Regulation of the DLG tumor suppressor by [beta]-catenin

• Published in: International journal of cancer 2012-11, Vol.131 (10), p.2223-2233
• Main Authors: Subbaiah, Vanitha Krishna, Narayan, Nisha, Massimi, Paola, Banks, Lawrence
• Format: Article
• Language: English
• Subjects: Cancer; Cell adhesion; Colorectal cancer; Medical research; Oncology; Proteins
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.27519

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 [beta]-catenin. Furthermore, many tumor types including breast and colon have increased levels of [beta]-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 [beta]-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 [beta]-catenin, MAGI-1 and Scribble. Furthermore, siRNA-mediated ablation of endogenous [beta]-catenin expression also enhances DLG stability. [beta]-catenin-induced degradation of DLG appears to be a consequence of a direct association between the two proteins and requires [beta]-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 [beta]-catenin. Taken together these studies suggest that one mechanism by which deregulated [beta]-catenin can contribute to tumorigenesis is through enhancing DLG degradation. [PUBLICATION ABSTRACT]