Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex.
The raptor-mTOR protein complex is a key component of a nutrient-sensitive signaling pathway that regulates cell size by controlling the accumulation of cellular mass. How nutrients regulate signaling through the raptor-mTOR complex is not well known. Here we show that a redox-sensitive mechanism regulates the phosphorylation of the raptor-mTOR effector S6K1, the interaction between raptor and mTOR, and the kinase activity of the raptor-mTOR complex. In cells treated with the oxidizing agents diamide or phenylarsine oxide, S6K1 phosphorylation increased and became insensitive to nutrient deprivation. Conversely, the reducing reagent BAL (British anti-Lewisite, also known as 2,3-dimercapto-1-propanol) inhibits S6K1 phosphorylation and stabilizes the interaction of mTOR and raptor to mimic the state of the complex under nutrient-deprived conditions. Our findings suggest that a redox-based signaling mechanism may participate in regulating the nutrient-sensitive raptor-mTOR complex and pathway.
Sarbassov
Dos D
DD
Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Sabatini
David M
DM
D048868:Adaptor Proteins, Signal Transducing; D001152:Arsenicals / Q000494:pharmacology; D002460:Cell Line; D003958:Diamide / Q000494:pharmacology; D004112:Dimercaprol / Q000494:pharmacology; D006801:Humans; D046912:Multiprotein Complexes; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D001152:Arsenicals; D046912:Multiprotein Complexes; D016877:Oxidants; D011506:Proteins; D034741:RNA, Small Interfering; C463659:RPTOR protein, human; D011994:Recombinant Proteins; D000076223:Regulatory-Associated Protein of mTOR; D004112:Dimercaprol; C029341:oxophenylarsine; D003958:Diamide; D011494:Protein Kinases; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1