Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, National Cancer Institute RAS Initiative, Inc., Frederick, MD 21702, USA.
Biomolecules. 2021 Mar 3;11(3):377. doi: 10.3390/biom11030377.
RAS proteins are mutated in approximately 20% of all cancers and are generally associated with poor clinical outcomes. RAS proteins are localized to the plasma membrane and function as molecular switches, turned on by partners that receive extracellular mitogenic signals. In the on-state, they activate intracellular signal transduction cascades. Membrane-bound RAS molecules segregate into multimers, known as nanoclusters. These nanoclusters, held together through weak protein-protein and protein-lipid associations, are highly dynamic and respond to cellular input signals and fluctuations in the local lipid environment. Disruption of RAS nanoclusters results in downregulation of RAS-mediated mitogenic signaling. In this review, we discuss the propensity of RAS proteins to display clustering behavior and the interfaces that are associated with these assemblies. Strategies to therapeutically disrupt nanocluster formation or the stabilization of signaling incompetent RAS complexes are discussed.
RAS 蛋白约占所有癌症的 20%，通常与不良临床结局相关。RAS 蛋白定位于质膜，作为分子开关发挥作用，由接收细胞外有丝分裂信号的伴侣分子激活。在开启状态下，它们激活细胞内信号转导级联反应。质膜结合的 RAS 分子分离成多聚体，称为纳米簇。这些纳米簇通过弱的蛋白质-蛋白质和蛋白质-脂质相互作用结合在一起，高度动态，并对细胞输入信号和局部脂质环境的波动做出反应。RAS 纳米簇的破坏导致 RAS 介导的有丝分裂信号下调。在这篇综述中，我们讨论了 RAS 蛋白显示聚类行为的倾向以及与这些组装相关的界面。讨论了治疗性破坏纳米簇形成或稳定无信号活性 RAS 复合物的策略。
