Waif1/5T4 Inhibits Wnt/β-Catenin Signaling and Activates Noncanonical Wnt Pathways by Modifying LRP6 Subcellular Localization
- Authors
- 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.
- ID
- ZDB-PUB-111129-1
- 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
-
- Zebrafish Proteins/metabolism*
- beta Catenin/metabolism*
- Cell Line
- Gene Expression Regulation, Developmental
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism*
- Animals
- Recombinant Proteins/genetics
- Recombinant Proteins/metabolism
- Xenopus Proteins/metabolism
- Neural Plate/embryology
- Neural Plate/metabolism
- Low Density Lipoprotein Receptor-Related Protein-6/genetics
- Low Density Lipoprotein Receptor-Related Protein-6/metabolism*
- Wnt Signaling Pathway*
- Xenopus/embryology
- Xenopus/genetics
- Xenopus/metabolism
- Intercellular Signaling Peptides and Proteins/metabolism
- Animals, Genetically Modified
- Frizzled Receptors/metabolism
- Molecular Sequence Data
- Humans
- Mesoderm/embryology
- Mesoderm/metabolism
- PubMed
- 22100263 Full text @ Dev. Cell
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.