Autoinhibition of Dishevelled protein regulated by its extreme C terminus plays a distinct role in Wnt/β-catenin and Wnt/planar cell polarity (PCP) signaling pathways

Qi, J., Lee, H.J., Saquet, A., Cheng, X.N., Shao, M., Zheng, J.J., Shi, D.L.
The Journal of biological chemistry   292: 5898-5908 (Journal)
Registered Authors
Shao, Ming, Shi, De-Li
PDZ domain, Wnt pathway, Wnt signaling, signal transduction, structural biology
MeSH Terms
  • Animals
  • Cell Membrane/genetics
  • Cell Membrane/metabolism
  • Cell Polarity/physiology*
  • Dishevelled Proteins/genetics
  • Dishevelled Proteins/metabolism*
  • HEK293 Cells
  • Humans
  • Protein Domains
  • Wnt Proteins/genetics
  • Wnt Proteins/metabolism*
  • Wnt Signaling Pathway/physiology*
  • Xenopus Proteins/genetics
  • Xenopus Proteins/metabolism*
  • Xenopus laevis
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • beta Catenin/genetics
  • beta Catenin/metabolism*
28223363 Full text @ J. Biol. Chem.
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, the functions of which have been well characterized in β-catenin-dependent canonical and β-catenin-independent noncanonical Wnt signaling. 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 reported previously 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 the PDZ domain results in Dvl autoinhibition in the Wnt signaling pathways. Therefore, the forced binding of the C terminus to the PDZ domain reduces the activity of Dvl in noncanonical Wnt signaling, whereas obstruction of this interaction releases Dvl autoinhibition, impairs its functional interaction with LRP6 in canonical Wnt signaling, and increases its specificity in noncanonical 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 autoinhibited state, accessible for regulation 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 cellular localization of Dvl may not truly represent the wild-type Dvl because those proteins cannot be autoinhibited.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes