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The discs-large (DLG) tumor suppressor plays essential roles in regulating cell polarity and proliferation. It localizes at sites of cell–cell contact where it acts as a scaffold for multiple protein interactions, including with the adenomatous polyposis coli (APC) tumor suppressor, which in turn regulates β-catenin. Furthermore, many tumor types including breast and colon have increased levels of β-catenin activity with correspondingly low levels of DLG expression. Here we provide evidence of a direct functional link between these apparently separate phenomena. We show that overexpressed β-catenin can enhance the turnover of DLG in a proteosome dependent manner. This effect is specific to DLG and is not seen with two other PDZ domain-containing targets of β-catenin, MAGI-1 and Scribble. Furthermore, siRNA-mediated ablation of endogenous β-catenin expression also enhances DLG stability. β-catenin-induced degradation of DLG appears to be a consequence of a direct association between the two proteins and requires β-catenin PDZ binding potential. In contrast, the enhanced turnover of DLG requires the unique N-terminal sequences and its PDZ domains. Finally, we also show that the capacity of DLG to inhibit transformed cell growth in an oncogene cooperation assay is inhibited by β-catenin. Taken together these studies suggest that one mechanism by which deregulated β-catenin can contribute to tumorigenesis is through enhancing DLG degradation.