Regulation of estrogen receptor alpha-mediated transcription by a direct interaction with protein phosphatase 2A.
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.
Lu
Qing
Q
Department of Medicine and Molecular Cardiology Research Institute, New England Medical Center Hospitals, Inc., Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Surks
Howard K
HK
Ebling
Heather
H
Baur
Wendy E
WE
Brown
Donald
D
Pallas
David C
DC
Karas
Richard H
RH
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
D047628:Estrogen Receptor alpha; D004967:Estrogens; D008024:Ligands; D011960:Receptors, Estrogen; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2