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

Abstract

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 (t1 ⁄2 ϳ 10 min) stimulation of transport, associated with an ϳ4-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.

Glucose Uptake Is Limiting in T Cell Activation and Requires CD28-Mediated Akt-Dependent and Independent Pathways

“…7E). These data suggest that Akt may not regulate Glut1 expression, but consistent with the role of Akt to regulate Glut1 trafficking in response to cytokine signaling (17,21,32), may increase Glut1 surface trafficking or glucose uptake activity.…”

“…Costimulation may also preferentially activate specific signaling pathways, such as CD28 activation of the PI3K/Akt pathway, to promote glucose uptake and metabolism. Activation of PI3K may be a particularly important regulator of glucose uptake, as PI3K inhibition prevented increased glucose metabolism after lymphocyte activation or cytokine stimulation, and decreased glucose uptake of leukemic cells (5,(21)(22)(23). Conversely, in addition to its ability to cause autoimmunity and lymphoma, expression of constitutively active Akt promoted increased glucose uptake and consumption in cell lines (20,23) and elevated glycolysis in primary T cells (24).…”

A GSK-3/TSC2/mTOR pathway regulates glucose uptake and GLUT1 glucose transporter expression

“…In one of the few reports, Nikoulina et al (37) found that inhibition of GSK-3 for 4 days increased both basal and insulin-stimulated glucose uptake in skeletal muscle without changing expression of either GLUT1 or GLUT4. Similarly, Bentley et al (4) showed that IL-3 stimulated translocation of GLUT1 to the cell surface of mast cells, and Wieman et al (42) found that this IL-3 effect on Fig. 6.…”

“…Previous studies on GLUT1 regulation have included evidence that cytokines, such as IL-3, can stimulate GLUT1-mediated glucose transport in mast cells via a PI3K-dependent mechanism (4). In addition, a number of investigators have shown that cellular metabolism and ATP availability play a significant role in regulating GLUT1 expression and function through both direct and indirect mechanisms.…”

“…The signaling pathways involved in acute insulin-stimulated GLUT4 translocation have been the subject of many studies over the past two decades. However, relatively few studies have examined the signaling systems involved in long-term regulation of GLUT1 mediated glucose uptake in noninsulin responsive tissues (4,5,11,18,36), and none of these previous reports have investigated the role of a signaling pathway that is an important regulator of cellular growth and metabolism, namely, the pathway that includes glycogen synthase kinase-3 (GSK-3), tuberous sclerosis complex (TSC), and mammalian target of rapamycin (mTOR).…”