Inhibitory signalling to the Arp2/3 complex steers cell migration

Abstract

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.

Bitter tastant responses in the amoeba Dictyostelium correlate with rat and human taste assays

“…There are many potential mechanisms behind this effect. Dictyostelium is a well-studied model for cell movement (Dang et al, 2013;Artemenko et al, 2014) and has been explored in a range of pharmacological studies for identifying chemical targets (Robery et al, 2013;Waheed et al, 2014;Lockley et al, 2015). Indeed, a large number of studies have identified changes in cell behavior (particularly in movement) caused by deletion of individual proteins (Chattwood et al, 2014;Fets et al, 2014;Wessels et al, 2014).…”

Interactions with Actin Monomers, Actin Filaments, and Arp2/3 Complex Define the Roles of WASP Family Proteins and Cortactin in Coordinately Regulating Branched Actin Networks

“…In addition to NPFs like WASP and cortactin, the A region is found in several inhibitors of Arp2/3 complex, including PICK1 (71), Gadkin (72), and Arpin (73). These proteins block branching nucleation by competing with WASP family proteins for binding to the complex.…”

NHE1 has a notable role in metastasis and drug resistance of T-cell acute lymphoblastic leukemia

“…Subsequently, the post-fixed specimens were dehydrated using a graded series of ethanol and then transferred to a graded series of t-butyl alcohols (freezing point 25.4˚C), the t-butyl alcohol substituted specimens were freeze-dried at 15˚C and at high vacuum (23). The experimental specimens were sputter-coated with platinum and then observed using a scanning electron microscope (S-750; Hitachi, Ltd., Tokyo, Japan) operating at 20 kV (24).…”