title: SrGAP2-Dependent Integration of Membrane Geometry and Slit-Robo-Repulsive Cues Regulates Fibroblast Contact Inhibition of Locomotion.
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.
authors.affiliation: Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
authors.forename: Rafael Dominik
authors.initials: RD
authors.lastname: Fritz
authors.affiliation: Department of Biosystems, Science and Engineering (D-BSSE), ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Menshykau
authors.affiliation: Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
authors.forename: Katrin
authors.initials: K
authors.lastname: Martin
authors.affiliation: Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reimann
authors.affiliation: Department of Neurological and Movement Sciences, Section of Physiology, University of Verona, Strada le Grazie 8, 37134 Verona, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Pontelli
authors.affiliation: Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland. Electronic address: olivier.pertz@izb.unibe.ch.
authors.forename: Olivier
authors.initials: O
authors.lastname: Pertz
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D015374:Biosensing Techniques; D002465:Cell Movement / Q000502:physiology*; D003260:Contact Inhibition / Q000502:physiology*; D003463:Cues; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D011554:Pseudopodia / Q000502:physiology; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D020690:GTPase-Activating Proteins; C107953:RAC1 protein, human; C501995:SRGAP2 protein, human; D020830:rac1 GTP-Binding Protein