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

The Journal of Cell Biology
Assaf ZaritskyAlan Hall

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-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.

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Citations

Mar 31, 2018·Journal of Leukocyte Biology·Keren B TurtonDeane F Mosher
Dec 14, 2017·The Journal of Cell Biology·Campbell D Lawson, Anne J Ridley
Aug 8, 2018·Molecular Carcinogenesis·Tiziana ParisiJacqueline A Lees
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Jul 16, 2019·The EMBO Journal·Fotine LibanjeFanny Jaulin
Dec 11, 2020·PLoS Computational Biology·Andreas Buttenschön, Leah Edelstein-Keshet
Apr 7, 2019·Cancer Research·Kacey VanderVorstKermit L Carraway
Apr 3, 2021·Journal of Cell Science·Meghan K Driscoll, Assaf Zaritsky
May 6, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Alamzeb KhanRichard W Pierce
Aug 21, 2021·Journal of Cell Science·Meghan K Driscoll, Assaf Zaritsky
Oct 11, 2021·Cancer Cell International·Yingyue LouDuo Zhang
Sep 21, 2021·Physical Biology·Elisabeth G Rens, Leah Edelstein-Keshet

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Methods Mentioned

BETA
GTPases
nucleotide exchange
GTPase
PCA
biosensors
PCR
scraping
protein assay

Software Mentioned

ImageJ
ZEISS
Primer
Axiovision
- Blast
PCA
Matlab

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