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J. Virol. doi:10.1128/JVI.01310-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The ankyrin repeat, host range protein of myxoma virus, M-T5, which activates Akt can be functionally replaced by cellular PIKE-A

Department of Microbiology and Immunology, University of Western Ontario and Robarts Research Institute, London, Ontario, Canada

^* To whom correspondence should be addressed. Email: mcfadden{at}robarts.ca.

	Abstract

The myxoma virus (MV) ankyrin-repeat host range factor, M-T5, has the ability to bind and activate cellular Akt, leading to permissive MV replication in a variety of diverse human cancer cell lines (Wang et al. 2006. Proc Natl Acad Sci U S A 103:4640-5). The susceptibility of permissive human cancer cells to MV infection is directly correlated with the basal or induced levels of phosphorylated Akt. When M-T5 is deleted from MV, the knockout virus, vMyxT5KO, can no longer productively infect a subset of the human cancer cells (designated Type II) that exhibit little or no endogenous phosphorylated Akt. In searching for a host counterpart of M-T5 we noted sequence similarity of M-T5 to a recently identified ankyrin-repeat cellular binding protein of Akt called PIKE-A. PIKE-A binds and activates the kinase activity of Akt in a GTP-dependent manner and promotes the invasiveness of human cancer cell lines. Here we demonstrate that transfected PIKE-A is able to rescue the ability of vMyxT5KO to productively infect Type II human cancer cells that were previously resistant to infection. As well, cancer cells that were completely non-permissive for both wild-type and vMyxT5KO infection (called Type III) were rendered fully permissive following ectopic expression of PIKE-A. We conclude that the MV M-T5 host range protein is functionally interchangeable with the host PIKE-A protein, and that the activation of host Akt by either M-T5 or PIKE-A is critical for the permissiveness of human cancer cells by MV.

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