IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis

G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that transmit diverse extracellular signals across a membrane. Herpesvirus genomes encode multiple GPCRs implicated in viral pathogenesis. Kaposi sarcoma-associated herpesvirus GPCR (kGPCR) activates proliferative pathways and, whe...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 27; pp. 11139 - 11144
Main Authors:	Wang, Yi, Lu, Xiaolu, Zhu, Lining, Shen, Yan, Chengedza, Shylet, Feng, Hao, Wang, Laiyee, Jung, Jae U., Gutkind, Julio S., Feng, Pinghui
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 02-07-2013 National Acad Sciences
Subjects:	Animals Biological Sciences Cell lines Cell nucleus Cellular immunity Endothelial cells Enzyme Activation HEK293 Cells Herpesvirus 8, Human - genetics Herpesvirus 8, Human - metabolism Herpesvirus 8, Human - pathogenicity Host-Pathogen Interactions - genetics Human herpesvirus 8 Human umbilical vein endothelial cells Humans I-kappa B Kinase - genetics I-kappa B Kinase - metabolism Kaposi sarcoma Kinases Lesions Membranes Mice Mice, Nude Paracrine Communication - genetics Phosphorylation Polymerase chain reaction Receptors, Chemokine - metabolism Sarcoma, Kaposi - etiology Sarcoma, Kaposi - genetics Sarcoma, Kaposi - metabolism Signal transduction Transcription Factor RelA - metabolism Transplantation, Heterologous Tumors Up-Regulation - genetics Viral Proteins - metabolism Virology sarcomagenesis inflammation associated
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Summary:	G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that transmit diverse extracellular signals across a membrane. Herpesvirus genomes encode multiple GPCRs implicated in viral pathogenesis. Kaposi sarcoma-associated herpesvirus GPCR (kGPCR) activates proliferative pathways and, when expressed in endothelium in mice, sufficiently induces angiogenic tumor resembling human Kaposi's sarcoma. IKKε, an IκB kinase (IKK)-related kinase, is implicated in inflammation-driven tumorigenesis. We report here that IKKε is critically required for kGPCR tumorigenesis and links kGPCR to NF-κB activation. Using kGPCR-induced tumor models, we found that IKKε expression was drastically up-regulated in Kaposi sarcoma-like lesions and that loss of IKKε abolished tumor formation. Moreover, kGPCR interacted with and activated IKKε. Activated IKKε promoted NF-κB subunit RelA (also known as p65) phosphorylation, which correlated with NF-κB activation and inflammatory cytokine expression. The robust expression of IKKε and phosphorylated RelA was observed in human Kaposi sarcoma. Finally, a kinase-defective mutant of IKKε effectively abrogated NF-κB activation and tumorigenesis induced by kGPCR. Collectively, our findings uncover a critical IKKε in promoting NF-κB activation and tumorigenesis induced by a viral GPCR.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Yuan Chang, University of Pittsburgh, Pittsburgh, PA, and approved May 20, 2013 (received for review November 14, 2012) Author contributions: Y.W. and P.F. designed research; Y.W., X.L., L.Z., Y.S., S.C., H.F., and P.F. performed research; L.W., J.U.J., J.S.G., and P.F. contributed new reagents/analytic tools; Y.W., X.L., and P.F. analyzed data; and Y.W., X.L., and P.F. wrote the paper. 1Y.W., X.L., and L.Z. contributed equally to this work.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1219829110