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

Takahiro Nobukuni, Manel Joaquin, Marta Roccio, Stephen G. Dann, So Young Kim, Pawan Gulati, Maya P. Byfield, Jonathan M. Backer, Francois Natt, Johannes L. Bos, Fried J.T. Zwartkruis, George Thomas

Research output: Contribution to journalArticle

576 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)14238-14243
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number40
DOIs
StatePublished - Oct 4 2005

Keywords

  • 56 Kinase 1
  • Endosomes
  • Insulin
  • Nutrients
  • PI3P

ASJC Scopus subject areas

  • General

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    Nobukuni, T., Joaquin, M., Roccio, M., Dann, S. G., Kim, S. Y., Gulati, P., Byfield, M. P., Backer, J. M., Natt, F., Bos, J. L., Zwartkruis, F. J. T., & Thomas, G. (2005). Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proceedings of the National Academy of Sciences of the United States of America, 102(40), 14238-14243. https://doi.org/10.1073/pnas.0506925102