Constitutive β-catenin signaling by the viral chemokine receptor US28

PLoS One. 2012;7(11):e48935. doi: 10.1371/journal.pone.0048935. Epub 2012 Nov 8.

Abstract

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cytomegalovirus / genetics
  • Cytomegalovirus / metabolism
  • HEK293 Cells
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Receptors, Chemokine / genetics*
  • Receptors, Chemokine / metabolism*
  • Receptors, Virus / genetics
  • Receptors, Virus / metabolism
  • Signal Transduction
  • Transcription, Genetic
  • Viral Proteins / genetics*
  • Viral Proteins / metabolism*
  • beta Catenin / genetics*
  • beta Catenin / metabolism*
  • rho-Associated Kinases / genetics
  • rho-Associated Kinases / metabolism

Substances

  • Receptors, Chemokine
  • Receptors, Virus
  • US28 receptor, Cytomegalovirus
  • Viral Proteins
  • beta Catenin
  • rho-Associated Kinases

Grant support

This work was supported by The Netherlands Organization for Scientific Research (to E.L., S.d.M., F.V. and M.J.S.), The Royal Netherlands Academy of Arts and Sciences (to M.J.S.) and Echo grant (to E.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.