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 [1Campellone K.G. Welch M.D. A nucleator arms race: cellular control of actin assembly.Nat. Rev. Mol. Cell Biol. 2010; 11: 237-251Crossref PubMed Scopus (681) Google Scholar]. It is unclear whether formins contribute to lamellipodial actin filament nucleation or serve as elongators of filaments nucleated by Arp2/3 complex [2Ridley A.J. Life at the leading edge.Cell. 2011; 145: 1012-1022Abstract Full Text Full Text PDF PubMed Scopus (697) Google Scholar]. Here we show that the Diaphanous-related formin FMNL2, also known as FRL3 or FHOD2 [3Schönichen A. Geyer M. Fifteen formins for an actin filament: a molecular view on the regulation of human formins.Biochim. Biophys. Acta. 2010; 1803: 152-163Crossref PubMed Scopus (173) Google Scholar], 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.