Figure 9

Schematic diagrams of rapamycin-sensitive and -resistant mTORC1 complexes in HCT116 cells. S6K and 4E-BP1, a negative regulator of eukaryotic initiation factor 4E(eIF4E), are the best characterised downstream targets of mTORC1. Although rapamycin treatment strongly inhibits S6K phosphorylation, it has a weaker effect on 4E-BP1 γ-band phosphorylation at Ser65. Less phosphorylated forms of 4E-BP1 bind to eIF4E leading to translational repression.⁸ Reducing PAT4 activity primarily affects the rapamycin-resistant form of mTORC1. This leads to a reduction in a Ser65-phosphorylated form of 4E-BP1, but has less effect on S6K phosphorylation. Other AATs in the SLC36 (PAT) and/or SLC38 family are likely to be involved in rapamycin-sensitive mTORC1 regulation, for example, PAT1 and SLC38A9. PP242 is an mTORC1 ATP-kinase inhibitor that acts on both the rapamycin-sensitive and -resistant forms of mTORC1. Arrows signify positive signals and cross-bars mark inhibitory signalling events.