Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase.
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.
Nobukuni
Takahiro
T
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
Joaquin
Manel
M
Roccio
Marta
M
Dann
Stephen G
SG
Kim
So Young
SY
Gulati
Pawan
P
Byfield
Maya P
MP
Backer
Jonathan M
JM
Natt
Francois
F
Bos
Johannes L
JL
Zwartkruis
Fried J T
FJ
Thomas
George
G
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
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