Estrogen receptor Phosphorylation

In addition to the foregoing, three further examples in this list (numbers 5-7) deserve consideration. These are (5) interaction of endocrine disrupters with the estrogen receptor, (6) the action of uncouplers of oxidative phosphorylation, and (7) mechanisms of oxidative stress. Until now only the first is well represented by biomarker assays that have been employed in ecotoxicology. 

The steroid hormone receptors are phophoproteins which are usually phosphorylated on several positions. The phosphorylation sites are mainly foimd in the N-terminal region of the receptors. Serine phosphorylation prevails. One rare example of tyrosine phosphorylation is described for the case of estrogen receptors. The consequences of phosphorylation for the receptor proteins are varied. It is conceivable, and in some cases experimentally proven, that it has influence on hormone binding, nuclear transport, DNA binding and transactivation. 

Kato, S., Endoh, H., Masuhiro, Y, Kitamoto, T., Uchiyama, S., Sasaki, H. Masushige, S., Gogoh, Y, Nishida, E., Kawashima, H., Metzger,D. and Chambon, P. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase (1995) Nature 270, 1491-1494... 

Arnold, S. F., Melamed, M., Yorojelkina, D. P., Notides, A. C., and Sasson. S. 1997. Estradiolbinding capacity of the human estrogen receptor is regulated by tyrosine phosphorylation. Mol. Endocrinol. 77 48-53. 

DeVito MJ, Ma X, Babish JG, et al. 1994. Dose-response relationships in mice following subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin CYP1A1, CYP1A2, estrogen receptor, and protein tyrosine phosphorylation. Toxicol Appl Pharmacol 124(l) 82-90. 

Aronica, S.M. and Katzenellenbogen, B.S. (1993) Stimulation of estrogen receptor-mediated transcription and alteration in the phosphorylation state of the rat uterine estrogen receptor by estrogen, cyclic adenosine monophosphate, and insulin-like growth factor-I. Molecular Endocrinology, 7, 743-752. 

Joel, P.B., Traish, A.M. and Lannigan, D.A. (1995) Estradiol and phorhol ester cause phosphorylation of serine 118 in the human estrogen receptor. Molecular Endocrinology, 9, 1041-1052. 

Le Goff, P., Montano, M.M., Schodin, D.J. and Katzenellenbogen, B.S. (1994) Phosphorylation of the human estrogen receptor. Identification of hormone-regulated sites and examination of their influence on transcriptional activity. The Journal of Biological Chemistry, 269, 4458-4466. 

Bates, G.J., Pace, P.E.,Thirunuvakkarasu, V., Taylor, J., Epstein, R.J., Fuller-Pace, F.V., Egly, J.M., Coombes, R.C. and Ali, S. (2002) Phosphorylation of human estrogen receptor a at serine 118 by two distinct signal transduction pathways revealed by phosphorylation-spedfic antisera. 

Fisher. T.L., Blenis, J. and Lannigan, D.A. (1998) pp90rskl regulates estrogen receptor-mediated transcription through phosphorylation of Ser-167. Molecular and Cellular Biology, 18, 1978-1984. 

Cheng X, Hart G W (2001). Alternative O-glycosylation/O-phosphorylation of serine-16 in murine estrogen receptor beta post-translational regulation of turnover and transactivation activity. J. Biol. Chem. 276 10570-10575. 

Duan, R., Xie, W., Burghardt, R.C., and Safe, S., Estrogen receptor-mediated activation of the serum response element in MCF-7 cells through MAPK-dependent phosphorylation of Elk-1, J. Biol Chem., 276, 11590-11598,2001. 

Thomas RS, Sarwar N, Phoenix F, Coombes RC, Ali S. Phosphorylation at serine 104 and 106 by Erkl/2 MAPK is important for estrogen receptor-alpha activity. J Mol Endoctin. 2008 40 173-84. 

Klinge, C.M., Wickramasinghe, N.S., Ivanova, M.M., and Dougherty, S.M. 2008. Resveratrol stimulates nitric oxide production by increasing estrogen receptor alpha-Src-caveo-lin-1 interaction and phosphorylation in human umbilical vein endothelial cells. FASEB J. 22 2185-2197. 

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