Rapamycin-FKBP12 complex blocks growth-factor activation of p70 S6 kinase, linking the drug to a specific mitogenic pathway.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | T cells; in vitro |
| Journal | Cell |
| Year | 1992 |
| Peer reviewed | Yes |
| Source | DOI 10.1016/0092-8674(92)90643-q · PMID 1377606 |
The macrolide rapamycin blocks cell cycle progression in yeast and various animal cells by an unknown mechanism. We demonstrate that rapamycin blocks the phosphorylation and activation of the 70 kd S6 protein kinases (pp70S6K) in a variety of animal cells. The structurally related drug FK506 had no effect on pp70S6K activation but at high concentrations reversed the rapamycin-induced block, confirming the requirement for the rapamycin and FK506 receptor, FKBP. Rapamycin also interfered with signaling by these S6 kinases, blocking serum-stimulated S6 phosphorylation and delaying entry of Swiss 3T3 cells into S phase. Neither rapamycin nor FK506 blocked activation of a distinct family of S6 kinases (RSKs) or the MAP kinases. These studies identify a rapamycin-sensitive signaling pathway, argue for a ubiquitous role for FKBPs in signal transduction, indicate that FK506-FKBP-calcineurin complexes do not interfere with pp70S6K signaling, and show that in fibroblasts pp70S6K, not RSK, is the physiological S6 kinase.
| Intervention | Rapamycin (± FK506) |
| Target | FKBP / p70 S6 kinase |
| Model | T cells; in vitro |
| Effect | Rapamycin blocks activation of the p70 S6 kinases; FK506 reverses it (FKBP-dependent) |