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 β-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.

中文翻译：

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Cdc25A使PKM2去磷酸化可促进Warburg效应和肿瘤发生。

许多类型的人类肿瘤细胞过表达双重特异性磷酸酶Cdc25A。Cdc25A使细胞周期蛋白依赖性激酶去磷酸化并调节细胞周期，但是Cdc25A的其他底物及其相关的细胞功能尚未确定。我们在这里证明，EGFR激活导致Y59处c-Src介导的Cdc25A磷酸化，与核丙酮酸激酶M2（PKM2）相互作用。Cdc25A在S37使PKM2去磷酸化，并促进依赖PKM2的β-catenin反式激活和c-Myc上调糖酵解基因GLUT1，PKM2和LDHA以及CDC25A的表达。因此，Cdc25A在正反馈环路中上调自身。Cdc25A介导的PKM2去磷酸化促进Warburg效应，细胞增殖和脑肿瘤发生。此外，我们确定了Cdc25A Y59磷酸化之间的正相关性，人胶质母细胞瘤标本中的Cdc25A和PKM2。此外，Cdc25A Y59磷酸化水平与神经胶质瘤恶性程度和预后相关。这些发现揭示了Cdc25A在控制细胞代谢中的工具功能，这对于EGFR促进的肿瘤发生至关重要。