FMNL formins boost lamellipodial force generation

Nat Commun. 2017 Mar 22:8:14832. doi: 10.1038/ncomms14832.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomechanical Phenomena
  • CRISPR-Cas Systems / genetics
  • Cell Movement
  • Fibroblasts / metabolism
  • Formins
  • Gene Knockdown Techniques
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Knockout
  • Models, Biological
  • NIH 3T3 Cells
  • Phenotype
  • Polymerization
  • Proteins / metabolism*
  • Pseudopodia / metabolism*
  • Pseudopodia / ultrastructure
  • RNA Interference

Substances

  • FMNL2 protein, mouse
  • FMNL3 protein, mouse
  • Formins
  • Intracellular Signaling Peptides and Proteins
  • Proteins