The Highly Recurrent PP2A Aα-Subunit Mutation P179R Alters Protein Structure and Impairs PP2A Enzyme Function to Promote Endometrial Tumorigenesis
The Highly Recurrent PP2A Aα-Subunit Mutation P179R Alters Protein Structure and Impairs PP2A Enzyme Function to Promote Endometrial Tumorigenesis
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DOI：
10.1158/0008-5472.can-19-0218
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发表时间：
2019-08-15
期刊：
影响因子：
11.2
通讯作者：
Narla, Goutham
中科院分区：
文献类型：
--
作者：
Taylor, Sarah E.;O'Connor, Caitlin M.;Narla, Goutham
蛋白磷酸酶2A（PP2A）A α亚基基因PPP2R1A的体细胞突变在高级别子宫内膜癌中非常普遍。最常复发的子宫内膜癌特异性突变位点P179促进子宫内膜癌恶性特征的结构、分子和生物学基础尚未完全确定。在这里，我们使用了一系列的结构，生物化学和生物学的方法来调查的影响，P179 R错义突变PP2A功能。增强采样分子动力学模拟表明，脯氨酸取代P179残基改变蛋白质的稳定构象。肿瘤衍生的PP2A突变体的晶体结构显示A亚基构象的显著变化。与PP2A催化亚基的结合显著受损，破坏全酶形成和酶活性。癌细胞依赖于PP2A破坏以获得持续的致瘤潜力，并且在患者来源的P179R突变细胞系中恢复野生型A α恢复酶功能并显著减弱体内肿瘤发生和转移。此外，小分子介导的PP2A的治疗性再活化显著抑制体内致瘤性。这些结果暗示PP2A功能失活是高级别子宫内膜癌疾病发病机制的关键组成部分。此外，他们强调PP2A再激活作为一个潜在的治疗策略，为患者谁港口P179 R PPP2R1A mutations.Significance：这项研究的特点是一个高度复发性，疾病特异性PP2A PPP2R1A突变作为子宫内膜癌的驱动程序和新的治疗发展的目标。
Somatic mutation of the protein phosphatase 2A (PP2A) A alpha-subunit gene PPP2R1A is highly prevalent in high-grade endometrial carcinoma. The structural, molecular, and biological basis by which the most recurrent endometrial carcinoma-specific mutation site P179 facilitates features of endometrial carcinoma malignancy has yet to be fully determined. Here, we used a series of structural, biochemical, and biological approaches to investigate the impact of the P179R missense mutation on PP2A function. Enhanced sampling molecular dynamics simulations showed that arginine-to-proline substitution at the P179 residue changes the protein's stable conformation profile. A crystal structure of the tumor-derived PP2A mutant revealed marked changes in A-subunit conformation. Binding to the PP2A catalytic subunit was significantly impaired, disrupting holoenzyme formation and enzymatic activity. Cancer cells were dependent on PP2A disruption for sustained tumorigenic potential, and restoration of wild-type A alpha in a patient-derived P179R-mutant cell line restored enzyme function and significantly attenuated tumorigenesis and metastasis in vivo. Furthermore, small molecule-mediated therapeutic reactivation of PP2A significantly inhibited tumorigenicity in vivo. These outcomes implicate PP2A functional inactivation as a critical component of high-grade endometrial carcinoma disease pathogenesis. Moreover, they highlight PP2A reactivation as a potential therapeutic strategy for patients who harbor P179R PPP2R1A mutations.Significance: This study characterizes a highly recurrent, disease-specific PP2A PPP2R1A mutation as a driver of endometrial carcinoma and a target for novel therapeutic development.