Purified FRAP (mTOR) as the mammalian FKBP12-rapamycin target homologous to yeast TOR1/2.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Bovine brain; in vitro |
| Journal | Nature |
| Year | 1994 |
| Peer reviewed | Yes |
| Source | DOI 10.1038/369756a0 · PMID 8008069 |
The structurally related natural products rapamycin and FK506 bind to the same intracellular receptor, FKBP12, yet the resulting complexes interfere with distinct signalling pathways. FKBP12-rapamycin inhibits progression through the G1 phase of the cell cycle in osteosarcoma, liver and T cells as well as in yeast, and interferes with mitogenic signalling pathways that are involved in G1 progression, namely with activation of the protein p70S6k (refs 5, 11-13) and cyclin-dependent kinases. Here we isolate a mammalian FKBP-rapamycin-associated protein (FRAP) whose binding to structural variants of rapamycin complexed to FKBP12 correlates with the ability of these ligands to inhibit cell-cycle progression. Peptide sequences from purified bovine FRAP were used to isolate a human cDNA clone that is highly related to the DRR1/TOR1 and DRR2/TOR2 gene products from Saccharomyces cerevisiae. Although it has not been previously demonstrated that either of the DRR/TOR gene products can bind the FKBP-rapamycin complex directly, these yeast genes have been genetically linked to a rapamycin-sensitive pathway and are thought to encode lipid kinases.
| Intervention | Biochemical (FKBP12-rapamycin complex) |
| Target | mTOR (FRAP) / FKBP12 |
| Model | Bovine brain; in vitro |
| Effect | Identifies the mammalian FKBP12-rapamycin target protein that controls G1 cell-cycle progression |