Department of Environmental Medicine, New York University Langone Medical Center, USA; Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, USA.
Institute of Pathology, Kings County Hospital Center, Brooklyn, NY, USA.
Semin Cancer Biol. 2021 Nov;76:301-309. doi: 10.1016/j.semcancer.2021.03.033. Epub 2021 Apr 1.
Ras proteins are small GTPases that participate in multiple signal cascades, regulating crucial cellular processes including cell survival, proliferation, and differentiation. Mutations or deregulated activities of Ras are frequently the driving force for oncogenic transformation and tumorigenesis. Posttranslational modifications play a crucial role in mediating the stability, activity, or subcellular localization/trafficking of numerous cellular regulators including Ras proteins. A series of recent studies reveal that Ras proteins are also regulated by sumoylation. All three Ras protein isoforms (HRas, KRas, and NRas) are modified by SUMO3. The conserved lysine42 appears to be the primary site for mediating sumoylation. Expression of KRas mutants compromised the activation of the Raf/MEK/ERK signaling axis, leading to a reduced rate of cell migration and invasion in vitro in multiple cell lines. Moreover, treatment of transformed pancreatic cells with a SUMO E2 inhibitor blocks cell migration in a concentration-dependent manner, which is associated with a reduced level of both KRas sumoylation and expression of mesenchymal cell markers. Furthermore, mouse xenograft experiments reveal that expression of a SUMO-resistant mutant appears to suppress tumor development in vivo. Combined, these studies indicate that sumoylation functions as an important mechanism in mediating the roles of Ras in cell proliferation, differentiation, and malignant transformation and that the SUMO-modification system of Ras oncoproteins can be explored as a new druggable target for various human malignancies.
Ras 蛋白是参与多种信号级联反应的小 GTP 酶，调节包括细胞存活、增殖和分化在内的关键细胞过程。Ras 的突变或活性失调通常是致癌转化和肿瘤发生的驱动力。翻译后修饰在调节包括 Ras 蛋白在内的许多细胞调节剂的稳定性、活性或亚细胞定位/运输中起着至关重要的作用。最近的一系列研究表明，Ras 蛋白也受到 SUMO 化的调节。所有三种 Ras 蛋白同工型（HRas、KRas 和 NRas）都被 SUMO3 修饰。保守的赖氨酸 42 似乎是介导 SUMO 化的主要位点。KRas 突变体的表达削弱了 Raf/MEK/ERK 信号轴的激活，导致体外多种细胞系的细胞迁移和侵袭速度降低。此外，用 SUMO E2 抑制剂处理转化的胰腺细胞以浓度依赖性方式阻断细胞迁移，这与 KRas SUMO 化水平降低和间充质细胞标志物的表达降低有关。此外，小鼠异种移植实验表明，表达 SUMO 抗性突变体似乎可以抑制体内肿瘤的发展。综上所述，这些研究表明 SUMO 化作为 Ras 在细胞增殖、分化和恶性转化中的作用的重要调节机制，Ras 癌蛋白的 SUMO 修饰系统可以作为各种人类恶性肿瘤的新的可用药靶进行探索。
