Editors' ChoiceNuclear Receptors

Regulating Estrogen Receptor’s Cytoplasmic Partners

Science Signaling  29 Jul 2008:
Vol. 1, Issue 30, pp. ec273
DOI: 10.1126/scisignal.130ec273

The estrogen (E2) receptor is best known for its actions as a transcriptional activator, but evidence continues to accumulate for rapid nongenomic effects of estrogen receptors outside the nucleus as well. Le Romancer et al. provide evidence that interaction of estrogen receptor alpha (Erα) with phosphoinositide 3-kinase (PI3K) and the tyrosine kinase Src depends on covalent modification of ERα by arginine methylation. The arginine methyltransferase PRMT1 (protein arginine methyltransferase 1) is known to associate with Erα and to regulate its transcriptional activity. Le Romancer et al. developed an antibody that appears to specifically recognize ERα that is dimethylated on R260. Immunoprecipitation of ERα from the human breast cancer cell line MCF-7 with this antibody showed that methylation of the receptor was increased within 5 min of treatment of cells with E2 and that the methylated form of the receptor was found exclusively in the cytoplasm (although the bulk of ERα was localized in the nucleus). Methylation of ERα was correlated with its association with Src and the p85 subunit of PI3K. Depletion of PRMT1 from cells by treating them with siRNA inhibited the formation of the protein complex. Examination of tyrosine phosphorylated proteins associated with the activated receptor identified focal adhesion kinase as a new component in the complex. In mouse NIH 3T3 cells transfected with wild-type ERα, phosphorylation of the kinase Akt was evident within 5 min of E2 treatment, but such regulation of Akt was diminished in cells expressing a mutant form of ERα in which the site of methylation was modified to prevent methylation. About half of the invasive human breast cancer samples tested showed abnormally high amounts of ERα methylation, but it remains to be determined how this relates to tumor phenotypes and dependence of tumor growth on E2.

M. Le Romancer, I. Treilleux, N. Leconte, Y. Robin-Lespinasse, S. Sentis, K. Bouchekioua-Bouzaghou, S. Goddard, S. Gobert-Gosse, L. Corbo, Regulation of estrogen rapid signaling through arginine methylation by PRMT1. Mol. Cell 31, 212-221 (2008). [PubMed]