Tyrosine phosphorylation inhibits PKM2 to promote the warburg effect and tumor growth

Taro D Hitosugi, Sumin Kang, Matthew G. Vander Heiden, Tae Wook Chung, Shannon Elf, Katherine Lythgoe, Shaozhong Dong, Sagar Lonial, Xu Wang, Georgia Z. Chen, Jianxin Xie, Ting Lei Gu, Roberto D. Polakiewicz, Johannes L. Roesel, Titus J. Boggon, Fadlo R. Khuri, D. Gary Gilliland, Lewis C. Cantley, Jonathan Kaufman, Jing Chen

Research output: Contribution to journalArticle

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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 (Y 105). 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.

Original languageEnglish (US)
JournalScience Signaling
Volume2
Issue number97
DOIs
StatePublished - Nov 17 2009
Externally publishedYes

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Phosphorylation
Pyruvate Kinase
Tyrosine
Tumors
Growth
Neoplasms
Cells
Receptor, Fibroblast Growth Factor, Type 1
Glucose
Oxidative Phosphorylation
Cell proliferation
Phenylalanine
Heterografts
Metabolism
Nude Mice
Protein-Tyrosine Kinases
Lactic Acid
Protein Isoforms
Switches
Cell Proliferation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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Tyrosine phosphorylation inhibits PKM2 to promote the warburg effect and tumor growth. / Hitosugi, Taro D; Kang, Sumin; Vander Heiden, Matthew G.; Chung, Tae Wook; Elf, Shannon; Lythgoe, Katherine; Dong, Shaozhong; Lonial, Sagar; Wang, Xu; Chen, Georgia Z.; Xie, Jianxin; Gu, Ting Lei; Polakiewicz, Roberto D.; Roesel, Johannes L.; Boggon, Titus J.; Khuri, Fadlo R.; Gilliland, D. Gary; Cantley, Lewis C.; Kaufman, Jonathan; Chen, Jing.

In: Science Signaling, Vol. 2, No. 97, 17.11.2009.

Research output: Contribution to journalArticle

Hitosugi, TD, Kang, S, Vander Heiden, MG, Chung, TW, Elf, S, Lythgoe, K, Dong, S, Lonial, S, Wang, X, Chen, GZ, Xie, J, Gu, TL, Polakiewicz, RD, Roesel, JL, Boggon, TJ, Khuri, FR, Gilliland, DG, Cantley, LC, Kaufman, J & Chen, J 2009, 'Tyrosine phosphorylation inhibits PKM2 to promote the warburg effect and tumor growth', Science Signaling, vol. 2, no. 97. https://doi.org/10.1126/scisignal.2000431
Hitosugi, Taro D ; Kang, Sumin ; Vander Heiden, Matthew G. ; Chung, Tae Wook ; Elf, Shannon ; Lythgoe, Katherine ; Dong, Shaozhong ; Lonial, Sagar ; Wang, Xu ; Chen, Georgia Z. ; Xie, Jianxin ; Gu, Ting Lei ; Polakiewicz, Roberto D. ; Roesel, Johannes L. ; Boggon, Titus J. ; Khuri, Fadlo R. ; Gilliland, D. Gary ; Cantley, Lewis C. ; Kaufman, Jonathan ; Chen, Jing. / Tyrosine phosphorylation inhibits PKM2 to promote the warburg effect and tumor growth. In: Science Signaling. 2009 ; Vol. 2, No. 97.
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