title: Synthetic polyamines promote rapid lamellipodial growth by regulating actin dynamics.
abstract: Cellular protrusions involved in motile processes are driven by site-directed assembly of actin filaments in response to Rho-GTPase signalling. So far, only chemical compounds depolymerizing actin or stabilizing filaments, inhibiting N-WASP, Arp2/3 or formins, have been used to eliminate the formation of protrusions, while Rho-GTPase-dominant positive strategies have been designed to stimulate protrusions. Here we describe the design of four polyamines (macrocyclic and branched acyclic), and show that they enter the cell and induce specific growth of actin-enriched lamellipodia within minutes. The largest increase in cell area is obtained with micromolar amounts of a branched polyamine harbouring an 8-carbon chain. These polyamines specifically target actin both in vitro and in vivo. Analysis of their effects on filament assembly dynamics and its regulation indicates that the polyamines act by slowing down filament dynamics and by enhancing actin nucleation. These compounds provide new opportunities to study the actin cytoskeleton in motile and morphogenetic processes.
authors.affiliation: Laboratory of Cell Physics, ISIS/IGBMC, Université de Strasbourg and CNRS (UMR 7006), 8 allée Gaspard Monge, Strasbourg 67083, France.
authors.forename: Iliana
authors.initials: I
authors.lastname: Nedeva
authors.forename: Girish
authors.initials: G
authors.lastname: Koripelly
authors.forename: David
authors.initials: D
authors.lastname: Caballero
authors.forename: Lionel
authors.initials: L
authors.lastname: Chièze
authors.forename: Bérangère
authors.initials: B
authors.lastname: Guichard
authors.forename: Benoît
authors.initials: B
authors.lastname: Romain
authors.forename: Erwan
authors.initials: E
authors.lastname: Pencreach
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Lehn
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Carlier
authors.forename: Daniel
authors.initials: D
authors.lastname: Riveline
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D011073:Polyamines / Q000138:chemical synthesis / Q000494:pharmacology*; D011554:Pseudopodia / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D000199:Actins; D011073:Polyamines