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  • The EMBO Journal (2006) 25, 1406 - 1417
  • doi:10.1038/sj.emboj.7601030

Published online: 2 March 2006

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

Kristopher K Frese1,ab, Isabel J Latorre1,ab, Sang-Hyuk Chung1, Georgina Caruana2, Alan Bernstein3, Stephen N Jones4, Lawrence A Donehower1, Monica J Justice5, Craig C Garner6 and Ronald T Javier1

  1. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
  2. Department of Anatomy and Cell Biology, Monash University, Clayton, Victoria, Australia
  3. Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
  4. Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA
  5. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
  6. Department of Psychiatry and Behavioral Science, Nancy Pritzker Laboratory, Stanford University, Palo Alto, CA, USA

Correspondence to:

Ronald T Javier, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA. Tel.: +1 713 798 3898; Fax: +1 713 798 3586; E-mail: rjavier@bcm.tmc.edu

aThese authors contributed equally to this work

bPresent address: Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA

Received 12 September 2005; Accepted 8 February 2006

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.

  • Keywords:

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