Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Crit Rev Biochem Mol Biol. 2020 Aug;55(4):386-407. doi: 10.1080/10409238.2020.1810622. Epub 2020 Aug 25.
The RAS and RHO family comprise two major branches of the RAS superfamily of small GTPases. These proteins function as regulated molecular switches and control cytoplasmic signaling networks that regulate a diversity of cellular processes, including cell proliferation and cell migration. In the early 1980s, mutationally activated genes encoding KRAS, HRAS and NRAS were discovered in human cancer and now comprise the most frequently mutated oncogene family in cancer. Only recently, exome sequencing studies identified cancer-associated alterations in two RHO family GTPases, RAC1 and RHOA. RAS and RHO proteins share significant identity in their amino acid sequences, protein structure and biochemistry. Cancer-associated RAS mutant proteins harbor missense mutations that are found primarily at one of three mutational hotspots (G12, G13 and Q61) and have been identified as gain-of-function oncogenic alterations. Although these residues are conserved in RHO family proteins, the gain-of-function mutations found in RAC1 are found primarily at a distinct hotspot. Unexpectedly, the cancer-associated mutations found with RHOA are located at different hotspots than those found with RAS. Furthermore, since the RHOA mutations suggested a loss-of-function phenotype, it has been unclear whether RHOA functions as an oncogene or tumor suppressor in cancer development. Finally, whereas RAS mutations are found in a broad spectrum of cancer types, RHOA and RAC1 mutations occur in a highly restricted range of cancer types. In this review, we focus on RHOA missense mutations found in cancer and their role in driving tumorigenesis, with comparisons to cancer-associated mutations in RAC1 and RAS GTPases.
RAS 和 RHO 家族由 RAS 超家族的小 GTP 酶的两个主要分支组成。这些蛋白质作为调节性分子开关发挥作用，控制细胞质信号网络，调节多种细胞过程，包括细胞增殖和细胞迁移。在 20 世纪 80 年代早期，在人类癌症中发现了突变激活的基因编码 KRAS、HRAS 和 NRAS，现在它们构成了癌症中最常突变的癌基因家族。直到最近，外显子组测序研究才确定了两个 RHO 家族 GTP 酶 RAC1 和 RHOA 中与癌症相关的改变。RAS 和 RHO 蛋白在其氨基酸序列、蛋白质结构和生物化学方面具有显著的同源性。与癌症相关的 RAS 突变蛋白携带有错义突变，这些突变主要发生在三个突变热点（G12、G13 和 Q61）之一，被鉴定为获得功能的致癌改变。尽管这些残基在 RHO 家族蛋白中保守，但在 RAC1 中发现的获得功能突变主要发生在一个独特的热点。出乎意料的是，在 RHOA 中发现的与癌症相关的突变位于与 RAS 不同的热点。此外，由于 RHOA 突变提示功能丧失表型，因此尚不清楚 RHOA 在癌症发展中是作为癌基因还是肿瘤抑制基因发挥作用。最后，尽管 RAS 突变发生在广泛的癌症类型中，但 RHOA 和 RAC1 突变仅发生在高度受限的癌症类型中。在这篇综述中，我们重点介绍了在癌症中发现的 RHOA 错义突变及其在驱动肿瘤发生中的作用，并与 RAC1 和 RAS GTP 酶中与癌症相关的突变进行了比较。
