title: Modeling the synergy of cofilin and Arp2/3 in lamellipodial protrusive activity.
abstract: Rapid polymerization of actin filament barbed ends generates protrusive forces at the cell edge, leading to cell migration. Two important regulators of free barbed ends, cofilin and Arp2/3, have been shown to work in synergy (net effect greater than additive). To explore this synergy, we model the dynamics of F-actin at the leading edge, motivated by data from EGF-stimulated mammary carcinoma cells. We study how synergy depends on the localized rates and relative timing of cofilin and Arp2/3 activation at the cell edge. The model incorporates diffusion of cofilin, membrane protrusion, F-actin capping, aging, and severing by cofilin and branch nucleation by Arp2/3 (but not G-actin recycling). In a well-mixed system, cofilin and Arp2/3 can each generate a large pulse of barbed ends on their own, but have little synergy; high synergy occurs only at low activation rates, when few barbed ends are produced. In the full spatially distributed model, both synergy and barbed-end production are significant over a range of activation rates. Furthermore, barbed-end production is greatest when Arp2/3 activation is delayed relative to cofilin. Our model supports a direct role for cofilin-mediated actin polymerization in stimulated cell migration, including chemotaxis and cancer invasion.
authors.affiliation: Department of Mathematics, University of British Columbia, Vancouver, Canada; Department of Mathematics and Statistics, Smith College, Northampton, Massachusetts.
authors.forename: Nessy
authors.initials: N
authors.lastname: Tania
authors.forename: John
authors.initials: J
authors.lastname: Condeelis
authors.forename: Leah
authors.initials: L
authors.lastname: Edelstein-Keshet
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D008954:Models, Biological; D021381:Protein Transport; D011554:Pseudopodia / Q000378:metabolism*; D014335:Tropomyosin / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D014335:Tropomyosin