Assignment of the human FKBP12-rapamycin-associated protein (FRAP) gene to chromosome 1p36 by fluorescence in situ hybridization

Rapamycin and the structurally related compound FK506 are potent immunosuppressive drugs. Both immunosuppressants mediate their cellular effect by binding to the same intracellular receptor, the FK506 binding protein (FKBP12) (8 and references therein). The FKBP12-FK506 complex interacts with and inhibits the calcium-activated protein phosphatase activity of calcineurin, which is required for the activation of the T lymphocyte via the T-cell receptor. In contrast, the immediate downstream target of the FKBP12-rapamycin complex has recently been identified as a protein called FKBP-rapamycin-associated protein (FRAP; also called RAFT1 and RAPT1). Biochemical studies demonstrated that FKBP12 and FRAP interact only in the presence of rapamycin, not in the presence of FK506. Likewise, genetic studies in yeast, using the two-hybrid system, demonstrated that FRAP and FKBP12 interact only when yeast are grown in the presence of rapamycin. The downstream target of the rapamycin-FKBP12-FRAP complex is unknown, but their interaction somehow arrests T cells at the G1 phase of the cell cycle, leading to a block in the T-cell response and immunosuppression. While the precise functions of FRAP and the highly related homologs DRR1/TOR1 and DRR2/TOR2 from the yeast Saccharomyces cerevisiae are unknown, they demonstrate amino acid homology to the catalytic domain of the p110 subunit of phosphatidylinositol 3-kinase.