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PNAS 102 (40): 14238-14243

Copyright © 2005 by the National Academy of Sciences.


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} or thomas{at}

© 2005 by The National Academy of Sciences of the USA

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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
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Leucine stimulates protein synthesis in skeletal muscle of neonatal pigs by enhancing mTORC1 activation.
A. Suryawan, A. S. Jeyapalan, R. A. Orellana, F. A. Wilson, H. V. Nguyen, and T. A. Davis (2008)
Am J Physiol Endocrinol Metab 295, E868-E875
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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
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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
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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
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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 »

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