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J. Biol. Chem., Vol. 280, Issue 38, 33006-33014, September 23, 2005

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Glycogen Synthase Kinase-3 Interacts with and Phosphorylates Estrogen Receptor and Is Involved in the Regulation of Receptor Activity^*

From the Hormones and Signal Transduction Group, German Cancer Research Center, 69120 Heidelberg, Germany

Like other steroid hormone receptors, estrogen receptor- (ER) 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 regulation. In this report we show by mutational analysis and in vitro kinase assays that ER 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 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 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 phosphorylation by GSK-3 stabilizes ER under resting conditions and modulates ER transcriptional activity upon ligand binding. Inhibition and constitutive activation of GSK-3, both, resulted in inhibition of ER transcriptional activity, indicating a function of active as well as inactive GSK-3 in ER regulation. These findings uncover a novel mechanism for the regulation of ER-mediated estrogen signaling controlled by a dual action of GSK-3.

Received for publication, June 21, 2005 , and in revised form, July 25, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Recipient of a guest-researcher fellowship from the German Cancer Research Center.

² To whom correspondence should be addressed: Hormones and Signal Transduction Group, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Tel.: 49-6221-423238; Fax: 49-6221-423237; E-mail: d.mayer{at}dkfz.de.

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