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J. Biol. Chem., Vol. 278, Issue 41, 39337-39348, October 10, 2003

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Interleukin-3-mediated Cell Survival Signals Include Phosphatidylinositol 3-Kinase-dependent Translocation of the Glucose Transporter GLUT1 to the Cell Surface^*

Johanne Bentley   ¶, Dalina Itchayanan   ||, Kay Barnes  , Elizabeth McIntosh , Xiuwen Tang **, C. Peter Downes **, Geoffrey D. Holman , Anthony D. Whetton , P. Jane Owen-Lynch  ¶¶ and Stephen A. Baldwin  ||||

From the School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, the ^**Department of Biochemistry, University of Dundee, Dundee DD1 5EH, Scotland, the School of Biology and Biochemistry, University of Bath, Bath BA2 7AY, and the Leukaemia Research Fund Unit, Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology, Manchester M60 1QD, United Kingdom

Maintenance of glucose uptake is a key component in the response of hematopoietic cells to survival factors. To investigate the mechanism of this response we employed the interleukin-3 (IL-3)-dependent murine mast cell line IC2.9. In these cells, hexose uptake decreased markedly upon withdrawal of IL-3, whereas its readdition led to rapid (t 10 min) stimulation of transport, associated with an 4-fold increase in V_max but no change in K_m. Immunocytochemistry and photoaffinity labeling revealed that IL-3 caused translocation of intracellular GLUT1 transporters to the cell surface, whereas a second transporter isoform, GLUT3, remained predominantly intracellular. The inhibitory effects of latrunculin B and jasplakinolide, and of nocodazole and colchicine, respectively, revealed a requirement for both the actin and microtubule cytoskeletons in GLUT1 translocation and transport stimulation. Both IL-3 stimulation of transport and GLUT1 translocation were also prevented by the phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002. The time courses for activation of phosphatidylinositol 3-kinase and its downstream target, protein kinase B, by IL-3 were consistent with a role in IL-3-induced transporter translocation and enhanced glucose uptake. We conclude that one component of the survival mechanisms elicited by IL-3 involves the subcellular redistribution of glucose transporters, thus ensuring the supply of a key metabolic substrate.

Received for publication, May 30, 2003 , and in revised form, July 11, 2003.

^* This work was supported in part by Yorkshire Cancer Research (United Kingdom), the Wellcome Trust, and the Leukaemia Research Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^¶ Present address: Division of Cancer Medicine Research, ICRF Clinical Centre, St. James's University Hospital, Leeds LS9 7TF, United Kingdom.

^|| Supported by a scholarship from the Royal Thai government.

^¶¶ Present address: Dept. of Biological Sciences, Lancaster University, Lancaster LA1 4YQ, United Kingdom.

^|||| To whom correspondence should be addressed: School of Biochemistry and Molecular Biology, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, United Kingdom. Tel.: 44-113-343-3173; Fax: 44-113-343-3167; E-mail: s.a.baldwin{at}leeds.ac.uk.

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