Beta-arrestin is a necessary component of Wnt/beta-catenin signaling in vitro and in vivo.
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.
Bryja
Vítezslav
V
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Gradl
Dietmar
D
Schambony
Alexandra
A
Arenas
Ernest
E
Schulte
Gunnar
G
D000818:Animals; D019390:Arrestins / Q000737:chemistry / Q000502:physiology*; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004625:Embryo, Nonmammalian / Q000737:chemistry / Q000502:physiology; D051379:Mice; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000737:chemistry / Q000502:physiology*; D029867:Xenopus Proteins / Q000737:chemistry / Q000502:physiology*; D014982:Xenopus laevis; D051176:beta Catenin / Q000737:chemistry / Q000502:physiology*; D000071557:beta-Arrestins
D019390:Arrestins; D051153:Wnt Proteins; D029867:Xenopus Proteins; D051176:beta Catenin; D000071557:beta-Arrestins