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

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Abstract

THE structurally related natural products rapamycin and FK506 bind to the same intracellular receptor, FKBP12, yet the resulting complexes interfere with distinct signalling pathways1,2. FKBP12–rapamycin inhibits progression through the Gl phase of the cell cycle in osteosarcoma3, liver4, 5 and T cells6, 7 as well as in yeast8 and interferes with mitogenic signalling pathways that are involved in Gl progression9, 10 namely with activation of the protein p70S6k (refs 5,11–13) and cyclin-dependent kinases3, 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 cerevisiae8, 17, 18. Although it has not been previously demonstrated that either of the DRR/TOR gene products can bind the FKBP–rapamycin complex directly17, 19 these yeast genes have been genetically linked to a rapamycin-sensitive pathway and are thought to encode lipid kinases17–20.

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