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.
Highlights
The Wnt/ß-catenin signaling pathway plays critical roles in embryonic development, stem cell self-renewal and regeneration [1,2]
In this study we show that the human cytomegalovirus (HCMV)-encoded G protein-coupled receptors (GPCRs) US28 positively modulates ß-catenin signaling, resulting in enhanced ß-catenin-dependent transcription
We have demonstrated that HCMV partly through expression of the constitutively active chemokine receptor US28 induces ßcatenin signaling upon infection
Summary
The Wnt/ß-catenin signaling pathway plays critical roles in embryonic development, stem cell self-renewal and regeneration [1,2]. The importance of GPCR-mediated signaling in onset and development of various types cancer [9] is underscored by the observation that ß-catenin activation is triggered by a 7TM spanning receptor, Frizzled which is activated by its cognate ligand Wnt [1]. The human protease-activated receptor-1 (PAR-1) stabilizes ß-catenin through phosphorylation of GSK-3ß at Ser9 These pathways converge on the Wnt signaling route to induce cytoplasmic ßcatenin accumulation, nuclear localization, and enhanced transcriptional activation [14]. Transcriptional profiling of US28-expressing fibroblasts indicated an overrepresentation of genes involved in the Wnt/ß-catenin signaling pathway [27] These observations suggest that US28 may facilitate transformation and development of intestinal neoplasia via activation of ß-catenin [26]. In this study we show that the viral chemokine receptor US28 positively modulates the ß-catenin pathway via a non-conventional novel pathway, involving Rho kinase
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