Beta-catenin is a cytoplasmic protein associated with the cadherin adhesion molecules and it is thought to be essential for cadherin- mediated cell adhesion. We found, however, that Beta-catenin is also highly homologous to an important developmental patterning gene in Drosophila, called armadillo. Moreover, we have discovered that Beta- catenin participates in process of embryonic axis induction in the frog Xenopus laevis. Its signaling activity appears to be independent of its role in cell adhesion. The main hypothesis of this proposal is that Beta- catenin acts as a signal transducing protein that effects intracellular targets, which lead ultimately to changes in gene expression. The overall goal of this project is to understand the molecular and cellular mechanism by which Beta-catenin effects developmental signaling in Xenopus. A primary effort will be the identification of targets for Beta-catenin in this signaling pathway. The roles of the APC tumor suppressor protein and the nuclear import of Beta-catenin, which have been implicated in this process, will be evaluated, and a search for new molecular targets will carried out. The role of phosphorylation in the regulation of Beta-catenin signaling will also be investigated. Finally, experiments are proposed to explore whether Beta-catenin participates in other developmental signaling events, including signals potentially initiated by cadherins and/or changes in cell-cell adhesion.
The specific aims of the proposal are: to analyze in detail the structural features of (Beta-catenin required for its axis inducing activity and protein interactions; to investigate whether Beta-catenin phosphorylation is associated with its signaling function; to determine whether Beta-catenin stimulates gap junction communication by its signaling activity or by enhancing cell adhesion; to analyze the role of the APC tumor suppressor protein in Beta-catenin signaling; to evaluate the role of nuclear import in (Beta-catenin axis inducing activity; to identify target proteins or pathways for (Beta-catenin signaling activity; and to investigate whether (Beta-catenin in participates in additional signaling events in Xenopus. The Xenopus axis induction model should provide important information about the mechanism of Beta-catenin signaling as well as the potential signaling functions of APC, which may be important for understanding its role as a tumor suppressor protein. This new signaling mechanism may be generally important, with roles in other developmental and pathophysiological processes, and could even be a mechanism for conveying information that arises from cell-cell contacts or cadherins.
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