Search
target of rapamycin 1 complex (TORC1 complex)
Function:
- nutrient/energy/redox sensor
- controls protein synthesis
- stimulated by insulin, growth factors, serum, phosphatidic acid, amino acids (particularly leucine), & oxidative stress
- growth factor-stimulated mTORC1 activation involves a AKT1- mediated phosphorylation of TSC1-TSC2, which leads to activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1
- amino-acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex & the Rag GTPases
- activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation & ribosome synthesis
- mTORC1 phosphorylates & activates S6K1 at Thr-389
- Thr-389 phosphorylation
- promotes protein synthesis by phosphorylating PDCD4 & targeting it for degradation
- stimulates subsequent phosphorylation of S6K1 by PDK1
- activated S6K1 can in turn stimulate initiation of protein synthesis through activation of S6K1
- S6K1 provides positive feedback with mTORC1 by phosphorylating mTOR's negative regulatory domain, releasing inhibition & stimulating mTOR activity
- mTORC1 phosphorylates EIF4EBP1 & releases it from inhibiting the elongation initiation factor 4E (eiF4E)
- mTORC1 phosphorylates at least 4 residues of EIF4EBP1 in a hierarchical manner
- non-phosphorylated 4E-BP1 binds tightly to the eIF4E, preventing it from binding to 5'-capped mRNAs & recruiting them to the ribosomal initiation complex
- upon phosphorylation by mTORC1, 4E-BP1 releases eIF4E, allowing it to perform its function.
- activity of mTORC1 appears to be regulated through a dynamic interaction between mTOR & Raptor, one which is mediated by LST8
- Raptor & mTOR share a strong N-terminal interaction & a weaker C-terminal interaction near mTOR's kinase domain
- when high nutrient/energy levels, the mTOR-RPTOR C-terminal interaction is weakened & possibly completely lost, allowing mTOR kinase activity to be turned on
- in low nutrient states, the mTOR-RPTOR C-terminal interaction is strengthened, essentially shutting off kinase function of mTOR
- mTORC1 binds to & is inhibited by FKBP12-rapamycin
Inhibition:
- inhibited by low nutrient levels, growth factor deprivation, reductive stress, rapamycin, & farnesylthiosalicylic acid
Structure:
- subunits include MTOR, LST8, RPTOR & AKT1S1
Notes:
- inhibition of mTORC1 may account for some of the benefits of caloric restriction
Related
target of rapamycin 2 complex (TORC2 complex)
General
molecular complex
Properties
SUBUNITS: FKBP12-rapamycin complex-associated protein
MOTIF: HEAT repeat {16-53}
Ser phosphorylation site {S567}
HEAT repeat {650-688}
HEAT repeat {859-897}
HEAT repeat {988-1025}
HEAT repeat {1069-1106}
HEAT repeat {1109-1148}
HEAT repeat {1150-1186}
MOTIF: Thr phosphorylation site {T1162}
Ser phosphorylation site {S1261}
FAT domain
NAME: FAT domain
SITE: 1382-1982
MOTIF: Tyr phosphorylation site
binding site
FOR-BINDING-OF: Paxillin
PI3K/PI4K {2182-2516}
MOTIF: Ser phosphorylation site {S2478}
Ser phosphorylation site {S2481}
FATC {2517-2549}
STATE: active state
target of rapamycin complex subunit LST8
COMPARTMENT: cytoplasm
MOTIF: WD repeat {1-37}
MOTIF: Thr phosphorylation site {T3}
Ser phosphorylation site {S4}
Thr phosphorylation site {T7}
WD repeat {40-80}
WD repeat {83-122}
WD repeat {126-165}
WD repeat {168-207}
WD repeat {218-257}
WD repeat {268-309}
proline-rich protein 5
MOTIF: RICTOR interaction {10-95}
MOTIF: alanine-rich region {24-27}
MOTIF: alanine residue (SEVERAL)
proline-rich region
RICTOR interaction {188-218}
Rapamycin-insensitive companion of mTOR
MOTIF: Ser phosphorylation site {S21}
serine-rich region {1016-1058}
MOTIF: serine residue (SEVERAL)
target of rapamycin complex 2 subunit MAPKAP1
COMPARTMENT: cytoplasm
cell nucleus
MOTIF: MAP3K2 interaction {2-184}
acetylation site
SITE: N-TERMINUS
EFFECTOR-BOUND: acetyl
Ser phosphorylation site {S270}
ATF2 interaction {468-522}
MOTIF: Ser phosphorylation site {S510}
References
- Wikipedia: Mammalian target of rapamycin
http://en.wikipedia.org/wiki/Mammalian_target_of_rapamycin
- UniProt :accession Q9BVC4
Components
FKBP12-rapamycin complex-associated protein; FK506-binding protein 12-rapamycin complex-associated protein 1; rapamycin target protein; RAPT1; mammalian target of rapamycin; mTOR (FRAP1, FRAP, FRAP2)
proline-rich protein 5 (PRR5)
Rapamycin-insensitive companion of mTOR (RICTOR, KIAA1999)
target of rapamycin complex 2 subunit MAPKAP1; TORC2 subunit MAPKAP1; mitogen-activated protein kinase 2-associated protein 1; stress-activated map kinase-interacting protein 1; SAPK-interacting protein 1; mSIN1 (MAPKAP1, MIP1, SIN1)
target of rapamycin complex subunit LST8; TORC subunit LST8; G protein beta subunit-like; Gable; protein GbetaL; mammalian lethal with SEC13 protein 8; mLST8 (MLST8, GBL, LST8)