Mechanisms of Armadillo/Beta-catenin degradation

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DESCRIPTION (provided by applicant): Inappropriate activation of the Wingless (Wg)/Wnt signaling pathway frequently results in human cancers, such as colon cancer. Wg signaling occurs by regulating the intracellular levels of the key effector protein, beta-catenin (called Armadillo (Arm) in Drosophila). Substantial experimental evidence suggests that Arm is negatively regulated by a multi-protein complex (the destruction complex) that targets Arm for degradation. Several fundamental questions still remain, however, concerning how the destruction complex functions. In particular, the role of the protein APC in the destruction complex remains unknown. To address the role of APC in the destruction complex, a structure/function analysis will be performed using Drosophila APC2 as a model for human APC, and the information gained from this analysis will be used to evaluate several models of APC function in the destruction complex. Secondly, the molecular composition of the E3 ubiquitin ligase that degrades Arm will be defined, specifically evaluating the importance of Roc proteins in Arm degradation. Finally, the hypothesis that APC proteins have a second function in transferring Arm from the destruction complex to E3 ubiquitin ligases will be investigated.