SOS1 and SOS2 are the most universal and widely expressed family of guanine exchange factors (GEFs) capable or activating RAS or RAC1 proteins in metazoan cells. SOS proteins contain a sequence of modular domains that are responsible for different intramolecular and intermolecular interactions modulating mechanisms of self-inhibition, allosteric activation and intracellular homeostasis. Despite their homology, analyses of SOS1/2-KO mice demonstrate functional prevalence of SOS1 over SOS2 in cellular processes including proliferation, migration, inflammation or maintenance of intracellular redox homeostasis, although some functional redundancy cannot be excluded, particularly at the organismal level. Specific SOS1 gain-of-function mutations have been identified in inherited RASopathies and various sporadic human cancers. SOS1 depletion reduces tumorigenesis mediated by RAS or RAC1 in mouse models and is associated with increased intracellular oxidative stress and mitochondrial dysfunction. Since WT RAS is essential for development of RAS-mutant tumors, the SOS GEFs may be considered as relevant biomarkers or therapy targets in RAS-dependent cancers. Inhibitors blocking SOS expression, intrinsic GEF activity, or productive SOS protein-protein interactions with cellular regulators and/or RAS/RAC targets have been recently developed and shown preclinical and clinical effectiveness blocking aberrant RAS signaling in RAS-driven and RTK-driven tumors.

译文

:SOS1和SOS2是最普遍和广泛表达的鸟嘌呤交换因子(GEF)家族,能够或激活后生动物细胞中的RAS或RAC1蛋白。 SOS蛋白包含一系列模块化结构域,这些结构域负责调节分子内和分子间的相互作用,从而调节自我抑制,变构激活和细胞内稳态。尽管它们具有同源性,但对SOS1 / 2-KO小鼠的分析显示,在细胞过程中SOS1在功能上普遍高于SOS2,包括增殖,迁移,炎症或细胞内氧化还原稳态的维持,尽管不能排除某些功能冗余,特别是在机体水平上。在遗传的RASopathies和各种散发性人类癌症中,已经确定了特定的SOS1功能获得性突变。 SOS1耗竭减少小鼠模型中由RAS或RAC1介导的肿瘤发生,并与细胞内氧化应激增加和线粒体功能障碍有关。由于WT RAS对于RAS突变肿瘤的发展必不可少,因此SOS GEF可被视为RAS依赖型癌症中的相关生物标志物或治疗靶标。最近已经开发了抑制SOS表达,内在GEF活性或生产性SOS蛋白-蛋白与细胞调节剂和/或RAS / RAC靶标相互作用的抑制剂,这些抑制剂在临床上和临床上均有效地阻断了RAS驱动和RTK驱动的肿瘤中异常RAS信号传导。

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