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ZFIN ID: ZDB-PUB-111129-1
Waif1/5T4 Inhibits Wnt/β-Catenin Signaling and Activates Noncanonical Wnt Pathways by Modifying LRP6 Subcellular Localization
Kagermeier-Schenk, B., Wehner, D., Ozhan-Kizil, G., Yamamoto, H., Li, J., Kirchner, K., Hoffmann, C., Stern, P., Kikuchi, A., Schambony, A., and Weidinger, G.
Date: 2011
Source: Developmental Cell   21(6): 1129-43 (Journal)
Registered Authors: Kagermeier-Schenk, Birgit, Özhan, Günes, Wehner, Daniel, Weidinger, Gilbert
Keywords: none
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Cell Line
  • Frizzled Receptors/metabolism
  • Gene Expression Regulation, Developmental
  • Humans
  • Intercellular Signaling Peptides and Proteins/metabolism
  • Low Density Lipoprotein Receptor-Related Protein-6/genetics
  • Low Density Lipoprotein Receptor-Related Protein-6/metabolism*
  • Mesoderm/embryology
  • Mesoderm/metabolism
  • Molecular Sequence Data
  • Neural Plate/embryology
  • Neural Plate/metabolism
  • Recombinant Proteins/genetics
  • Recombinant Proteins/metabolism
  • Wnt Signaling Pathway*
  • Xenopus/embryology
  • Xenopus/genetics
  • Xenopus/metabolism
  • Xenopus Proteins/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/metabolism*
  • beta Catenin/metabolism*
PubMed: 22100263 Full text @ Dev. Cell
FIGURES
ABSTRACT

Wnt proteins can activate distinct signaling pathways, but little is known about the mechanisms regulating pathway selection. Here we show that the metastasis-associated transmembrane protein Wnt-activated inhibitory factor 1 (Waif1/5T4) interferes with Wnt/β-catenin signaling and concomitantly activates noncanonical Wnt pathways. Waif1 inhibits β-catenin signaling in zebrafish and Xenopus embryos as well as in mammalian cells, and zebrafish waif1a acts as a direct feedback inhibitor of wnt8-mediated mesoderm and neuroectoderm patterning during zebrafish gastrulation. Waif1a binds to the Wnt coreceptor LRP6 and inhibits Wnt-induced LRP6 internalization into endocytic vesicles, a process that is required for pathway activation. Thus, Waif1a modifies Wnt/β-catenin signaling by regulating LRP6 subcellular localization. In addition, Waif1a enhances β-catenin-independent Wnt signaling in zebrafish embryos and Xenopus explants by promoting a noncanonical function of Dickkopf1. These results suggest that Waif1 modulates pathway selection in Wnt-receiving cells.

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