Chung J, Kuo C J, Crabtree G R, Blenis J
Department of Cellular and Molecular Physiology, Harvard Medical School, Boston, Massachusetts 02115.
Cell. 1992 Jun 26;69(7):1227-36. doi: 10.1016/0092-8674(92)90643-q.
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.
大环内酯类药物雷帕霉素通过未知机制阻断酵母和多种动物细胞的细胞周期进程。我们证明，雷帕霉素可阻断多种动物细胞中70 kd S6蛋白激酶（pp70S6K）的磷酸化及激活。结构相关药物FK506对pp70S6K激活无作用，但在高浓度时可逆转雷帕霉素诱导的阻断作用，证实了对雷帕霉素和FK506受体FKBP的需求。雷帕霉素还干扰这些S6激酶的信号传导，阻断血清刺激的S6磷酸化，并延迟瑞士3T3细胞进入S期。雷帕霉素和FK506均未阻断一个不同的S6激酶家族（RSKs）或丝裂原活化蛋白激酶的激活。这些研究确定了一条对雷帕霉素敏感的信号通路，表明FKBP在信号转导中具有普遍作用，表明FK506 - FKBP - 钙调神经磷酸酶复合物不干扰pp70S6K信号传导，并表明在成纤维细胞中，生理状态下的S6激酶是pp70S6K而非RSK。
