FMNL2 drives actin-based protrusion and migration downstream of Cdc42.

Abstract

Cell migration entails protrusion of lamellipodia, densely packed networks of actin filaments at the cell front. Filaments are generated by nucleation, likely mediated by Arp2/3 complex and its activator Scar/WAVE. It is unclear whether formins contribute to lamellipodial actin filament nucleation or serve as elongators of filaments nucleated by Arp2/3 complex. Here we show that the Diaphanous-related formin FMNL2, also known as FRL3 or FHOD2, accumulates at lamellipodia and filopodia tips. FMNL2 is cotranslationally modified by myristoylation and regulated by interaction with the Rho-guanosine triphosphatase Cdc42. Abolition of myristoylation or Cdc42 binding interferes with proper FMNL2 activation, constituting an essential prerequisite for subcellular targeting. In vitro, C-terminal FMNL2 drives elongation rather than nucleation of actin filaments in the presence of profilin. In addition, filament ends generated by Arp2/3-mediated branching are captured and efficiently elongated by the formin. Consistent with these biochemical properties, RNAi-mediated silencing of FMNL2 expression decreases the rate of lamellipodia protrusion and, accordingly, the efficiency of cell migration. Our data establish that the FMNL subfamily member FMNL2 is a novel elongation factor of actin filaments that constitutes the first Cdc42 effector promoting cell migration and actin polymerization at the tips of lamellipodia.

• Authors: Jennifer Block, Dennis Breitsprecher, Sonja Kühn, Moritz Winterhoff, Frieda Kage, Robert Geffers, Patrick Duwe, Jennifer L Rohn, Buzz Baum, Cord Brakebusch, Matthias Geyer, Theresia E B Stradal, Jan Faix, Klemens Rottner
• Journal: Current biology : CB (Curr Biol) Vol. 22 Issue 11 Pg. 1005-12 (Jun 05 2012) ISSN: 1879-0445 [Electronic] England
• PMID: 22608513 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Actins
• FMNL2 protein, human
• Formins
• Proteins
• cdc42 GTP-Binding Protein

Topics

• Actin Cytoskeleton (metabolism)
• Actins (metabolism)
• Animals
• Cell Movement
• Formins
• HeLa Cells
• Humans
• Mice
• NIH 3T3 Cells
• Polymerization
• Proteins (metabolism)
• Pseudopodia (metabolism)
• Signal Transduction
• cdc42 GTP-Binding Protein (metabolism)