%0 Journal Article
%T Dishevelled-3 C-terminal His single amino acid repeats are obligate for Wnt5a activation of non-canonical signaling
%A Li Ma
%A Ying Wang
%A Craig C Malbon
%A Hsien-yu Wang
%J Journal of Molecular Signaling
%D 2010
%I Ubiquity Press
%R 10.1186/1750-2187-5-19
%X Dvl1, Dvl2, and Dvl3 are expressed at varying levels in mouse totipotent F9 embryonal teratocarcinoma cells. The expression of each endogenous Dvl isoform, as defined by knock-down with siRNA, was obligate for Wnt5a to activate NF-AT-sensitive transcription. Elements upstream of effectors, e.g., cGMP phosphodiesterase and Ca2+-mobilization, were blocked by knock-down of any one of the Dvls; thus, with respect to Wnt5a activation of NF-AT Dvls are not redundant. Among the three Dvl isoforms, the C-terminal sequence of Dvl3 is the most divergent. Deletion of region of Dvl3 abolishes Wnt5a-stimulated signaling. Alanine (Ala)-substitution of histidine (His) single amino acid repeats at 637,638 and/or 647,648 in Dvl3, like C-terminal deletion, abolishes Wnt 5a signal propagation. Phenylalanine (Phe)-substitution of the same His-repeats in Dvl3 mimics Wnt5a stimulated NF-AT-sensitive transcription.The C-terminal third of Dvl3 and His single amino acid repeats 637,638 and 647,648 (which are unique to and conserved in Dvl3) are essential for Wnt5a activation of the non-canonical pathway, but not the Wnt3a activation of the canonical pathway.Wnt signaling is essential for normal embryonic patterning, development, cellular proliferation and homeostasis [1-4]. Wnt ligands initiate intracellular signaling pathways by binding to the G-protein-coupled receptors (GPCR), Frizzleds (Fzs) [5-9]. The Wnt-sensitive pathways include the canonical (Wnt/¦Â-catenin) and the non-canonical (planar cell polarity and Wnt/Ca2+) pathways [10-15]. For the canonical pathway, absent Wnt, cellular ¦Â-catenin is subjected to proteasome mediated degradation by the destruction complex that includes, among other proteins, Axin and the product of the adenomatous polyposis coli gene, which facilitate the phosphorylation of ¦Â-catenin by the Ser/Thr protein kinase glycogen synthase kinase 3¦Â[16-20]. This phosphorylation that occurs in the absence of Wnt3a fosters ubiquitination and degradation of ¦Â-catenin [2
%U http://www.jmolecularsignaling.com/content/5/1/19