| First Author | Maritzen T | Year | 2012 |
| Journal | Proc Natl Acad Sci U S A | Volume | 109 |
| Issue | 26 | Pages | 10382-7 |
| PubMed ID | 22689987 | Mgi Jnum | J:185589 |
| Mgi Id | MGI:5429457 | Doi | 10.1073/pnas.1206468109 |
| Citation | Maritzen T, et al. (2012) Gadkin negatively regulates cell spreading and motility via sequestration of the actin-nucleating ARP2/3 complex. Proc Natl Acad Sci U S A 109(26):10382-7 |
| abstractText | Regulation of actin dynamics is key to many cell physiological processes, ranging from protrusion formation and control of cell shape to cellular motility, endocytosis, and vesicle movement. The actin-related protein (ARP)2/3 complex is a major actin nucleator organizing branched filament networks in lamellipodial protrusions and during cell migration downstream of nucleation-promoting factors (NPFs). Although many NPFs have been characterized in detail, only few ARP2/3 inhibitors are known. Here, we identify the trans-Golgi network (TGN)/endosomally localized adaptor protein (AP)-1-associated adaptor protein Gadkin as a negative regulator of ARP2/3 function. Loss of Gadkin is associated with a partial redistribution of ARP2/3 to the plasma membrane and with increased cell spreading and migration, phenotypes that depend on the presence of a functional ARP2/3 complex. Gadkin directly binds to ARP2/3 via a conserved tryptophan-based acidic cluster motif reminiscent of ARP2/3-binding sequences of NPFs but fails to facilitate ARP2/3-mediated actin assembly. Consistent with an inhibitory role of Gadkin on ARP2/3 function, ARP2/3 is found on motile Gadkin-containing endosomal vesicles under migration-inhibiting conditions from where it relocalizes to the plasma membrane following activation of NPFs. Together with the observation that Gadkin-mediated inhibition of cell spreading requires its binding to ARP2/3, these data indicate that Gadkin is a negative regulator of ARP2/3 function present on intracellular membranes. |
