Dynamic regulation of RAS and RAS signaling.
Dynamic regulation of RAS and RAS signaling.
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DOI：
10.1042/bcj20220234
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发表时间：
2023-01-13
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RAS蛋白调节细胞生理学的大多数方面。它们在30%的人类癌症和4%的称为Rasopathies的发育障碍中发生突变。它们在活跃的GTP结合状态和不活跃的GDP结合状态之间循环。当活跃时，它们可以与控制基本生化和生物过程的广泛效应物相互作用。新出现的证据表明，RAS蛋白不是简单的开关，而是复杂的信息处理设备，通过整合外部和内部线索来计算细胞命运决定。这种计算功能的一个关键组成部分是RAS激活和下游信号传导的动态调节，允许RAS产生丰富而细致入微的生物输出谱。我们讨论了最近的研究结果如何RAS及其下游信号的动态调节。从野生型和突变型RAS蛋白的结构和生化特性及其激活周期开始，我们研究了更高的分子组装，效应器相互作用和下游信号输出，所有这些都在动态调节方面。我们还考虑如何计算和数学建模方法有助于分析和理解RAS在健康和疾病中的多效性功能。
RAS proteins regulate most aspects of cellular physiology. They are mutated in 30% of human cancers and 4% of developmental disorders termed Rasopathies. They cycle between active GTP-bound and inactive GDP-bound states. When active, they can interact with a wide range of effectors that control fundamental biochemical and biological processes. Emerging evidence suggests that RAS proteins are not simple on/off switches but sophisticated information processing devices that compute cell fate decisions by integrating external and internal cues. A critical component of this compute function is the dynamic regulation of RAS activation and downstream signaling that allows RAS to produce a rich and nuanced spectrum of biological outputs. We discuss recent findings how the dynamics of RAS and its downstream signaling is regulated. Starting from the structural and biochemical properties of wild-type and mutant RAS proteins and their activation cycle, we examine higher molecular assemblies, effector interactions and downstream signaling outputs, all under the aspect of dynamic regulation. We also consider how computational and mathematical modeling approaches contribute to analyze and understand the pleiotropic functions of RAS in health and disease.