title: Regulation of estrogen receptor alpha-mediated transcription by a direct interaction with protein phosphatase 2A.
abstract: 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.
authors.affiliation: Department of Medicine and Molecular Cardiology Research Institute, New England Medical Center Hospitals, Inc., Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
authors.forename: Howard K
authors.initials: HK
authors.lastname: Surks
authors.forename: Heather
authors.initials: H
authors.lastname: Ebling
authors.forename: Wendy E
authors.initials: WE
authors.lastname: Baur
authors.forename: Donald
authors.initials: D
authors.lastname: Brown
authors.forename: David C
authors.initials: DC
authors.lastname: Pallas
authors.forename: Richard H
authors.initials: RH
authors.lastname: Karas
mesh_terms: D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000378:metabolism; D006801:Humans; D008024:Ligands; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D051381:Rats; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D008024:Ligands; D011960:Receptors, Estrogen; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2