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XB-ART-44474
Dev Cell 2011 Dec 13;216:1129-43. doi: 10.1016/j.devcel.2011.10.015.
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Waif1/5T4 inhibits Wnt/β-catenin signaling and activates noncanonical Wnt pathways by modifying LRP6 subcellular localization.

Kagermeier-Schenk B , Wehner D , Ozhan-Kizil G , Yamamoto H , Li J , Kirchner K , Hoffmann C , Stern P , Kikuchi A , Schambony A , Weidinger G .


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.

PubMed ID: 22100263
Article link: Dev Cell
Grant support: [+]

Species referenced: Xenopus
Genes referenced: axin1 axin2l cdx4 ctnnb1 dkk1 foxa1 gsc lrp6 nodal3.2 otx2 sp5l tpbg wnt3a wnt8a


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