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Proc Natl Acad Sci U S A
2012 Apr 03;10914:E812-20. doi: 10.1073/pnas.1114802109.
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Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled.
Tauriello DV, Jordens I, Kirchner K, Slootstra JW, Kruitwagen T, Bouwman BA, Noutsou M, Rüdiger SG, Schwamborn K, Schambony A, Maurice MM.
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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.
Fig. 3. XFz7 motifs I and II are essential for Wnt-mediated signaling and XDvl2 recruitment in Xenopus embryos. (A) XFz7 iLoop3 motif I and II mutants display decreased Wnt3a-induced signaling. Indicated motif I and II XFz7 mutants were tested in the TOPFlash luciferase reporter assay as in Fig. 2A. (Left) Shown are the average normalized values of three individual experiments; error bars indicate SDs. Mock, empty vector. (Right) Color-coded activity map of tested XFz7 iLoop3 residues (as in Fig. 2C). (B) XFz7 motif II mutants are defective in secondary axis formation in Xenopus embryos. Ventral injections of combined mRNAs encoding for XFz7 variants and XWnt8 were used to compare β-catenin–mediated secondary axis formation. The primary axis is indicated by straight lines, and (partial) secondary axes are indicated by dotted lines. (C) Quantification of the results presented in B. XFz7 I425A caused severe embryonic lethality and was not quantified. Shown are the average percentages of axis duplication of three independent experiments; error bars depict SEs. The number of counted embryos per condition is indicated. (D) Colocalization of XFz7 motif I and II mutants and XDvl2-GFP in Xenopus animal cap explants is impaired. (Scale bars: 100 μm.) (E) Quantification of the results in D (as in Fig. 2 D and E). The number of counted cells is indicated.
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