Fascin Regulates Nuclear Movement and Deformation in Migrating Cells

Fascin is an F-actin-bundling protein shown to stabilize filopodia and regulate adhesion dynamics in migrating cells, and its expression is correlated with poor prognosis and increased metastatic potential in a number of cancers. Here, we identified the nuclear envelope protein nesprin-2 as a binding partner for fascin in a range of cell types in vitro and in vivo. Nesprin-2 interacts with fascin through a direct, F-actin-independent interaction, and this binding is distinct and separable from a role for fascin within filopodia at the cell periphery. Moreover, disrupting the interaction between fascin and nesprin-2 C-terminal domain leads to specific defects in F-actin coupling to the nuclear envelope, nuclear movement, and the ability of cells to deform their nucleus to invade through confined spaces. Together, our results uncover a role for fascin that operates independently of filopodia assembly to promote efficient cell migration and invasion. [Display omitted] •Fascin binds directly to nesprin-2 at the nuclear envelope•Fascin-nesprin-2 binding occurs independently of fascin-actin bundling•The fascin-nesprin-2 complex regulates nuclear movement in migration•Uncoupling the fascin-nesprin complex reduces nuclear deformation and cell invasion Fascin is an F-actin-bundling protein that is significantly upregulated in most cancers and correlates with poor prognosis. Jayo et al. show that fascin can associate directly with the nuclear envelope protein nesprin-2. This complex is required for nuclear movement and deformation during cell invasion through 3D matrices.