Wnt-1 is a mammary oncogene which causes hyperplasia and tumorigenesis when activated in mouse mammary gland and causes transformation of certain mammary epithelial cells in culture. The gene normally functions in fetal brain morphogenesis. Wnt-1 encodes a secreted protein that acts in cell-cell signalling. The goal of this research proposal is to investigate the mechanism of action of Wnt-1 in mammary cell transformation, using two recently identified sources of soluble Wnt-1 proteins. The active form of Wnt-1 protein and any associated factors will be characterized, and used to investigate early molecular responses to Wnt-1 in mammary cells, and to identify and characterize Wnt receptors. The effects of Wnt signals on plakoglobin and beta-catenin will be evaluated, as well as other mammalian homologs of components of the putative Wnt-1 signaling pathway in Drosophila. Proteins that are rapidly tyrosine phosphorylated in response to Wnt-1 will be characterized. Radiolabeled Wnt-1 will be used to demonstrate specific binding to cells and to identify receptors by cross-linking and affinity labeling.
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