Roles of fascin in cell adhesion and motility

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Many cell interactions depend on the assembly of cell protrusions; these include cell attachment and migration in the extracellular matrix, cell–cell communication, and the ability of cells to sense their local environment. Cell protrusions are extensions of the plasma membrane that are supported internally by actin-based structures that impart mechanical stiffness. Fascin is a small, globular actin-bundling protein that has emerging roles in diverse forms of cell protrusions and in cytoplasmic actin bundles. The fascin–actin interaction is under complex regulation from the extracellular matrix, peptide factors and other actin-binding proteins. Recent developments advance our understanding of the multifaceted regulation of fascin and the roles of fascin-containing structures in cell adhesion, motility and invasion in the life of vertebrate organisms.

Introduction

Fascin is a 55kDa globular protein that organizes F-actin into well-ordered, tightly packed parallel bundles in vitro and in cells. Fascins have been well-conserved in animal evolution: homologues are present in Drosophila, echinoderms and the platyhelminth Schmidtea mediterranea 1.•, 2. (Figure 1a,c). Vertebrate genomes encode three forms of fascin: fascin-1, which is widely expressed by mesenchymal tissues and in the nervous system (Figure 1b); fascin-2, which is expressed by retinal photoreceptor cells; and fascin-3, which is testis-specific 1.•, 3., 4., 5., 6.. The focus of this article is on fascin-1 (also known as fascin), which contributes to the organization of two major forms of actin-based structures: cortical cell protrusions that mediate cell interactions and migration, and cytoplasmic microfilament bundles that contribute to cell architecture and to intracellular movements. During embryogenesis, fascin-1 and Drosophila fascin are expressed by many motile cell populations, principally in the developing nervous system and in the mesoderm and its derivatives (Figure 1a,b) [3].

As an actin-crosslinking protein, fascin contains two actin-binding sites. Its actin-bundling activity is inhibited by phosphorylation of residue serine-39 by protein kinase Cα (PKCα), which blocks the activity of the N-terminal actin-binding site (reviewed in [1]). It is not known which serine phosphatase(s) might act to reverse phosphorylation in vivo. The association of fascin with F-actin is strongly regulated by the extracellular matrix (ECM) environment of cells (Figure 1d). The molecular basis for this regulation has been studied with regard to thrombospondin (TSP)-1 and fibronectin (FN) and depends on distinct activity states of PKCα and small GTPases; these different states are achieved via ligation of alternate adhesion receptors (Figure 2a). (Earlier references and details of the experimental evidence for these processes are provided in [1].) The consequences of the interaction of fascin with F-actin are also modulated by the interplay between fascin-1 and other actin-binding proteins (Figure 2b), but there is a gap in our understanding of how these interactions are linked functionally to extracellular cues. Recent publications expand our knowledge in three important areas: how fascin contributes to the formation of filopodial cell protrusions; the mechanisms by which fascin and fascin protrusions are regulated in cell adhesion and migration; and additional biological contexts in which fascin participates in motility structures.

Section snippets

Assembly and biomechanics of unipolar actin bundles

The Arp2/3 complex (where Arp stands for actin-related protein) is a major mediator of actin polymerization that nucleates branching networks of F-actin. Lamellipodia are formed from Arp2/3-dependent branching networks, but it remains uncertain how the Arp2/3 complex contributes to the assembly of unipolar, tightly packed actin filaments in filopodia. Borisy and collaborators used platinum replica electron microscopy to make an intensive analysis of the spatial organization of actin filaments

Cellular regulation of fascin protrusions

In living cells and tissues, actin nucleation and filament reorganization are controlled spatially and temporally by extracellular cues and the activities of cell-signaling pathways. In the assembly of protrusions in which actin is bundled by fascin, ECM components such as TSP-1, TSP-2 and tenascin-C activate stable bundling whereas FN acts to inhibit bundling or render it transient (Figure 2b; [1]). TSP-1 and TSP-2 are homotrimeric glycoproteins in which each subunit contains multiple domains

Roles of fascin in motility and invasion

Many of the studies described above demonstrate how closely the formation of fascin-containing protrusions is linked with the activation of cell migration by physiological stimuli. Two new biological contexts where fascin participates in motility and invasion have recently emerged: the movement of intracellular pathogenic bacteria and the clinical aggressiveness of human carcinomas.

Expanding frontiers

These new insights into the roles of fascin in adhesion and motility are producing new questions. A prime question concerns the mechanism by which fascin protein is upregulated in carcinomas. In pancreatic adenocarcinomas, increased levels of fascin-1 mRNA have been documented, but it is not yet clear whether the molecular basis of the increase is transcriptional or post-transcriptional [26]. Transcriptional regulation of the human fascin-1 gene has been mainly studied in dendritic cells, where

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

I thank Joann Otto, Adele De Arcangelis and Elisabeth Georges-Labouesse, Marek Skacel, and Pavel Tomancak and Amy Beaton, BDGP, for images; Amy Beaton for helpful discussion, and past and present members of the laboratory for their discussions. Supported by NIH grant GM068073.

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      Therefore, Fascin Threonine 403 phosphorylation was likely to affect the binding function of Fascin. Fascin is the primary actin cross-linker in filopodia and shows no amino acid sequence homology with other actin-binding proteins (Adams, 2004; Vignjevic et al., 2006, 2003). Previous reports have expounded the actin-bundling activity and filopodial formation of Fascin mutants (Yang et al., 2013).

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