Journal Article

FMNL formins boost lamellipodial force generation

Geyer, Matthias, Schnittler, Hans-Joachim, Dimchev, Georgi, Carlier, Marie-France, Rottner, Klemens, Kage, Frieda, Stradal, Theresia E. B., Block, Jennifer, Sixt, Michael, Freise, Anika, Kollasser, Jana, Faix, Jan, Brakebusch, Cord, Dimchev, Vanessa, Käs, Josef, Mueller, Jan, Thalheim, Tobias, Brühmann, Stefan, Winterhoff, Moritz

2017

Overview

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. Actin polymerization in lamellipodia of cells is regulated by the Arp2/3 complex and FMNL family formins. Here the authors show that both FMNL2 and FMNL3 contribute to lamellipodium protrusion and structure, and abolishing FMNL2/3 reduces protrusion force generation and migration, without affecting Arp2/3 incorporation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/28 / 13/1 / 13/106 / 13/109 / 14/3 / 14/34 / 14/35 / 14/63 / 38/89 / 42/70 / 631/80/128/1276 / 631/80/84/1756 / 631/80/84/2338 / 82/80 / 82/83 / 96/44 / 96/95 / Animals / Biology / Biomechanical Phenomena / Cell Movement / CRISPR-Cas Systems - genetics / Fibroblasts - metabolism / Gene Knockdown Techniques / Humanities and Social Sciences / Inactivation / Intracellular Signaling Peptides and Proteins - metabolism / Life Sciences / Melanoma / Melanoma, Experimental - pathology / Mice / Mice, Knockout / Models, Biological / multidisciplinary / NIH 3T3 Cells / Phenotype / Polymerization / Proteins / Proteins - metabolism / Pseudopodia - metabolism / Pseudopodia - ultrastructure / RNA Interference / Science / Science (multidisciplinary)