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Dev Biol
2007 Jun 01;3061:50-65. doi: 10.1016/j.ydbio.2007.02.041.
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Analysis of dishevelled localization and function in the early sea urchin embryo.
Leonard JD
,
Ettensohn CA
.
???displayArticle.abstract??? Dishevelled (Dsh) is a key signaling molecule in the canonical Wnt pathway. Although the mechanism by which Dsh transduces a Wnt signal remains elusive, the subcellular localization of Dsh may be critical for its function. In the early sea urchin embryo, Dsh is concentrated in punctate structures within the cytoplasm of vegetal blastomeres. In these cells, Dsh stabilizes beta-catenin and causes it to accumulate in nuclei, resulting in the activation of transcriptional gene regulatory networks that drive mesoderm and endoderm formation. Here, we present a systematic mutational analysis of Lytechinus variegatus Dsh (LvDsh) that identifies motifs required for its vegetal cortical localization (VCL). In addition to a previously identified lipid-binding motif near the N-terminus of Dsh (Weitzel, H.E., Illies, M.R., Byrum, C.A., Xu, R., Wikramanayake, A.H., Ettensohn, C.A., 2004. Differential stability of beta-catenin along the animal-vegetal axis of the sea urchin embryo mediated by dishevelled. Development 131, 2947-56), we identify a short (21 amino acid) motif between the PDZ and DEP domains that is required for VCL. Phosphorylation of threonine residues in this region regulates both the targeting and stability of LvDsh. We also identify functional nuclear import and export signals within LvDsh. We provide additional evidence that LvDsh is active locally in the vegetal region of the embryo but is inactive in animal blastomeres and show that the inability of LvDsh to function in animal cells is not a consequence of impaired nuclear import. The DIX domain of LvDsh functions as a potent dominant negative when overexpressed (Weitzel, H.E., Illies, M.R., Byrum, C.A., Xu, R., Wikramanayake, A.H., Ettensohn, C.A., 2004. Differential stability of beta-catenin along the animal-vegetal axis of the sea urchin embryo mediated by dishevelled. Development 131, 2947-56). Here, we show that the dominant negative effect of DIX is dependent on a highly conserved, lipid-binding motif that includes residues K57 and E58. The dominant negative effect of DIX is not a consequence of blocking VCL or the nuclear import of LvDsh. We provide evidence that isolated DIX domains interact with full-length LvDsh in vivo. In addition, we show that the K57/E58 lipid-binding motif of DIX is essential for this interaction. We propose that binding of the isolated DIX domain to full-length Dsh may be facilitated by interactions with lipids, and that this interaction may inhibit signaling by a) preventing endogenous Dsh from interacting with Axin, or b) blocking the ability of Dsh to recruit other proteins, such as GBP/Frat1, to the beta-catenin degradation complex.
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