Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, McGovern Medical School, TX, USA.
Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center and University of Texas Health Science Center, TX, USA.
FEBS Lett. 2023 Mar;597(6):892-908. doi: 10.1002/1873-3468.14569. Epub 2023 Jan 18.
Mutations of rat sarcoma virus (RAS) oncogenes (HRAS, KRAS and NRAS) can contribute to the development of cancers and genetic disorders (RASopathies). The spatiotemporal organization of RAS is an important property that warrants further investigation. In order to function, wild-type or oncogenic mutants of RAS must be localized to the inner leaflet of the plasma membrane (PM), which is driven by interactions between their C-terminal membrane-anchoring domains and PM lipids. The isoform-specific RAS-lipid interactions promote the formation of nanoclusters on the PM. As main sites for effector recruitment, these nanoclusters are biologically important. Since the spatial distribution of lipids is sensitive to changing environments, such as mechanical and electrical perturbations, RAS nanoclusters act as transducers to convert external stimuli to intracellular mitogenic signalling. As such, effective inhibition of RAS oncogenesis requires consideration of the complex interplay between RAS nanoclusters and various cell surface and extracellular stimuli. In this review, we discuss in detail how, by sorting specific lipids in the PM, RAS nanoclusters act as transducers to convert external stimuli into intracellular signalling.
大鼠肉瘤病毒（RAS）癌基因（HRAS、KRAS 和 NRAS）的突变可导致癌症和遗传疾病（RAS 病）的发生。RAS 的时空组织是一个重要的特性，值得进一步研究。为了发挥功能，RAS 的野生型或致癌突变体必须定位于质膜（PM）的内小叶，这是由它们的 C 末端膜锚定结构域与 PM 脂质之间的相互作用驱动的。同种型特异性的 RAS-脂质相互作用促进了 PM 上纳米簇的形成。作为效应器募集的主要位点，这些纳米簇具有重要的生物学意义。由于脂质的空间分布对机械和电扰动等环境变化敏感，RAS 纳米簇充当传感器，将外部刺激转化为细胞内有丝分裂信号。因此，有效抑制 RAS 致癌作用需要考虑 RAS 纳米簇与各种细胞表面和细胞外刺激之间的复杂相互作用。在这篇综述中，我们详细讨论了 RAS 纳米簇如何通过在 PM 中分拣特定的脂质，充当传感器将外部刺激转化为细胞内信号。
