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

Assaf Zaritsky, Yun Yu Tseng, M. Angeles Rabadán, Shefali Krishna, Michael Overholtzer, Gaudenz Danuser, Alan Hall

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14 Scopus citations

Abstract

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-ARH GEF18 and ARH GEF3-ARH GEF28-ARH GEF11 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.

Original languageEnglish (US)
Pages (from-to)1543-1556
Number of pages14
JournalJournal of Cell Biology
Volume216
Issue number6
DOIs
StatePublished - Jun 1 2017

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Zaritsky, A., Tseng, Y. Y., Rabadán, M. A., Krishna, S., Overholtzer, M., Danuser, G., & Hall, A. (2017). Diverse roles of guanine nucleotide exchange factors in regulating collective cell migration. Journal of Cell Biology, 216(6), 1543-1556. https://doi.org/10.1083/jcb.201609095