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.
Subscribe

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

RESEARCH ARTICLES

Tyrosine Phosphorylation Inhibits PKM2 to Promote the Warburg Effect and Tumor Growth

Taro Hitosugi1, Sumin Kang1, Matthew G. Vander Heiden2, Tae-Wook Chung1, Shannon Elf1, Katherine Lythgoe1, Shaozhong Dong1, Sagar Lonial1, Xu Wang1, Georgia Z. Chen1, Jianxin Xie3, Ting-Lei Gu3, Roberto D. Polakiewicz3, Johannes L. Roesel4, Titus J. Boggon5, Fadlo R. Khuri1, D. Gary Gilliland6, Lewis C. Cantley2, Jonathan Kaufman1, and Jing Chen1*

1 Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
2 Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
3 Cell Signaling Technology, Inc. (CST), Danvers, MA 01923, USA.
4 Novartis Pharma AG, CH-4002 Basel, Switzerland.
5 Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
6 Howard Hughes Medical Institute, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA.

Abstract: The Warburg effect describes a pro-oncogenic metabolism switch such that cancer cells take up more glucose than normal tissue and favor incomplete oxidation of glucose even in the presence of oxygen. To better understand how tyrosine kinase signaling, which is commonly increased in tumors, regulates the Warburg effect, we performed phosphoproteomic studies. We found that oncogenic forms of fibroblast growth factor receptor type 1 inhibit the pyruvate kinase M2 (PKM2) isoform by direct phosphorylation of PKM2 tyrosine residue 105 (Y105). This inhibits the formation of active, tetrameric PKM2 by disrupting binding of the PKM2 cofactor fructose-1,6-bisphosphate. Furthermore, we found that phosphorylation of PKM2 Y105 is common in human cancers. The presence of a PKM2 mutant in which phenylalanine is substituted for Y105 (Y105F) in cancer cells leads to decreased cell proliferation under hypoxic conditions, increased oxidative phosphorylation with reduced lactate production, and reduced tumor growth in xenografts in nude mice. Our findings suggest that tyrosine phosphorylation regulates PKM2 to provide a metabolic advantage to tumor cells, thereby promoting tumor growth.

* To whom correspondence should be addressed. E-mail: jchen{at}emory.edu

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

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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 »
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