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

Kagermeier-Schenk B., Wehner D., Oezhan-Kizil G., Yamamoto H., Li J., Kirchner K., ...Daha Fazla

DEVELOPMENTAL CELL, cilt.21, sa.6, ss.1129-1143, 2011 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 21 Sayı: 6
  • Basım Tarihi: 2011
  • Doi Numarası: 10.1016/j.devcel.2011.10.015
  • Dergi Adı: DEVELOPMENTAL CELL
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.1129-1143
  • Dokuz Eylül Üniversitesi Adresli: Hayır

Özet

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.