLASMA MEMBRANE LOCALIZATION OF ESTROGEN RECEPTOR a ENABLES ESTRADIOL-INDUCED NON GENOMIC EFFECTS

17b-estradiol (E2)-induced rapid functions (from seconds to minutes) can be attributed to a fraction of nuclear estrogen receptor-a (ERa) localized at the plasma membrane. As a potential mechamism, we postulated that palmitoylation of the Cys447 residue may explain the ability of ERa to associate to plasma membrane making possible E2-dependent rapid functions [e.g., extracellular regulated kinase (ERK) activation]. Here we confirm that the mutation of the Cys447 residue to Ala impairs ERa palmitoylation and report direct evidence that palmitoylation allows ERa plasma membrane association, interaction with caveolin-1 and non genomic ERa activities [i.e., ERK and AKT activation, cyclin D1 promoter activity, DNA synthesis] in transfected ER-devoid HeLa cells. Moreover, both ERa palmitoylation and its interaction with caveolin-1 was reduced by E2. Remarkably, in a human epatoma cell line (HepG2), which physiologically expresses ERa, ERa is palmitoylated, E2 negatively regulated ERa palmitoylation and the palmitoylation is required for E2-induced MAPK/ERK and PI3K/AKT signalling pathways activation. These data point to the physiologic role of palmitoylation in the regulation of the ERa non genomic functions that lead to cell proliferation.