Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake.
In multicellular organisms, constituent cells depend on extracellular signals for growth, proliferation, and survival. When cells are withdrawn from growth factors, they undergo apoptosis. Expression of constitutively active forms of the serine/threonine kinase Akt/PKB can prevent apoptosis upon growth factor withdrawal. Akt-mediated survival depends in part on the maintenance of glucose metabolism, suggesting that reduced glucose utilization contributes to growth factor withdrawal-induced death. However, it is unclear how restricting access to extracellular glucose alone would lead to the metabolic collapse observed after growth factor withdrawal. We report herein that growth factor withdrawal results in the loss of surface transporters for not only glucose but also amino acids, low-density lipoprotein, and iron. This coordinated decline in transporters and receptors for extracellular molecules creates a catabolic state characterized by atrophy and a decline in the mitochondrial membrane potential. Activated forms of Akt maintained these transporters on the cell surface in the absence of growth factor through an mTOR-dependent mechanism. The mTOR inhibitor rapamycin diminished Akt-mediated increases in cell size, mitochondrial membrane potential, and cell survival. These results suggest that growth factors control cellular growth and survival by regulating cellular access to extracellular nutrients in part by modulating the activity of Akt and mTOR.
Edinger
Aimee L
AL
Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Thompson
Craig B
CB
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002460:Cell Line / Q000187:drug effects; D048429:Cell Size; D002470:Cell Survival; D002784:Cholesterol / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D006133:Growth Substances / Q000378:metabolism*; D007377:Interleukin-3 / Q000494:pharmacology; D007501:Iron / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D051020:bcl-X Protein
D000596:Amino Acids; C494812:Bcl2l1 protein, mouse; D004791:Enzyme Inhibitors; D027282:Fusion Regulatory Protein 1, Heavy Chain; D051272:Glucose Transporter Type 1; D006133:Growth Substances; D007377:Interleukin-3; D008077:Lipoproteins, LDL; D009004:Monosaccharide Transport Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011973:Receptors, LDL; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein; D002784:Cholesterol; D007501:Iron; D011494:Protein Kinases; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; D020123:Sirolimus