title: Constitutive β-catenin signaling by the viral chemokine receptor US28.
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.
authors.affiliation: Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, VU University Amsterdam, The Netherlands.
authors.forename: Ellen V
authors.initials: EV
authors.lastname: Langemeijer
authors.forename: Erik
authors.initials: E
authors.lastname: Slinger
authors.forename: Sabrina
authors.initials: S
authors.lastname: de Munnik
authors.forename: Andreas
authors.initials: A
authors.lastname: Schreiber
authors.forename: David
authors.initials: D
authors.lastname: Maussang
authors.forename: Henry
authors.initials: H
authors.lastname: Vischer
authors.forename: Folkert
authors.initials: F
authors.lastname: Verkaar
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: Marco
authors.initials: M
authors.lastname: Siderius
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Smit
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D019707:Receptors, Chemokine / Q000235:genetics* / Q000378:metabolism*; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D019707:Receptors, Chemokine; D011991:Receptors, Virus; C411191:US28 receptor, Cytomegalovirus; D014764:Viral Proteins; D051176:beta Catenin; D054460:rho-Associated Kinases