title: Cofilin activity downstream of Pak1 regulates cell protrusion efficiency by organizing lamellipodium and lamella actin networks.
abstract: Protrusion of the leading edge of migrating epithelial cells requires precise regulation of two actin filament (F-actin) networks, the lamellipodium and the lamella. Cofilin is a downstream target of Rho GTPase signaling that promotes F-actin cycling through its F-actin-nucleating, -severing, and -depolymerizing activity. However, its function in modulating lamellipodium and lamella dynamics, and the implications of these dynamics for protrusion efficiency, has been unclear. Using quantitative fluorescent speckle microscopy, immunofluorescence, and electron microscopy, we establish that the Rac1/Pak1/LIMK1 signaling pathway controls cofilin activity within the lamellipodium. Enhancement of cofilin activity accelerates F-actin turnover and retrograde flow, resulting in widening of the lamellipodium. This is accompanied by increased spatial overlap of the lamellipodium and lamella networks and reduced cell-edge protrusion efficiency. We propose that cofilin functions as a regulator of cell protrusion by modulating the spatial interaction of the lamellipodium and lamella in response to upstream signals.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Violaine
authors.initials: V
authors.lastname: Delorme
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Machacek
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Céline
authors.initials: C
authors.lastname: DerMardirossian
authors.affiliation: Infectious Diseases Program, The Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Anderson
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Torsten
authors.initials: T
authors.lastname: Wittmann
authors.affiliation: Infectious Diseases Program, The Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
authors.forename: Dorit
authors.initials: D
authors.lastname: Hanein
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Clare
authors.initials: C
authors.lastname: Waterman-Storer
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: gdanuser@scripps.edu.
authors.forename: Gaudenz
authors.initials: G
authors.lastname: Danuser
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: bokoch@scripps.edu.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Bokoch
mesh_terms: D051339:Actin Depolymerizing Factors / Q000502:physiology*; D000199:Actins / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement; D004847:Epithelial Cells / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D054461:Lim Kinases / Q000378:metabolism; D008840:Microfilament Proteins / Q000502:physiology*; D011554:Pseudopodia / Q000502:physiology*; D015398:Signal Transduction; D054462:p21-Activated Kinases / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D008840:Microfilament Proteins; C515892:LIMK1 protein, human; D054461:Lim Kinases; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein