Grewal Thomas, Koese Meryem, Tebar Francesc, Enrich Carlos
Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia.
Genes Cancer. 2011 Mar;2(3):288-97. doi: 10.1177/1947601911407330.
Ever since their discovery as cellular counterparts of viral oncogenes more than 25 years ago, much progress has been made in understanding the complex networks of signal transduction pathways activated by oncogenic Ras mutations in human cancers. The activity of Ras is regulated by nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), and much emphasis has been put into the biochemical and structural analysis of the Ras/GAP complex. The mechanisms by which GAPs catalyze Ras-GTP hydrolysis have been clarified and revealed that oncogenic Ras mutations confer resistance to GAPs and remain constitutively active. However, it is yet unclear how cells coordinate the large and divergent GAP protein family to promote Ras inactivation and ensure a certain biological response. Different domain arrangements in GAPs to create differential protein-protein and protein-lipid interactions are probably key factors determining the inactivation of the 3 Ras isoforms H-, K-, and N-Ras and their effector pathways. In recent years, in vitro as well as cell- and animal-based studies examining GAP activity, localization, interaction partners, and expression profiles have provided further insights into Ras inactivation and revealed characteristics of several GAPs to exert specific and distinct functions. This review aims to summarize knowledge on the cell biology of RasGAP proteins that potentially contributes to differential regulation of spatiotemporal Ras signaling.
自25多年前作为病毒癌基因的细胞对应物被发现以来，在理解人类癌症中致癌性Ras突变激活的信号转导通路复杂网络方面已经取得了很大进展。Ras的活性受核苷酸交换因子（GEFs）和GTP酶激活蛋白（GAPs）的调节，并且对Ras/GAP复合物的生化和结构分析给予了很大重视。GAPs催化Ras-GTP水解的机制已经阐明，并揭示致癌性Ras突变赋予对GAPs的抗性并保持组成性激活。然而，目前尚不清楚细胞如何协调庞大且多样的GAP蛋白家族以促进Ras失活并确保特定的生物学反应。GAPs中不同的结构域排列以产生不同的蛋白质-蛋白质和蛋白质-脂质相互作用可能是决定3种Ras亚型H-Ras、K-Ras和N-Ras及其效应途径失活的关键因素。近年来，基于体外以及细胞和动物的研究，考察GAP活性、定位、相互作用伙伴和表达谱，为Ras失活提供了进一步的见解，并揭示了几种GAP发挥特定和独特功能的特征。本综述旨在总结关于RasGAP蛋白细胞生物学的知识，这些知识可能有助于对时空Ras信号进行差异调节。
