Abstract
ABSTRACTCell 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.IMPORTANCE Merkel cell polyomavirus (MCPyV) is the most recently discovered human tumor virus. It causes the majority of cases of Merkel cell carcinoma (MCC), an aggressive skin cancer. However, the molecular mechanisms implicating MCPyV-encoded proteins in cancer development are yet to be fully elucidated. This study builds upon our previous observations, which demonstrated that the MCPyV ST antigen enhances cell motility, providing a potential link between MCPyV protein expression and the highly metastatic nature of MCC. Here, we show that MCPyV ST remodels the actin cytoskeleton, promoting the formation of filopodia, which is essential for MCPyV ST-induced cell motility, and we also implicate the activity of specific Rho family GTPases, Cdc42 and RhoA, in these processes. Moreover, we describe a novel mechanism for the activation of Rho-GTPases and the cell motility pathway due to the interaction between MCPyV ST and the cellular phosphatase catalytic subunit PP4C, which leads to the specific dephosphorylation of β1 integrin. These findings may therefore provide novel strategies for therapeutic intervention for disseminated MCC.
Highlights
Cell motility and migration is a complex, multistep, and multicomponent process intrinsic to progression and metastasis
The results demonstrated that Merkel cell polyomavirus (MCPyV) small tumor antigen (ST) expression led to the upregulation of the microtubuleassociated protein stathmin, which affects microtubule dissociation [46]
We have previously shown the importance of the interaction between MCPyV ST and PP4C with regard to MCPyV ST-induced cell motility using a deletion mutant of MCPyV termed enhanced green fluorescent protein (EGFP)-STΔ95–111
Summary
Cell motility and migration is a complex, multistep, and multicomponent process intrinsic to progression and metastasis. We describe a novel mechanism for the activation of Rho-GTPases and the cell motility pathway due to the interaction between MCPyV ST and the cellular phosphatase catalytic subunit PP4C, which leads to the specific dephosphorylation of 1 integrin These findings may provide novel strategies for therapeutic intervention for disseminated MCC. The fast-growing barbed ends of actin filaments are oriented toward the plasma membrane, and the elongation of these protrusions pushes the leading edge forward, promoting cell migration [1] This complex cell motility process occurs via the remodeling of the actin cytoskeleton, which is controlled by the Rho family GTPases, a large group of signaling molecules that act as signal mediators in the motility pathway. Integrins play a well-recognized role in cancer progression [19]
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