Endocytic vesicles act as vehicles for glucose uptake in response to growth factor stimulation

Glycolysis is a fundamental cellular process, yet its regulatory mechanisms remain incompletely understood. Here, we show that a subset of glucose transporter 1 (GLUT1/SLC2A1) co-endocytoses with platelet-derived growth factor (PDGF) receptor (PDGFR) upon PDGF-stimulation. Furthermore, multiple glycolytic enzymes localize to these endocytosed PDGFR/GLUT1-containing vesicles adjacent to mitochondria. Contrary to current models, which emphasize the importance of glucose transporters on the cell surface, we find that PDGF-stimulated glucose uptake depends on receptor/transporter endocytosis. Our results suggest that growth factors generate glucose-loaded endocytic vesicles that deliver glucose to the glycolytic machinery in proximity to mitochondria, and argue for a new layer of regulation for glycolytic control governed by cellular membrane dynamics.

[1]  A. Nanbo,et al.  Interaction between PI3K and the VDAC2 channel tethers Ras-PI3K-positive endosomes to mitochondria and promotes endosome maturation. , 2023, Cell reports.

[2]  Anushya Muruganujan,et al.  The Gene Ontology resource: enriching a GOld mine , 2020, Nucleic Acids Res..

[3]  Suyong Choi,et al.  Phosphatidylinositol 3-kinase signalling is spatially organized at endosomal compartments by microtubule-associated protein 4 , 2020, Nature Cell Biology.

[4]  A. Balmain,et al.  KRAS4A Directly Regulates Hexokinase 1 , 2019, Nature.

[5]  T. Tsuboi,et al.  Green Fluorescent Protein-Based Glucose Indicators Report Glucose Dynamics in Living Cells. , 2019, Analytical chemistry.

[6]  R. Escalante,et al.  VPS13A is closely associated with mitochondria and is required for efficient lysosomal degradation , 2019, Disease Models & Mechanisms.

[7]  Samara L. Reck-Peterson,et al.  The cytoplasmic dynein transport machinery and its many cargoes , 2018, Nature Reviews Molecular Cell Biology.

[8]  H. Schöler,et al.  Dynarrestin, a Novel Inhibitor of Cytoplasmic Dynein. , 2018, Cell chemical biology.

[9]  Dimitri Krainc,et al.  Mitochondria-lysosome contacts regulate mitochondrial fission via Rab7 GTP hydrolysis , 2018, Nature.

[10]  B. Ueberheide,et al.  LINE-1 protein localization and functional dynamics during the cell cycle , 2018, eLife.

[11]  P. Bastiaens,et al.  Assay to visualize specific protein oxidation reveals spatio-temporal regulation of SHP2 , 2017, Nature Communications.

[12]  G. Rivas,et al.  Macromolecular Crowding In Vitro, In Vivo, and In Between. , 2016, Trends in biochemical sciences.

[13]  D. Choquet,et al.  Self-propelling vesicles define glycolysis as the minimal energy machinery for neuronal transport , 2016, Nature Communications.

[14]  P. De Camilli,et al.  Membrane fission by dynamin: what we know and what we need to know , 2016, The EMBO journal.

[15]  T. Müller,et al.  Identification and Optimization of the First Highly Selective GLUT1 Inhibitor BAY‐876 , 2016, ChemMedChem.

[16]  Y. Kalaidzidis,et al.  Signal processing by the endosomal system. , 2016, Current opinion in cell biology.

[17]  C. Thompson,et al.  The Emerging Hallmarks of Cancer Metabolism. , 2016, Cell metabolism.

[18]  Richard D. Byrne,et al.  Endomembrane PtdIns(3,4,5)P3 activates the PI3K–Akt pathway , 2015, Journal of Cell Science.

[19]  Mauro Ferrari,et al.  Principles of nanoparticle design for overcoming biological barriers to drug delivery , 2015, Nature Biotechnology.

[20]  Jing Ma,et al.  A Protein Kinase C Phosphorylation Motif in GLUT1 Affects Glucose Transport and is Mutated in GLUT1 Deficiency Syndrome. , 2015, Molecular cell.

[21]  J. Vigoreaux,et al.  The Structural and Functional Coordination of Glycolytic Enzymes in Muscle: Evidence of a Metabolon? , 2014, Biology.

[22]  Keisuke Ito,et al.  Metabolic requirements for the maintenance of self-renewing stem cells , 2014, Nature Reviews Molecular Cell Biology.

[23]  P. De Camilli,et al.  Dynamin triple knockout cells reveal off target effects of commonly used dynamin inhibitors , 2013, Journal of Cell Science.

[24]  C. Heldin,et al.  Structural and functional properties of platelet-derived growth factor and stem cell factor receptors. , 2013, Cold Spring Harbor perspectives in biology.

[25]  A. Sorkin,et al.  Endocytosis of receptor tyrosine kinases. , 2013, Cold Spring Harbor perspectives in biology.

[26]  Johannes E. Schindelin,et al.  Fiji: an open-source platform for biological-image analysis , 2012, Nature Methods.

[27]  Alan R. Saltiel,et al.  Regulation of glucose transport by insulin: traffic control of GLUT4 , 2012, Nature Reviews Molecular Cell Biology.

[28]  Xianhua Wang,et al.  Central Role of Mitofusin 2 in Autophagosome-Lysosome Fusion in Cardiomyocytes* , 2012, The Journal of Biological Chemistry.

[29]  Brad T. Sherman,et al.  DAVID-WS: a stateful web service to facilitate gene/protein list analysis , 2012, Bioinform..

[30]  Susumu Goto,et al.  KEGG for integration and interpretation of large-scale molecular data sets , 2011, Nucleic Acids Res..

[31]  Karl-Johan Leuchowius,et al.  Proximity ligation assays: a recent addition to the proteomics toolbox , 2010, Expert review of proteomics.

[32]  B. Thorens,et al.  Glucose transporters in the 21st Century. , 2010, American journal of physiology. Endocrinology and metabolism.

[33]  M. Tomita,et al.  Capillary electrophoresis mass spectrometry-based saliva metabolomics identified oral, breast and pancreatic cancer-specific profiles , 2009, Metabolomics.

[34]  A. Sorkin,et al.  Endocytosis and signalling: intertwining molecular networks , 2009, Nature Reviews Molecular Cell Biology.

[35]  A. Terzic,et al.  Adenylate Kinase and AMP Signaling Networks: Metabolic Monitoring, Signal Communication and Body Energy Sensing , 2009, International journal of molecular sciences.

[36]  Masaru Tomita,et al.  Depiction of metabolome changes in histidine-starved Escherichia coli by CE-TOFMS. , 2008, Molecular bioSystems.

[37]  D. Stolz,et al.  Characterization of Endocytic Vesicles Using Magnetic Microbeads Coated with Signalling Ligands , 2005, Traffic.

[38]  M. Sitbon,et al.  The Ubiquitous Glucose Transporter GLUT-1 Is a Receptor for HTLV , 2003, Cell.

[39]  John Eric Wilson.  Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function , 2003, Journal of Experimental Biology.

[40]  J. Schlessinger.  Cell Signaling by Receptor Tyrosine Kinases , 2000, Cell.

[41]  S. Tarui,et al.  Insulin and epidermal growth factor stimulate glycolysis in quiescent 3T3 fibroblasts with no changes in key glycolytic enzyme activities. , 1984, Endocrinologia japonica.

[42]  E. Rozengurt,et al.  Glycolysis in quiescent cultures of 3T3 cells. Stimulation by serum, epidermal growth factor, and insulin in intact cells and persistence of the stimulation after cell homogenization. , 1978, The Journal of biological chemistry.

[43]  S. Colowick,et al.  Stimulation of sugar uptake in cultured fibroblasts by epidermal growth factor (EGF) and EGF‐binding arginine esterase , 1976, Journal of cellular physiology.

[44]  Rocío Aliaga-Isla.  What We Know and What We Need to Know , 2017 .

[45]  W. House,et al.  Detection of mycoplasma in cell cultures. , 1967, The Journal of pathology and bacteriology.