Ras has been extensively studied as a promoter of cell proliferation, whereas few studies have explored its role in migration. To investigate the direct and immediate effects of Ras activity on cell motility or polarity, we focused on RasGAPs, C2GAPB in Dictyostelium amoebae and RASAL3 in HL-60 neutrophils and macrophages. In both cellular systems, optically recruiting the respective RasGAP to the cell front extinguished pre-existing protrusions and changed migration direction. However, when these respective RasGAPs were recruited uniformly to the membrane, cells polarized and moved more rapidly, whereas targeting to the back exaggerated these effects. These unexpected outcomes of attenuating Ras activity naturally had strong, context-dependent consequences for chemotaxis. The RasGAP-mediated polarization depended critically on myosin II activity and commenced with contraction at the cell rear, followed by sustained mTORC2-dependent actin polymerization at the front. These experimental results were captured by computational simulations in which Ras levels control front- and back-promoting feedback loops. The discovery that inhibiting Ras activity can produce counterintuitive effects on cell migration has important implications for future drug-design strategies targeting oncogenic Ras.

Ras 作为细胞增殖的促进剂已被广泛研究，但很少有研究探讨其在迁移中的作用。为了研究 Ras 活性对细胞运动或极性的直接影响，我们重点研究了阿米巴盘基网柄菌中的 RasGAP、C2GAPB 以及 HL-60 中性粒细胞和巨噬细胞中的 RASAL3。在这两种细胞系统中，通过光学方式将各自的 RasGAP 募集到细胞前端，消除了先前存在的突起并改变了迁移方向。然而，当这些各自的 RasGAP 被均匀地募集到膜上时，细胞极化并移动得更快，而靶向背面则加剧了这些效应。 Ras 活性减弱的这些意想不到的结果自然会对趋化性产生强烈的、依赖于环境的后果。 RasGAP 介导的极化主要取决于肌球蛋白 II 活性，并从细胞后部的收缩开始，然后在前部进行持续的 mTORC2 依赖性肌动蛋白聚合。这些实验结果是通过计算模拟获得的，其中 Ras 水平控制前向和后向促进反馈回路。抑制 Ras 活性会对细胞迁移产生违反直觉的影响，这一发现对于未来针对致癌 Ras 的药物设计策略具有重要意义。