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Originally published In Press as doi:10.1074/jbc.M210949200 on December 3, 2002

J. Biol. Chem., Vol. 278, Issue 7, 4639-4645, February 14, 2003
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Regulation of Estrogen Receptor alpha -mediated Transcription by a Direct Interaction with Protein Phosphatase 2A*

Qing LuDagger , Howard K. SurksDagger , Heather EblingDagger , Wendy E. BaurDagger , Donald Brown§, David C. Pallas, and Richard H. KarasDagger ||

From the Dagger  Department of Medicine and Molecular Cardiology Research Institute, New England Medical Center Hospitals, Inc., Tufts University School of Medicine, Boston, Massachusetts 02111, the  Department of Biochemistry, Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia 30322, and the § Tufts University School of Veterinary Medicine, North Grafton, Massachusetts 01536

Estrogen receptor alpha  (ERalpha ) mediates the effects of estrogen by altering gene expression following hormone binding. It has recently been shown that kinase-mediated phosphorylation of ERalpha also transcriptionally activates the receptor in the absence of estrogen. We now report that ERalpha -dependent gene expression also is regulated by protein phosphatase 2A (PP2A). ERalpha co-immunoprecipitates with enzymatically active PP2A. ERalpha binds directly to the catalytic subunit of PP2A, which dephosphorylates serine 118 of the receptor. Amino acids 176-182 in the A/B domain of ERalpha are required for the interaction between PP2A and the receptor. Phosphatase inhibition disrupts the ERalpha -PP2A complex and induces formation of an ERalpha -activated mitogen-activated protein kinase complex, phosphorylation of ERalpha on serine 118, and transcriptional activation. These findings demonstrate that estrogen receptors exist in complexes with phosphatases as well as kinases. We propose a new model of ligand-independent activation of estrogen receptors in which the level of phosphorylation of ERalpha , and hence its transcriptional activation, is determined by the net effect of these counterregulatory pathways.

* This work was supported in part by National Institutes of Health Grant HL61290 (to R. H. K.). Under agreements between Upstate Biotechnology Inc. and Emory University and Calbiochem and Emory University, D. Pallas is entitled to a share of sales royalty received by the University from these companies. In addition, this same author serves as a consultant to Upstate Biotechnology Inc. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| Established Investigator of the American Heart Association. To whom correspondence should be addressed: Molecular Cardiology Research Center, Tufts-New England Medical Center, 750 Washington St., Box 80, Boston, MA 02111. Tel.: 617-636-8776; Fax: 617-636-1444; E-mail: rkaras@lifespan.org.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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