At the leading edge of migrating cells, polymerisation of branched actin filaments, driven by the Arp2/3 complex, promotes the formation of membrane protrusions known as lamellipodia. Here, lamellipodia promote the directional persistence of cell migration, and depletion of Arp2/3 inhibitory proteins (thus increasing lamellipodia formation) enhances migration persistence. However, it is mechanistically unclear how migrating cells adapt to these changes. In this study (Fokin et al., 2024), Alexis Gautreau and colleagues knock out three negative regulators of Arp2/3 – arpin, ARPC1A and CYFIP2. Using MCF10A mammary epithelial cells (in vitro) and zebrafish endodermal cells (in vivo), the authors show that knockout (KO) of all three Arp2/3 inhibitory proteins increases migration persistence significantly more than single or double KOs; triple-KO cells display a ‘super-migrator’ phenotype, with the greatest persistence. Delving into the underlying mechanisms, the authors assess changes in gene expression and find that the intermediate filament protein vimentin, and its transcriptional regulator ZEB2, are heterogeneously downregulated in triple-KO cells; re-expression of vimentin largely restores migratory phenotypes, suggesting that vimentin downregulation contributes to the super-migrator phenotype. Together, these findings shed light on how the Arp2/3 complex and regulators of branched actin impact cell migration, and how cells adapt to altered actin dynamics through changes in gene expression.
