title: Waif1/5T4 inhibits Wnt/β-catenin signaling and activates noncanonical Wnt pathways by modifying LRP6 subcellular localization.
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.
authors.affiliation: Biotechnology Center and Center for Regenerative Therapies, Technische Universität Dresden, Tatzberg 47, 01307 Dresden, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Kagermeier-Schenk
authors.forename: Daniel
authors.initials: D
authors.lastname: Wehner
authors.forename: Günes
authors.initials: G
authors.lastname: Ozhan-Kizil
authors.forename: Hideki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Katharina
authors.initials: K
authors.lastname: Kirchner
authors.forename: Christian
authors.initials: C
authors.lastname: Hoffmann
authors.forename: Peter
authors.initials: P
authors.lastname: Stern
authors.forename: Akira
authors.initials: A
authors.lastname: Kikuchi
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schambony
authors.forename: Gilbert
authors.initials: G
authors.lastname: Weidinger
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002460:Cell Line; D051157:Frizzled Receptors / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000196:embryology / Q000378:metabolism; D008969:Molecular Sequence Data; D054258:Neural Plate / Q000196:embryology / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D014981:Xenopus / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029867:Xenopus Proteins / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495266:CTNNB1 protein, Xenopus; D051157:Frizzled Receptors; D036341:Intercellular Signaling Peptides and Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D011994:Recombinant Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C495269:ctnnb1 protein, zebrafish; C110182:dkk1 protein, Xenopus; C501128:dkk1b protein, zebrafish