Waif1/5T4 Inhibits Wnt/β-Catenin Signaling and Activates Noncanonical Wnt Pathways by Modifying LRP6 Subcellular Localization

Birgit Kagermeier-Schenk, Daniel Wehner, Günes Özhan-Kizil, Hideki Yamamoto, Jian Li, Katharina Kirchner, Christian Hoffmann, Peter Stern, Akira Kikuchi, Alexandra Schambony, Gilbert Weidinger

    Research output: Contribution to journalArticlepeer-review

    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. © 2011 Elsevier Inc.
    Original languageEnglish
    Pages (from-to)1129-1143
    Number of pages14
    JournalDevelopmental cell
    Volume21
    Issue number6
    DOIs
    Publication statusPublished - 13 Dec 2011

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