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PNAS 102 (40): 14238-14243

Copyright © 2005 by the National Academy of Sciences.

BIOCHEMISTRY

Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase

Takahiro Nobukuni *, {dagger} {ddagger}, Manel Joaquin *, {dagger} {ddagger}, Marta Roccio {ddagger}, §, Stephen G. Dann {dagger}, So Young Kim *, Pawan Gulati {dagger}, Maya P. Byfield ¶, Jonathan M. Backer ¶, Francois Natt ||, Johannes L. Bos §, Fried J. T. Zwartkruis §, **, and George Thomas *, {dagger}, **

*Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland; {dagger}Genome Research Institute, University of Cincinnati, 2180 East Galbraith Road, Cincinnati, OH 45237; §Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Centre Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461; and ||Novartis Institutes for Biomedical Research, Lichstrasse 35, CH-4002 Basel, Switzerland

Communicated by Joseph Schlessinger, Yale University School of Medicine, New Haven, CT, August 11, 2005

Received for publication July 28, 2005.

Abstract: During the evolution of metazoans and the rise of systemic hormonal regulation, the insulin-controlled class 1 phosphatidylinositol 3OH-kinase (PI3K) pathway was merged with the primordial amino acid-driven mammalian target of rapamycin (mTOR) pathway to control the growth and development of the organism. Insulin regulates mTOR function through a recently described canonical signaling pathway, which is initiated by the activation of class 1 PI3K. However, how the amino acid input is integrated with that of the insulin signaling pathway is unclear. Here we used a number of molecular, biochemical, and pharmacological approaches to address this issue. Unexpectedly, we found that a major pathway by which amino acids control mTOR signaling is distinct from that of insulin and that, instead of signaling through components of the insulin/class 1 PI3K pathway, amino acids mediate mTOR activation by signaling through class 3 PI3K, hVps34.

Key Words: insulin • nutrients • S6 kinase 1 • endosomes • PI3P

Author contributions: M.P.B., J.M.B., J.L.B., F.J.T.Z., and G.T advised research; J.L.B., F.J.T.Z., and G.T. guided research; T.N., M.J., M.R., S.G.D., S.Y.K., and P.G. performed research; F.N. contributed new reagents/analytical tools; and G.T. wrote the paper.

Abbreviations: PI3K, phosphatidylinositol 3OH-kinase; PI3P, phosphatidylinositol 3-phosphate; mTOR, mammalian target of rapamycin; G{beta}L, G-protein-{beta}-subunit-like protein; TSC, tuberous sclerosis complex; S6K1, S6 kinase 1; siRNA, short interfering RNA; 4E-BP1, initiation factor 4E binding protein; FYVE, Fab1/YOTB/ZK632.12/Vac1/EEA1.

{ddagger} T.N., M.J., and M.R. contributed equally to this work.

** To whom correspondence may be addressed. E-mail: g.j.t.zwartkruis{at}med.uu.nl or thomas{at}genomescience.org.

© 2005 by The National Academy of Sciences of the USA

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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S. P. Cobbold, E. Adams, C. A. Farquhar, K. F. Nolan, D. Howie, K. O. Lui, P. J. Fairchild, A. L. Mellor, D. Ron, and H. Waldmann (2009)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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F. Meric-Bernstam and A. M. Gonzalez-Angulo (2009)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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K. Inoki and K.-L. Guan (2009)
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   Abstract »    Full Text »    PDF »
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M. J. Drummond, H. C. Dreyer, C. S. Fry, E. L. Glynn, and B. B. Rasmussen (2009)
J Appl Physiol 106, 1374-1384
   Abstract »    Full Text »    PDF »
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M. Miyazaki and K. A. Esser (2009)
J Appl Physiol 106, 1367-1373
   Abstract »    Full Text »    PDF »
Expression of growth-related genes in young and older human skeletal muscle following an acute stimulation of protein synthesis.
M. J. Drummond, M. Miyazaki, H. C. Dreyer, B. Pennings, S. Dhanani, E. Volpi, K. A. Esser, and B. B. Rasmussen (2009)
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   Abstract »    Full Text »    PDF »
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J. Avruch, X. Long, S. Ortiz-Vega, J. Rapley, A. Papageorgiou, and N. Dai (2009)
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   Abstract »    Full Text »    PDF »
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C. C. Thoreen, S. A. Kang, J. W. Chang, Q. Liu, J. Zhang, Y. Gao, L. J. Reichling, T. Sim, D. M. Sabatini, and N. S. Gray (2009)
J. Biol. Chem. 284, 8023-8032
   Abstract »    Full Text »    PDF »
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M. Miyazaki and K. A. Esser (2009)
Am J Physiol Cell Physiol 296, C583-C592
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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H. SAKAGAMI, K. KISHINO, O. AMANO, Y. KANDA, S. KUNII, Y. YOKOTE, H. OIZUMI, and T. OIZUMI (2009)
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   Abstract »    Full Text »    PDF »
Regulation of placental amino acid transporter activity by mammalian target of rapamycin.
S. Roos, Y. Kanai, P. D. Prasad, T. L. Powell, and T. Jansson (2009)
Am J Physiol Cell Physiol 296, C142-C150
   Abstract »    Full Text »    PDF »
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M. G. MacKenzie, D. L. Hamilton, J. T. Murray, P. M. Taylor, and K. Baar (2009)
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   Abstract »    Full Text »    PDF »
Regulation of amino acid transporters by glucose and growth factors in cultured primary human trophoblast cells is mediated by mTOR signaling.
S. Roos, O. Lagerlof, M. Wennergren, T. L. Powell, and T. Jansson (2009)
Am J Physiol Cell Physiol 297, C723-C731
   Abstract »    Full Text »    PDF »
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T. Maehama, M. Tanaka, H. Nishina, M. Murakami, Y. Kanaho, and K. Hanada (2008)
J. Biol. Chem. 283, 35053-35059
   Abstract »    Full Text »    PDF »
Leptin-enhanced neointimal hyperplasia is reduced by mTOR and PI3K inhibitors.
J. Shan, T. B. Nguyen, H. Totary-Jain, H. Dansky, S. O. Marx, and A. R. Marks (2008)
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   Abstract »    Full Text »    PDF »
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E. Itakura, C. Kishi, K. Inoue, and N. Mizushima (2008)
Mol. Biol. Cell 19, 5360-5372
   Abstract »    Full Text »    PDF »
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F. Zhang, N. A. Gaur, J. Hasek, S.-j. Kim, H. Qiu, M. J. Swanson, and A. G. Hinnebusch (2008)
Mol. Cell. Biol. 28, 6796-6818
   Abstract »    Full Text »    PDF »
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X. Wang, B. D. Fonseca, H. Tang, R. Liu, A. Elia, M. J. Clemens, U.-A. Bommer, and C. G. Proud (2008)
J. Biol. Chem. 283, 30482-30492
   Abstract »    Full Text »    PDF »
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K. Evans, Z. Nasim, J. Brown, E. Clapp, A. Amin, B. Yang, T. P. Herbert, and A. Bevington (2008)
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   Abstract »    Full Text »    PDF »
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G. Juhasz, J. H. Hill, Y. Yan, M. Sass, E. H. Baehrecke, J. M. Backer, and T. P. Neufeld (2008)
J. Cell Biol. 181, 655-666
   Abstract »    Full Text »    PDF »
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A. Suryawan, A. S. Jeyapalan, R. A. Orellana, F. A. Wilson, H. V. Nguyen, and T. A. Davis (2008)
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   Abstract »    Full Text »    PDF »
The Switch I Region of Rheb Is Critical for Its Interaction with FKBP38.
D. Ma, X. Bai, S. Guo, and Y. Jiang (2008)
J. Biol. Chem. 283, 25963-25970
   Abstract »    Full Text »    PDF »
Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum.
E. L. Axe, S. A. Walker, M. Manifava, P. Chandra, H. L. Roderick, A. Habermann, G. Griffiths, and N. T. Ktistakis (2008)
J. Cell Biol. 182, 685-701
   Abstract »    Full Text »    PDF »
An in vivo and in vitro assessment of TOR signaling cascade in rainbow trout (Oncorhynchus mykiss).
I. Seiliez, J.-C. Gabillard, S. Skiba-Cassy, D. Garcia-Serrana, J. Gutierrez, S. Kaushik, S. Panserat, and S. Tesseraud (2008)
Am J Physiol Regulatory Integrative Comp Physiol 295, R329-R335
   Abstract »    Full Text »    PDF »
Phospholipase D1 is an effector of Rheb in the mTOR pathway.
Y. Sun, Y. Fang, M.-S. Yoon, C. Zhang, M. Roccio, F. J. Zwartkruis, M. Armstrong, H. A. Brown, and J. Chen (2008)
PNAS 105, 8286-8291
   Abstract »    Full Text »    PDF »
The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1.
Y. Sancak, T. R. Peterson, Y. D. Shaul, R. A. Lindquist, C. C. Thoreen, L. Bar-Peled, and D. M. Sabatini (2008)
Science 320, 1496-1501
   Abstract »    Full Text »    PDF »
A Central Role for Neuronal AMP-Activated Protein Kinase (AMPK) and Mammalian Target of Rapamycin (mTOR) in High-Protein Diet-Induced Weight Loss.
E. R. Ropelle, J. R. Pauli, M. F. A. Fernandes, S. A. Rocco, R. M. Marin, J. Morari, K. K. Souza, M. M. Dias, M. C. Gomes-Marcondes, J. A.R. Gontijo, et al. (2008)
Diabetes 57, 594-605
   Abstract »    Full Text »    PDF »
IL-2- and IL-15-induced activation of the rapamycin-sensitive mTORC1 pathway in malignant CD4+ T lymphocytes.
M. Marzec, X. Liu, M. Kasprzycka, A. Witkiewicz, P. N. Raghunath, M. El-Salem, E. Robertson, N. Odum, and M. A. Wasik (2008)
Blood 111, 2181-2189
   Abstract »    Full Text »    PDF »
Leucine-enriched essential amino acid and carbohydrate ingestion following resistance exercise enhances mTOR signaling and protein synthesis in human muscle.
H. C. Dreyer, M. J. Drummond, B. Pennings, S. Fujita, E. L. Glynn, D. L. Chinkes, S. Dhanani, E. Volpi, and B. B. Rasmussen (2008)
Am J Physiol Endocrinol Metab 294, E392-E400
   Abstract »    Full Text »    PDF »
Bnip3 Mediates the Hypoxia-induced Inhibition on Mammalian Target of Rapamycin by Interacting with Rheb.
Y. Li, Y. Wang, E. Kim, P. Beemiller, C.-Y. Wang, J. Swanson, M. You, and K.-L. Guan (2007)
J. Biol. Chem. 282, 35803-35813
   Abstract »    Full Text »    PDF »
Activation by insulin and amino acids of signaling components leading to translation initiation in skeletal muscle of neonatal pigs is developmentally regulated.
A. Suryawan, R. A. Orellana, H. V. Nguyen, A. S. Jeyapalan, J. R. Fleming, and T. A. Davis (2007)
Am J Physiol Endocrinol Metab 293, E1597-E1605
   Abstract »    Full Text »    PDF »
Autophagy: process and function.
N. Mizushima (2007)
Genes & Dev. 21, 2861-2873
   Abstract »    Full Text »    PDF »
Tuberous Sclerosis Complex Proteins 1 and 2 Control Serum-Dependent Translation in a TOP-Dependent and -Independent Manner.
B. Bilanges, R. Argonza-Barrett, M. Kolesnichenko, C. Skinner, M. Nair, M. Chen, and D. Stokoe (2007)
Mol. Cell. Biol. 27, 5746-5764
   Abstract »    Full Text »    PDF »
The Role of Phosphoinositide 3-Kinase Pathway Inhibitors in the Treatment of Lung Cancer.
J. A. Engelman (2007)
Clin. Cancer Res. 13, 4637s-4640s
   Abstract »    Full Text »    PDF »
Nutrient signalling in the regulation of human muscle protein synthesis.
S. Fujita, H. C. Dreyer, M. J. Drummond, E. L. Glynn, J. G. Cadenas, F. Yoshizawa, E. Volpi, and B. B. Rasmussen (2007)
J. Physiol. 582, 813-823
   Abstract »    Full Text »    PDF »

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