The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism

Kathryn E. Wellen, Chao Lu, Anthony Mancuso, Johanna M.S. Lemons, Michael Ryczko, James W. Dennis, Joshua D. Rabinowitz, Hilary A. Coller, Craig B. Thompson

Research output: Contribution to journalArticle

234 Scopus citations

Abstract

Glucose and glutamine serve as the two primary carbon sources in proliferating cells, and uptake of both nutrients is directed by growth factor signaling. Although either glucose or glutamine can potentially support mitochondrial tricarboxylic acid (TCA) cycle integrity and ATP production, we found that glucose deprivation led to a marked reduction in glutamine uptake and progressive cellular atrophy in multiple mammalian cell types. Despite the continuous presence of growth factor and an abundant supply of extracellular glutamine, interleukin-3 (IL-3)-dependent cells were unable to maintain TCA cycle metabolite pools or receptor-dependent signal transduction when deprived of glucose. This was due at least in part to down-regulation of IL-3 receptor α (IL-3Rα) surface expression in the absence of glucose. Treatment of glucose-starved cells with N-acetylglucosamine (GlcNAc) to maintain hexosamine biosynthesis restored mitochondrial metabolism and cell growth by promoting IL-3-dependent glutamine uptake and metabolism. Thus, glucose metabolism through the hexosamine biosynthetic pathway is required to sustain sufficient growth factor signaling and glutamine uptake to support cell growth and survival.

Original languageEnglish (US)
Pages (from-to)2784-2799
Number of pages16
JournalGenes and Development
Volume24
Issue number24
DOIs
StatePublished - Dec 15 2010

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

Keywords

  • Glucose
  • Glutamine
  • Glycosylation
  • Growth factor signaling
  • Hexosamine
  • Metabolism

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    Wellen, K. E., Lu, C., Mancuso, A., Lemons, J. M. S., Ryczko, M., Dennis, J. W., Rabinowitz, J. D., Coller, H. A., & Thompson, C. B. (2010). The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes and Development, 24(24), 2784-2799. https://doi.org/10.1101/gad.1985910