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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-04, Vol.109 (14), p.E812-E820
• Main Authors: Tauriello, Daniele V. F, Jordens, Ingrid, Kirchner, Katharina, Slootstra, Jerry W, Kruitwagen, Tom, Bouwman, Britta A. M, Noutsou, Maria, Rüdiger, Stefan G. D, Schwamborn, Klaus, Schambony, Alexandra, Maurice, Madelon M
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - metabolism; adulthood; Amino Acid Sequence; beta Catenin - metabolism; Biological Sciences; Cell Line; cultured cells; Dishevelled Proteins; Fluorescence Polarization; Frizzled Receptors - chemistry; Frizzled Receptors - metabolism; Humans; Microscopy, Confocal; Molecular Sequence Data; Phosphoproteins - chemistry; Phosphoproteins - metabolism; PNAS Plus; Protein Binding; Signal Transduction; Wnt Proteins - metabolism; Xenopus; Xenopus Proteins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1114802109

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.