Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
Department of Biosystems, Science and Engineering (D-BSSE), ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
Dev Cell. 2015 Oct 12;35(1):78-92. doi: 10.1016/j.devcel.2015.09.002. Epub 2015 Oct 1.
Migrating fibroblasts undergo contact inhibition of locomotion (CIL), a process that was discovered five decades ago and still is not fully understood at the molecular level. We identify the Slit2-Robo4-srGAP2 signaling network as a key regulator of CIL in fibroblasts. CIL involves highly dynamic contact protrusions with a specialized actin cytoskeleton that stochastically explore cell-cell overlaps between colliding fibroblasts. A membrane curvature-sensing F-BAR domain pre-localizes srGAP2 to protruding edges and terminates their extension phase in response to cell collision. A FRET-based biosensor reveals that Rac1 activity is focused in a band at the tip of contact protrusions, in contrast to the broad activation gradient in contact-free protrusions. SrGAP2 specifically controls the duration of Rac1 activity in contact protrusions, but not in contact-free protrusions. We propose that srGAP2 integrates cell edge curvature and Slit-Robo-mediated repulsive cues to fine-tune Rac1 activation dynamics in contact protrusions to spatiotemporally coordinate CIL.
迁移成纤维细胞经历接触抑制的运动（CIL），这一过程是五十年前发现的，但在分子水平上仍未完全理解。我们确定 Slit2-Robo4-srGAP2 信号网络是成纤维细胞中 CIL 的关键调节因子。CIL 涉及具有特殊肌动蛋白细胞骨架的高度动态接触突起，这些突起随机探索碰撞成纤维细胞之间的细胞-细胞重叠。膜曲率感应 F-BAR 结构域将 srGAP2 预定位到突出的边缘，并在细胞碰撞时终止其延伸阶段。基于 FRET 的生物传感器显示，Rac1 活性集中在接触突起尖端的一个带中，与无接触突起中的广泛激活梯度形成对比。SrGAP2 特异性控制接触突起中 Rac1 活性的持续时间，但不控制无接触突起中 Rac1 活性的持续时间。我们提出，srGAP2 将细胞边缘曲率和 Slit-Robo 介导的排斥信号整合在一起，以微调接触突起中 Rac1 的激活动力学，从而在时空上协调 CIL。
