Viral factors interact with host cellular proteins, leading to dysregulation of signaling pathways. The Wnt pathway is known to participate in embryonic development and oncogenesis under dysregulation conditions. A downstream factor of the Wnt signaling pathway, beta-catenin, activates T-cell factor (TCF)-dependent transcription, which contributes to cell proliferation and tumorigenesis. In this study, we demonstrated that viral protein kinase (vPK) encoded by Kaposi's sarcoma-associated herpesvirus inhibits the Wnt signaling pathway without affecting nuclear localization and expression of beta-catenin. Coimmunoprecipitation and chromatin immunoprecipitation assays revealed that vPK interacts with beta-catenin, reducing the binding affinity on TCF binding regions as well as interactions of beta-catenin with TCF4. Overexpression of vPK led to reduced mRNA expression of cyclin D1, a well-known transcriptional product of Wnt signaling, suggesting that vPK effectively regulates the host signaling pathway through direct interactions with cellular proteins. (C) 2018 Elsevier Inc. All rights reserved.