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The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism
Kathryn E. Wellen1,
Johanna M.S. Lemons2,
James W. Dennis3,
Joshua D. Rabinowitz4,
Hilary A. Coller5,, and
Craig B. Thompson1,6
1 Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; 2 Deparment of Chemistry, Princeton University, Princeton, New Jersey 08544, USA; 3 Department of Molecular Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada; 4 Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA; 5 Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA
Glucose and glutamine serve as the two primary carbon sourcesin proliferating cells, and uptake of both nutrients is directedby growth factor signaling. Although either glucose or glutaminecan potentially support mitochondrial tricarboxylic acid (TCA)cycle integrity and ATP production, we found that glucose deprivationled to a marked reduction in glutamine uptake and progressivecellular atrophy in multiple mammalian cell types. Despite thecontinuous presence of growth factor and an abundant supplyof extracellular glutamine, interleukin-3 (IL-3)-dependent cellswere unable to maintain TCA cycle metabolite pools or receptor-dependentsignal transduction when deprived of glucose. This was due atleast in part to down-regulation of IL-3 receptor (IL-3R) surfaceexpression in the absence of glucose. Treatment of glucose-starvedcells with N-acetylglucosamine (GlcNAc) to maintain hexosaminebiosynthesis restored mitochondrial metabolism and cell growthby promoting IL-3-dependent glutamine uptake and metabolism.Thus, glucose metabolism through the hexosamine biosyntheticpathway is required to sustain sufficient growth factor signalingand glutamine uptake to support cell growth and survival.
Metabolic Pathway Alterations that Support Cell Proliferation.
M. G. Vander Heiden, S. Y. Lunt, T. L. Dayton, B. P. Fiske, W. J. Israelsen, K. R. Mattaini, N. I. Vokes, G. Stephanopoulos, L. C. Cantley, C. M. Metallo, et al. (2011)
Cold Spring Harb Symp Quant Biol
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