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Journal Article

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

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Citation

Kagermeier-Schenk, B., Wehner, D., Oezhan-Kizil, G., Yamamoto, H., Li, J., Kirchner, K., et al. (2011). Waif1/5T4 Inhibits Wnt/beta-Catenin Signaling and Activates Noncanonical Wnt Pathways by Modifying LRP6 Subcellular Localization. Developmental Cell, 21(6), 1129-1143. doi:10.1016/j.devcel.2011.10.015.


Cite as: https://hdl.handle.net/21.11116/0000-0009-ACD0-A
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/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.