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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Biosensing Techniques
  • Cell Movement / physiology*
  • Contact Inhibition / physiology*
  • Cues*
  • Fibroblasts / cytology*
  • Fibroblasts / metabolism
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • HEK293 Cells
  • Humans
  • Pseudopodia / physiology
  • Signal Transduction
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism*


  • GTPase-Activating Proteins
  • RAC1 protein, human
  • SRGAP2 protein, human
  • rac1 GTP-Binding Protein