Abstract
The intracellular signaling molecule Dishevelled (Dvl) mediates canonical and non-canonical Wnt signaling via its PDZ domain. Different pathways diverge at this point by a mechanism that remains unclear. Here we show that the peptide-binding pocket of the Dvl PDZ domain can be occupied by Dvl's own highly conserved C-terminus, inducing a closed conformation. In Xenopus, Wnt-regulated convergent extension (CE) is readily affected by Dvl mutants unable to form the closed conformation than by wild-type Dvl. We also demonstrate that while Dvl cooperates with other Wnt pathway elements to activate canonical Wnt signaling, the open conformation of Dvl more effectively activates Jun N-terminal kinase (JNK). These results suggest that together with other players in the Wnt signaling pathway, the conformational change of Dvl regulates Wnt stimulated JNK activity in the non-canonical Wnt signaling.
Highlights
The multiple Wnt signaling–related pathways are crucial to various developmental processes (Logan and Nusse, 2004; Angers and Moon, 2009)
In a Xenopus model, that disruption of this intramolecular interaction activates Jun N-terminal kinase (JNK) and enhances the convergent extension (CE) phenotype associated with activation of non-canonical Wnt signaling
After our initial pull-down test indicated that Dvl C-terminus might interact with the Dvl PDZ domain, we decided to use two different biophysical assays to determine the binding affinity of the Dvl PDZ domain for the Dvl-C peptide and for a peptide derived from the C-terminus of Drosophila Dsh (‘Dsh-C peptide’)
Summary
The multiple Wnt signaling–related pathways are crucial to various developmental processes (Logan and Nusse, 2004; Angers and Moon, 2009). To examine how the conformational change of Dvl affects the Wnt-regulated CE phenotype (associated with the non-canonical Wnt signaling), we injected three different doses of wild-type XDsh and of XDsh-CΔ8 mRNA into the dorsal blastomeres of 4-cell Xenopus embryos.
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