| First Author | Wang Y | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 27 | Pages | 11139-44 |
| PubMed ID | 23771900 | Mgi Jnum | J:198717 |
| Mgi Id | MGI:5499040 | Doi | 10.1073/pnas.1219829110 |
| Citation | Wang Y, et al. (2013) IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis. Proc Natl Acad Sci U S A 110(27):11139-44 |
| abstractText | 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. IKKepsilon, an IkappaB kinase (IKK)-related kinase, is implicated in inflammation-driven tumorigenesis. We report here that IKKepsilon is critically required for kGPCR tumorigenesis and links kGPCR to NF-kappaB activation. Using kGPCR-induced tumor models, we found that IKKepsilon expression was drastically up-regulated in Kaposi sarcoma-like lesions and that loss of IKKepsilon abolished tumor formation. Moreover, kGPCR interacted with and activated IKKepsilon. Activated IKKepsilon promoted NF-kappaB subunit RelA (also known as p65) phosphorylation, which correlated with NF-kappaB activation and inflammatory cytokine expression. The robust expression of IKKepsilon and phosphorylated RelA was observed in human Kaposi sarcoma. Finally, a kinase-defective mutant of IKKepsilon effectively abrogated NF-kappaB activation and tumorigenesis induced by kGPCR. Collectively, our findings uncover a critical IKKepsilon in promoting NF-kappaB activation and tumorigenesis induced by a viral GPCR. |
