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Sci. Signal., 17 November 2009
Vol. 2, Issue 97, p. ra73
[DOI: 10.1126/scisignal.2000431]

RESEARCH ARTICLES

Editor's Summary

A Malignant Metabolic Switch
Cancer cells show aberrant metabolism, consuming more glucose than do healthy cells and producing lactate even in the presence of abundant oxygen, rather than shifting to oxidative phosphorylation. This phenomenon is called the Warburg effect, after Otto Warburg, who described it many years ago. Building on recent research implicating inhibition of the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2) by phosphotyrosine binding as critical to the Warburg effect—and tumorigenesis—Hitosugi et al. explored the role of signaling from oncogenic forms of the fibroblast growth factor receptor type 1 (FGFR1) in mediating this metabolic switch. They found that FGFR1, a receptor tyrosine kinase, phosphorylated a tyrosine residue (Y105) on PKM2 itself. Further analysis revealed that this tyrosine residue was commonly phosphorylated in human cancers and that a mutant form of PKM2 lacking this tyrosine residue inhibited both "Warburg metabolism" and tumor growth. They thus propose that phosphorylation of PKM2 by oncogenic tyrosine kinases provides the very phosphotyrosine that binds to and inhibits PKM2 to induce the Warburg effect and promote tumor growth.

Citation: T. Hitosugi, S. Kang, M. G. Vander Heiden, T.-W. Chung, S. Elf, K. Lythgoe, S. Dong, S. Lonial, X. Wang, G. Z. Chen, J. Xie, T.-L. Gu, R. D. Polakiewicz, J. L. Roesel, T. J. Boggon, F. R. Khuri, D. G. Gilliland, L. C. Cantley, J. Kaufman, J. Chen, Tyrosine Phosphorylation Inhibits PKM2 to Promote the Warburg Effect and Tumor Growth. Sci. Signal. 2, ra73 (2009).

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