Fritz, Rafael DominikRafael DominikFritzMenshykau, DenisDenisMenshykauMartin, KatrinKatrinMartinReimann, AndreasAndreasReimannPontelli, ValeriaValeriaPontelliPertz, OlivierOlivierPertz2024-10-242024-10-242015-10-12https://boris-portal.unibe.ch/handle/20.500.12422/141840Migrating 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.en500 - Science::570 - Life sciences; biologyarticle10.7892/boris.818532643940010.1016/j.devcel.2015.09.002