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Link of the unique oncogenic properties of adenovirus type 9 E4‐ORF1 to a select interaction with the candidate tumor suppressor protein ZO‐2

Adenovirus type 9 (Ad9) is distinct among human adenoviruses because it elicits solely mammary tumors in animals and its primary oncogenic determinant is the E4 region‐encoded ORF1 (E4‐ORF1) protein. We report here that the PDZ domain‐containing protein ZO‐2, which is a candidate tumor suppressor protein, is a cellular target for tumorigenic Ad9 E4‐ORF1 but not for non‐tumorigenic wild‐type E4‐ORF1 proteins encoded by adenovirus types 5 and 12. Complex formation was mediated by the C‐terminal PDZ domain‐binding motif of Ad9 E4‐ ORF1 and the first PDZ domain of ZO‐2, and in cells this interaction resulted in aberrant sequestration of ZO‐2 within the cytoplasm. Furthermore, transformation‐defective Ad9 E4‐ORF1 mutants exhibited impaired binding to and sequestration of ZO‐2 in cells, and overexpression of wild‐type ZO‐2, but not mutant ZO‐2 lacking the second and third PDZ domains, interfered with Ad9 E4‐ORF1‐induced focus formation. Our results suggest that the select capacity to complex with the candidate tumor suppressor protein ZO‐2 is key to defining the unique transforming and tumorigenic properties of the Ad9 E4‐ORF1 oncoprotein.