Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking.
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.
Wieman
Heather L
HL
Department of Pharmacology and Cancer Biology, and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27710, USA.
Wofford
Jessica A
JA
Rathmell
Jeffrey C
JC
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology*; D005947:Glucose / Q000493:pharmacokinetics*; D051272:Glucose Transporter Type 1 / Q000187:drug effects / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology; D007377:Interleukin-3 / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D020691:rab GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
D016207:Cytokines; D005947:Glucose; D051272:Glucose Transporter Type 1; D038362:Glycogen Synthase Kinase 3; D007377:Interleukin-3; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C495678:Slc2a1 protein, mouse; C546843:mTOR protein, mouse