FMNL2 Drives Actin-Based Protrusion and Migration Downstream of Cdc42

• DOI: 10.1016/j.cub.2012.03.064
• Publication Date: 2012-05-17T15:17:04Z
• 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. Str...; Jan Faix; Klemens Rottner
• Keywords: 0301 basic medicine; Agricultural and Biological Sciences(all); Biochemistry, Genetics and Molecular Biology(all); Formins; Proteins; Actins; Polymerization; Actin Cytoskeleton; Mice; 03 medical and health sciences; Cell Movement; Report; NIH 3T3 Cells; Animals; Humans; Pseudopodia; cdc42 GTP-Binding Protein; HeLa Cells; Signal Transduction

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.