Inhibitory signalling to the Arp2/3 complex steers cell migration

Irene Dang, Roman Gorelik, Carla Sousa-Blin, Emmanuel Derivery, Veronique Henriot, Violaine David, Ksenia Oguievetskaia, Goran Lakisic, Fabienne Pierre, Alexis Gautreau

 Nature. 2013; 503(7475):281-4. 

Speaker: Yi-Ying Tsai (蔡怡瑩)                                   Time: 13:10~14:00, March. 05, 2014

Commentator: Dr. Yao Chang (張堯 博士)         Place: Room 601

Abstract

Cell migration is essential for many physiological and pathological processes. But how cells regulate directional migration is not well known. At the front of migrating cells, branched actin filaments drive the extension of plasma membrane protrusions called lamellipodia by WAVE (Wiskott–Aldrich syndrome protein (WASP) -family verprolin-homologous protein) -Arp2/3 (The actin-related proteins 2 and 3) machinery in response to Rac signaling (1, 2). WAVE is characterized by carboxy-terminal tripartite domain, VCA. The A motif binds to the Arp2/3 complex and induces its activation (3). Arp2/3 inhibitory proteins were identified to contain a similar A motif to regulate Arp2/3 nucleation in endosomes (4). The authors wondered if there are Arp2/3 inhibitory proteins in lamellipodia to regulate cell migration. In this study, the authors identified a new migration-regulating protein, Arpin, which is named for its Arp2/3 inhibition activity. In response toRac signaling, Arpin competed with VCA for Arp2/3 binding and thus inhibited actin polymerization. The distribution of Arpin overlapped with lamellipodial markers, such as WAVE proteins. These results indicate that Arpin inhibits Arp2/3 complex at the lamellipodia. After deletion of Arpin, cell spreading and protrusion velocity of lamellipodia increased. Furthermore, Arpin depletion increased cell speed and directional persistence both in mammalian cells and Dictyostelium discoideum. The migration route of these depletion cells became much straighter. Conversely, injection of Arpin into fish keratocytes reduced their cell speed, protrusion, and lamellipodia persistence but increased angular deviation. These results indicate that Arpin plays a role in slowing cells down and allowing them to turn. Taken together, the Rac-WAVE-Arp2/3 pathway provides efficient and straight migration, whereas Rac-Arpin-Arp2/3 pathway provides an inhibitory effect to steer cell migration.

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