title: Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled.
abstract: 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.
authors.affiliation: Department of Cell Biology,  University Medical Center Utrecht, 3584 CX Utrecht,  The Netherlands.
authors.forename: Daniele V F
authors.initials: DV
authors.lastname: Tauriello
authors.forename: Ingrid
authors.initials: I
authors.lastname: Jordens
authors.forename: Katharina
authors.initials: K
authors.lastname: Kirchner
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Slootstra
authors.forename: Tom
authors.initials: T
authors.lastname: Kruitwagen
authors.forename: Britta A M
authors.initials: BA
authors.lastname: Bouwman
authors.forename: Maria
authors.initials: M
authors.lastname: Noutsou
authors.forename: Stefan G D
authors.initials: SG
authors.lastname: Rüdiger
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwamborn
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schambony
authors.forename: Madelon M
authors.initials: MM
authors.lastname: Maurice
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D002460:Cell Line; D000072261:Dishevelled Proteins; D005454:Fluorescence Polarization; D051157:Frizzled Receptors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D029867:Xenopus Proteins; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000606586:DVL1 protein, Xenopus; D000072261:Dishevelled Proteins; D051157:Frizzled Receptors; D010750:Phosphoproteins; D051153:Wnt Proteins; D029867:Xenopus Proteins; D051176:beta Catenin