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PKM2 tyrosine phosphorylation and glutamine metabolism signal a different view of the Warburg effect

Chi V Dang1

  • 1Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. cvdang@jhmi.edu

Science Signaling
|November 19, 2009
PubMed

Insights

Fibroblast growth factor receptor 1 (FGFR1) phosphorylates pyruvate kinase M2 (PKM2), reducing lactate production in cancer cells. This finding challenges the traditional view of the Warburg effect, linking glycolysis to other metabolic pathways.

Area of Science:

  • Oncology
  • Biochemistry
  • Cell Metabolism

Background:

  • The Warburg effect describes cancer cells' high rate of glucose conversion to lactate.
  • Receptor tyrosine kinases play roles in cancer cell growth and metabolism.
  • Pyruvate kinase M2 (PKM2) is a key enzyme in glycolysis.

Purpose of the Study:

  • To investigate the direct interaction between FGFR1 and PKM2.
  • To elucidate the impact of FGFR1-mediated PKM2 phosphorylation on cellular metabolism.
  • To re-evaluate the Warburg effect in light of new findings on cancer cell metabolism.

Main Methods:

  • Investigated the direct phosphorylation of PKM2 by FGFR1.
  • Utilized site-directed mutagenesis to alter a critical tyrosine residue in PKM2 (Tyr105 to Phe).
  • Assessed cellular lactate production, oxygen consumption, and proliferation under hypoxic conditions.

Main Results:

  • FGFR1 directly phosphorylates PKM2, reducing its activity and subsequent lactate production.
  • Mutating Tyr105 in PKM2 to Phe increased enzyme activity but decreased lactate production.
  • Decreased lactate production correlated with increased oxygen consumption and reduced hypoxic cell proliferation.

Conclusions:

  • Tyrosine phosphorylation of PKM2 by FGFR1 paradoxically decreases PKM2 activity, challenging the Warburg effect.
  • Cancer cell metabolism is intricately linked between glycolysis, the tricarboxylic acid cycle, and glutamine metabolism.
  • This study necessitates a revised understanding of the Warburg effect, incorporating cross-talk between metabolic pathways.

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