Diverse roles of guanine nucleotide exchange factors in regulating collective cell migration

J Cell Biol. 2017 Jun 5;216(6):1543-1556. doi: 10.1083/jcb.201609095. Epub 2017 May 16.


Efficient collective migration depends on a balance between contractility and cytoskeletal rearrangements, adhesion, and mechanical cell-cell communication, all controlled by GTPases of the RHO family. By comprehensive screening of guanine nucleotide exchange factors (GEFs) in human bronchial epithelial cell monolayers, we identified GEFs that are required for collective migration at large, such as SOS1 and β-PIX, and RHOA GEFs that are implicated in intercellular communication. Down-regulation of the latter GEFs differentially enhanced front-to-back propagation of guidance cues through the monolayer and was mirrored by down-regulation of RHOA expression and myosin II activity. Phenotype-based clustering of knockdown behaviors identified RHOA-ARHGEF18 and ARHGEF3-ARHGEF28-ARHGEF11 clusters, indicating that the latter may signal through other RHO-family GTPases. Indeed, knockdown of RHOC produced an intermediate between the two phenotypes. We conclude that for effective collective migration, the RHOA-GEFs → RHOA/C → actomyosin pathways must be optimally tuned to compromise between generation of motility forces and restriction of intercellular communication.

Publication types

  • Video-Audio Media
  • Research Support, N.I.H., Extramural

MeSH terms

  • Actomyosin / metabolism
  • Bronchi / cytology
  • Bronchi / enzymology*
  • Cell Line
  • Cell Movement*
  • Epithelial Cells / enzymology*
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Phenotype
  • RNA Interference
  • Rho Guanine Nucleotide Exchange Factors / genetics
  • Rho Guanine Nucleotide Exchange Factors / metabolism
  • SOS1 Protein / genetics
  • SOS1 Protein / metabolism
  • Signal Transduction*
  • Time Factors
  • Transfection
  • Wound Healing
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism*
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism*
  • rhoC GTP-Binding Protein


  • ARHGEF11 protein, human
  • ARHGEF18 protein, human
  • ARHGEF3 protein, human
  • Guanine Nucleotide Exchange Factors
  • Rho Guanine Nucleotide Exchange Factors
  • SOS1 Protein
  • RHOA protein, human
  • Actomyosin
  • RHOC protein, human
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein
  • rhoC GTP-Binding Protein