Signal integration and modulation by the Axin complex during Wnt/b-catenin signaling

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Throughout development and in the adult, cells receive specific signals that they must interpret precisely according to the signal's strength. Secreted proteins of the Wnt family represent one such signal. Wnts elicit precise changes in gene expression mediated by increased levels of the transcription factor Beta-catenin. Too much, or too little, of this signal leads to patterning defects and/or disease. Wnts induce a Beta-catenin signal by blocking the function of the central pathway regulator, a protein complex assembled around the scaffold protein Axin. Multiple, potentially conflicting, inputs interact within the Axin complex. How these different inputs are integrated and dynamically controlled during Wnt signal transduction remains unclear. The focus of this project is to establish a dynamic model of Wnt/B-catenin signaling by identifying the location of the Axin complex and its sub-complexes during signal transduction. Genetic manipulations will then be used to determine the functional significance of the findings.The current model of the Wnt/B-catenin pathway is based largely on studies using overexpression in tissue culture, and protein-protein interactions in vitro. The functional significance of these findings for normal signaling in vivo remains unclear. Significantly, in the proposed studies, the Wnt/B-catenin pathway will be analyzed in the model organism Drosophila, allowing its analysis in the normal cellular context and under physiological conditions. Additionally, visualization of the Axin protein complexes in real-time will establish a dynamic picture of Wnt signaling not achieved in previous studies. These studies are expected to identify novel regulatory interactions and may open the Wnt pathway to pharmacological intervention. This project will provide an opportunity for one graduate student, and two undergraduate students to engage in cutting edge research. In addition, it will allow the PI to introduce K-12 students to basic development and genetics and to promote a science-based curriculum in local schools.