P-catenin is a component of the cadherin adhesion protein complex and an intracellular signal transducing protein in the Wnt pathway, p-catenin is regulated by the ARC tumor suppressor protein, and mutations in both p-catenin and E-cadherin are implicated in many forms of cancer. The two overall objectives of the project are to determine the mechanism underlying the cytoplasmic regulation of p-catenin signaling, and to determine how cadherins affect p-catenin signaling, cell differentiation, and tumor cell growth. Nuclear import of p-catenin is important for signaling and occurs by a novel mechanism involving its interaction with the nuclear pore. The mechanism of p-catenin nuclear pore docking and its regulation by the Wnt signaling pathway will be studied, p-catenin signaling is regulated by a very large protein complex that includes ARC, axin, and the kinase GSKSp. The properties of the intact complex will be studied using an in vitro p-catenin signaling assay, phosphorylation assays, and analyses of p-catenin interactions. The complex will also be purified in order to identify key protein components. Furthermore, the role of a recently identified second ARC protein, APC-2, in p-catenin signaling in the early Xenopus embryo will be evaluated. Cadherin expression antagonizes p-catenin signaling by binding it up at the plasma membrane, providing a potential mechanism to couple changes in cell adhesion to regulation of gene expression. The possibility that cadherin regulation of p-catenin signaling plays an important role in development of the neural crest in the Xenopus embryo, an epithelial-mesenchymal transition, will be explored. Similarly, experiments will be done to determine the relative contributions of regulating P-cateninsignaling or enhancing cell adhesion to the tumor suppressor function of E-cadherin. Experiments will also be performed to determine whether E-cadherin can directly generate signals that mediate contact inhibition of cell growth. These experiments should help us understand the mechanisms of p-catenin-mediated signaling and provide insights into the relationships between cell adhesion, tissue morphogenesis, and tumor growth.
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