QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 18, Issue 4, 1437-1446, April 2007

This Article Full Text Full Text (PDF) All Versions of this Article: E06-07-0593v1 18/4/1437    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wieman, H. L. Articles by Rathmell, J. C. Search for Related Content PubMed PubMed Citation Articles by Wieman, H. L. Articles by Rathmell, J. C.

Cytokine Stimulation Promotes Glucose Uptake via Phosphatidylinositol-3 Kinase/Akt Regulation of Glut1 Activity and Trafficking

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

Submitted July 11, 2006; Revised December 22, 2006; Accepted February 2, 2007
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 (IL)3, 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 mammalian target of rapamycin (mTOR)/regulatory associated protein of mTOR (RAPTOR) and inhibition of glycogen synthase kinase (GSK)3. Although 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)

Abbreviations used: 2-DOG, 2-deoxy-D-glucose; CHX, cycloheximide; GFP, green fluorescent protein; GSK, glycogen synthase kinase 3; HRP, horseradish peroxidase; IL, interleukin; LDL, low-density lipoprotein; myrAkt, myristoylated Akt; PBS, phosphate-buffered saline; PI3K, phosphatidylinositol 3-kinase; TfR, transferrin receptor.

This article has been cited by other articles:

				A. Borthakur, R. K. Gill, S. Tyagi, A. Koutsouris, W. A. Alrefai, G. A. Hecht, K. Ramaswamy, and P. K. Dudeja The Probiotic Lactobacillus acidophilus Stimulates Chloride/Hydroxyl Exchange Activity in Human Intestinal Epithelial Cells J. Nutr., July 1, 2008; 138(7): 1355 - 1359. [Abstract] [Full Text] [PDF]

				S. R. Jacobs, C. E. Herman, N. J. MacIver, J. A. Wofford, H. L. Wieman, J. J. Hammen, and J. C. Rathmell Glucose Uptake Is Limiting in T Cell Activation and Requires CD28-Mediated Akt-Dependent and Independent Pathways J. Immunol., April 1, 2008; 180(7): 4476 - 4486. [Abstract] [Full Text] [PDF]

				J. A. Wofford, H. L. Wieman, S. R. Jacobs, Y. Zhao, and J. C. Rathmell IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival Blood, February 15, 2008; 111(4): 2101 - 2111. [Abstract] [Full Text] [PDF]

				R. T. Woodland, C. J. Fox, M. R. Schmidt, P. S. Hammerman, J. T. Opferman, S. J. Korsmeyer, D. M. Hilbert, and C. B. Thompson Multiple signaling pathways promote B lymphocyte stimulator dependent B-cell growth and survival Blood, January 15, 2008; 111(2): 750 - 760. [Abstract] [Full Text] [PDF]

				M. M. Juntilla, J. A. Wofford, M. J. Birnbaum, J. C. Rathmell, and G. A. Koretzky Akt1 and Akt2 are required for {alpha}beta thymocyte survival and differentiation PNAS, July 17, 2007; 104(29): 12105 - 12110. [Abstract] [Full Text] [PDF]