Inhibitory signalling to the Arp2/3 complex steers cell migration

Irene Dang, Roman Gorelik, Carla Sousa-Blin, Emmanuel Derivery, Christophe Guérin, Joern Linkner, Maria Nemethova, Julien G. Dumortier, Florence A. Giger, Tamara A. Chipysheva, Valeria D. Ermilova, Sophie Vacher, Valérie Campanacci, Isaline Herrada, Anne-Gaelle Planson, Susan Fetics, Véronique Henriot, Violaine David, Ksenia Oguievetskaia, Goran Lakisic, Fabienne Pierre, Anika Steffen, Adeline Boyreau, Nadine Peyriéras, Klemens Rottner, Sophie Zinn-Justin, Jacqueline Cherfils, Ivan Bièche, Antonina Y. Alexandrova, Nicolas B. David, J. Victor Small, Jan Faix, Laurent Blanchoin, Alexis Gautreau

Cell migration requires the generation of branched actin networks that power the protrusion of the plasma membrane in lamellipodia. The actin-related proteins 2 and 3 (Arp2/3) complex is the molecular machine that nucleates these branched actin networks. This machine is activated at the leading edge of migrating cells by Wiskott-Aldrich syndrome protein (WASP)-family verprolin-homologous protein (WAVE, also known as SCAR). The WAVE complex is itself directly activated by the small GTPase Rac, which induces lamellipodia. However, how cells regulate the directionality of migration is poorly understood. Here we identify a new protein, Arpin, that inhibits the Arp2/3 complex in vitro, and show that Rac signalling recruits and activates Arpin at the lamellipodial tip, like WAVE. Consistently, after depletion of the inhibitory Arpin, lamellipodia protrude faster and cells migrate faster. A major role of this inhibitory circuit, however, is to control directional persistence of migration. Indeed, Arpin depletion in both mammalian cells and Dictyostelium discoideum amoeba resulted in straighter trajectories, whereas Arpin microinjection in fish keratocytes, one of the most persistent systems of cell migration, induced these cells to turn. The coexistence of the Rac-Arpin-Arp2/3 inhibitory circuit with the Rac-WAVE-Arp2/3 activatory circuit can account for this conserved role of Arpin in steering cell migration.