Constitutive β-catenin signaling by the viral chemokine receptor US28

E.V. Langemeijer, E. Slinger, S.M. de Munnik, A. Schreiber, D. Maussang, H.F. Vischer, F. Verkaar, R. Leurs, M.H. Siderius, M.J. Smit

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Abstract

Chronic activation of Wnt/ß-catenin signaling is found in a variety of human malignancies including melanoma, colorectal and hepatocellular carcinomas. Interestingly, expression of the HCMV-encoded chemokine receptor US28 in intestinal epithelial cells promotes intestinal neoplasia in transgenic mice, which is associated with increased nuclear accumulation of ß-catenin. In this study we show that this viral receptor constitutively activates ß-catenin and enhances ß-catenin-dependent transcription. Our data illustrate that this viral receptor does not activate ß-catenin via the classical Wnt/Frizzled signaling pathway. Analysis of US28 mediated signaling indicates the involvement of the Rho-Rho kinase (ROCK) pathway in the activation of ß-catenin. Moreover, cells infected with HCMV show significant increases in ß-catenin stabilization and signaling, which is mediated to a large extent by expression of US28. The modulation of the ß-catenin signal transduction pathway by a viral chemokine receptor provides alternative regulation of this pathway, with potential relevance for the development of colon cancer and virus-associated diseases. © 2012 Langemeijer et al.
Original languageEnglish
Pages (from-to)e48935
JournalPLoS ONE
Volume7
DOIs
Publication statusPublished - 2012

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