FKBPs and the Akt/mTOR pathway

FK506-binding proteins (FKBP) belong to the immunophilin family and are best known for their ability to enable the immunosuppressive properties of FK506 and rapamycin. For rapamycin, this is achieved by inducing inhibitory ternary complexes with the kinase mTOR. The essential accessory protein for this gain-of-function was thought to be FKBP12. We recently showed that this view might be too restricted, since larger FK506-binding proteins can functionally substitute for FKBP12 in mammalian cells. Recent studies have also shown that FK506-binding proteins can modulate Akt-mTOR signaling in the absence of rapamycin. Here we discuss the role of FK506-binding proteins for the mechanism of rapamycin as well as their intrinsic actions on the Akt/mTOR pathway

Large FK506-Binding Proteins Shape the Pharmacology of Rapamycin

The immunosuppressant and anticancer drug rapamycin works by inducing inhibitory protein complexes with the kinase mTOR, an important regulator of growth and proliferation. The obligatory accessory partner of rapamycin is believed to be FK506-binding protein 12 (FKBP12). Here we show that rapamycin complexes of larger FKBP family members can tightly bind to mTOR and potently inhibit its kinase activity. Cocrystal structures with FKBP51 and FKBP52 reveal the modified molecular binding mode of these alternative ternary complexes in detail. In cellular model systems, FKBP12 can be functionally replaced by larger FKBPs. When the rapamycin dosage is limiting, mTOR inhibition of S6K phosphorylation can be enhanced by FKBP51 overexpression in mammalian cells, whereas FKBP12 is dispensable. FKBP51 could also enable the rapamycin-induced hyper-phosphorylation of Akt, which depended on higher FKBP levels than rapamycin-induced inhibition of S6K phosphorylation. These insights provide a mechanistic rationale for preferential mTOR inhibition in specific cell or tissue types by engaging specific FKBP homologs