The Identification and Cloning of the Wnt-l Receptor.
Final rept. 30 Sep 94-30 Sep 97
NATIONAL INSTITUTES OF HEALTH BETHESDA MD
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Ectopic activation of members of the wnt family, such as wnt-1, causes the formation of mammary tumors in mice, providing a model for breast cancer. However, Wnt receptors, essential components mediating Wnt oncogenic functions,had not been identified previously. In Drosophila, a member of the Frizzled Fz family of seven transmembrane receptors, the Drosophila Frizzled 2 DFz2, was shown to function as a receptor for the Wingless, the ortholog of Wnt-1. This implies that the large family of Fz proteins are likely receptors for Wnt molecules. However, the scarcity of soluble Wnt proteins complicates the study of ligand-receptor relationships and their specificity. We developed an approach in Xenopus embryos to persue such study. In Xenopus embryos, the WinglessWnt-1 subclass of Wnt molecules induces axis duplication whereas the Wnt-5A subclass does not. This difference could be explained by distinct signal transduction pathways or by a lack of Wnt-5A receptors during axis formation. We found that Wnt-5A induces axis duplication in the presence of hFz5, a member of the Frizzled family of seven transmembrane receptors. Wnt-5AhFz5 signaling is antagonized by glycogen synthase kinase 3 and by the N-terminal ectodomain of hFz5. These results identify hFz5 as a receptor for Wnt-5A. In addition, we found that a secreted Frizzled related protein, FRP, is an antagonist for Wnt. This study illustrated a general approach for studying Wnt-Fz interactions.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology