Inoki Ken, Ouyang Hongjiao, Li Yong, Guan Kun-Liang
Life Science Institute, University of Michigan Medical School, 5450 Medical Science I Bldg., Ann Arbor, MI 48109-0606, USA.
Microbiol Mol Biol Rev. 2005 Mar;69(1):79-100. doi: 10.1128/MMBR.69.1.79-100.2005.
Target of rapamycin (TOR) proteins are members of the phosphatidylinositol kinase-related kinase (PIKK) family and are highly conserved from yeast to mammals. TOR proteins integrate signals from growth factors, nutrients, stress, and cellular energy levels to control cell growth. The ribosomal S6 kinase 1 (S6K) and eukaryotic initiation factor 4E binding protein 1(4EBP1) are two cellular targets of TOR kinase activity and are known to mediate TOR function in translational control in mammalian cells. However, the precise molecular mechanism of TOR regulation is not completely understood. One of the recent breakthrough studies in TOR signaling resulted in the identification of the tuberous sclerosis complex gene products, TSC1 and TSC2, as negative regulators for TOR signaling. Furthermore, the discovery that the small GTPase Rheb is a direct downstream target of TSC1-TSC2 and a positive regulator of the TOR function has significantly advanced our understanding of the molecular mechanism of TOR activation. Here we review the current understanding of the regulation of TOR signaling and discuss its function as a signaling nexus to control cell growth during normal development and tumorigenesis.
雷帕霉素靶蛋白(TOR)是磷脂酰肌醇激酶相关激酶(PIKK)家族的成员,从酵母到哺乳动物都高度保守。TOR蛋白整合来自生长因子、营养物质、应激和细胞能量水平的信号,以控制细胞生长。核糖体S6激酶1(S6K)和真核起始因子4E结合蛋白1(4EBP1)是TOR激酶活性的两个细胞靶点,已知它们在哺乳动物细胞的翻译控制中介导TOR功能。然而,TOR调节的确切分子机制尚未完全了解。最近在TOR信号传导方面的一项突破性研究导致鉴定出结节性硬化症复合基因产物TSC1和TSC2是TOR信号传导的负调节因子。此外,小GTP酶Rheb是TSC1-TSC2的直接下游靶点以及TOR功能的正调节因子这一发现,显著推进了我们对TOR激活分子机制的理解。在这里,我们综述了目前对TOR信号传导调节的理解,并讨论了其作为信号枢纽在正常发育和肿瘤发生过程中控制细胞生长的功能。