Regulation of the Subcellular Localization of the G-protein Subunit Regulator GPSM3 through Direct Association with 14-3-3 Protein

From the Department of Pharmacology and.
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2012; 287(37):31270-9. DOI: 10.1074/jbc.M112.394379
Source: PubMed


G-protein signaling modulator-3 (GPSM3), also known as G18 or AGS4, is a member of the Gα(i/o)-Loco (GoLoco) motif containing proteins. GPSM3 acts through its two GoLoco motifs to exert GDP dissociation inhibitor activity over Gα(i) subunits; recently revealed is the existence of an additional regulatory site within GPSM3 directed toward monomeric Gβ subunits during their biosynthesis. Here, using in silico and proteomic approaches, we have found that GPSM3 also interacts directly with numerous members of the 14-3-3 protein family. This interaction is dependent on GPSM3 phosphorylation, creating a mode II consensus 14-3-3 binding site. 14-3-3 binding to the N-terminal disordered region of GPSM3 confers stabilization from protein degradation. The complex of GPSM3 and 14-3-3 is exclusively cytoplasmic, and both moieties mutually control their exclusion from the nucleus. Phosphorylation of GPSM3 by a proline-directed serine/threonine kinase and the resultant association of 14-3-3 is the first description of post-translational regulation of GPSM3 subcellular localization, a process that likely regulates important spatio-temporal aspects of G-protein-coupled receptor signaling modulation by GPSM3.

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    • "In the present study, we detected AGS4/Gpsm3 mRNA in the rat kidney similar to previously published studies (Cao et al. 2004), but we were unable to confirm the protein translation or localization in the kidney. A recent study has shown that AGS4/GPSM3 can interact with intracellular proteins, such as 14-3-3, to reduce protein degradation (Giguere et al. 2012), which may be absent in the kidney. This could alter the rate of degradation of AGS4/GPSM3 protein and could be one contributing factor leading to the inability to detect this protein in the kidney sections. "
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