Oncogenic function for the Dlg1 mammalian homolog of the Drosophila discs-large tumor suppressor
Department of Cell Biology
Medical Subject Headings
1-Phosphatidylinositol 3-Kinase; Animals; Cell Membrane; *Cell Transformation, Viral; Genes, ras; Humans; Mice; Nerve Tissue Proteins; Oncogene Proteins, Viral; Protein Transport; Transfection; Tumor Suppressor Proteins
The fact that several different human virus oncoproteins, including adenovirus type 9 E4-ORF1, evolved to target the Dlg1 mammalian homolog of the membrane-associated Drosophila discs-large tumor suppressor has implicated this cellular factor in human cancer. Despite a general belief that such interactions function solely to inactivate this suspected human tumor suppressor protein, we demonstrate here that E4-ORF1 specifically requires endogenous Dlg1 to provoke oncogenic activation of phosphatidylinositol 3-kinase (PI3K) in cells. Based on our results, we propose a model wherein E4-ORF1 binding to Dlg1 triggers the resulting complex to translocate to the plasma membrane and, at this site, to promote Ras-mediated PI3K activation. These findings establish the first known function for Dlg1 in virus-mediated cellular transformation and also surprisingly expose a previously unrecognized oncogenic activity encoded by this suspected cellular tumor suppressor gene.
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Citation: EMBO J. 2006 Mar 22;25(6):1406-17. Epub 2006 Mar 2. Link to article on publisher's site