mTOR

Table of Contents

mTOR is a serine/threonine-protein kinase

mTOR pathway

The mTOR pathway is implicated in physiological mechanisms of development, growth, proliferation and metabolism [1]. And its disregulation, in diseases such as epilepsy and cancer. A key function of this pathway is to "regulate the growth in animals in response to nutrients and nutrient-induced signals by controling anabolic and catabolic responses of cells" [2]. mTOR operates through mTORC1 and mTORC2 complexes. mTORC1 signaling requires Raptor protein to function, while mTORC2 requires Rictor to operate. Rapamycin inhibits mTOR signaling by preventing assembly of mTORC1.

Canonical pathway of mTORC1 (by thropic factors)

As summarized in [3]:

  • Activation of receptor of tyrosine kinase
  • Activation of class I phosphatidylinositol 3-kinase (PI3K)
  • PI3K converts PIP2 into PIP3
    • This reaction can be reversed by Pten.
  • PIP3 recruits PDK1 and Akt to the plasma membrane
  • PDK1 phosphorylates and activates Akt
  • Active Akt phosphorylates Tsc2 at multiple sites
  • Tsc2 is thereby blocked while associated to Tsc1/Tsc2
  • This allows Rheb-GTP to accumulate as an activator of mTORC1
  • Active mTORC1 phosphorylates S6Ks and 4EBP1
  • PI3K-Akt -> phosphoinositide-3' kinase
  • ERK -> extracellular signal-regulated kinases
  • Active Akt and ERKs phosphorylate and inactivate tuberin (Tsc2)
  • Tuberin (Tsc2), hamartin (Tsc1) and TBC1D7 forms Tsc
  • Tsc2 acts as a guanosine triphosphate (GTPase)-activating protein (GAP) toward Ras homolog enriched in brain protein (Rheb)
  • Rheb activates mTORC1
  • Inactivation of Rheb by Tsc leads to mTORC1 inhibition
[1]
T. Ravizza, M. Scheper, R. Di Sapia, J. Gorter, E. Aronica, and A. Vezzani, “mTOR and neuroinflammation in epilepsy: implications for disease progression and treatment,” Nat. rev. neurosci., vol. 25, no. 5, pp. 334–350, May 2024, doi: 10.1038/s41583-024-00805-1. Available: https://www.nature.com/articles/s41583-024-00805-1. [Accessed: Nov. 03, 2025]
[2]
J. Cherfils, “Encoding allostery in mTOR signaling: The structure of the rag GTPase/ragulator complex,” Molecular cell, vol. 68, no. 5, pp. 823–824, Dec. 2017, doi: 10.1016/j.molcel.2017.11.027. Available: https://www.sciencedirect.com/science/article/pii/S1097276517308869. [Accessed: Nov. 03, 2025]
[3]
O. Meyuhas, “Ribosomal protein s6 phosphorylation: Four decades of research,” Int rev cell mol biol, vol. 320, pp. 41–73, 2015, doi: 10.1016/bs.ircmb.2015.07.006