FMNL formins boost lamellipodial force generation

Frieda Kage, Moritz Winterhoff, Vanessa Dimchev, Jan Mueller, Tobias Thalheim, Anika Freise, Stefan Brühmann, Jana Kollasser, Jennifer Block, Georgi Dimchev, Matthias Geyer, Hans-Joachim Schnittler, Cord Brakebusch, Theresia E. B. Stradal, Marie-France Carlier, Michael Sixt, Josef Käs, Jan Faix and Klemens Rottner ()
Additional contact information
Frieda Kage: Zoological Institute, Technische Universität Braunschweig
Moritz Winterhoff: Institute for Biophysical Chemistry, Hannover Medical School
Vanessa Dimchev: Zoological Institute, Technische Universität Braunschweig
Jan Mueller: Institute of Science and Technology Austria
Tobias Thalheim: Soft Matter Physics Group, Institut für experimentelle Physik I, Leipzig University
Anika Freise: Zoological Institute, Technische Universität Braunschweig
Stefan Brühmann: Institute for Biophysical Chemistry, Hannover Medical School
Jana Kollasser: Biomedical Institute, BRIC, University of Copenhagen
Jennifer Block: Molecular Cell Biology Group, Helmholtz Centre for Infection Research
Georgi Dimchev: Zoological Institute, Technische Universität Braunschweig
Matthias Geyer: Institute of Innate Immunity, University of Bonn
Hans-Joachim Schnittler: Institute of Anatomy and Vascular Biology, Westfälische Wilhelms-Universität Münster
Cord Brakebusch: Biomedical Institute, BRIC, University of Copenhagen
Theresia E. B. Stradal: Helmholtz Centre for Infection Research
Marie-France Carlier: Cytoskeleton Dynamics and Motility Group, Laboratoire d'Enzymologie et Biochimie Structurales
Michael Sixt: Institute of Science and Technology Austria
Josef Käs: Soft Matter Physics Group, Institut für experimentelle Physik I, Leipzig University
Jan Faix: Institute for Biophysical Chemistry, Hannover Medical School
Klemens Rottner: Zoological Institute, Technische Universität Braunschweig

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract Migration frequently involves Rac-mediated protrusion of lamellipodia, formed by Arp2/3 complex-dependent branching thought to be crucial for force generation and stability of these networks. The formins FMNL2 and FMNL3 are Cdc42 effectors targeting to the lamellipodium tip and shown here to nucleate and elongate actin filaments with complementary activities in vitro. In migrating B16-F1 melanoma cells, both formins contribute to the velocity of lamellipodium protrusion. Loss of FMNL2/3 function in melanoma cells and fibroblasts reduces lamellipodial width, actin filament density and -bundling, without changing patterns of Arp2/3 complex incorporation. Strikingly, in melanoma cells, FMNL2/3 gene inactivation almost completely abolishes protrusion forces exerted by lamellipodia and modifies their ultrastructural organization. Consistently, CRISPR/Cas-mediated depletion of FMNL2/3 in fibroblasts reduces both migration and capability of cells to move against viscous media. Together, we conclude that force generation in lamellipodia strongly depends on FMNL formin activity, operating in addition to Arp2/3 complex-dependent filament branching.

Date: 2017
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DOI: 10.1038/ncomms14832

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