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 language | English |
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Article number | e00940-17 |
Journal | Journal of Virology |
Volume | 92 |
Issue number | 2 |
DOIs | |
Publication status | Published - 1 Jan 2018 |
Bibliographical note
Funding Information:The work was funded in part by a BBSRC DTP studentship (BB/J014443/1), an MRC DTG studentship (95505126), and a Royal Society University Research Fellowship to J.M. (UF100419).
Publisher Copyright:
© 2018 American Society for Microbiology.
Keywords
- Cell migration
- Cell motility
- DNA viruses
- Merkel cell
- Polyomavirus
- Tumor virus