CoChat
Sign Up
Cited by 593Metabolism, Diabetes, and CancerPI3K/AKT/mTOR signaling in cancerCellular transport and secretion

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

Open access
Wieman, Heather L., Wofford, Jessica A., Rathmell, Jeffrey C.·2007·Molecular Biology of the Cell
DOI 10.1091/mbc.e06-07-0593PMC PMC1838986
Open this paper in CoChat — free account

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1091/mbc.e06-07-0593

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • PI3K/Akt effects on glucose metabolism are also mediated via HIF-independent mechanisms.

    “While the effect of the PI3K/Akt signalling pathway on glycolysis has been shown to be mediated in part via its regulation of HIF-1α expression and transcriptional activity in hypoxia [133,134], several lines of evidence have shown that its effects on glucose metabolism are also mediated via HIF-independent mechanisms.”

    From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [135]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 45

  1. Asano T., et al. The role of N-glycosylation of GLUT1 for glucose transport activity. J. Biol. Chem. 1991;266:24632–24636. [PubMed] [Google Scholar]
  2. Barnes K., McIntosh E., Whetton A. D., Daley G. Q., Bentley J., Baldwin S. A. Chronic myeloid leukaemia: an investigation into the role of Bcr-Abl-induced abnormalities in glucose transport regulation. Oncogene. 2005;24:3257–3267. doi: 10.1038/sj.onc.1208461. [DOI] [PubMed] [Google Scholar] · DOI
  3. Barthel A., Okino S. T., Liao J., Nakatani K., Li J., Whitlock J. P., Jr, Roth R. A. Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J. Biol. Chem. 1999;274:20281–20286. doi: 10.1074/jbc.274.29.20281. [DOI] [PubMed] [Google Scholar] · DOI
  4. Bentley J., Itchayanan D., Barnes K., McIntosh E., Tang X., Downes C. P., Holman G. D., Whetton A. D., Owen-Lynch P. J., Baldwin S. A. Interleukin-3-mediated cell survival signals include phosphatidylinositol 3-kinase-dependent translocation of the glucose transporter GLUT1 to the cell surface. J. Biol. Chem. 2003;278:39337–39348. doi: 10.1074/jbc.M305689200. [DOI] [PubMed] [Google Scholar] · DOI
  5. Ciofani M., Zuniga-Pflucker J. C. Notch promotes survival of pre-T cells at the beta-selection checkpoint by regulating cellular metabolism. Nat. Immunol. 2005;6:881–888. doi: 10.1038/ni1234. [DOI] [PubMed] [Google Scholar] · DOI
  6. Cong L. N., Chen H., Li Y., Zhou L., McGibbon M. A., Taylor S. I., Quon M. J. Physiological role of Akt in insulin-stimulated translocation of GLUT4 in transfected rat adipose cells. Mol. Endocrinol. 1997;11:1881–1890. doi: 10.1210/mend.11.13.0027. [DOI] [PubMed] [Google Scholar] · DOI
  7. Dang C. V. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol. Cell Biol. 1999;19:1–11. doi: 10.1128/mcb.19.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  8. Deshmukh M., Vasilakos J., Deckwerth T. L., Lampe P. A., Shivers B. D., Johnson E. M., Jr Genetic and metabolic status of NGF-deprived sympathetic neurons saved by an inhibitor of ICE family proteases. J. Cell Biol. 1996;135:1341–1354. doi: 10.1083/jcb.135.5.1341. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  9. Edinger A. L., Thompson C. B. Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol. Biol. Cell. 2002;13:2276–2288. doi: 10.1091/mbc.01-12-0584. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  10. Foran P. G., Fletcher L. M., Oatey P. B., Mohammed N., Dolly J. O., Tavare J. M. Protein kinase B stimulates the translocation of GLUT4 but not GLUT1 or transferrin receptors in 3T3–L1 adipocytes by a pathway involving SNAP-23, synaptobrevin-2, and/or cellubrevin. J. Biol. Chem. 1999;274:28087–28095. doi: 10.1074/jbc.274.40.28087. [DOI] [PubMed] [Google Scholar] · DOI
  11. Fox C. J., Hammerman P. S., Cinalli R. M., Master S. R., Chodosh L. A., Thompson C. B. The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor. Genes Dev. 2003;17:1841–1854. doi: 10.1101/gad.1105003. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  12. Frauwirth K. A., Thompson C. B. Regulation of T lymphocyte metabolism. J. Immunol. 2004;172:4661–4665. doi: 10.4049/jimmunol.172.8.4661. [DOI] [PubMed] [Google Scholar] · DOI
  13. Gatenby R. A., Gillies R. J. Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer. 2004;4:891–899. doi: 10.1038/nrc1478. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  14. Gonzalez E., McGraw T. E. Insulin signaling diverges into Akt-dependent and -independent signals to regulate the recruitment/docking and the fusion of GLUT4 vesicles to the plasma membrane. Mol. Biol. Cell. 2006;17:4484–4493. doi: 10.1091/mbc.E06-07-0585. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  15. Gottlob K., Majewski N., Kennedy S., Kandel E., Robey R. B., Hay N. Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev. 2001;15:1406–1418. doi: 10.1101/gad.889901. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  16. Heilig C. W., Saunders T., Brosius F. C., 3rd, Moley K., Heilig K., Baggs R., Guo L., Conner D. Glucose transporter-1-deficient mice exhibit impaired development and deformities that are similar to diabetic embryopathy. Proc. Natl. Acad. Sci. USA. 2003;100:15613–15618. doi: 10.1073/pnas.2536196100. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  17. Jope R. S., Johnson G. V. The glamour and gloom of glycogen synthase kinase-3. Trends Biochem. Sci. 2004;29:95–102. doi: 10.1016/j.tibs.2003.12.004. [DOI] [PubMed] [Google Scholar] · DOI
  18. Kan O., Baldwin S. A., Whetton A. D. Apoptosis is regulated by the rate of glucose transport in an interleukin 3 dependent cell line. J. Exp. Med. 1994;180:917–923. doi: 10.1084/jem.180.3.917. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  19. Kandel E. S., Hay N. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp. Cell Res. 1999;253:210–229. doi: 10.1006/excr.1999.4690. [DOI] [PubMed] [Google Scholar] · DOI
  20. Kansara M., Berridge M. V. Oncogenes modulate cell sensitivity to apoptosis induced by glucose deprivation. Anticancer Res. 2004;24:2503–2510. [PubMed] [Google Scholar]
  21. Krauss S., Brand M. D., Buttgereit F. Signaling takes a breath–new quantitative perspectives on bioenergetics and signal transduction. Immunity. 2001;15:497–502. doi: 10.1016/s1074-7613(01)00205-9. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  22. Lachaal M., Spangler R. A., Jung C. Y. Adenosine and adenosine triphosphate modulate the substrate binding affinity of glucose transporter GLUT1 in vitro. Biochim. Biophys. Acta. 2001;1511:123–133. doi: 10.1016/s0005-2736(01)00272-3. [DOI] [PubMed] [Google Scholar] · DOI
  23. Larance M., et al. Characterization of the role of the Rab GTPase-activating protein AS160 in insulin-regulated GLUT4 trafficking. J. Biol. Chem. 2005;280:37803–37813. doi: 10.1074/jbc.M503897200. [DOI] [PubMed] [Google Scholar] · DOI
  24. Levine K. B., Cloherty E. K., Fidyk N. J., Carruthers A. Structural and physiologic determinants of human erythrocyte sugar transport regulation by adenosine triphosphate. Biochemistry. 1998;37:12221–12232. doi: 10.1021/bi980585y. [DOI] [PubMed] [Google Scholar] · DOI
  25. Lin S. X., Grant B., Hirsh D., Maxfield F. R. Rme-1 regulates the distribution and function of the endocytic recycling compartment in mammalian cells. Nat. Cell Biol. 2001;3:567–572. doi: 10.1038/35078543. [DOI] [PubMed] [Google Scholar] · DOI
  26. Liu Q., Vera J. C., Peng H., Golde D. W. The predicted ATP-binding domains in the hexose transporter GLUT1 critically affect transporter activity. Biochemistry. 2001;40:7874–7881. doi: 10.1021/bi002850x. [DOI] [PubMed] [Google Scholar] · DOI
  27. Macheda M. L., Rogers S., Best J. D. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J. Cell Physiol. 2005;202:654–662. doi: 10.1002/jcp.20166. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  28. Maxfield F. R., McGraw T. E. Endocytic recycling. Nat. Rev. Mol. Cell Biol. 2004;5:121–132. doi: 10.1038/nrm1315. [DOI] [PubMed] [Google Scholar] · DOI
  29. Moley K. H., Mueckler M. M. Glucose transport and apoptosis. Apoptosis. 2000;5:99–105. doi: 10.1023/a:1009697908332. [DOI] [PubMed] [Google Scholar] · DOI
  30. Piper R. C., Hess L. J., James D. E. Differential sorting of two glucose transporters expressed in insulin-sensitive cells. Am. J. Physiol. 1991;260:C570–C580. doi: 10.1152/ajpcell.1991.260.3.C570. [DOI] [PubMed] [Google Scholar] · DOI
  31. Plas D. R., Rathmell J. C., Thompson C. B. Homeostatic control of lymphocyte survival: potential origins and implications. Nat. Immunol. 2002;3:515–521. doi: 10.1038/ni0602-515. [DOI] [PubMed] [Google Scholar] · DOI
  32. Plas D. R., Talapatra S., Edinger A. L., Rathmell J. C., Thompson C. B. Akt and Bcl-xL promote growth factor-independent survival through distinct effects on mitochondrial physiology. J. Biol. Chem. 2001;276:12041–12048. doi: 10.1074/jbc.M010551200. [DOI] [PubMed] [Google Scholar] · DOI
  33. Rathmell J. C., Farkash E. A., Gao W., Thompson C. B. IL-7 enhances the survival and maintains the size of naive T cells. J. Immunol. 2001;167:6869–6876. doi: 10.4049/jimmunol.167.12.6869. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  34. Rathmell J. C., Fox C. J., Plas D. R., Hammerman P. S., Cinalli R. M., Thompson C. B. Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival. Mol. Cell Biol. 2003;23:7315–7328. doi: 10.1128/MCB.23.20.7315-7328.2003. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  35. Rathmell J. C., Vander Heiden M. G., Harris M. H., Frauwirth K. A., Thompson C. B. In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability. Mol. Cell. 2000;6:683–692. doi: 10.1016/s1097-2765(00)00066-6. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  36. Roberts M. S., Woods A. J., Dale T. C., Van Der Sluijs P., Norman J. C. Protein kinase B/Akt acts via glycogen synthase kinase 3 to regulate recycling of alpha v beta 3 and alpha 5 beta 1 integrins. Mol. Cell Biol. 2004;24:1505–1515. doi: 10.1128/MCB.24.4.1505-1515.2004. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  37. Thompson J. E., Thompson C. B. Putting the rap on Akt. J. Clin. Oncol. 2004;22:4217–4226. doi: 10.1200/JCO.2004.01.103. [DOI] [PubMed] [Google Scholar] · DOI
  38. Tremblay F., Gagnon A., Veilleux A., Sorisky A., Marette A. Activation of the mammalian target of rapamycin pathway acutely inhibits insulin signaling to Akt and glucose transport in 3T3–L1 and human adipocytes. Endocrinology. 2005;146:1328–1337. doi: 10.1210/en.2004-0777. [DOI] [PubMed] [Google Scholar] · DOI
  39. Ullrich O., Reinsch S., Urbe S., Zerial M., Parton R. G. Rab11 regulates recycling through the pericentriolar recycling endosome. J. Cell Biol. 1996;135:913–924. doi: 10.1083/jcb.135.4.913. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  40. Vander Heiden M. G., Chandel N. S., Williamson E. K., Schumacker P. T., Thompson C. B. Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria. Cell. 1997;91:627–637. doi: 10.1016/s0092-8674(00)80450-x. [DOI] [PubMed] [Google Scholar] · DOI
  41. Vander Heiden M. G., Plas D. R., Rathmell J. C., Fox C. J., Harris M. H., Thompson C. B. Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol. Cell Biol. 2001;21:5899–5912. doi: 10.1128/MCB.21.17.5899-5912.2001. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  42. Warburg O. On the origin of cancer cells. Science. 1956;123:309–314. doi: 10.1126/science.123.3191.309. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  43. Watson R. T., Kanzaki M., Pessin J. E. Regulated membrane trafficking of the insulin-responsive glucose transporter 4 in adipocytes. Endocr. Rev. 2004;25:177–204. doi: 10.1210/er.2003-0011. [DOI] [PubMed] [Google Scholar] · DOI
  44. Welsh G. I., Hers I., Berwick D. C., Dell G., Wherlock M., Birkin R., Leney S., Tavare J. M. Role of protein kinase B in insulin-regulated glucose uptake. Biochem. Soc. Trans. 2005;33:346–349. doi: 10.1042/BST0330346. [DOI] [PubMed] [Google Scholar] · DOI
  45. Zeigerer A., McBrayer M. K., McGraw T. E. Insulin stimulation of GLUT4 exocytosis, but not its inhibition of endocytosis, is dependent on RabGAP AS160. Mol. Biol. Cell. 2004;15:4406–4415. doi: 10.1091/mbc.E04-04-0333. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI

Cited by

Sorted by citations

Authors
Wieman, H. L., Wofford, J. A., & Rathmell, J. C.
Affiliations
Duke University (US)
Corresponding author
Rathmell, Jeffrey C.
ORCID
Venue
Molecular Biology of the Cell
Publisher
American Society for Cell Biology (ASCB)
Published
2007-04
Volume
18
Issue
4
Pages
1437-1446
ISSN
  • 1059-1524 (ISSN-L)
  • 1939-4586
DOI
10.1091/mbc.e06-07-0593
PMC
PMC1838986
OpenAlex
W2166268973
Cited by
593
References
1
Citations by year
2026: 15 · 2025: 22 · 2024: 30 · 2023: 41 · 2022: 46 · 2021: 41 · 2020: 46 · 2019: 50 · 2018: 40 · 2017: 33 · 2016: 28 · 2015: 25 · 2014: 30 · 2013: 30 · 2012: 33
FWCI
8.22
Type
journal article
Language
en
Open access
Locations
  • Molecular Biology of the Cell (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • V Foundation for Cancer Research
  • Sidney Kimmel Foundation for Cancer Research
  • Sidney Kimmel Foundation
  • National Institute of Allergy and Infectious Diseases (R01AI063345)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
interleukin-3, GLUT1, glucose uptake, glucose transporter trafficking, phosphatidylinositol 3-kinase, Akt, Rab11a, endosomal recycling, glycogen synthase kinase-3, cytokine signaling, hematopoietic cells, glucose metabolism
MeSH terms
rab11 GTP-Binding Proteins, Animals, Cell Line, Cell Membrane, Glucose, Hematopoietic Stem Cells, Interleukin-3, Protein Kinases, Cytokines, Phosphatidylinositol 3-Kinases, Sirolimus, rab GTP-Binding Proteins, Protein Transport, Glycogen Synthase Kinase 3, Proto-Oncogene Proteins c-akt, Glucose Transporter Type 1, Mice, TOR Serine-Threonine Kinases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review