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IMPDH2 dephosphorylation under FGFR signaling promotes S-phase progression and tumor growth

Bei Zhou1, Qin Zhao1, Guofang Hou1

  • 1Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Cell Reports
|December 31, 2024
PubMed

Insights

Phosphorylation of Inosine monophosphate dehydrogenase 2 (IMPDH2) by CDK1 inhibits its activity. Fibroblast growth factor receptor (FGFR) signaling promotes IMPDH2 dephosphorylation, enhancing cancer cell proliferation and poor prognosis.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Cancer Biology

Background:

  • Inosine monophosphate dehydrogenase 2 (IMPDH2) is upregulated in human cancers.
  • The role of IMPDH2 in cancer under growth signaling pathways is not fully understood.

Purpose of the Study:

  • To investigate the regulation of IMPDH2 activity by growth signaling pathways.
  • To elucidate the mechanism linking IMPDH2 to tumorigenesis and patient prognosis.

Main Methods:

  • Western blotting and immunoprecipitation to study protein interactions and modifications.
  • Enzyme activity assays to measure IMPDH2 catalytic function.
  • Cell proliferation assays and analysis of patient data.

Main Results:

  • CDK1 phosphorylates IMPDH2 at Serine 122, reducing its catalytic activity and allosteric modulation.
  • FGFR signaling activates protein phosphatase 2A (PP2A) to dephosphorylate IMPDH2-Ser122, increasing its activity.
  • IMPDH2 dephosphorylation supports guanine nucleotide synthesis, S-phase progression, and cell proliferation.
  • Low IMPDH2-Ser122 phosphorylation correlates with poor prognosis in colorectal cancer patients.

Conclusions:

  • FGFR signaling regulates IMPDH2 activity through a PP2A-mediated dephosphorylation mechanism.
  • Enhanced IMPDH2 activity due to dephosphorylation contributes to FGFR-driven tumorigenesis.
  • IMPDH2-Ser122 phosphorylation serves as a prognostic marker in colorectal cancer.
Keywords:
CDK1CP: CancerFGFRPP2AS-phase progressionallosteric regulationphosphorylationpurine homeostasistumor cell growth.◼◼◼IMPDH2

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