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Merkel cell polyomavirus small T antigen drives cell motility via Rho-GTPase-induced filopodia formation

Stakaitytė, Gabrielė, Nwogu, Nnenna, Dobson, Samuel J., Knight, Laura M., Wasson, Christopher W., Salguero Bodes, Francisco, Blackbourn, David, Blair, G. Eric, Mankouri, Jamel, Macdonald, Andrew and Whitehouse, Adrian (2017) Merkel cell polyomavirus small T antigen drives cell motility via Rho-GTPase-induced filopodia formation Journal of Virology, 92 (2), e00940-17. pp. 1-21.

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Abstract

Cell motility and migration is a complex, multi-step, and multi-component process, intrinsic to progression and metastasis. Motility is dependent on the activity of integrin receptors and Rho-family GTPases resulting in the remodelling of the actin cytoskeleton and formation of various motile actin-based protrusions. Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high likelihood of recurrence and metastasis. Merkel cell polyomavirus (MCPyV) is associated with the majority of MCC cases, and MCPyV-induced tumourigenesis largely depends on the expression of the small tumour antigen (ST). Since the discovery of MCPyV, a number of mechanisms have been suggested to account for replication and tumourigenesis, but to date, little is known about potential links between MCPyV T antigen expression and the metastatic nature of MCC. Previously, we have described the action of MCPyV ST on the microtubule network and how this impacts on cell motility and migration. Here we demonstrate that MCPyV ST affects the actin cytoskeleton, to promote the formation of filopodia, through a mechanism involving the catalytic subunit of protein phosphatase 4 (PP4C). We also show that MCPyV ST-induced cell motility is dependent upon the activity of Rho-family GTPases Cdc42 and RhoA. In addition, our results indicate that the MCPyV ST-PP4C interaction results in the dephosphorylation of β1 integrin, likely driving the cell motility pathway. These findings describe a novel mechanism by which a tumour virus induces cell motility, which may ultimately lead to cancer metastasis and provides opportunities and strategies for targeted interventions for disseminated MCC.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Veterinary Medicine
Authors :
NameEmailORCID
Stakaitytė, Gabrielė
Nwogu, Nnenna
Dobson, Samuel J.
Knight, Laura M.
Wasson, Christopher W.
Salguero Bodes, Franciscof.salguerobodes@surrey.ac.uk
Blackbourn, Davidd.blackbourn@surrey.ac.uk
Blair, G. Eric
Mankouri, Jamel
Macdonald, Andrew
Whitehouse, Adrian
Date : 1 November 2017
Funders : Biotechnology and Biological Sciences Research Council (BBSRC)
Identification Number : 10.1128/JVI.00940-17
Copyright Disclaimer : Copyright © 2017 Stakaityte et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Uncontrolled Keywords : DNA viruses; Tumour virus; Cell motility; Cell migration; Merkel cell; Polyomavirus
Depositing User : Clive Harris
Date Deposited : 20 Nov 2017 10:55
Last Modified : 14 Mar 2018 13:15
URI: http://epubs.surrey.ac.uk/id/eprint/844950

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