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

Gabriele Stakaityte, Nnenna Nwogu, Samuel J. Dobson, Laura M. Knight, Christopher W. Wasson, Francisco J. Salguero, David J. Blackbourn, G. Eric Blair, Jamel Mankouri, Andrew Macdonald, Adrian Whitehouse*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

Cell motility and migration is a complex, multistep, and multicomponent process intrinsic to progression and metastasis. Motility is dependent on the activities of integrin receptors and Rho family GTPases, resulting in the remodeling 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 tumorigenesis largely depends on the expression of the small tumor antigen (ST). Since the discovery of MCPyV, a number of mechanisms have been suggested to account for replication and tumorigenesis, but to date, little is known about potential links between MCPyV T antigen expression and the metastatic nature of MCC. Previously, we described the action of MCPyV ST on the microtubule network and how it impacts 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 activities of the 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 tumor virus induces cell motility, which may ultimately lead to cancer metastasis, and provides opportunities and strategies for targeted interventions for disseminated MCC.

Original languageEnglish
Article numbere00940-17
JournalJournal of Virology
Volume92
Issue number2
DOIs
Publication statusPublished - 1 Jan 2018

Keywords

  • Cell migration
  • Cell motility
  • DNA viruses
  • Merkel cell
  • Polyomavirus
  • Tumor virus

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