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Genes & Dev. 24 (24): 2784-2799

Copyright © 2010 by Cold Spring Harbor Laboratory Press.

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

Kathryn E. Wellen1, Chao Lu1, Anthony Mancuso1, Johanna M.S. Lemons2, Michael Ryczko3, 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

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 {alpha} (IL-3R{alpha}) 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.

Key Words: Metabolism • glucose • glutamine • hexosamine • growth factor signaling • glycosylation

Received for publication August 24, 2010. Accepted for publication October 29, 2010.

6 Corresponding author.

E-MAIL craig{at}mail.med.upenn.edu; FAX (215) 746-5511.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1985910.

Supplemental material is available for this article.

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