Regulation of estrogen receptor α-mediated transcription by a direct interaction with protein phosphatase 2A
Regulation of estrogen receptor α-mediated transcription by a direct interaction with protein phosphatase 2A
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DOI：
10.1074/jbc.m210949200
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发表时间：
2003-02-14
影响因子：
4.8
通讯作者：
Karas, RH
中科院分区：
文献类型：
--
作者：
Lu, Q;Surks, HK;Karas, RH
雌激素受体a （er - α）通过改变激素结合后的基因表达来调节雌激素的作用。最近有研究表明，在缺乏雌激素的情况下，激酶介导的erα磷酸化也能转录激活受体。我们现在报道erα依赖的基因表达也受蛋白磷酸酶2A （PP2A）的调节。erα与酶活性PP2A共免疫沉淀。erα直接与PP2A的催化亚基结合，使受体的丝氨酸118去磷酸化。erα A/B结构域的氨基酸176-182是PP2A与受体相互作用所必需的。磷酸酶抑制破坏erα - pp2a复合体，诱导erα激活的丝裂原激活的蛋白激酶复合体的形成，丝氨酸118上erα的磷酸化和转录激活。这些发现表明雌激素受体存在于与磷酸酶和激酶的复合物中。我们提出了一种新的配体非依赖性雌激素受体激活模型，其中erα磷酸化水平及其转录激活由这些反调控途径的净效应决定。
Estrogen receptor a (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.