Oncogenic function for the Dlg1 mammalian homolog of the Drosophila discs-large tumor suppressor.
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.
Frese
Kristopher K
KK
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
Latorre
Isabel J
IJ
Chung
Sang-Hyuk
SH
Caruana
Georgina
G
Bernstein
Alan
A
Jones
Stephen N
SN
Donehower
Lawrence A
LA
Justice
Monica J
MJ
Garner
Craig C
CC
Javier
Ronald T
RT
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002472:Cell Transformation, Viral; D058534:Class I Phosphatidylinositol 3-Kinases; D000074288:Discs Large Homolog 1 Protein; D011905:Genes, ras / Q000502:physiology; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport; D000074407:SAP90-PSD95 Associated Proteins; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; C101120:E4 protein, Adenovirus 9; D009419:Nerve Tissue Proteins; D009856:Oncogene Proteins, Viral; D000074407:SAP90-PSD95 Associated Proteins; D025521:Tumor Suppressor Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human