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

Mol Cell. 2012 Mar 9;45(5):598-609. doi: 10.1016/j.molcel.2012.01.001. Epub 2012 Feb 2.


Pyruvate kinase isoform M2 (PKM2) is a glycolysis enzyme catalyzing conversion of phosphoenolpyruvate (PEP) to pyruvate by transferring a phosphate from PEP to ADP. We report here that PKM2 localizes to the cell nucleus. The levels of nuclear PKM2 correlate with cell proliferation. PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as a phosphate donor. ADP competes with the protein substrate binding, indicating that the substrate may bind to the ADP site of PKM2. Our experiments suggest that PKM2 dimer is an active protein kinase, while the tetramer is an active pyruvate kinase. Expression of a PKM2 mutant that exists as a dimer promotes cell proliferation, indicating that protein kinase activity of PKM2 plays a role in promoting cell proliferation. Our study reveals an important link between metabolism alteration and gene expression during tumor transformation and progression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation
  • Gene Expression Regulation*
  • Humans
  • MAP Kinase Kinase 5 / genetics
  • MAP Kinase Kinase 5 / metabolism
  • Phosphorylation
  • Pyruvate Kinase / genetics
  • Pyruvate Kinase / metabolism
  • Pyruvate Kinase / physiology*
  • STAT3 Transcription Factor / metabolism
  • Transcription, Genetic*


  • STAT3 Transcription Factor
  • Pyruvate Kinase
  • MAP Kinase Kinase 5
  • MAP2K5 protein, human