Estrogen receptor (ER)alpha-mediated non genomic events are now defined as necessary and sufficient for 17-estradiol (E2)-induced cell cycle-regulating genes (e.g., cyclin D1) and G1/S phase transition. Although ER interaction with specific membrane proteins and ER lipid modifications have been proposed for ER membrane localization, the biochemical bases for ER interaction with the plasma membrane are unknown. As a potential mechanism, we demonstrated that S-palmitoylation of the Cys447 residue may explain the ability of ER to associate to plasma membrane making possible E2-dependent rapid functions. Cell lines expressing transfected or endogenous human ER (HeLa and HepG2, respectively) or the ER non-palmitoylable Cys447Ala mutant transfected in HeLa cells have been used as experimental models. Here, we report direct evidence that ER is a palmitoylated protein. The mutation of the Cys447 residue to Ala impairs ER palmitoylation and results in the loss of ER plasma membrane localization and interaction with caveolin-1. In turn, E2-induced rapid non-genomic signals (i.e., ERK and AKT activation, cyclin D1 promoter activity and DNA synthesis) are also prevented. Remarkably, both ER palmitoylation and its interaction with caveolin-1 are slowly reduced by E2 in time and dose dependent fashion. The cell stimulation with other ER ligands (i.e., naringenin, a natural flavonoid broadly present in the western diet, and tamoxifen) induces an extremely rapid reduction of ER palmitoylation and its interaction with caveolin-1, impairing the activation of signal molecules (AKT and ERK-2 phoshorylation). As a whole, these data indicate that palmitoylation can be regarded as a regulatory device enabling ERalpha to initiate non-genomic signal transduction pathways that lead cell to proliferate.
Galluzzo, P., Marino, M. (2005). LIGAND-INDUCED REGULATION OF ER alpha PALMITOYLATION. In European Network of Excellence CASCADE Summer School on Endocrinology: Nuclear Receptors and their Ligands in Metabolism and Disease Bregenz, Austria. (pp.15). non disponibile : non disponibile.