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

Authors: Maritzen, T  Zech, T  Schmidt, MR  Krause, E  Machesky, LM  Haucke, V 
Citation: Maritzen T, etal., Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10382-7. doi: 10.1073/pnas.1206468109. Epub 2012 Jun 11.
Pubmed: (View Article at PubMed) PMID:22689987
DOI: Full-text: DOI:10.1073/pnas.1206468109

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.

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CRRD Object Information
CRRD ID: 8554651
Created: 2014-05-08
Species: All species
Last Modified: 2014-05-08
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.