Selective PDZ protein-dependent stimulation of phosphatidylinositol 3-kinase by the adenovirus E4-ORF1 oncoprotein.
While PDZ domain-containing proteins represent cellular targets for several different viral oncoproteins, including human papillomavirus E6, human T-cell leukemia virus type 1 Tax, and human adenovirus E4-ORF1, the functional consequences for such interactions have not been elucidated. Here we report that, at the plasma membrane of cells, the adenovirus E4-ORF1 oncoprotein selectively and potently stimulates phosphatidylinositol 3-kinase (PI3K), triggering a downstream cascade of events that includes activation of both protein kinase B and p70S6-kinase. This activity of E4-ORF1 could be abrogated by overexpression of its PDZ-protein targets or by disruption of its PDZ domain-binding motif, which was shown to mediate complex formation between E4-ORF1 and PDZ proteins at the plasma membrane of cells. Furthermore, E4-ORF1 mutants unable to activate the PI3K pathway failed to transform cells in culture or to promote tumors in animals, and drugs that block either PI3K or p70S6-kinase inhibited E4-ORF1-induced transformation of cells. From these results, we propose that the transforming and tumorigenic potentials of the adenovirus E4-ORF1 oncoprotein depend on its capacity to activate PI3K through a novel PDZ protein-dependent mechanism of action.
Frese
Kristopher K
KK
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
Lee
Siu Sylvia
SS
Thomas
Darby L
DL
Latorre
Isabel J
IJ
Weiss
Robert S
RS
Glaunsinger
Britt A
BA
Javier
Ronald T
RT
D017504:Adenovirus E4 Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins / Q000378:metabolism; D051858:Forkhead Transcription Factors; D015674:Mammary Neoplasms, Animal / Q000209:etiology; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D011920:Rats, Inbred WF; D020123:Sirolimus / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000071161:Forkhead Box Protein O1
D017504:Adenovirus E4 Proteins; D018797:Cell Cycle Proteins; D002867:Chromones; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D009025:Morpholines; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D020123:Sirolimus; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C493962:Cdkn1b protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one