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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.

Author information

1
Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
2
Department of Biosystems, Science and Engineering (D-BSSE), ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
3
Department of Neurological and Movement Sciences, Section of Physiology, University of Verona, Strada le Grazie 8, 37134 Verona, Italy.
4
Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland. Electronic address: olivier.pertz@izb.unibe.ch.

Abstract

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.

PMID:
26439400
DOI:
10.1016/j.devcel.2015.09.002
[Indexed for MEDLINE]
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