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The Wnt/beta-catenin signaling pathway is crucial for proper embryonic development and tissue homeostasis. The phosphoprotein dishevelled (Dvl) is an integral part of Wnt signaling and has recently been shown to interact with the multifunctional scaffolding protein beta-arrestin. Using Dvl deletion constructs, we found that beta-arrestin binds a region N-terminal of the PDZ domain of Dvl, which contains casein kinase 1 (CK1) phosphorylation sites. Inhibition of Wnt signaling by CK1 inhibitors reduced the binding of beta-arrestin to Dvl. Moreover, mouse embryonic fibroblasts lacking beta-arrestins were able to phosphorylate LRP6 in response to Wnt-3a but decreased the activation of Dvl and blocked beta-catenin signaling. In addition, we found that beta-arrestin can bind axin and forms a trimeric complex with axin and Dvl. Furthermore, treatment of Xenopus laevis embryos with beta-arrestin morpholinos reduced the activation of endogenous beta-catenin, decreased the expression of the beta-catenin target gene, Xnr3, and blocked axis duplication induced by X-Wnt-8, CK1epsilon, or DshDeltaDEP, but not by beta-catenin. Thus, our results identify beta-arrestin as a necessary component for Wnt/beta-catenin signaling, linking Dvl and axin, and open a vast array of signaling avenues and possibilities for cross-talk with other beta-arrestin-dependent signaling pathways.
Fig. 5. β-Arrestin is not sufficient but necessary for Wnt/β-catenin signaling in vivo. (A) Percentage of secondary axis induction in Xenopus embryos injected with XWnt-8, DshδDEP, and β-arrestin RNA. n, no. of analyzed embryos per condition. (B) Effect of β-arrestin morpholino (β-arrMO) treatment on XWnt-8-, DshδDEP-, CK1ε-, and β-catenin-induced axis duplication; n, no. of analyzed embryos per condition. (C) Representative photographs of embryos. Secondary axis formation (arrowheads) is best seen by the appearance of a secondary neural tube in neurula (XWnt-8, β-catenin), tailbud (CK1ε), and tadpole stages (DshδDEP). Arrows indicate the endogenous axes. (D) Immunoblotting of Xenopus lysates analyzed for β-catenin dephosphorylation (ABC) and β-arrestin levels (A1CT). Filled arrowheads indicate Xenopus β-arrestin signal. Open arrowhead indicates an unspecific band serving as loading control. Gene expression (Xnr3) was examined in Xenopus embryos by quantitative RT-PCR. (E) Error bars show mean ± SD.
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