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Phosphorylation
Department of Molecular Endocrinology and Bone Biology, Merck Research Laboratories (L.L., J.E.F., N.W., A.S., Q.S., J.Y., F.C., S.W., E.T.B., A.S., S.P.R., L.P.F., A.A.R.), West Point, Pennsylvania 19486; Department of Medicinal Chemistry, Merck Research Laboratories (S.K., H.Y.C., Q.T., F.D., M.L.H.), Rahway, New Jersey 07065; and Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine (G.A.R.), Philadelphia, Pennsylvania 19104
Address all correspondence and requests for reprints to: Dr. Alfred Reszka, Molecular Endocrinology and Bone Biology, Merck Research Laboratories, WP26A-1000, West Point, Pennsylvania 19486.
Estrogen receptor 
(ER) serine 118 (Ser118) phosphorylation modulates activation function-1 (AF1) function. Correct positioning of helix 12 promotes agonist-dependent recruitment of cyclin-dependent kinase-7 to catalyze this event. In this study we show robust cyclin-dependent kinase-7-independent, AF2 antagonist-induced Ser118 phosphorylation. Estradiol (E2) and ICI-182,780 (ICI-780) induce Ser118 phosphorylation of wild-type ER and either of two helix 12 mutants, suggesting AF2-independent action, probably via shedding of 90-kDa heat shock protein. With E2 treatment, the predominantly nuclear, phosphorylated ER in COS-1 cells is detergent soluble. Although levels of ICI-780-induced phosphorylation are profound, Ser118-phosphorylated ER is aggregated over the nucleus or in the cytoplasm, fractionating with the cell debris and making detection in cleared lysates improbable. Selective ER modulators (SERMs) elicit a mixed response with phosphorylated ER in both detergent-soluble and -insoluble compartments. Apparent ligand-induced loss of ER protein from cleared lysates is thus due to ligand-induced redistribution into the pellet, not degradation. The COS-1 response to ICI-780 can be mimicked in MCF-7 cells treated with a proteasome inhibitor to block authentic ligand-induced degradation. With SERMs and antagonists, the magnitude of Ser118-phosphorylated receptor redistribution into the insoluble fraction of COS-1 cells correlates with the magnitude of authentic ER degradation in MCF-7 cells. A strong inverse correlation with ligand-induced uterotropism in vivo (P < 0.0001) and direct correlation with AF2-independent transrepression of the matrix metalloprotease-1 promoter in endometrial cells in vitro are seen. These data suggest that ligand-induced Ser118 phosphorylation of ER can be AF2 independent. Furthermore, they identify translocation of Ser118-phosphorylated ER out of the nucleus, leading to cytoplasmic aggregation, as an antagonist pathway that may precede receptor degradation.
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