Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled

Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):E812-20. doi: 10.1073/pnas.1114802109. Epub 2012 Mar 12.


Wnt binding to members of the seven-span transmembrane Frizzled (Fz) receptor family controls essential cell fate decisions and tissue polarity during development and in adulthood. The Fz-mediated membrane recruitment of the cytoplasmic effector Dishevelled (Dvl) is a critical step in Wnt/β-catenin signaling initiation, but how Fz and Dvl act together to drive downstream signaling events remains largely undefined. Here, we use an Fz peptide-based microarray to uncover a mechanistically important role of the bipartite Dvl DEP domain and C terminal region (DEP-C) in binding a three-segmented discontinuous motif in Fz. We show that cooperative use of two conserved motifs in the third intracellular loop and the classic C-terminal motif of Fz is required for DEP-C binding and Wnt-induced β-catenin activation in cultured cells and Xenopus embryos. Within the complex, the Dvl DEP domain mainly binds the Fz C-terminal tail, whereas a short region at the Dvl C-terminal end is required to bind the Fz third loop and stabilize the Fz-Dvl interaction. We conclude that Dvl DEP-C binding to Fz is a key event in Wnt-mediated signaling relay to β-catenin. The discontinuous nature of the Fz-Dvl interface may allow for precise regulation of the interaction in the control of Wnt-dependent cellular responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Cell Line
  • Dishevelled Proteins
  • Fluorescence Polarization
  • Frizzled Receptors / chemistry
  • Frizzled Receptors / metabolism*
  • Humans
  • Microscopy, Confocal
  • Molecular Sequence Data
  • Phosphoproteins / chemistry
  • Phosphoproteins / metabolism*
  • Protein Binding
  • Signal Transduction*
  • Wnt Proteins / metabolism*
  • Xenopus Proteins
  • beta Catenin / metabolism*


  • Adaptor Proteins, Signal Transducing
  • DVL1 protein, Xenopus
  • Dishevelled Proteins
  • Frizzled Receptors
  • Phosphoproteins
  • Wnt Proteins
  • Xenopus Proteins
  • beta Catenin