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Journal of Virology, May 2007, p. 4787-4797, Vol. 81, No. 9
0022-538X/07/$08.00+0     doi:10.1128/JVI.02855-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A New Crucial Protein Interaction Element That Targets the Adenovirus E4-ORF1 Oncoprotein to Membrane Vesicles{triangledown}

Sang-Hyuk Chung,1 Kristopher K. Frese,1,{dagger} Robert S. Weiss,1,{ddagger} B. V. Venkataram Prasad,2 and Ronald T. Javier1*

Department of Molecular Virology and Microbiology,1 Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 770302

Received 23 December 2006/ Accepted 10 February 2007

Human adenovirus type 9 exclusively elicits mammary tumors in experimental animals, and the primary oncogenic determinant of this virus is the E4-ORF1 oncogene, as opposed to the well-known E1A and E1B oncogenes. The tumorigenic potential of E4-ORF1, as well as its ability to oncogenically stimulate phosphatidylinositol 3-kinase (PI3K), depends on a carboxyl-terminal PDZ domain-binding motif (PBM) that mediates interactions with several different membrane-associated cellular PDZ proteins, including MUPP1, PATJ, MAGI-1, ZO-2, and Dlg1. Nevertheless, because certain E4-ORF1 mutations that alter neither the sequence nor the function of the PBM abolish E4-ORF1-induced PI3K activation and cellular transformation, we reasoned that E4-ORF1 must possess an additional crucial protein element. In the present study, we identified seven E4-ORF1 amino acid residues that define this new element, designated domain 2, and showed that it mediates binding to a 70-kDa cellular phosphoprotein. We also discovered that domain 2 or the PBM independently promotes E4-ORF1 localization to cytoplasmic membrane vesicles and that this activity of domain 2 depends on E4-ORF1 trimerization. Consistent with the latter observation, molecular-modeling analyses predicted that E4-ORF1 trimerization brings together six out of seven domain 2 residues at each of the three subunit interfaces. These findings importantly demonstrate that PI3K activation and cellular transformation induced by E4-ORF1 require two separate protein interaction elements, domain 2 and the PBM, each of which targets E4-ORF1 to vesicle membranes in cells.

* Corresponding author. Mailing address: Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. Phone: (713) 798-3898. Fax: (713) 798-3586. E-mail: rjavier{at}bcm.edu

{triangledown} Published ahead of print on 21 February 2007.

{dagger} Present address: Cancer Research United Kingdom, Cambridge Research Institute, Cambridge CB2 0RE, United Kingdom.

{ddagger} Present address: Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

Journal of Virology, May 2007, p. 4787-4797, Vol. 81, No. 9
0022-538X/07/$08.00+0     doi:10.1128/JVI.02855-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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