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

D.V.F. Tauriello, I. Jordens, K. Kirchner, J.W. Slootstra, T. Kruitwagen, B.A.M. Bouwman, M. Noutsou, S.G.D. Rüdiger, K. Schwamborn, A. Schambony, M.M. Maurice

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Pages (from-to)E812-E820
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number14
Publication statusPublished - 3 Apr 2012


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


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