A mammalian protein targeted by G1-arresting rapamycin-receptor complex

THE structurally related natural products rapamycin and FK506 bind to the same intracellular receptor, FKBP12, yet the resulting complexes interfere with distinct signalling pathways^1,2. FKBP12-rapamycin inhibits progression through the Gl phase of the cell cycle in osteosarcoma³, liver^{4, 5} and T cells^{6, 7} as well as in yeast⁸ and interferes with mitogenic signalling pathways that are involved in Gl progression^{9, 10} namely with activation of the protein p70^S6k (refs 5,11-13) and cyclin-dependent kinases^{3, 14-16}. 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 ^{8, 17, 18}. Although it has not been previously demonstrated that either of the DRR/TOR gene products can bind the FKBP-rapamycin complex directly^{17, 19} these yeast genes have been genetically linked to a rapamycin-sensitive pathway and are thought to encode lipid kinases^17-20.