Gelsolin and Non-muscle Myosin IIA Interact to Mediate Calcium-regulated Collagen Phagocytosis

Abstract

Background: Fibroblasts can remodel the extracellular matrix by phagocytosis, but how the adhesion mechanisms are regulated is not well understood. Results: Non-muscle myosin IIA provides a docking site for the actin-severing protein to localize at collagen adhesion sites and remodel actin filaments there. Conclusion: Gelsolin binds to non-muscle myosin IIA at collagen adhesions and enables phagocytosis to occur in a calciumdependent manner. Significance: Dissection of the mechanisms by which collagen phagocytosis is mediated may provide new insights into fibrotic conditions under which phagocytosis is perturbed.

Supervillin couples myosin-dependent contractility to podosomes and enables their turnover

“…Our results are consistent with reports showing that siRNA-induced knockdown of supervillin decreases the number of invadopodia-induced holes in matrix degradation by MDA-MB-231 cells (Crowley et al, 2009) and that biochemical inhibition of myosin II reduces matrix degradation by invadopodia (Alexander et al, 2008). For instance, supervillin-mediated recycling of podosome components might be independent of myosin II function, whereas multiple pathways, separately including supervillin and gelsolin, could provide input to myosin-II-mediated mechanosensing and/or matrix metalloproteinase secretion (Alexander et al, 2008;Arora et al, 2011;Myers et al, 2011).…”

Extracellular matrix component signaling in cancer

“…The α1 and α2 integrin chains have been described on dermal myofibroblasts, but data on their expression in CAFs are limited [34,35]. In one histochemical study of colon adenocarcinomas α-smooth muscle actin (α-SMA) positive, β-PDGFR negative stromal cells, expressed high levels of α1β1 and α5β1 and some α2β1 [35].…”

Collagen remodeling by phagocytosis is determined by collagen substrate topology and calcium-dependent interactions of gelsolin with nonmuscle myosin IIA in cell adhesions

“…We found that gelsolin and NMMIIA are enriched in cell adhesions that mediate collagen phagocytosis but only when cells are plated on a beaded and not on planar collagen substrates. Further, NMMIIA binds gelsolin at collagen adhesion sites; this Ca 2+ -dependent interaction enables actin remodeling at adhesion sites (Arora et al ., 2011), which is required for collagen phagocytosis. One of the regulatory systems that enable phagocytosis involves activation of stretch-sensitive, Ca 2+ -permeable channels when cells attach and stretch over small, collagen-coated beads.…”

“…, 1981; Weeds and Maciver, 1993) and plays an important role in FcγR-mediated phagocytosis but not in complement-receptor–mediated phagocytosis (Serrander et al ., 2000). Gelsolin associates with NMMIIA at collagen-binding sites; this association is required for actin assembly and adhesion to collagen (Arora et al ., 2011), but it is not known whether gelsolin interacts with NMMIIA directly and how this interaction is regulated to affect adhesion to collagen.…”

“…With the use of purified, full-length, and isolated domains of NMMIIA and gelsolin we show that gelsolin interacts with the coiled-coil domain of NMMIIA in a Ca 2+ -dependent manner. This interaction controls actin filament assembly (Arora et al ., 2011) and contributes to adhesion and phagocytosis of collagen.…”