Intersection of two key signal integrators in the cell: activator of G protein Signaling 3 and Dishevelled-2

Abstract

Activator of G protein Signaling 3 (AGS3) was discovered as a one of several receptor independent activators of G protein signaling, which are postulated to provide a platform of divergence between canonical and noncanonical G protein signaling pathways. Similarly, Dishevelled serves as a point of divergence for β-catenin-dependent and -independent signaling pathways involving the family of Frizzled (FZD) ligands and cell surface WNT receptors. We recently discovered the apparent regulated localization of Dishevelled (DVL2) and AGS3 to distinct cellular puncta suggesting that perhaps the two proteins interact as part of various cell signaling systems. To address this hypothesis, we asked the following questions: 1) does AGS3 signaling pathways influence the activation of β-catenin regulated transcription through the WNT-Frizzled-Dishevelled axis and 2) is the AGS3 and DVL2 interaction regulated? The interaction of AGS3 and DVL2 was regulated by protein phosphorylation, subcellular distribution, and a cell surface G protein-coupled receptor. These data and the commonality of functional system impacts observed with AGS3 and DVL2 suggest that the AGS3-DVL2 complex presents an unexpected path for functional integration within the cell.