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.[1]References
- Regulation of estrogen receptor alpha-mediated transcription by a direct interaction with protein phosphatase 2A. Lu, Q., Surks, H.K., Ebling, H., Baur, W.E., Brown, D., Pallas, D.C., Karas, R.H. J. Biol. Chem. (2003) [Pubmed]
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