@article{eb8879b0dc464b9797d445bda588ae36,
title = "Four Key Steps Control Glycolytic Flux in Mammalian Cells",
abstract = "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. Here, we perform a systematic analysis of glycolytic flux control in mammalian cells. We identify four key flux-controlling steps: glucose import and phosphorylation, fructose-1,6-bisphosphate production, and lactate export. In contrast, enzyme steps in lower glycolysis do not control pathway flux. Activation of glycolysis in cancer and immune cells is associated with enhanced expression of enzymes catalyzing these four key flux-controlling steps.",
keywords = "GLUT, MCT1, PFK, PFKFB, flux control, glycolysis, metabolic control analysis, metabolism, metabolomics, optogenetics",
author = "Tanner, {Lukas Bahati} and Goglia, {Alexander G.} and Wei, {Monica H.} and Talen Sehgal and Parsons, {Lance R.} and Park, {Junyoung O.} and Eileen White and Toettcher, {Jared E.} and Rabinowitz, {Joshua D.}",
note = "Funding Information: The authors thank Wenyun Lu for help with mass spectrometry analysis, Max Homilius for help with the TCGA data analysis, Jing Fan for initial efforts exploring glycolytic enzyme concentration changes induced by Ras, and Gregory S. Ducker and the other Rabinowitz lab members for helpful comments and discussions. This work was supported by grants from the NIH ( R01 CA163591 ) to E.W. and J.D.R., from the NIH ( DP1 DK113643 ) and from Stand Up To Cancer (Dream Team Translational Research grant SU2C-AACR-DT2016 ) to J.D.R., by grants from the NIH ( DP2EB024247 ) and from the American Cancer Society ( IRG-15-168-01 ) to J.E.T., by an Early Postdoc Mobility fellowship from the Swiss National Science Foundation ( P2SKP3-148484 ) to L.B.T., and by an NIH National Cancer Institute fellowship ( F30CA206408 ) to A.G.G. Stand Up To Cancer is a program of the Entertainment Industry Foundation, administered by the American Association for Cancer Research. Funding Information: The authors thank Wenyun Lu for help with mass spectrometry analysis, Max Homilius for help with the TCGA data analysis, Jing Fan for initial efforts exploring glycolytic enzyme concentration changes induced by Ras, and Gregory S. Ducker and the other Rabinowitz lab members for helpful comments and discussions. This work was supported by grants from the NIH (R01 CA163591) to E.W. and J.D.R., from the NIH (DP1 DK113643) and from Stand Up To Cancer (Dream Team Translational Research grant SU2C-AACR-DT2016) to J.D.R., by grants from the NIH (DP2EB024247) and from the American Cancer Society (IRG-15-168-01) to J.E.T., by an Early Postdoc Mobility fellowship from the Swiss National Science Foundation (P2SKP3-148484) to L.B.T., and by an NIH National Cancer Institute fellowship (F30CA206408) to A.G.G. Stand Up To Cancer is a program of the Entertainment Industry Foundation, administered by the American Association for Cancer Research. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = jul,
day = "25",
doi = "10.1016/j.cels.2018.06.003",
language = "English (US)",
volume = "7",
pages = "49--62.e8",
journal = "Cell Systems",
issn = "2405-4712",
publisher = "Cell Press",
number = "1",
}