Dishevelled (Dvl) is a key intracellular signaling molecule that mediates the activation of divergent Wnt pathways. It contains three highly conserved domains known as DIX, PDZ and DEP, whose functions in beta-catenin-dependent canonical Wnt and beta-catenin-independent non-canonical Wnt signaling have been well characterized. The C-terminal region is also highly conserved from invertebrates to vertebrates. However, its function in regulating the activation of different Wnt signals remains unclear. We previously reported that Dvl conformational change triggered by the highly conserved PDZ-binding C-terminus is important for the pathway specificity. Here we provide further evidence demonstrating that binding of the C-terminus to PDZ domain results in Dvl auto-inhibition in the Wnt signaling pathways. Therefore, forced binding of the C-terminus to PDZ domain reduced the activity of Dvl in non-canonical Wnt signaling, while obstruction of this interaction releases Dvl auto-inhibition, impairs its functional interaction with LRP6 in canonical Wnt signaling and increases its specificity in non-canonical Wnt signaling, which is closely correlated with an enhanced Dvl membrane localization. Our findings highlight the importance of the C-terminus in keeping Dvl in an appropriate auto-inhibited state, accessible for regulations by other partners to switch pathway specificity. Particularly, the C-terminally tagged Dvl fusion proteins that have been widely used to study the function and the cellular localization of Dvl may not truly represent the wild-type Dvl because those proteins cannot be auto-inhibited.
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