Figure 5.
Pharmacologic inhibitors of mTOR and calcineurin signaling. Rapamycin, cyclosporin A (CsA), and FK506 are all immunosuppressive agents with similar structure yet diverse mechanisms of action. All three agents are activated by binding to cis-trans peptidyl-prolyl isomerase proteins called immunophilins. CsA binds to cyclophilin, whereas FK506 and rapamycin bind to FKBP12. Both CsA and FK506 inhibit TCR-induced calcineurin activation and thus inhibit the translocation of NF-AT to the nucleus. In doing so, they block the expression of NF-AT-dependent genes of activation such as IL-2 as well as NF-AT-induced inhibitory genes such as Cbl-b. As such, in addition to being potent immunosuppressive agents, these compounds also block the induction of TCR-induced tolerance. However, rapamycin and similar drugs termed rapalogs, when bound to FKBP12, inhibit the interaction of RAPTOR and mTOR and thus inhibit mTORC1 activation. Prolonged exposure of T cells to rapamycin can also impair mTORC2 activity by an as yet undefined mechanism. In contrast, mTOR kinase inhibitors function as ATP-competitive inhibitors at the mTOR catalytic domain to specifically and potently inhibit both mTORC1 and mTORC2. Wortmannin and LY94002 can block mTOR activity by inhibiting PI3K activity, which is upstream of mTOR. Additionally, molecules that mimic the effects of AMP, such as metformin, can inhibit mTOR activity by activating AMPK, which in turn promotes the ability of TSC2 to inhibit mTORC1. Dashed lines indicate that the exact mechanism is unknown, black lines show activating signals, and red lines show inhibitory signals.