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Regulation of the DLG tumor suppressor by β‐catenin
Author(s) -
Subbaiah Vanitha Krishna,
Narayan Nisha,
Massimi Paola,
Banks Lawrence
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27519
Subject(s) - pdz domain , adenomatous polyposis coli , suppressor , catenin , microbiology and biotechnology , biology , carcinogenesis , cell growth , scaffold protein , cell , immunoprecipitation , cytoplasm , oncogene , cancer research , wnt signaling pathway , signal transduction , cell culture , cancer , cell cycle , colorectal cancer , genetics
Abstract 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.