1. Figure 1 The mTOR signalling pathway
Figure 1 | The mTOR signalling pathway. Three primary signalling pathways converge to regulate mechanistic target of rapamycin (mTOR). The growth factor pathway (1) comprises phosphatidylinositol 3-kinases (PI3Ks), phosphoinositide-dependent kinase 1 (PDK1), and RAC-alpha serine/threonine-protein kinase (AKT). PI3K activation triggers PDK1 to phosphorylate and activate AKT. AKT directly phospho-inhibits tuberin (TSC2), which leads to mTOR activation via GTP-binding protein Rheb (RHEB), resulting in phosphorylation of protein S6 kinase beta-1 (S6K1) or eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). The energy-sensing arm of the pathway (2) responds to low or insufficient ambient cellular ATP. The serine/threonine protein kinase STK11 (also known as liver kinase B1, LKB1) phosphorylates AMPK, which results in TSC2-mediated mTOR inhibition. When ATP levels are repleted, diminished LKB1 complex activity releases inhibition of mTOR. The amino acid sensor (3) GAP activity towards rags (GATOR1) complex6 (DEP domain-containing protein 5, DEPDC5; nitrogen permease regulator proteins NPRL2 and NPRL3) regulates mTOR in response to changes in levels of amino acids, especially leucine and arginine: when amino acids are low, GATOR1 inhibits mTOR signalling; when levels are normal, GATOR1 inhibition of mTOR is released10,11. The downstream substrates of mTOR include S6K1, ribosomal S6 (S6), and 4E-BP1, which modulate translation of mRNAs — particularly those that contain a terminal oligopyrimidine tract in the 5'untranslated region8,9,12.
Crino, P. B. (2016) The mTOR signalling cascade: paving new roads to cure neurological disease
Nat. Rev. Neurol. doi: /nrneurol