Oncogenic function for the Dlg1 mammalian homolog of the Drosophila discs-large tumor suppressor

Abstract

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.

Description

Keywords

adenovirus, Dlg1, E4-ORF1, PI 3-kinase, tumor suppressor

Citation

Copyright 2006 EMBO Journal. Recommended citation: Frese, Kristopher K., Isabel J. Latorre, Sang?Hyuk Chung, Georgina Caruana, Alan Bernstein, Stephen N. Jones, Lawrence A. Donehower, Monica J. Justice, Craig C. Garner, and Ronald T. Javier. "Oncogenic function for the Dlg1 mammalian homolog of the Drosophila discs?large tumor suppressor." The EMBO journal 25, no. 6 (2006): 1406-1417. DOI: 10.1038/sj.emboj.7601030. URL: https://www.embopress.org/doi/full/10.1038/sj.emboj.7601030. Reproduced in accordance with the original publisher's licensing terms and with permission from the author(s).