Journal
DEVELOPMENTAL CELL
Volume 21, Issue 6, Pages 1129-1143Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2011.10.015
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Funding
- DFG [SFB655, SCHA965/3-2]
- Cancer Research UK [R112021]
- Grants-in-Aid for Scientific Research [21249017, 23590333, 22019025] Funding Source: KAKEN
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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/beta-catenin signaling and concomitantly activates noncanonical Wnt pathways. Waif1 inhibits beta-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/beta-catenin signaling by regulating LRP6 subcellular localization. In addition, Waif1a enhances beta-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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