Selective PDZ protein-dependent stimulation of phosphatidylinositol 3-kinase by the adenovirus E4-ORF1 oncoprotein

Oncogene. 2003 Feb 6;22(5):710-21. doi: 10.1038/sj.onc.1206151.


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenovirus E4 Proteins / drug effects
  • Adenovirus E4 Proteins / genetics
  • Adenovirus E4 Proteins / metabolism*
  • Animals
  • Cell Cycle Proteins / metabolism
  • Chromones / pharmacology
  • Cyclin-Dependent Kinase Inhibitor p27
  • DNA-Binding Proteins / metabolism
  • Forkhead Transcription Factors
  • Mammary Neoplasms, Animal / etiology
  • Morpholines / pharmacology
  • Mutation
  • Nerve Tissue Proteins
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Rats
  • Rats, Inbred WF
  • Sirolimus / pharmacology
  • Transcription Factors / metabolism
  • Transfection
  • Tumor Suppressor Proteins / metabolism


  • Adenovirus E4 Proteins
  • Cdkn1b protein, rat
  • Cell Cycle Proteins
  • Chromones
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Morpholines
  • Nerve Tissue Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Foxo1 protein, rat
  • Cyclin-Dependent Kinase Inhibitor p27
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Sirolimus