Gadkin negatively regulates cell spreading and motility via sequestration of the actin-nucleating ARP2/3 complex.

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 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 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 duanyu372/3 function. Loss of Gadkin is associated with a partial redistribution of duanyu372/3 to the plasma membrane and with increased cell spreading and migration, phenotypes that depend on the presence of a functional duanyu372/3 complex. Gadkin directly binds to duanyu372/3 via a conserved tryptophan-based acidic cluster motif reminiscent of sequences of NPFs but fails to facilitate actin assembly. Consistent with an inhibitory role of Gadkin on duanyu372/3 function, duanyu372/3 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 these data indicate that Gadkin is a negative regulator of duanyu372/3 function present on intracellular membranes.

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