Tyrosine phosphorylation inhibits PKM2 to promote the warburg effect and tumor growth Academic Article uri icon

Overview

MeSH Major

  • Glycolysis
  • Neoplasms
  • Pyruvate Kinase
  • Tyrosine

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.

publication date

  • November 17, 2009

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2812789

Digital Object Identifier (DOI)

  • 10.1126/scisignal.2000431

PubMed ID

  • 19920251

Additional Document Info

start page

  • ra73

volume

  • 2

number

  • 97