PKM2 dephosphorylation by Cdc25A promotes the Warburg effect and tumorigenesis
PKM2 dephosphorylation by Cdc25A promotes the Warburg effect and tumorigenesis
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Cdc25A 使 PKM2 去磷酸化促进 Warburg 效应和肿瘤发生
DOI：
10.1038/ncomms12431
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发表时间：
2016-08-01
影响因子：
16.6
通讯作者：
Lu, Zhimin
中科院分区：
文献类型：
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作者：
Liang, Ji;Cao, Ruixiu;Lu, Zhimin
许多类型的人类肿瘤细胞过度表达双特异性磷酸酶CDC25A。CDc25A可去磷酸化细胞周期蛋白依赖的蛋白激酶，调节细胞周期，但其其他底物及其相关的细胞功能尚不清楚。在这里，我们证明了EGFR的激活导致c-Src介导的CDc25A在Y59位的磷酸化，并与核中丙酮酸激酶M2(PKM2)相互作用。CDC25A在S37使PKM2去磷酸化，并促进PKM2依赖的β-连环素反式激活和糖酵解基因GLUT1、PKM2和LDHA以及CDC25A的c-Myc上调表达；因此，CDC25A在正反馈循环中上调自身。CDC25A介导的PKM2去磷酸化促进Warburg效应、细胞增殖和脑肿瘤的发生。此外，我们还发现在人脑胶质母细胞瘤标本中，CDC25A Y59磷酸化、CDC25A和PKM2之间存在正相关关系。此外，CDC25A Y59的磷酸化水平与胶质瘤的恶性程度和预后相关。这些发现揭示了CDC25A在控制细胞代谢方面的工具功能，这对于EGFR促进的肿瘤发生是必不可少的。
Many types of human tumour cells overexpress the dual-specificity phosphatase Cdc25A. Cdc25A dephosphorylates cyclin-dependent kinase and regulates the cell cycle, but other substrates of Cdc25A and their relevant cellular functions have yet to be identified. We demonstrate here that EGFR activation results in c-Src-mediated Cdc25A phosphorylation at Y59, which interacts with nuclear pyruvate kinase M2 (PKM2). Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2-dependent beta-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop. Cdc25A-mediated PKM2 dephosphorylation promotes the Warburg effect, cell proliferation and brain tumorigenesis. In addition, we identify positive correlations among Cdc25A Y59 phosphorylation, Cdc25A and PKM2 in human glioblastoma specimens. Furthermore, levels of Cdc25A Y59 phosphorylation correlate with grades of glioma malignancy and prognosis. These findings reveal an instrumental function of Cdc25A in controlling cell metabolism, which is essential for EGFR-promoted tumorigenesis.