GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR.
mTOR and raptor are components of a signaling pathway that regulates mammalian cell growth in response to nutrients and growth factors. Here, we identify a member of this pathway, a protein named GbetaL that binds to the kinase domain of mTOR and stabilizes the interaction of raptor with mTOR. Like mTOR and raptor, GbetaL participates in nutrient- and growth factor-mediated signaling to S6K1, a downstream effector of mTOR, and in the control of cell size. The binding of GbetaL to mTOR strongly stimulates the kinase activity of mTOR toward S6K1 and 4E-BP1, an effect reversed by the stable interaction of raptor with mTOR. Interestingly, nutrients and rapamycin regulate the association between mTOR and raptor only in complexes that also contain GbetaL. Thus, we propose that the opposing effects on mTOR activity of the GbetaL- and raptor-mediated interactions regulate the mTOR pathway.
Kim
Do-Hyung
DH
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Nine Cambridge Center, 02142, USA.
Sarbassov
D D
DD
Ali
Siraj M
SM
Latek
Robert R
RR
Guntur
Kalyani V P
KV
Erdjument-Bromage
Hediye
H
Tempst
Paul
P
Sabatini
David M
DM
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence / Q000235:genetics; D001483:Base Sequence / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000502:physiology*; D048429:Cell Size; D005057:Eukaryotic Cells / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D021122:Protein Subunits / Q000235:genetics / Q000302:isolation & purification*; D011506:Proteins / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism*; D000076223:Regulatory-Associated Protein of mTOR; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D000076242:mTOR Associated Protein, LST8 Homolog
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C555285:MLST8 protein, human; D046911:Macromolecular Substances; D010750:Phosphoproteins; D021122:Protein Subunits; D011506:Proteins; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; D000076242:mTOR Associated Protein, LST8 Homolog; D011494:Protein Kinases; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448959:ribosomal protein S6 kinase, 70kD, polypeptide 2; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus