Fascin in Cell Migration: More Than an Actin Bundling Protein

Abstract

Fascin, an actin-binding protein, regulates many developmental migrations and contributes to cancer metastasis. Specifically, Fascin promotes cell motility, invasion, and adhesion by forming filopodia and invadopodia through its canonical actin bundling function. In addition to bundling actin, Fascin has non-canonical roles in the cell that are thought to promote cell migration. These non-canonical functions include regulating the activity of other actin-binding proteins, binding to and regulating microtubules, mediating mechanotransduction to the nucleus via interaction with the Linker of the Nucleoskeleton and Cytoskeleton (LINC) Complex, and localizing to the nucleus to regulate nuclear actin, the nucleolus, and chromatin modifications. The many functions of Fascin must be coordinately regulated to control cell migration. While much remains to be learned about such mechanisms, Fascin is regulated by post-translational modifications, prostaglandin signaling, protein-protein interactions, and transcriptional means. Here, we review the structure of Fascin, the various functions of Fascin and how they contribute to cell migration, the mechanisms regulating Fascin, and how Fascin contributes to diseases, specifically cancer metastasis.

Keywords: LINC Complex; actin; cancer metastasis; fascin; mechanotransduction; microtubules; migration; nuclear actin; nucleolus; prostaglandins.

Figure 1

Fascin bundling mechanism and actin-binding domains. (A) Schematic of Fascin bundling two actin filaments (red). (B) Schematic of the domains and binding site of Fascin. The four β-trefoil domains of Fascin are in different shades of blue. Actin-binding areas of Fascin are in gold. In B, the different protein interaction sites and post-translational modifications are labeled.

Figure 2

Schematic of the canonical and non-canonical functions of Fascin. Canonically, Fascin (blue) bundles actin filaments (red) to form structures such as filopodia (A). Fascin also regulates other actin-binding proteins, such as increasing the processivity of the actin elongating factor, Ena (green, B), and inhibiting Non-muscle Myosin II (purple) activity (C). At the nuclear periphery, Fascin mediates mechanotransduction by interacting with the Linker of the Nucleoskeleton and Cytoskeleton (LINC) complex (gold, D). In addition to binding actin, Fascin also binds to microtubules (orange, E). Fascin also localizes to the nucleus, where it likely regulates nuclear actin and nucleolar morphology (F). Schematic is not drawn to scale.