TY - JOUR
T1 - Cortactin releases the brakes in actin- based motility by enhancing WASP-VCA detachment from Arp2/3 branches
AU - Siton, Orit
AU - Ideses, Yaron
AU - Albeck, Shira
AU - Unger, Tamar
AU - Bershadsky, Alexander D.
AU - Gov, Nir S.
AU - Bernheim-Groswasser, Anne
N1 - Funding Information:
A.D.B. is grateful to A.M. Weaver for kindly providing the WT cortactin construct and to S. Weed for the constructs of the NTA fragment and DDW mutant. A.B.-G. is grateful to P. Lappalainen for kindly providing mouse capping protein construct, to H. Higgs for his kind gift of the profilin construct, and to L. Blanchoin for the cofilin construct. We thank Yellena Mirsky with the help with FRAP experiments. We would like to thank Alexander Mogilner, Gilad Haran, and David Gillo for careful reading of the manuscript and useful comments. A.B.-G. thanks the Israel Cancer Association (grant no. 20070020B) and the Israel Science Foundation (grants no. 551/04 and 1534/10) for financial support. A.D.B. holds the Joseph Moss Professorial Chair in Biomedical Research and acknowledges support from the Israel Science Foundation, Minerva Foundation, and Maurice Janin Fund. N.S.G. thanks the Alvin and Gertrude Levine Career Development Chair and the Binational Science Foundation grant no. 2006285 for their support.
PY - 2011/12/20
Y1 - 2011/12/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84155163062&partnerID=8YFLogxK
U2 - 10.1016/j.cub.2011.11.010
DO - 10.1016/j.cub.2011.11.010
M3 - Article
AN - SCOPUS:84155163062
SN - 0960-9822
VL - 21
SP - 2092
EP - 2097
JO - Current Biology
JF - Current Biology
IS - 24
ER -