More than a hundred proteins comprise the RAS superfamily of small GTPases. This family can be divided into RAS, RHO, RAB, RAN, ARF, and RAD subfamilies, with each shown to play distinct roles in human cells in both health and disease. The RAS subfamily has a well-established role in human cancer with the three genes, HRAS, KRAS, and NRAS being the commonly mutated in tumors. These RAS mutations, most often functionally activating, are especially common in pancreatic, lung, and colorectal cancers. Efforts to inhibit RAS and related GTPases have produced inhibitors targeting the downstream effectors of RAS signaling, including inhibitors of the RAF-mitogen-activated protein kinase/extracellular signal-related kinase (ERK)-ERK kinase pathway and the phosphoinositide-3-kinase-AKT-mTOR kinase pathway. A third effector arm of RAS signaling, mediated by RAL (RAS like) has emerged in recent years as a critical driver of RAS oncogenic signaling and has not been targeted until recently. RAL belongs to the RAS branch of the RAS superfamily and shares a high structural similarity with RAS. In human cells, there are two genes, RALA and RALB, both of which have been shown to play roles in the proliferation, survival, and metastasis of a variety of human cancers, including lung, colon, pancreatic, prostate, skin, and bladder cancers. In this review, we summarize the latest knowledge of RAL in the context of human cancer and the recent advancements in the development of cancer therapeutics targeting RAL small GTPases.

中文翻译：

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RAL GTPases：生物学和作为癌症治疗靶点的潜力


小 GTP 酶的 RAS 超家族由一百多种蛋白质组成。该家族可分为 RAS、RHO、RAB、RAN、ARF 和 RAD 亚家族，每个亚家族在健康和疾病的人类细胞中发挥着不同的作用。 RAS 亚家族在人类癌症中具有明确的作用，其中HRAS 、 KRAS和NRAS三个基因是肿瘤中常见的突变。这些RAS突变通常具有功能激活作用，在胰腺癌、肺癌和结直肠癌中尤其常见。抑制 RAS 和相关 GTP 酶的努力已经产生了针对 RAS 信号传导下游效应器的抑制剂，包括 RAF 丝裂原激活蛋白激酶/细胞外信号相关激酶 (ERK)-ERK 激酶途径和磷酸肌醇-3-激酶-的抑制剂。 AKT-mTOR 激酶通路。近年来，由 RAL（RAS 样）介导的 RAS 信号传导的第三个效应臂已成为 RAS 致癌信号传导的关键驱动因素，直到最近才成为靶点。 RAL属于RAS超家族的RAS分支，与RAS具有高度的结构相似性。在人类细胞中，有两个基因， RALA和RALB ，这两个基因已被证明在多种人类癌症的增殖、存活和转移中发挥作用，包括肺癌、结肠癌、胰腺癌、前列腺癌、皮肤癌和膀胱癌癌症。在这篇综述中，我们总结了 RAL 在人类癌症方面的最新知识以及针对 RAL 小 GTP 酶的癌症疗法开发的最新进展。