期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 280, 期 38, 页码 33006-33014出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M506758200
关键词
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Like other steroid hormone receptors, estrogen receptor-alpha (ER alpha) 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 ER alpha regulation. In this report we show by mutational analysis and in vitro kinase assays that ER alpha is a substrate for glycogen synthase kinase-3 (GSK-3) in vitro and is phosphorylated on two sites, the Ser-102, -104, and -106 motif and Ser-118, both located in the N-terminal transcription activation function (AF-1) domain. GSK-3 forms a complex with ER alpha 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 Ser-102, -104, and -106 and Ser-118 in vivo and to explore the role of these serines in the regulation of ER alpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of Ser-104 and -106 and Ser-118, which suggests these serine residues as targets for GSK-3 in vivo. Our results further suggest that ER alpha phosphorylation by GSK-3 stabilizes ER alpha under resting conditions and modulates ER alpha transcriptional activity upon ligand binding. Inhibition and constitutive activation of GSK-3, both, resulted in inhibition of ER alpha transcriptional activity, indicating a function of active as well as inactive GSK-3 in ER alpha regulation. These findings uncover a novel mechanism for the regulation of ER alpha-mediated estrogen signaling controlled by a dual action of GSK-3.
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