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Mol. Biol. Cell 13 (7): 2276-2288

Copyright © 2002 by The American Society for Cell Biology.

Vol. 13, Issue 7, 2276-2288, July 2002

Akt Maintains Cell Size and Survival by Increasing mTOR-dependent Nutrient Uptake

Aimee L. Edinger, and Craig B. Thompson*

Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104

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 When cells are withdrawn from growth factors, they undergo apoptosis.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.

* Corresponding author. E-mail address: drt{at}mail.med.upenn.edu.

Molecular Biology of the Cell
Vol. 13, 2276-2288, July 2002
Copyright © 2002 by The American Society for Cell Biology

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mTOR-targeted therapy of cancer with rapamycin derivatives.
S. Vignot, S. Faivre, D. Aguirre, and E. Raymond (2005)
Ann. Onc. 16, 525-537
   Abstract »    Full Text »    PDF »
Activation of the PI3K/mTOR pathway by BCR-ABL contributes to increased production of reactive oxygen species.
J. H. Kim, S. C. Chu, J. L. Gramlich, Y. B. Pride, E. Babendreier, D. Chauhan, R. Salgia, K. Podar, J. D. Griffin, and M. Sattler (2005)
Blood 105, 1717-1723
   Abstract »    Full Text »    PDF »
The Pim kinases control rapamycin-resistant T cell survival and activation.
C. J. Fox, P. S. Hammerman, and C. B. Thompson (2005)
J. Exp. Med. 201, 259-266
   Abstract »    Full Text »    PDF »
Akt up-regulation increases resistance to microtubule-directed chemotherapeutic agents through mammalian target of rapamycin.
D. J. VanderWeele, R. Zhou, and C. M. Rudin (2004)
Mol. Cancer Ther. 3, 1605-1613
   Abstract »    Full Text »    PDF »
Luteolin Inhibits Vascular Endothelial Growth Factor-Induced Angiogenesis; Inhibition of Endothelial Cell Survival and Proliferation by Targeting Phosphatidylinositol 3'-Kinase Activity.
E. Bagli, M. Stefaniotou, L. Morbidelli, M. Ziche, K. Psillas, C. Murphy, and T. Fotsis (2004)
Cancer Res. 64, 7936-7946
   Abstract »    Full Text »    PDF »
The PP2A-Associated Protein {alpha}4 Is an Essential Inhibitor of Apoptosis.
M. Kong, C. J. Fox, J. Mu, L. Solt, A. Xu, R. M. Cinalli, M. J. Birnbaum, T. Lindsten, and C. B. Thompson (2004)
Science 306, 695-698
   Abstract »    Full Text »    PDF »
Putting the Rap on Akt.
J. E. Thompson and C. B. Thompson (2004)
J. Clin. Oncol. 22, 4217-4226
   Abstract »    Full Text »    PDF »
Activation of PI3K Is Indispensable for Interleukin 7-mediated Viability, Proliferation, Glucose Use, and Growth of T Cell Acute Lymphoblastic Leukemia Cells.
J. T. Barata, A. Silva, J. G. Brandao, L. M. Nadler, A. A. Cardoso, and V. A. Boussiotis (2004)
J. Exp. Med. 200, 659-669
   Abstract »    Full Text »    PDF »
Akt Stimulates Aerobic Glycolysis in Cancer Cells.
R. L. Elstrom, D. E. Bauer, M. Buzzai, R. Karnauskas, M. H. Harris, D. R. Plas, H. Zhuang, R. M. Cinalli, A. Alavi, C. M. Rudin, et al. (2004)
Cancer Res. 64, 3892-3899
   Abstract »    Full Text »    PDF »
Extracellular ATP-mediated Signaling for Survival in Hyperoxia-induced Oxidative Stress.
S. Ahmad, A. Ahmad, M. Ghosh, C. C. Leslie, and C. W. White (2004)
J. Biol. Chem. 279, 16317-16325
   Abstract »    Full Text »    PDF »
Regulation of T Lymphocyte Metabolism.
K. A. Frauwirth and C. B. Thompson (2004)
J. Immunol. 172, 4661-4665
   Abstract »    Full Text »    PDF »
Seasonal, tissue-specific regulation of Akt/protein kinase B and glycogen synthase in hibernators.
K. L. Hoehn, S. F. Hudachek, S. A. Summers, and G. L. Florant (2004)
Am J Physiol Regulatory Integrative Comp Physiol 286, R498-R504
   Abstract »    Full Text »    PDF »
Activation of the RAS/Cyclic AMP Pathway Suppresses a TOR Deficiency in Yeast.
T. Schmelzle, T. Beck, D. E. Martin, and M. N. Hall (2004)
Mol. Cell. Biol. 24, 338-351
   Abstract »    Full Text »    PDF »
Differential Effects of Rapamycin on Mammalian Target of Rapamycin Signaling Functions in Mammalian Cells.
A. L. Edinger, C. M. Linardic, G. G. Chiang, C. B. Thompson, and R. T. Abraham (2003)
Cancer Res. 63, 8451-8460
   Abstract »    Full Text »    PDF »
RhoB controls Akt trafficking and stage-specific survival of endothelial cells during vascular development.
I. Adini, I. Rabinovitz, J. F. Sun, G. C. Prendergast, and L. E. Benjamin (2003)
Genes & Dev. 17, 2721-2732
   Abstract »    Full Text »    PDF »
Akt promotes increased mammalian cell size by stimulating protein synthesis and inhibiting protein degradation.
J. Faridi, J. Fawcett, L. Wang, and R. A. Roth (2003)
Am J Physiol Endocrinol Metab 285, E964-E972
   Abstract »    Full Text »    PDF »
Akt activation disrupts mammary acinar architecture and enhances proliferation in an mTOR-dependent manner.
J. Debnath, S. J. Walker, and J. S. Brugge (2003)
J. Cell Biol. 163, 315-326
   Abstract »    Full Text »    PDF »

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