How does it work

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Vertebrate genomes encode three forms of fascin: fascin-1, which is widely expressed by mesenchymal tissues and in the nervous system; fascin-2, which is expressed by retinal photoreceptor cells; and fascin-3, which is testis-specific (Adams, 2004). However the other proteins will not be focussed on.

Sequence alignment indicates that the members of the fascin family form a distinct class of proteins as they share a high degree of sequence identity with one another, but do not have signicant sequence similarities with other known proteins. Unlike the homodimeric and flexible protein a-actinin, fascin appears to be a monomeric and compact molecule that crosslinks actin laments via two distinct actin-binding sites, one of which has been localized to the carboxyl-terminal half of the molecule. However, its actin-bundling activity is inhibited by phosphorylation of residue serine-39 by protein kinase Ca (PKCa), which blocks the activity of the N-terminal actin-binding site. Presumably because of its compact structure (S.C.A. et al., unpublished results), fascin organizes actin laments into tight bundles. In living cells, fascin localizes to a number of highly dynamic cellular structures that require strong mechanical support, including stress fibers, microvilli, microspikes, and lamellipodia. For instance, fascin helps organize actin laments into well-ordered bundles inside microvilli that rapidly elongate from the surface of a sea-urchin egg after fertilization at the points of sperm contact. Fascin is also located in the core actin bundles of filopodia formed during the activation of coelomoytes (phagocytic cells from the coelomic cavity). Filopodia are thin rod-like cellular protrusions that serve an exploratory role in motile cells. In the growth cones of migrating axons, filopodia effectively “scan” the local environment “in search” of guidance cues that direct the axon toward its target (Albrecht-Buehler, 1976; Davenport et al., 1993; Dent and Gertler, 2003; Koleske, 2003). Filopodial turning, elongation, and retraction are key events involved in this process and require filopodia to be flexible enough to wave about yet rigid enough to protrude many microns past the cell surface. However, there is no established molecular mechanism that explains how fascin molecules are recruited to filopodia. One possibility is a higher affinity for actin filaments in filopodia than elsewhere in the cell. Activation by dephosphorylation is one way that has been reported to achieve this higher affinity (Aratyn et al. 2007). Studies done by Vignjevic with the use of small-interfering RNAs (siRNA) showed that depletion in fascin resulted in fewer filopodia and those present contained loosely bundled actin. Inactive fascin (S39E) was found only at filopodia tips, whereas active fascin (S39A) was localised along the entire filopodial shafts. This proposes that fascin is recruited as an inactive form (phosphorylated) by the tip content of nascent filopodia where it is then dephosphorylated and activated allowing actin bundling during filopodial extension. B lymphocyte activation is accompanied by extensive membrane ruffling and pseudopod formation, which appears to be mediated by fascin. Moreover, fascin is thought to be responsible for the generation of dynamic membrane protrusions, including microvilli on the apical surface and lamellipodia at the basolateral surface, of motile epithelial cells. These observations together with the actin-bundling activity of fascin and its intracellular localization suggest that fascin plays a key role in coordinating the organization of the cytoskeleton, directing the extension of plasma membrane, and providing mechanical support to cellular protrusions (Tseng et al. 2001).

Figure 1

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