Fascin in Cell Migration: More Than an Actin Bundling Protein

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Fascin in Cell Migration: More Than an Actin Bundling Protein biology Review Fascin in Cell Migration: More Than an Actin Bundling Protein Maureen C. Lamb and Tina L. Tootle * Anatomy and Cell Biology Department, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; [email protected] * Correspondence: [email protected] Received: 23 October 2020; Accepted: 13 November 2020; Published: 17 November 2020 Simple Summary: Cell migration is an essential biological process that regulates both development and diseases, such as cancer metastasis. Therefore, understanding the factors that promote cell migration is crucial. One of the factors known to regulate cell migration is the actin-binding protein, Fascin. Fascin is typically thought to promote cell migration through bundling actin to form migratory structures such as filopodia and invadapodia. However, Fascin has many other functions in the cell that may contribute to cell migration. How these novel functions promote cell migration and are regulated is still not well understood. Here, we review the structure of Fascin, the many functions of Fascin and how they may promote cell migration, how Fascin is regulated, and Fascin’s role in diseases such as cancer metastasis. 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: fascin; migration; cancer metastasis; mechanotransduction; actin; microtubules; LINC Complex; nuclear actin; nucleolus; prostaglandins 1. Introduction Fascin is an actin-binding protein that promotes different modes of cell migration, including during embryonic development and cancer metastasis [1,2]. One means by which Fascin promotes migration is by crosslinking or bundling actin filaments together [3,4]. Through this function, Fascin aids in the formation of many actin-rich migratory structures such as filopodia [5–7], lamellipodia [5], stress fibers [8], and microspikes [9,10]. Fascin also localizes to actin-rich adhesive structures such as focal adhesions [8], invadopodia [11], and podocytes [12,13]. Due to its roles in cell migration, Fascin has frequently been studied in the context of cancer. Fascin is absent in adult epithelial tissue [14] but is highly expressed in many types of carcinomas. High Fascin expression is correlated with poor Biology 2020, 9, 403; doi:10.3390/biology9110403 www.mdpi.com/journal/biology Biology 2020, 9, x FOR PEER REVIEW 2 of 17 Biologypoor prognosis2020, 9, 403 and increased metastasis (reviewed in [4]). For this reason, Fascin is a prognostic2 of 18 biomarker and a potential therapeutic target of metastatic carcinomas [2,4]. While studies on Fascin prognosishave centered and increasedaround Fascin’s metastasis canonical (reviewed actin inbund [4]).ling For function, this reason, Fascin Fascin also is has a prognostic non-canonical, biomarker non- andbundling a potential functions therapeutic in the cell. target In of this metastatic review, carcinomaswe discuss [Fascin’s2,4]. While structure studies and on Fascinexpression, have centered explore aroundhow both Fascin’s the canonical canonical and actin non-canonical bundling function, functions Fascin of Fascin also haspromote non-canonical, migration, non-bundling examine the functionsvarious mechanisms in the cell. In regulating this review, Fascin, we discuss and Fascin’sconsider structure how the and different expression, functions explore of how Fascin both may the canonicalcontribute and to diseases. non-canonical functions of Fascin promote migration, examine the various mechanisms regulating Fascin, and consider how the different functions of Fascin may contribute to diseases. 2. Fascin Structure, Expression, and Functions 2. Fascin Structure, Expression, and Functions Fascin promotes cell migration not only through its conserved actin bundling activity, but also by itsFascin non-canonical promotes functions. cell migration In this not section, only through we review its conserved the structure actin of bundlingFascin, how activity, it bundles but also actin, by itsand non-canonical Fascin’s expression functions. pattern In this during section, developm we reviewent and the structurein adult oftissues. Fascin, Then, how we it bundles discuss actin,how andFascin Fascin’s promotes expression cell migration pattern through during both development its canonical and actin in adultbundling tissues. function Then, and we non-canonical discuss how Fascinfunctions: promotes modulating cell migration the activity through of other both actin-bi its canonicalnding proteins actin bundling [8,15,16], function binding and to non-canonical microtubules functions:[17], interacting modulating with the the Linker activity of of the other Nucleosk actin-bindingeleton proteinsand Cytoskeleton [8,15,16], binding (LINC) to Complex microtubules [18], [and17], interactinghaving nuclear with roles the Linker [19]. of the Nucleoskeleton and Cytoskeleton (LINC) Complex [18], and having nuclear roles [19]. 2.1. Structure of Fascin 2.1. Structure of Fascin Fascin was initially discovered in sea urchins [20] and later found in Drosophila [21,22], Xenopus [23], Fascinmouse was[24], initiallyand humans discovered [25,26]. inFascin sea urchinsis a globular [20] andprotein later of foundapproximately in Drosophila 55kDa [and21,22 is], Xenopuscomprised [23 of], mousefour β-trefoil [24], and domains humans (Figure [25,26]. 1) Fascin [26]. Each is a globular β-trefoil protein domain of contains approximately six two-stranded 55kDa and isβ-hairpins comprised oriented of four inβ-trefoil a trifold domains symmetry (Figure [27,28].1)[ 26 The]. Each fourβ β-trefoil-trefoils domain of Fascin contains are arranged six two-stranded into two βlobes-hairpins (Figure oriented 1B) [26]. in aThis trifold structure symmetry allows [27 a,28 monomer]. The four of βFascin-trefoils to ofbundle Fascin actin, are arranged while most into actin two lobesbundlers (Figure function1B) [ as26 ].dimers This structure(Figure 1A). allows Fascin a monomer has three distinct of Fascin surface to bundle areas actin, able to while bind most actin; actin two bundlerslarger actin-binding function as areas dimers are (Figure in the 1cleftsA). Fascin of β-trefoils has three 1 and distinct 2, and surface β-trefoils areas 1 and able 4, to while bind a actin; third twosmaller larger area actin-binding is in β-trefoil areas 3 (Figure are in the 1A,B) clefts [29,30]. of β-trefoils Based 1 on and cryoEM 2, and β analysis-trefoils 1of and actin 4, whilebundled a third by smallerFascin in area filopodia, is in β-trefoil the two 3 (Figure larger1 actin-bindingA,B) [ 29,30]. Basedareas on(referred cryoEM to analysis as actin-binding of actin bundled site 1) bybind Fascin to a insingle filopodia, actin filament, the two largerwhile actin-bindingthe actin-binding areas area (referred in β-trefoil to as 3 actin-binding (referred to as site actin-binding 1) bind to a singlesite 2) actinbinds filament, to a second while actin the filament. actin-binding The two area sites in βof-trefoil actin bundling 3 (referred are to approximately as actin-binding 5 nm site apart, 2) binds which to a secondalong with actin Fascin filament. being The monomeric, two sites of causes actin Fascin bundling to be are the approximately tightest actin 5 bundler nm apart, with which approximately along with Fascin8.1 nm beingbetween monomeric, actin filaments causes Fascin[29,31]. to Recent be the X- tightestray crystallography, actin bundler withalong approximately with the systematic 8.1 nm betweenmutagenesis actin of filaments Fascin, reveals [29,31]. that Recent mutation X-ray in crystallography, one of the actin-binding along with sites the systematicimpairs the mutagenesis other site’s ofactin-binding Fascin, reveals activity, that mutationsuggesting in there one of is thecoordinate actin-bindingd regulation sites impairs between the Fascin’s other site’s actin-binding actin-binding sites activity,[29]. suggesting there is coordinated regulation between Fascin’s actin-binding sites [29]. AB ACTIN FILAMENT ACTIN BINDING SITE 1 PHOSPHORYLATION SERINE 39 ACTIN BINDING ACTIN BINDING AREA AREA UBIQUITINATION LYSINE 247 & 250 β1 β1 β2 β4 β3 β2 β4 MICROTUBULE BINDING β3 NESPRIN 2 BINDING PHOSPHORYLATION SERINE 274 ACTIN BINDING AREA ACTIN FILAMENT ACTIN BINDING SITE 2 Figure 1. Fascin bundling mechanism and actin-binding domains. ( A) Schematic of Fascin bundling two actin filamentsfilaments (red).(red). (B) Schematic
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