Institute of Molecular Tumor Biology, Faculty of Medicine, University of Münster, Münster, Germany.
Institute of Molecular Tumor Biology, Faculty of Medicine, University of Münster, Münster, Germany.
Int Rev Cell Mol Biol. 2021;361:21-105. doi: 10.1016/bs.ircmb.2020.10.005. Epub 2020 Dec 2.
The RAL proteins RALA and RALB belong to the superfamily of small RAS-like GTPases (guanosine triphosphatases). RAL GTPases function as molecular switches in cells by cycling through GDP- and GTP-bound states, a process which is regulated by several guanine exchange factors (GEFs) and two heterodimeric GTPase activating proteins (GAPs). Since their discovery in the 1980s, RALA and RALB have been established to exert isoform-specific functions in central cellular processes such as exocytosis, endocytosis, actin organization and gene expression. Consequently, it is not surprising that an increasing number of physiological functions are discovered to be controlled by RAL, including neuronal plasticity, immune response, and glucose and lipid homeostasis. The critical importance of RAL GTPases for oncogenic RAS-driven cellular transformation and tumorigenesis still attracts most research interest. Here, RAL proteins are key drivers of cell migration, metastasis, anchorage-independent proliferation, and survival. This chapter provides an overview of normal and pathological functions of RAL GTPases and summarizes the current knowledge on the involvement of RAL in human disease as well as current therapeutic targeting strategies. In particular, molecular mechanisms that specifically control RAL activity and RAL effector usage in different scenarios are outlined, putting a spotlight on the complexity of the RAL GTPase signaling network and the emerging theme of RAS-independent regulation and relevance of RAL.
RAL 蛋白 RALA 和 RALB 属于小 Ras 样 GTP 酶（鸟苷三磷酸酶）超家族。RAL GTPases 通过 GDP 和 GTP 结合状态的循环在细胞中作为分子开关发挥作用，该过程受几种鸟嘌呤核苷酸交换因子（GEFs）和两种异源二聚体 GTP 酶激活蛋白（GAPs）调节。自 20 世纪 80 年代发现以来，RALA 和 RALB 已被确定在细胞内的中央过程中发挥同工型特异性功能，例如胞吐作用、胞吞作用、肌动蛋白组织和基因表达。因此，越来越多的生理功能被发现受 RAL 控制，包括神经元可塑性、免疫反应以及葡萄糖和脂质稳态，这并不奇怪。RAL GTPases 对致癌 RAS 驱动的细胞转化和肿瘤发生的关键重要性仍然吸引着大多数研究兴趣。在这里，RAL 蛋白是细胞迁移、转移、非锚定依赖性增殖和存活的关键驱动因素。本章概述了 RAL GTPases 的正常和病理功能，并总结了 RAL 参与人类疾病的最新知识以及当前的治疗靶向策略。特别是，概述了特定控制 RAL 活性和 RAL 效应物在不同情况下使用的分子机制，重点介绍了 RAL GTPase 信号网络的复杂性以及 RAS 独立调节和 RAL 相关性的新兴主题。
