Lu Qing, Surks Howard K, Ebling Heather, Baur Wendy E, Brown Donald, Pallas David C, Karas Richard H
Department of Medicine and Molecular Cardiology Research Institute, New England Medical Center Hospitals, Inc., Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
J Biol Chem. 2003 Feb 14;278(7):4639-45. doi: 10.1074/jbc.M210949200. Epub 2002 Dec 3.
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.
雌激素受体α（ERα）通过在激素结合后改变基因表达来介导雌激素的作用。最近研究表明，激酶介导的ERα磷酸化在无雌激素的情况下也能转录激活该受体。我们现在报告，ERα依赖性基因表达也受蛋白磷酸酶2A（PP2A）调控。ERα与具有酶活性的PP2A共免疫沉淀。ERα直接与PP2A的催化亚基结合，该亚基使受体的丝氨酸118去磷酸化。ERα的A/B结构域中的氨基酸176 - 182是PP2A与受体相互作用所必需的。磷酸酶抑制会破坏ERα - PP2A复合物，并诱导形成ERα激活的丝裂原活化蛋白激酶复合物、ERα丝氨酸118的磷酸化以及转录激活。这些发现表明雌激素受体与磷酸酶以及激酶形成复合物存在。我们提出了一种雌激素受体非配体依赖性激活的新模型，其中ERα的磷酸化水平及其转录激活由这些反调节途径的净效应决定。
