This Article Full Text Full Text (PDF) Other Versions of this Article: JVI.01310-06v1 81/5/2340    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Werden, S. J. Articles by McFadden, G. Search for Related Content PubMed PubMed Citation Articles by Werden, S. J. Articles by McFadden, G.

M-T5, the Ankyrin Repeat, Host Range Protein of Myxoma Virus, Activates Akt and Can Be Functionally Replaced by Cellular PIKE-A

Steven J. Werden, John W. Barrett, Gen Wang, Marianne M. Stanford, and Grant McFadden^*

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

Received 21 June 2006/ Accepted 28 November 2006

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 (G. Wang, J. W. Barrett, M. Stanford, S. J. Werden, J. B. Johnston, X. Gao, M. Sun, J. Q. Cheng, and G. McFadden, Proc. Natl. Acad. Sci. USA 103:4640-4645, 2006). 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 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. Also, cancer cells that were completely nonpermissive 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 for MV.

Published ahead of print on 6 December 2006.

Present address: Institute for Nutrisciences and Health, National Research Council of Canada, Charlottetown, Prince Edward Island, C1A 5T1 Canada.

This article has been cited by other articles:

• Lun, X. Q., Zhou, H., Alain, T., Sun, B., Wang, L., Barrett, J. W., Stanford, M. M., McFadden, G., Bell, J., Senger, D. L., Forsyth, P. A. (2007). Targeting Human Medulloblastoma: Oncolytic Virotherapy with Myxoma Virus Is Enhanced by Rapamycin. Cancer Res. 67: 8818-8827 [Abstract] [Full Text]