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]

RESEARCH

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:
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