RAPAMYCIN FKBP SPECIFICALLY BLOCKS GROWTH-DEPENDENT ACTIVATION OF AND SIGNALING BY THE 70 KD S6 PROTEIN-KINASES
RAPAMYCIN FKBP SPECIFICALLY BLOCKS GROWTH-DEPENDENT ACTIVATION OF AND SIGNALING BY THE 70 KD S6 PROTEIN-KINASES
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DOI：
10.1016/0092-8674(92)90643-q
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发表时间：
1992-06-26
期刊：
影响因子：
64.5
通讯作者：
BLENIS, J
中科院分区：
文献类型：
--
作者：
CHUNG, J;KUO, CJ;BLENIS, J
大环内酯类雷帕霉素通过一种未知的机制阻止酵母和各种动物细胞的细胞周期进程。我们证明了雷帕霉素阻断了多种动物细胞中70kdS6蛋白激酶(Pp70S6K)的磷酸化和激活。结构上相关的药物FK506对pp70S6K的激活没有影响，但在高浓度时逆转了雷帕霉素诱导的阻断，证实了对雷帕霉素和FK506受体FKBP的需求。雷帕霉素也干扰了这些S6激酶的信号传递，阻断了血清刺激的S6磷酸化，延迟了瑞士3T3细胞进入S期。雷帕霉素和FK506都不能阻断一组不同的S6激酶(RSK)或MAP激酶的激活。这些研究确定了一条雷帕霉素敏感的信号通路，证明了FKBP在信号转导中的普遍作用，表明FK506-FKBP-钙调神经磷酸酶复合体不干扰pp70S6K信号转导，并表明在成纤维细胞中，pp70S6K而不是RSK是生理上的S6激酶。
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.