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Dev Cell. 2015 Oct 12;35(1):78-92. doi: 10.1016/j.devcel.2015.09.002. Epub 2015 Oct 1.

SrGAP2-Dependent Integration of Membrane Geometry and Slit-Robo-Repulsive Cues Regulates Fibroblast Contact Inhibition of Locomotion.

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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.
Department of Neurological and Movement Sciences, Section of Physiology, University of Verona, Strada le Grazie 8, 37134 Verona, Italy.
Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland. Electronic address:


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.

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