title: 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.affiliation: Institute of Genetics, University of Bonn, Karlrobert-Kreiten-Strasse 13, 53115 Bonn, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Block
authors.forename: Dennis
authors.initials: D
authors.lastname: Breitsprecher
authors.forename: Sonja
authors.initials: S
authors.lastname: Kühn
authors.forename: Moritz
authors.initials: M
authors.lastname: Winterhoff
authors.forename: Frieda
authors.initials: F
authors.lastname: Kage
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.forename: Patrick
authors.initials: P
authors.lastname: Duwe
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Rohn
authors.forename: Buzz
authors.initials: B
authors.lastname: Baum
authors.forename: Cord
authors.initials: C
authors.lastname: Brakebusch
authors.forename: Matthias
authors.initials: M
authors.lastname: Geyer
authors.forename: Theresia E B
authors.initials: TE
authors.lastname: Stradal
authors.forename: Jan
authors.initials: J
authors.lastname: Faix
authors.forename: Klemens
authors.initials: K
authors.lastname: Rottner
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement; D000080865:Formins; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D058105:Polymerization; D011506:Proteins / Q000378:metabolism*; D011554:Pseudopodia / Q000378:metabolism*; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000199:Actins; C476208:FMNL2 protein, human; D000080865:Formins; D011506:Proteins; D020764:cdc42 GTP-Binding Protein