Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


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


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).

Read the Full Text

Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death.
N. A. Graham, M. Tahmasian, B. Kohli, E. Komisopoulou, M. Zhu, I. Vivanco, M. A. Teitell, H. Wu, A. Ribas, R. S. Lo, et al. (2014)
Mol Syst Biol 8, 589
   Abstract »    Full Text »    PDF »
Missense Mutations in Pyruvate Kinase M2 Promote Cancer Metabolism, Oxidative Endurance, Anchorage Independence, and Tumor Growth in a Dominant Negative Manner.
M. A. Iqbal, F. A. Siddiqui, N. Chaman, V. Gupta, B. Kumar, P. Gopinath, and R. N. K. Bamezai (2014)
J. Biol. Chem. 289, 8098-8105
   Abstract »    Full Text »    PDF »
JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1{alpha}-mediated glucose metabolism.
H.-J. Wang, Y.-J. Hsieh, W.-C. Cheng, C.-P. Lin, Y.-s. Lin, S.-F. Yang, C.-C. Chen, Y. Izumiya, J.-S. Yu, H.-J. Kung, et al. (2014)
PNAS 111, 279-284
   Abstract »    Full Text »    PDF »
Cancer Usurps Skeletal Muscle as an Energy Repository.
Y. Luo, J. Yoneda, H. Ohmori, T. Sasaki, K. Shimbo, S. Eto, Y. Kato, H. Miyano, T. Kobayashi, T. Sasahira, et al. (2014)
Cancer Res. 74, 330-340
   Abstract »    Full Text »    PDF »
Proviral Insertion in Murine Lymphomas 2 (PIM2) Oncogene Phosphorylates Pyruvate Kinase M2 (PKM2) and Promotes Glycolysis in Cancer Cells.
Z. Yu, X. Zhao, L. Huang, T. Zhang, F. Yang, L. Xie, S. Song, P. Miao, L. Zhao, X. Sun, et al. (2013)
J. Biol. Chem. 288, 35406-35416
   Abstract »    Full Text »    PDF »
Rheb and mammalian target of rapamycin in mitochondrial homoeostasis.
M. J. Groenewoud and F. J. T. Zwartkruis (2013)
Open Bio 3, 130185
   Abstract »    Full Text »    PDF »
Direct Measurements of Oscillatory Glycolysis in Pancreatic Islet {beta}-Cells Using Novel Fluorescence Resonance Energy Transfer (FRET) Biosensors for Pyruvate Kinase M2 Activity.
M. J. Merrins, A. R. Van Dyke, A. K. Mapp, M. A. Rizzo, and L. S. Satin (2013)
J. Biol. Chem. 288, 33312-33322
   Abstract »    Full Text »    PDF »
Pulmonary Arterial Hypertension: Challenges in Translational Research and a Vision for Change.
G. Sutendra and E. D. Michelakis (2013)
Science Translational Medicine 5, 208sr5
   Full Text »    PDF »
Fueling Immunity: Insights into Metabolism and Lymphocyte Function.
E. L. Pearce, M. C. Poffenberger, C.-H. Chang, and R. G. Jones (2013)
Science 342, 1242454
   Abstract »    Full Text »    PDF »
Integrated phosphoproteomic and metabolomic profiling reveals NPM-ALK-mediated phosphorylation of PKM2 and metabolic reprogramming in anaplastic large cell lymphoma.
S. R. P. McDonnell, S. R. Hwang, D. Rolland, C. Murga-Zamalloa, V. Basrur, K. P. Conlon, D. Fermin, T. Wolfe, A. Raskind, C. Ruan, et al. (2013)
Blood 122, 958-968
   Abstract »    Full Text »    PDF »
Pharmacologic Activation of PKM2 Slows Lung Tumor Xenograft Growth.
K. M. Parnell, J. M. Foulks, R. N. Nix, A. Clifford, J. Bullough, B. Luo, A. Senina, D. Vollmer, J. Liu, V. McCarthy, et al. (2013)
Mol. Cancer Ther. 12, 1453-1460
   Abstract »    Full Text »    PDF »
Protein Tyrosine Phosphatase 1B Regulates Pyruvate Kinase M2 Tyrosine Phosphorylation.
A. Bettaieb, J. Bakke, N. Nagata, K. Matsuo, Y. Xi, S. Liu, D. AbouBechara, R. Melhem, K. Stanhope, B. Cummings, et al. (2013)
J. Biol. Chem. 288, 17360-17371
   Abstract »    Full Text »    PDF »
Reciprocal Regulation of Protein Kinase and Pyruvate Kinase Activities of Pyruvate Kinase M2 by Growth Signals.
X. Gao, H. Wang, J. J. Yang, J. Chen, J. Jie, L. Li, Y. Zhang, and Z.-R. Liu (2013)
J. Biol. Chem. 288, 15971-15979
   Abstract »    Full Text »    PDF »
M2 pyruvate kinase provides a mechanism for nutrient sensing and regulation of cell proliferation.
H. P. Morgan, F. J. O'Reilly, M. A. Wear, J. R. O'Neill, L. A. Fothergill-Gilmore, T. Hupp, and M. D. Walkinshaw (2013)
PNAS 110, 5881-5886
   Abstract »    Full Text »    PDF »
Proliferation-Independent Control of Tumor Glycolysis by PDGFR-Mediated AKT Activation.
C. Ran, H. Liu, Y. Hitoshi, and M. A. Israel (2013)
Cancer Res. 73, 1831-1843
   Abstract »    Full Text »    PDF »
Allosteric Regulation of PKM2 Allows Cellular Adaptation to Different Physiological States.
D. Y. Gui, C. A. Lewis, and M. G. Vander Heiden (2013)
Science Signaling 6, pe7
   Abstract »    Full Text »    PDF »
M2 isoform of pyruvate kinase is dispensable for tumor maintenance and growth.
M. Cortes-Cros, C. Hemmerlin, S. Ferretti, J. Zhang, J. S. Gounarides, H. Yin, A. Muller, A. Haberkorn, P. Chene, W. R. Sellers, et al. (2013)
PNAS 110, 489-494
   Abstract »    Full Text »    PDF »
Dual roles of PKM2 in cancer metabolism.
S. Wu and H. Le (2013)
Acta Biochim Biophys Sin 45, 27-35
   Abstract »    Full Text »    PDF »
Metabolic changes in cancer: beyond the Warburg effect.
W. Wu and S. Zhao (2013)
Acta Biochim Biophys Sin 45, 18-26
   Abstract »    Full Text »    PDF »
The Metabolomic Signature of Malignant Glioma Reflects Accelerated Anabolic Metabolism.
P. Chinnaiyan, E. Kensicki, G. Bloom, A. Prabhu, B. Sarcar, S. Kahali, S. Eschrich, X. Qu, P. Forsyth, and R. Gillies (2012)
Cancer Res. 72, 5878-5888
   Abstract »    Full Text »    PDF »
Cancer Metabolism: What we Can Learn from Proteomic Analysis by Mass Spectrometry.
W. Zhou, L. A. Liotta, and E. F. Petricoin (2012)
Cancer Genomics Proteomics 9, 373-381
   Abstract »    Full Text »    PDF »
Manipulation of PK-M mutually exclusive alternative splicing by antisense oligonucleotides.
Z. Wang, H. Y. Jeon, F. Rigo, C. F. Bennett, and A. R. Krainer (2012)
Open Bio 2, 120133
   Abstract »    Full Text »    PDF »
Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells.
M. Tamada, M. Suematsu, and H. Saya (2012)
Clin. Cancer Res. 18, 5554-5561
   Abstract »    Full Text »    PDF »
Signaling in Control of Cell Growth and Metabolism.
P. S. Ward and C. B. Thompson (2012)
Cold Spring Harb Perspect Biol 4, a006783
   Abstract »    Full Text »    PDF »
The updated biology of hypoxia-inducible factor.
S. N. Greer, J. L. Metcalf, Y. Wang, and M. Ohh (2012)
EMBO J. 31, 2448-2460
   Abstract »    Full Text »    PDF »
Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors.
M. Nieborowska-Skorska, P. K. Kopinski, R. Ray, G. Hoser, D. Ngaba, S. Flis, K. Cramer, M. M. Reddy, M. Koptyra, T. Penserga, et al. (2012)
Blood 119, 4253-4263
   Abstract »    Full Text »    PDF »
Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation.
J. Ye, A. Mancuso, X. Tong, P. S. Ward, J. Fan, J. D. Rabinowitz, and C. B. Thompson (2012)
PNAS 109, 6904-6909
   Abstract »    Full Text »    PDF »
Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons.
Z. Wang, D. Chatterjee, H. Y. Jeon, M. Akerman, M. G. Vander Heiden, L. C. Cantley, and A. R. Krainer (2012)
J Mol Cell Biol 4, 79-87
   Abstract »    Full Text »    PDF »
Modulation of Glucose Metabolism by CD44 Contributes to Antioxidant Status and Drug Resistance in Cancer Cells.
M. Tamada, O. Nagano, S. Tateyama, M. Ohmura, T. Yae, T. Ishimoto, E. Sugihara, N. Onishi, T. Yamamoto, H. Yanagawa, et al. (2012)
Cancer Res. 72, 1438-1448
   Abstract »    Full Text »    PDF »
Targeting glucose metabolism for cancer therapy.
R. B. Hamanaka and N. S. Chandel (2012)
J. Exp. Med. 209, 211-215
   Abstract »    Full Text »    PDF »
Tyrosine Phosphorylation of Lactate Dehydrogenase A Is Important for NADH/NAD+ Redox Homeostasis in Cancer Cells.
J. Fan, T. Hitosugi, T.-W. Chung, J. Xie, Q. Ge, T.-L. Gu, R. D. Polakiewicz, G. Z. Chen, T. J. Boggon, S. Lonial, et al. (2011)
Mol. Cell. Biol. 31, 4938-4950
   Abstract »    Full Text »    PDF »
Warburg Effect and Redox Balance.
R. B. Hamanaka and N. S. Chandel (2011)
Science 334, 1219-1220
   Abstract »    Full Text »    PDF »
Targeting the Warburg Effect That Arises in Tumor Cells Expressing Membrane Type-1 Matrix Metalloproteinase.
T. Sakamoto, D. Niiya, and M. Seiki (2011)
J. Biol. Chem. 286, 14691-14704
   Abstract »    Full Text »    PDF »
Regulation of Metabolism by Hypoxia-Inducible Factor 1.
G. L. Semenza (2011)
Cold Spring Harb Symp Quant Biol 76, 347-353
   Abstract »    Full Text »    PDF »
Turning on a Fuel Switch of Cancer: hnRNP Proteins Regulate Alternative Splicing of Pyruvate Kinase mRNA.
M. Chen, J. Zhang, and J. L. Manley (2010)
Cancer Res. 70, 8977-8980
   Abstract »    Full Text »    PDF »
Pyruvate kinase M2 is a target of the tumor-suppressive microRNA-326 and regulates the survival of glioma cells.
B. Kefas, L. Comeau, N. Erdle, E. Montgomery, S. Amos, and B. Purow (2010)
Neuro Oncology 12, 1102-1112
   Abstract »    Full Text »    PDF »
Evidence for an Alternative Glycolytic Pathway in Rapidly Proliferating Cells.
M. G. Vander Heiden, J. W. Locasale, K. D. Swanson, H. Sharfi, G. J. Heffron, D. Amador-Noguez, H. R. Christofk, G. Wagner, J. D. Rabinowitz, J. M. Asara, et al. (2010)
Science 329, 1492-1499
   Abstract »    Full Text »    PDF »
Science Signaling Podcast: 15 December 2009.
P. S. Mischel and A. M. VanHook (2009)
Science Signaling 2, pc23
   Abstract »    Full Text »
PKM2 Tyrosine Phosphorylation and Glutamine Metabolism Signal a Different View of the Warburg Effect.
C. V. Dang (2009)
Science Signaling 2, pe75
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882