title: Merkel cell polyomavirus small T antigen mediates microtubule destabilization to promote cell motility and migration.
abstract: Merkel cell carcinoma (MCC) is an aggressive skin cancer of neuroendocrine origin with a high propensity for recurrence and metastasis. Merkel cell polyomavirus (MCPyV) causes the majority of MCC cases due to the expression of the MCPyV small and large tumor antigens (ST and LT, respectively). Although a number of molecular mechanisms have been attributed to MCPyV tumor antigen-mediated cellular transformation or replication, to date, no studies have investigated any potential link between MCPyV T antigen expression and the highly metastatic nature of MCC. Here we use a quantitative proteomic approach to show that MCPyV ST promotes differential expression of cellular proteins implicated in microtubule-associated cytoskeletal organization and dynamics. Intriguingly, we demonstrate that MCPyV ST expression promotes microtubule destabilization, leading to a motile and migratory phenotype. We further highlight the essential role of the microtubule-associated protein stathmin in MCPyV ST-mediated microtubule destabilization and cell motility and implicate the cellular phosphatase catalytic subunit protein phosphatase 4C (PP4C) in the regulation of this process. These findings suggest a possible molecular mechanism for the highly metastatic phenotype associated with MCC.
  
  
  OBJECTIVE
  Merkel cell polyomavirus (MCPyV) causes the majority of cases of Merkel cell carcinoma (MCC), an aggressive skin cancer with a high metastatic potential. However, the molecular mechanisms leading to virally induced cancer development have yet to be fully elucidated. In particular, no studies have investigated any potential link between the virus and the highly metastatic nature of MCC. We demonstrate that the MCPyV small tumor antigen (ST) promotes the destabilization of the host cell microtubule network, which leads to a more motile and migratory cell phenotype. We further show that MCPyV ST induces this process by regulating the phosphorylation status of the cellular microtubule-associated protein stathmin by its known association with the cellular phosphatase catalytic subunit PP4C. These findings highlight stathmin as a possible biomarker of MCC and as a target for novel antitumoral therapies.
authors.affiliation: School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Knight
authors.affiliation: School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Stakaityte
authors.affiliation: School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wood
authors.affiliation: School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: Hussein
authors.initials: H
authors.lastname: Abdul-Sada
authors.affiliation: School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Griffiths
authors.affiliation: School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Howell
authors.affiliation: School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Wheat
authors.affiliation: School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: G Eric
authors.initials: GE
authors.lastname: Blair
authors.affiliation: School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Steven
authors.affiliation: School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Macdonald
authors.affiliation: School of Biosciences & Medicine, University of Surrey, Surrey, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Blackbourn
authors.affiliation: School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom a.whitehouse@leeds.ac.uk.
authors.forename: Adrian
authors.initials: A
authors.lastname: Whitehouse
mesh_terms: D000957:Antigens, Viral, Tumor / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D006801:Humans; D059965:Merkel cell polyomavirus / Q000502:physiology*; D008870:Microtubules / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D020543:Proteome / Q000032:analysis; D050777:Stathmin / Q000378:metabolism
chemical_list: D000957:Antigens, Viral, Tumor; D020543:Proteome; C493995:STMN1 protein, human; D050777:Stathmin; D010749:Phosphoprotein Phosphatases; C080406:protein phosphatase 4