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Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase

Xueliang Gao1, Haizhen Wang, Jenny J Yang

  • 1Department of Biology, Georgia State University, Atlanta, GA 30303, USA.

Molecular Cell
|February 7, 2012
PubMed

Insights

Pyruvate kinase M2 (PKM2) acts as a nuclear protein kinase, promoting cell proliferation by activating gene transcription. This enzyme links metabolic changes to gene expression in tumor development.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Pyruvate kinase isoform M2 (PKM2) is a key glycolytic enzyme.
  • PKM2 traditionally functions in the cytoplasm.
  • Altered metabolism is a hallmark of cancer.

Purpose of the Study:

  • To investigate the non-metabolic functions of PKM2.
  • To determine the role of nuclear PKM2 in gene regulation and cell proliferation.
  • To elucidate the mechanism of PKM2's protein kinase activity.

Main Methods:

  • Immunofluorescence to determine PKM2 subcellular localization.
  • Western blotting to assess nuclear PKM2 levels and STAT3 phosphorylation.
  • In vitro kinase assays using PEP and ADP.
  • Cell proliferation assays with PKM2 mutants.

Main Results:

  • PKM2 was found to localize in the cell nucleus.
  • Nuclear PKM2 levels correlated positively with cell proliferation rates.
  • PKM2 demonstrated protein kinase activity, phosphorylating STAT3 at Y705 and activating MEK5 transcription.
  • The dimeric form of PKM2 showed protein kinase activity, while the tetrameric form exhibited pyruvate kinase activity.
  • A PKM2 mutant favoring the dimeric form enhanced cell proliferation.

Conclusions:

  • PKM2 possesses nuclear protein kinase activity, distinct from its glycolytic function.
  • Nuclear PKM2 regulates gene transcription, contributing to cell proliferation.
  • This dual role highlights a critical connection between cellular metabolism and gene expression in tumorigenesis.

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