Oncogenic KRAS signaling activates mTORC1 through COUP-TFII-mediated lactate production

EMBO Rep. 2019 Jun;20(6):e47451. doi: 10.15252/embr.201847451. Epub 2019 Apr 15.


Oncogenic signals contribute to enhanced glycolysis and mTORC1 activity, leading to rapid cell proliferation in cancer. Regulation of glycolysis and mTORC1 by PI3K/Akt signaling is well established, but how KRAS-induced MEK signaling regulates these pathways remains poorly understood. Here, we report a role for MEK-driven lactate production in mTORC1 activation in KRAS-activated cells. KRAS/MEK-induced upregulation of the chicken ovalbumin upstream promoter transcriptional factor II (COUP-TFII) increases the expression of lactate dehydrogenase A (LDHA), resulting in lactate production and mTORC1 activation. Further, lactate inhibits the interaction of TSC2 and Rheb, leading to the cellular activation of mTORC1 irrespective of growth factor stimulation. These findings suggest that COUP-TFII is a novel oncogenic mediator, connecting KRAS signaling and glycolysis, and leading to mTORC1 activation and cellular growth.

Keywords: KRAS; COUP‐TFII; glycolysis; lactate; mTORC1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • COUP Transcription Factor II / genetics
  • COUP Transcription Factor II / metabolism*
  • Cell Line, Tumor
  • Gene Expression
  • Gene Knockdown Techniques
  • Glycolysis
  • Humans
  • Lactic Acid / biosynthesis*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Models, Biological
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Ras Homolog Enriched in Brain Protein / metabolism
  • Signal Transduction*
  • Tuberous Sclerosis Complex 2 Protein / metabolism


  • COUP Transcription Factor II
  • KRAS protein, human
  • RHEB protein, human
  • Ras Homolog Enriched in Brain Protein
  • TSC2 protein, human
  • Tuberous Sclerosis Complex 2 Protein
  • Lactic Acid
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins p21(ras)