Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth.

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 Y(105) is common in human cancers. The presence of a PKM2 mutant in which phenylalanine is substituted for Y(105) (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.

• Authors: Taro 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
• Journal: Science signaling (Sci Signal) Vol. 2 Issue 97 Pg. ra73 (Nov 17 2009) ISSN: 1937-9145 [Electronic] United States
• PMID: 19920251 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fructosediphosphates
• Tyrosine
• Adenosine Triphosphate
• Pyruvate Kinase
• Receptor, Fibroblast Growth Factor, Type 1
• Glucose
• fructose-1,6-diphosphate

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Cell Line
• Cell Line, Tumor
• Cell Proliferation
• Fructosediphosphates (metabolism)
• Glucose (metabolism)
• Glycolysis (physiology)
• Humans
• Immunoblotting
• K562 Cells
• Male
• Mice
• Mice, Nude
• Mutation
• Neoplasms (genetics, metabolism, pathology)
• Neoplasms, Experimental (genetics, metabolism, pathology)
• Oxygen Consumption
• Phosphorylation
• Proteomics (methods)
• Pyruvate Kinase (genetics, metabolism)
• Receptor, Fibroblast Growth Factor, Type 1 (genetics, metabolism)
• Transplantation, Heterologous
• Tumor Burden
• Tyrosine (metabolism)