Journal
SCIENCE SIGNALING
Volume 2, Issue 97, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2000431
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Funding
- NCI NIH HHS [R01 CA120272-01, T32 CA009172, R01 CA120272, R01 CA120272-03, R01 CA140515, CA120272, R01 CA120272-04, R01 CA120272-02] Funding Source: Medline
- NIGMS NIH HHS [R01 GM056203] Funding Source: Medline
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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.
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