Constitutive ?-catenin signaling by the viral chemokine receptor US28.

ABSTRACT: Chronic activation of Wnt/?-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 ?-catenin. In this study we show that this viral receptor constitutively activates ?-catenin and enhances ?-catenin-dependent transcription. Our data illustrate that this viral receptor does not activate ?-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 ?-catenin. Moreover, cells infected with HCMV show significant increases in ?-catenin stabilization and signaling, which is mediated to a large extent by expression of US28. The modulation of the ?-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.

SUBMITTER: Langemeijer EV 

PROVIDER: S-EPMC3493591 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature