FKBPs and the Akt/mTOR pathway

Abstract

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.

Keywords: Akt; FK506 binding protein; FKBP; PKB; mTOR; rapamycin.

Figure 1. Role of FKBPs in the Akt/mTOR pathway. Pathways downstream of mTOR are shown in blue; negative feedback mechanisms exerted by mTOR on Akt are shown as open arrows. mTOR functions that are affected by rapamycin only in certain cell types are dotted orange. Larger FKBPs that can replace the established FKBP12 as a presenting protein for rapamycin are indicated. RTK, receptor tyrosin kinase; IRS, insulin receptor substrate; PI3K, phosphoinositide 3-kinase; PDK1, phosphoinositide-dependent kinase I; Grb10, growth factor receptor-bound protein 10; PHLPP, PH domain and leucine rich repeat protein phosphatase; TSC, tuberous sclerosis complex; PRAS40, proline-rich Akt/PKB substrate 40 kDa; Rheb, Ras homolog enriched in brain

Figure 2. Model of the interaction of larger FKBP homologs with mTOR. The kinase domain of mTOR (pdb 4JSP) is shown as filled surface with the FRB domain colored orange, the N-terminal lobe yellow, and the C-terminal lobe pink. The FAT domain of mTOR is located on the back side of the kinase domain and not shown for clarity. ATPγS in the active site is shown as brown sticks and the bound mLst8 is shown as green cartoon. FKBP12 (dark blue) and the FK506-binding domain of FKBP51 (teal) have been modeled on the FRB domain based on their ternary complex crystal structures (2FAP and 4DRI) and are shown as cartoons. Rapamycin is shown as red sticks sandwiched between FKBP51 and FRB. The additional N-terminal loop of FKBP51 is shown in cyan, S27 and K28 of FKBP51 and Q41 and D42 of mLst8 are shown in sticks. The end of the FK506-binding domain of FKBP51, which is followed by a FKBP-like domain in full-length FKBP51, is indicated as spheres.