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PKM2 dephosphorylation by Cdc25A promotes the Warburg effect and tumorigenesis

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  • Ji Liang

    (Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science)

  • Ruixiu Cao

    (Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science)

  • Yajuan Zhang

    (Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science)

  • Yan Xia

    (The University of Texas MD Anderson Cancer Center)

  • Yanhua Zheng

    (The University of Texas MD Anderson Cancer Center
    The Institute of Cell Metabolism and Disease, Shanghai Key Laboratory of Pancreatic Cancer, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University)

  • Xinjian Li

    (The University of Texas MD Anderson Cancer Center)

  • Liwei Wang

    (Renji Hospital, School of Medicine, Shanghai Jiaotong University
    National Laboratory of Oncogene and Cancer Related Genes Foundation)

  • Weiwei Yang

    (Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science)

  • Zhimin Lu

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center
    Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston)

Abstract

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.

Suggested Citation

  • Ji Liang & Ruixiu Cao & Yajuan Zhang & Yan Xia & Yanhua Zheng & Xinjian Li & Liwei Wang & Weiwei Yang & Zhimin Lu, 2016. "PKM2 dephosphorylation by Cdc25A promotes the Warburg effect and tumorigenesis," Nature Communications, Nature, vol. 7(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12431
    DOI: 10.1038/ncomms12431
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