Meta-Biol

• Pathways

Palmitoylation of the estrogen receptor is dynamic. Binding of 17 beta-estradiol induces depalmitoylation by an unidentified protein palmitoyl hydrolase, releasing cytosolic ESRs that are free to interact with signaling proteins to initiate rapid non-genomic signaling (Marino et al, 2008; La Rosa et al, 2012; reviewed in Levin, 2005; Arnal et al, 2017). Dynamic palmitoylation cycles also impact the phosphorylation and degradation of ESR1. Mutation of C447 increases the susceptibility of ESR1 to degradation (La Rosa et al, 2012). Mutation of the palmitoyl acceptor cysteine 447 to alanine also abrogates phosphorylation of serine 118, a major N-terminal domain phosphorylation site that contributes to transcriptional activity. As phosphorylation of S118 itself likely occurs as a result of MAPK activation downstream of estrogen-stimulated membrane ESR1, the rapid non-genomic response to estrogen stimulation is interconnected with the classical transcriptional response.