PKM2 tyrosine phosphorylation and glutamine metabolism signal a different view of the Warburg effect.
New evidence suggests that the receptor tyrosine kinase FGFR1 (fibroblast growth factor receptor 1) directly phosphorylates pyruvate kinase M2 (PKM2), resulting in reduced conversion of phosphoenolpyruvate to pyruvate, which is further catabolized to lactate by lactate dehydrogenase A. Mutation of the critical tyrosine Tyr(105) to Phe rendered PKM2 more active but was associated with decreased cellular lactate production, increased oxygen consumption, and decreased hypoxic cell proliferation relative to wild-type PKM2. The apparent paradoxical effect of growth signaling through tyrosine phosphorylation, which decreases rather than increases PKM2 activity, stimulates a revised perspective of the Warburg effect. This effect, which describes the propensity for cancer cells to convert glucose to lactate at a high rate, must now accommodate links among glycolysis, the tricarboxylic acid cycle, and glutamine metabolism in cancer cells.
Dang
Chi V
CV
Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. cvdang@jhmi.edu
D000818:Animals; D049109:Cell Proliferation; D002952:Citric Acid Cycle / Q000502:physiology; D005973:Glutamine / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation; D055503:Protein Multimerization; D011770:Pyruvate Kinase / Q000737:chemistry / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism*
D005973:Glutamine; D014443:Tyrosine; D011770:Pyruvate Kinase; D051496:Receptor, Fibroblast Growth Factor, Type 1