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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
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PKM2 dephosphorylation by Cdc25A promotes the Warburg effect and tumorigenesis

Ji Liang1,2, Ruixiu Cao1,2, Yajuan Zhang1,2

  • 1Key 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 200031, China.

Nature Communications
|August 4, 2016
PubMed

Insights

Cdc25A phosphatase promotes brain tumor growth by regulating cell metabolism and pyruvate kinase M2 (PKM2) activity. Its phosphorylation at Y59 correlates with glioma malignancy and poor prognosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Human tumor cells frequently overexpress Cdc25A, a phosphatase regulating the cell cycle.
  • While Cdc25A's role in cell cycle regulation is known, its other substrates and functions remain largely uncharacterized.

Purpose of the Study:

  • To investigate the role of Cdc25A in tumorigenesis beyond cell cycle regulation.
  • To identify novel substrates and functions of Cdc25A in cancer, particularly in relation to EGFR signaling and cell metabolism.

Main Methods:

  • Investigated the interaction between Cdc25A, EGFR, c-Src, and pyruvate kinase M2 (PKM2).
  • Analyzed Cdc25A-mediated phosphorylation of PKM2 and its downstream effects on gene expression and cellular processes.
  • Examined human glioblastoma specimens to correlate Cdc25A Y59 phosphorylation with tumor grade and patient prognosis.

Main Results:

  • EGFR activation leads to c-Src-mediated Cdc25A phosphorylation at Y59, which then interacts with PKM2.
  • Cdc25A dephosphorylates PKM2 at S37, promoting β-catenin transactivation and c-Myc-driven expression of glycolytic genes (GLUT1, PKM2, LDHA).
  • This interaction creates a positive feedback loop, upregulating CDC25A and promoting the Warburg effect, cell proliferation, and brain tumorigenesis.

Conclusions:

  • Cdc25A plays a critical role in controlling cell metabolism, essential for EGFR-promoted tumorigenesis.
  • Cdc25A-mediated PKM2 dephosphorylation drives the Warburg effect and supports tumor growth.
  • Cdc25A Y59 phosphorylation is a potential biomarker for glioma malignancy and prognosis.

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