title: Cortactin releases the brakes in actin- based motility by enhancing WASP-VCA detachment from Arp2/3 branches.
abstract: Cortactin is involved in invadopodia and podosome formation [1], pathogens and endosome motility [2], and persistent lamellipodia protrusion [3, 4]; its overexpression enhances cellular motility and metastatic activity [5-8]. Several mechanisms have been proposed to explain cortactin's role in Arp2/3-driven actin polymerization [9, 10], yet its direct role in cell movement remains unclear. We use a biomimetic system to study the mechanism of cortactin-mediated regulation of actin-driven motility [11]. We tested the role of different cortactin variants that interact with Arp2/3 complex and actin filaments distinctively. We show that wild-type cortactin significantly enhances the bead velocity at low concentrations. Single filament experiments show that cortactin has no significant effect on actin polymerization and branch stability, whereas it strongly affects the branching rate driven by Wiskott-Aldrich syndrome protein (WASP)-VCA fragment and Arp2/3 complex. These results lead us to propose that cortactin plays a critical role in translating actin polymerization at a bead surface into motion, by releasing WASP-VCA from the new branching site. This enhanced release has two major effects: it increases the turnover rate of branching per WASP molecule, and it decreases the friction-like force caused by the binding of the moving surface with respect to the growing actin network.
authors.affiliation: Department of Chemical Engineering and Ilse Kats Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Siton
authors.forename: Yaron
authors.initials: Y
authors.lastname: Ideses
authors.forename: Shira
authors.initials: S
authors.lastname: Albeck
authors.forename: Tamar
authors.initials: T
authors.lastname: Unger
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Bershadsky
authors.forename: Nir S
authors.initials: NS
authors.lastname: Gov
authors.forename: Anne
authors.initials: A
authors.lastname: Bernheim-Groswasser
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D051377:Actin-Related Protein 2 / Q000378:metabolism*; D051378:Actin-Related Protein 3 / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement; D051356:Cortactin / Q000378:metabolism*; D004926:Escherichia coli; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D051379:Mice; D017434:Protein Structure, Tertiary; D011817:Rabbits; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D051316:Wiskott-Aldrich Syndrome Protein / Q000378:metabolism*
chemical_list: D051377:Actin-Related Protein 2; D051378:Actin-Related Protein 3; D051356:Cortactin; D011994:Recombinant Proteins; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; D005982:Glutathione Transferase