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首页> 外文期刊>Molecular and Cellular Biology >Phosphorylation of MNAR Promotes Estrogen Activation of Phosphatidylinositol 3-Kinase
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Phosphorylation of MNAR Promotes Estrogen Activation of Phosphatidylinositol 3-Kinase

机译：MNAR的磷酸化促进磷脂酰肌醇3-激酶的雌激素活化。

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Estrogen actions are mediated by a complex interface of direct control of gene expression (the so-called “genomic action”) and by regulation of cell signaling/phosphorylation cascades, referred to as the “nongenomic,” or extranuclear, action. We have previously described the identification of MNAR (modulator of nongenomic action of estrogen receptor) as a novel scaffold protein that regulates estrogen receptor alpha (ERα) activation of cSrc. In this study, we have investigated the role of MNAR in 17β-estradiol (E2)-induced activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Consistent with our previous results, a direct correlation was established between MNAR expression levels and E2-induced activation of PI3 and Akt kinases. Endogenous MNAR, ERα, cSrc, and p85, the regulatory subunit of PI3 kinase, interacted in MCF7 cells treated with E2. The interaction between p85 and MNAR required activation of cSrc and MNAR phosphorylation on Tyr 920. Consequently, the mutation of this tyrosine to alanine (Y920A) abrogated the interaction between MNAR and p85 and the E2-induced activation of the PI3K/Akt pathway, which was required for the E2-induced protection of MCF7 cells from apoptosis. Nonetheless, the Y920A mutant potentiated the E2-induced activation of the Src/MAPK pathway and MCF7 cell proliferation, as observed with the wild-type MNAR. These results provide new and important insights into the molecular mechanisms of E2-induced regulation of cell proliferation and apoptosis.
机译：雌激素作用是由直接控制基因表达的复杂界面（所谓的“基因组作用”）和细胞信号转导/磷酸化级联的调节介导的，被称为“非基因组”或核外作用。我们之前已经描述了MNAR（雌激素 r 受体的 n 非经济性 a 部分的 m 调节剂）的鉴定为一种新型的支架蛋白，可调节cSrc的雌激素受体α（ERα）激活。在这项研究中，我们研究了MNAR在17β-雌二醇（E2）诱导的磷脂酰肌醇3-激酶（PI3K）/ Akt途径激活中的作用。与我们之前的结果一致，在MNAR表达水平与E2诱导的PI3和Akt激酶激活之间建立了直接的相关性。内源性MNAR，ERα，cSrc和p85（PI3激酶的调节亚基）在用E2处理的MCF7细胞中相互作用。 p85和MNAR之间的相互作用需要激活Tyr 920上的cSrc和MNAR磷酸化。因此，该酪氨酸突变为丙氨酸（Y920A）废除了MNAR和p85之间的相互作用以及E2诱导的PI3K / Akt途径的激活。是E2诱导的MCF7细胞免于凋亡所必需的。尽管如此，如野生型MNAR所观察到的，Y920A突变体增强了E2诱导的Src / MAPK途径激活和MCF7细胞增殖。这些结果为E2诱导的细胞增殖和凋亡调控的分子机制提供了新的重要见解。

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