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.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Genetically Modified
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Cell Line
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Frizzled Receptors / metabolism
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Gene Expression Regulation, Developmental
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Humans
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Intercellular Signaling Peptides and Proteins / metabolism
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Low Density Lipoprotein Receptor-Related Protein-6 / genetics
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Low Density Lipoprotein Receptor-Related Protein-6 / metabolism*
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Mesoderm / embryology
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Mesoderm / metabolism
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Molecular Sequence Data
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Neural Plate / embryology
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Neural Plate / metabolism
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Wnt Signaling Pathway*
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Xenopus / embryology
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Xenopus / genetics
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Xenopus / metabolism
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Xenopus Proteins / metabolism
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Zebrafish / embryology
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Zebrafish / genetics
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Zebrafish / metabolism*
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Zebrafish Proteins / metabolism*
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beta Catenin / metabolism*
Substances
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CTNNB1 protein, Xenopus
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Frizzled Receptors
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Intercellular Signaling Peptides and Proteins
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Low Density Lipoprotein Receptor-Related Protein-6
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Recombinant Proteins
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Xenopus Proteins
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Zebrafish Proteins
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beta Catenin
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ctnnb1 protein, zebrafish
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dkk1 protein, Xenopus
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dkk1b protein, zebrafish
Associated data
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GENBANK/JN653073
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GENBANK/JN653074
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GENBANK/JN653075
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GENBANK/JN653076
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GENBANK/JN653077