title: Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase.
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.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nobukuni
authors.forename: Manel
authors.initials: M
authors.lastname: Joaquin
authors.forename: Marta
authors.initials: M
authors.lastname: Roccio
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Dann
authors.forename: So Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Pawan
authors.initials: P
authors.lastname: Gulati
authors.forename: Maya P
authors.initials: MP
authors.lastname: Byfield
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Backer
authors.forename: Francois
authors.initials: F
authors.lastname: Natt
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Bos
authors.forename: Fried J T
authors.initials: FJ
authors.lastname: Zwartkruis
authors.forename: George
authors.initials: G
authors.lastname: Thomas
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D006801:Humans; D008856:Microscopy, Fluorescence; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D000076205:Ras Homolog Enriched in Brain Protein; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D020559:Monomeric GTP-Binding Proteins; D009479:Neuropeptides; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D011506:Proteins; D034741:RNA, Small Interfering; D000076205:Ras Homolog Enriched in Brain Protein; D000076223:Regulatory-Associated Protein of mTOR; D058570:TOR Serine-Threonine Kinases; C490211:RHEB protein, human; C463659:RPTOR protein, human; C546842:MTOR protein, human