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. 2020 Nov 26;11:612510. doi: 10.3389/fphys.2020.612510

Figure 6.

Figure 6

Diurnal regulation of the mTOR pathway. During the light phase (ZT0-ZT12), mice are sleeping and therefore fasting. Fasting is a specific stimulus that drivers AMP accumulation at the expense of ATP. AMP accumulation triggers AMPK activation via phosphorylation at Threonine 172 (Thr-172) mediated by LKB1. The active AMPK can phosphorylate RAPTOR at serine 792 (Ser-792) which subsequently interacts with 14-3-3 and inhibits mTOR. In parallel, AMPK can phosphorylate TSC2 at an unknown phosphosite. The phosphorylated TSC2 inhibits the conversion of RHEB-GDP (inactive) to the active form RHEB-GTP, which is a positive regulator of mTOR. As a consequence, the mTOR pathway is shut down. On the other hand, at night (ZT12-ZT24) when mice are active and they are feeding, the internal level of insulin is increasing. This event promotes the PI3K-AKT cascade, which ends with an active form of AKT phosphorylating TSC2 at different sites (Thr-1462, Ser-939, Ser-981, Ser-1130, Ser-1132). The hyperphosphorylated TSC2 inhibits the conversion of RHEB-GTP to RHEB GDP, thus the active RHEB-GTP can turn on the mTOR pathway. AMP, Adenosine MonoPhosphate; ATP, Adenosine TriPhosphate; LKB1, Liver Kinase B1; AMPK, 5′ Adenosine Monophosphate-activated Protein Kinase; TSC2, Tuberous Sclerosis Complex 2; RHEB, Ras Homolog Enriched in Brain; GTP, Guanosine TriPhosphate; GDP, Guanosine DiPhosphate; IRS1, Insulin Receptor Substrate 1; PI3K, PhosphatidylInositol-3-Kinase; PIP2, Phosphatidylinositol 4,5-bisphosphate; PIP3, Phosphatidylinositol (3,4,5)-trisphosphate; AKT, AKR Thymoma; mTOR, mammalian Target Of Rapamycin; p, phosphorylated; s, serine.