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

More general terms

• molecular complex

Additional terms

• target of rapamycin 2 complex (TORC2 complex)