Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Sci. Signal., 3 August 2010
Vol. 3, Issue 133, p. ra58
[DOI: 10.1126/scisignal.2001180]

RESEARCH ARTICLES

HCMV-Encoded Chemokine Receptor US28 Mediates Proliferative Signaling Through the IL-6–STAT3 Axis

Erik Slinger1, David Maussang1, Andreas Schreiber1, Marco Siderius1, Afsar Rahbar2, Alberto Fraile-Ramos3,4, Sergio A. Lira5, Cecilia Söderberg-Nauclér2, and Martine J. Smit1*

1 Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, the Netherlands.
2 Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital Solna and Karolinska Institutet, 171 76 Stockholm, Sweden.
3 Department of Molecular and Cell Biology, Centro Nacional de Biotecnologia, Consejo Superior de Investigaciones Cientificas, Campus Universidad Autonoma de Madrid, 28006 Madrid, Spain.
4 MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
5 Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.

Abstract: US28 is a viral G protein (heterotrimeric guanosine triphosphate–binding protein)–coupled receptor encoded by the human cytomegalovirus (HCMV). In addition to binding and internalizing chemokines, US28 constitutively activates signaling pathways linked to cell proliferation. Here, we show increased concentrations of vascular endothelial growth factor and interleukin-6 (IL-6) in supernatants of US28-expressing NIH 3T3 cells. Increased IL-6 was associated with increased activation of the signal transducer and activator of transcription 3 (STAT3) through upstream activation of the Janus-activated kinase JAK1. We used conditioned growth medium, IL-6–neutralizing antibodies, an inhibitor of the IL-6 receptor, and short hairpin RNA targeting IL-6 to show that US28 activates the IL-6–JAK1–STAT3 signaling axis through activation of the transcription factor nuclear factor {kappa}B and the consequent production of IL-6. Treatment of cells with a specific inhibitor of STAT3 inhibited US28-dependent [3H]thymidine incorporation and foci formation, suggesting a key role for STAT3 in the US28-mediated proliferative phenotype. US28 also elicited STAT3 activation and IL-6 secretion in HCMV-infected cells. Analyses of tumor specimens from glioblastoma patients demonstrated colocalization of US28 and phosphorylated STAT3 in the vascular niche of these tumors. Moreover, increased phospho-STAT3 abundance correlated with poor patient outcome. We propose that US28 induces proliferation in HCMV-infected tumors by establishing a positive feedback loop through activation of the IL-6–STAT3 signaling axis.

* To whom correspondence should be addressed. E-mail: mj.smit{at}few.vu.nl

Citation: E. Slinger, D. Maussang, A. Schreiber, M. Siderius, A. Rahbar, A. Fraile-Ramos, S. A. Lira, C. Söderberg-Nauclér, M. J. Smit, HCMV-Encoded Chemokine Receptor US28 Mediates Proliferative Signaling Through the IL-6–STAT3 Axis. Sci. Signal. 3, ra58 (2010).

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
International Union of Basic and Clinical Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors.
F. Bachelerie, A. Ben-Baruch, A. M. Burkhardt, C. Combadiere, J. M. Farber, G. J. Graham, R. Horuk, A. H. Sparre-Ulrich, M. Locati, A. D. Luster, et al. (2014)
Pharmacol. Rev. 66, 1-79
   Abstract »    Full Text »    PDF »
Human cytomegalovirus immediate early proteins promote degradation of connexin 43 and disrupt gap junction communication: implications for a role in gliomagenesis.
Z. Khan, K.-C. Yaiw, V. Wilhelmi, H. Lam, A. Rahbar, G. Stragliotto, and C. Soderberg-Naucler (2014)
Carcinogenesis 35, 145-154
   Abstract »    Full Text »    PDF »
Cidofovir: A Novel Antitumor Agent for Glioblastoma.
P. Hadaczek, T. Ozawa, L. Soroceanu, Y. Yoshida, L. Matlaf, E. Singer, E. Fiallos, C. D. James, and C. S. Cobbs (2013)
Clin. Cancer Res. 19, 6473-6483
   Abstract »    Full Text »    PDF »
Human Cytomegalovirus IE1 Protein Disrupts Interleukin-6 Signaling by Sequestering STAT3 in the Nucleus.
J. M. Reitsma, H. Sato, M. Nevels, S. S. Terhune, and C. Paulus (2013)
J. Virol. 87, 10763-10776
   Abstract »    Full Text »    PDF »
Cytomegalovirus Contributes to Glioblastoma in the Context of Tumor Suppressor Mutations.
R. L. Price, J. Song, K. Bingmer, T. H. Kim, J.-Y. Yi, M. O. Nowicki, X. Mo, T. Hollon, E. Murnan, C. Alvarez-Breckenridge, et al. (2013)
Cancer Res. 73, 3441-3450
   Abstract »    Full Text »    PDF »
Activation of IL-6R/JAK1/STAT3 Signaling Induces De Novo Resistance to Irreversible EGFR Inhibitors in Non-Small Cell Lung Cancer with T790M Resistance Mutation.
S. M. Kim, O.-J. Kwon, Y. K. Hong, J. H. Kim, F. Solca, S.-J. Ha, R. A. Soo, J. G. Christensen, J. H. Lee, and B. C. Cho (2012)
Mol. Cancer Ther. 11, 2254-2264
   Abstract »    Full Text »    PDF »
Consensus on the role of human cytomegalovirus in glioblastoma.
K. Dziurzynski, S. M. Chang, A. B. Heimberger, R. F. Kalejta, S. R. McGregor Dallas, M. Smit, L. Soroceanu, C. S. Cobbs, and the HCMV and Gliomas Symposium (2012)
Neuro Oncology 14, 246-255
   Abstract »    Full Text »    PDF »
Significant Association of Multiple Human Cytomegalovirus Genomic Loci with Glioblastoma Multiforme Samples.
P. Ranganathan, P. A. Clark, J. S. Kuo, M. S. Salamat, and R. F. Kalejta (2012)
J. Virol. 86, 854-864
   Abstract »    Full Text »    PDF »
Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis.
N. Sen, X. Che, J. Rajamani, L. Zerboni, P. Sung, J. Ptacek, and A. M. Arvin (2012)
PNAS 109, 600-605
   Abstract »    Full Text »    PDF »
Paracrine inhibition of GM-CSF signaling by human cytomegalovirus in monocytes differentiating to dendritic cells.
J. Carlier, H. Martin, B. Mariame, B. Rauwel, C. Mengelle, H. Weclawiak, A. Coaquette, C. Vauchy, P. Rohrlich, N. Kamar, et al. (2011)
Blood 118, 6783-6792
   Abstract »    Full Text »    PDF »
Inhibition of Inflammatory Interleukin-6 Activity via Extracellular Signal-Regulated Kinase-Mitogen-Activated Protein Kinase Signaling Antagonizes Human Cytomegalovirus Reactivation from Dendritic Cells.
M. B. Reeves and T. Compton (2011)
J. Virol. 85, 12750-12758
   Abstract »    Full Text »    PDF »
Intragraft Cytomegalovirus Protein Expression Is Associated With Reduced Renal Allograft Survival.
M. Dzabic, A. Rahbar, K.-C. Yaiw, M. Naghibi, P. Religa, B. Fellstrom, E. Larsson, and C. Soderberg-Naucler (2011)
Clinical Infectious Diseases 53, 969-976
   Abstract »    Full Text »    PDF »
Human Cytomegalovirus US28 Found in Glioblastoma Promotes an Invasive and Angiogenic Phenotype.
L. Soroceanu, L. Matlaf, V. Bezrookove, L. Harkins, R. Martinez, M. Greene, P. Soteropoulos, and C. S. Cobbs (2011)
Cancer Res. 71, 6643-6653
   Abstract »    Full Text »    PDF »
Glioma-Associated Cytomegalovirus Mediates Subversion of the Monocyte Lineage to a Tumor Propagating Phenotype.
K. Dziurzynski, J. Wei, W. Qiao, M. A. Hatiboglu, L.-Y. Kong, A. Wu, Y. Wang, D. Cahill, N. Levine, S. Prabhu, et al. (2011)
Clin. Cancer Res. 17, 4642-4649
   Abstract »    Full Text »    PDF »
Is Cytomegalovirus a Therapeutic Target in Glioblastoma?.
J. H. Sampson and D. A. Mitchell (2011)
Clin. Cancer Res. 17, 4619-4621
   Abstract »    Full Text »    PDF »
Herpes viruses and tumours in kidney transplant recipients. The role of immunosuppression.
C. Ponticelli (2011)
Nephrol. Dial. Transplant. 26, 1769-1775
   Abstract »    Full Text »    PDF »
Receptors, Signaling Networks, and Disease.
N. Cuesta, N. B. Martin-Cofreces, C. Murga, and H. M. van Santen (2011)
Science Signaling 4, mr3
   Abstract »    Full Text »    PDF »
Science Signaling Podcast: 4 January 2011.
M. B. Yaffe and A. M. VanHook (2011)
Science Signaling 4, pc1
   Abstract »    Full Text »
Science Signaling Podcast: 3 August 2010.
M. J. Smit and A. M. VanHook (2010)
Science Signaling 3, pc16
   Abstract »    Full Text »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882