mTORC1

• • extrinsic signals -> come from a different cell or tissue and signals for a cellular response to be part of a larger physiological process (tissue level)
  • intrinsic signals -> come from cues within the same cell and respond within the cell as well to indicate metabolic flux, nutrient availability, or damage in the cell

  
• usually there is cell stress/damage -> sensor system specific to the stress -> signal transduction -> outcome which can be:

  • adapt and survive -> delaying cell cycle, increase fuel/metabolic flux, repair damage
  • apoptosis if cell stress is too great to be fixed

  
• Rapamycin (complex 1) determines the fates of the mTORC1's targets

  • mitogenic cues:
  • PI3K/Akt signals activate mTORC1
  • MAPK signals activate mTORC1
  • metabolic cues:
  • amino acid availability activates mTORC1
  • glucose deprivation inactivates mTORC1 *
  • other stress/damage inactivates mTORC1 *
• active mTORC1 stimulates anabolism, high nutrients

  • inhibit 4EBP1 -> inhibitor of protein, lipid, nucleotide synthesis
  • stimulate S6K -> kinase for protein, lipid, nucleotide synthesis

  inactive mTORC1 stimulates catabolism, low nutrients

  • inhibit TFEB/TFE3 -> stimulates lysosome biogenesis (when TFEB is on)
  • inhibit ULK1 -> stimulates autophagy (when ULK1 is on)

  
• activation of mTORC1 by MITOGENIC cues (GF), Akt activates mTORC1

  • P~ Akt phosphorylates TSC2 which inactivates TSC1/2 complex (inactivates Rheb) -> this is inhibiting the inhibitor thus Rheb is left on -> Rheb binds and activates mTORC1

  
• activation of mTORC1 by METABOLIC cues (amino acids, AA), AA activate mTORC1

  • high amino acids [] are sensed by V-ATPase at lysosome membrane which leads to active membrane bound Ragulator (GEF for Rag A/B GTPase) -> once GTP bound, Rag A/B causes mTORC1 binding to lysosome so it can get activated by Rheb (lipid anchored protein at lysosome)
  • THUS there are 2 GTPases, Rag A/B GTPase localizes mTORC1 to membrane and Rheb GTPase activates mTORC1

  
• activated mTORC1 promotes

  • biomass production -> ribosome biogenesis, translation
  • lipid biosynthesis
  • shift in glucose metabolism AWAY from oxidative phosphorylation (to maximize ATP production) and TOWARDS glycolysis (to maximize production of biochemical building blocks)