Four Key Steps Control Glycolytic Flux in Mammalian Cells.

TitleFour Key Steps Control Glycolytic Flux in Mammalian Cells.
Publication TypeJournal Article
Year of Publication2018
AuthorsTanner, LBahati, Goglia, AG, Wei, MH, Sehgal, T, Parsons, LR, Park, JO, White, E, Toettcher, JE, Rabinowitz, JD
JournalCell Syst
Date Published2018 07 25
KeywordsAnimals, Biological Transport, Cell Line, Genes, ras, Glucose, Glycolysis, HEK293 Cells, Hexokinase, Humans, Isoenzymes, Lactic Acid, Mammals, Mice, Models, Biological, Neoplasms, NIH 3T3 Cells, Phosphofructokinase-1

<p>Altered glycolysis is a hallmark of diseases including diabetes and cancer. Despite intensive study of the contributions of individual glycolytic enzymes, systems-level analyses of flux control through glycolysis remain limited. Here, we overexpress in two mammalian cell lines the individual enzymes catalyzing each of the 12 steps linking extracellular glucose to excreted lactate, and find substantial flux control at four steps: glucose import, hexokinase, phosphofructokinase, and lactate export (and not at any steps of lower glycolysis). The four flux-controlling steps are specifically upregulated by the Ras oncogene: optogenetic Ras activation rapidly induces the transcription of isozymes catalyzing these four steps and enhances glycolysis. At least one isozyme catalyzing each of these four steps is consistently elevated in human tumors. Thus, in the studied contexts, flux control in glycolysis is concentrated in four key enzymatic steps. Upregulation of these steps in tumors likely underlies the Warburg effect.</p>

Alternate JournalCell Syst
PubMed ID29960885
PubMed Central IDPMC6062487
Grant ListDP1 DK113643 / DK / NIDDK NIH HHS / United States
DP2 EB024247 / EB / NIBIB NIH HHS / United States
F30 CA206408 / CA / NCI NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States