Regulation of Estrogen Rapid Signaling through Arginine Methylation by PRMT1

Abstract

Evidence is emerging that estrogen receptor alpha (ERalpha) is central to the rapid transduction of estrogen signaling to the downstream kinase cascades; however, the mechanisms underlying this nongenomic function are not fully understood. Here we report a paradigm of ERalpha regulation through arginine methylation by PRMT1, which transiently methylates arginine 260 within the ERalpha DNA-binding domain. This methylation event is required for mediating the extranuclear function of the receptor by triggering its interaction with the p85 subunit of PI3K and Src. Furthermore, we find that the focal adhesion kinase (FAK), a Src substrate involved in the migration process, is also recruited in this complex. Our data indicate that the methylation of ERalpha is a physiological process occurring in the cytoplasm of normal and malignant epithelial breast cells and that ERalpha is hypermethylated in a subset of breast cancers.

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…These study findings implicate the regulation of the subcellular localization of ERα by MTA1s as a mechanism for enhancing ERα extranu-clear actions by nuclear exclusion [91]. Recent studies also found that the ERα was methylated posttranslationally, and methylated ERα was predominantly present in the cytoplasm, suggesting that deregulation of arginine methylase may have consequences in the activation of ERα extranuclear actions [61]. Collectively, these emerging results suggest that ER extranuclear signaling has the potential to affect breast cancer cell migration and metastasis.…”

“…Palmitoylation at cysteine 447 localizes ERα to the plasma membrane and is responsible for the ligand-induced activation of MAPK and PI3K/Akt pathways in breast cancer cells [60]. Another mechanism proposed is that protein arginine N-methyltransferase 1 (PRMT1) methylates ERα at argi-nine 260 in the DNA-binding domain of the ERα mediating the extranuclear function of the receptor [61]. This would then facilitate the interaction between Src/focal adhesion kinase and p85 leading to the propagation of the signal to downstream transduction cascades [61].…”

“…Another mechanism proposed is that protein arginine N-methyltransferase 1 (PRMT1) methylates ERα at argi-nine 260 in the DNA-binding domain of the ERα mediating the extranuclear function of the receptor [61]. This would then facilitate the interaction between Src/focal adhesion kinase and p85 leading to the propagation of the signal to downstream transduction cascades [61]. This information provides compelling evidence to support the existence of a functional extranuclear signaling pathway for E2 in breast cancer cells.…”

Les modifications post-traductionnelles orchestrent l’action du récepteur des œstrogènes εRα dans les tumeurs mammaires

“…ER est méthylé par l'arginine méthyl-transférase PRMT1 sur l'arginine 260 localisée dans le domaine de liaison à l'ADN, et cette modification est essentielle à la formation d'un macrocomplexe qui contient ER/Src/PI3K/FAK (focal adhesion kinase). La méthylation de ER est rapide et transitoire, ce qui suggère l'existence d'une régulation fine de ce processus [19]. La cartographie des modifications post-traductionnelles de ER montre que ces modifications sont concentrées autour de la région charnière, ce qui laisse supposer des relations entre ces différentes modifications (Figure 2 A et B).…”

“…Une étude pour déterminer si la méthylation de ERpeut être considérée comme un marqueur diagnostique et/ou pronostique dans les cancers du sein est en cours [19]. Une étude réalisée sur 267 tumeurs du sein invasives a montré qu'une mutation somatique dans le gène ERa (A908G), conduisant à la substitution de la lysine 303 en arginine, est présente dans 50 % des tumeurs et est associée à un mauvais pronostic.…”