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Papers In Press, published online ahead of print August 1, 2005
Department of Hormones and Signal Transduction Group, German Cancer Research Center, Heidelberg 69120
Corresponding Author: d.mayer{at}dkfz.de
Like other steroid hormone receptors, estrogen receptor-a (ERa) is a substrate for protein kinases, and phosphorylation has profound effects on the function and activity of this receptor. A number of different kinases have been implicated in ERa regulation. In this report we show by mutational analysis and in vitro kinase assays that ERa is a substrate for glycogen synthase kinase-3 (GSK-3) in vitro and is phosphorylated on two sites, the Ser102,104,106 motif and Ser118, both located in the N-terminal transcription activation function (AF-1) domain. GSK-3 forms a complex with ERa in vivo as demonstrated by co-immunoprecipitation from cell lysates. The GSK-3 inhibitor lithium chloride was used to determine the role of GSK-3 in phosphorylation of Ser102,104,106 and Ser118 in vivo and to explore the role of these serines in the regulation of ERa function. Treatment of cells with lithium chloride resulted in dephosphorylation of Ser104,106 and Ser118 which suggests these serine residues as targets for GSK-3 in vivo. Our results further suggest that ERa phosphorylation by GSK-3 stabilizes ERa under resting conditions and modulates ERa transcriptional activity upon ligand binding. Inhibition and constitutive activation of GSK-3 both resulted in inhibition of ERa transcriptional activity indicating a function of active as well as inactive GSK-3 in ERa regulation. These findings uncover a novel mechanism for the regulation of ERa-mediated estrogen signaling controlled by a dual action of GSK-3.
J. Biol. Chem, 10.1074/jbc.M506758200
Submitted on June 21, 2005
Revised on July 25, 2005
Accepted on August 1, 2005
Glycogen synthase kinase-3 interacts with and phosphorylates estrogen receptor-
and is involved in the regulation of receptor activity
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