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MBC in Press, published online ahead of print February 14, 2007
Mol. Biol. Cell 10.1091/mbc.E06-07-0593

A more recent version of this article appeared on April 1, 2007
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Submitted on July 11, 2006
Revised on December 22, 2006
Accepted on February 2, 2007

Cytokine Stimulation Promotes Glucose Uptake via PI3K/Akt Regulation of Glut1 Activity and Trafficking

Heather L. Wieman, Jessica A. Wofford, and Jeffrey C. Rathmell

Department of Pharmacology and Cancer Biology, Department of Immunology, and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27710

Monitoring Editor: Ben Margolis

Cells require growth factors to support glucose metabolism for survival and growth. It is unclear, however, how noninsulin growth factors may regulate glucose uptake and glucose transporters. We show that the hematopoietic growth factor, interleukin-3 (IL3), maintained the glucose transporter, Glut1, on the cell surface and promoted Rab11a-dependent recycling of intracellular Glut1. IL3 required phosphatidylinositol-3 kinase activity to regulate Glut1 trafficking and activated Akt was sufficient to maintain glucose uptake and surface Glut1 in the absence of IL3. To determine how Akt may regulate Glut1, we analyzed the role of Akt activation of mTOR/RAPTOR and inhibition of GSK3. While Akt did not require mTOR/RAPTOR to maintain surface Glut1 levels, inhibition of mTOR/RAPTOR by rapamycin greatly diminished glucose uptake, suggesting Akt-stimulated mTOR/RAPTOR may promote Glut1 transporter activity. In contrast, inhibition of GSK3 did not affect Glut1 internalization but nevertheless maintained surface Glut1 levels in IL3-deprived cells, possibly via enhanced recycling of internalized Glut1. In addition, Akt attenuated Glut1 internalization through a GSK3-independent mechanism. These data demonstrate that intracellular trafficking of Glut1 is a regulated component of growth factor-stimulated glucose uptake and that Akt can promote Glut1 activity and recycling as well as prevent Glut1 internalization.

Address correspondence to: Jeffrey C. Rathmell (jeff.rathmell{at}duke.edu)




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