title: The oncogenic protein kinase Tpl-2/Cot contributes to Epstein-Barr virus-encoded latent infection membrane protein 1-induced NF-kappaB signaling downstream of TRAF2.
abstract: The Epstein-Barr virus-encoded latent infection membrane protein 1 (LMP1) is a pleiotropic protein, the activities of which include effects on cell transformation and phenotype, growth, and survival. The ability of LMP1 to mediate at least some of these phenomena could be attributed to the activation of the transcription factor NF-kappaB. LMP1 promotes NF-kappaB activation through the recruitment of the adapter protein TRAF2 and the formation of a dynamic multiprotein complex that includes the NF-kappaB kinase, the IkappaB kinases, and their downstream targets, IkappaBs and p105. In this study, we have identified the oncogenic kinase Tpl-2/Cot as a novel component of LMP1-induced NF-kappaB signaling. We show that Tpl-2 is expressed in primary biopsies from patients with nasopharyngeal carcinoma and Hodgkin's disease, where LMP1 is also found. Inducible expression of LMP1 promotes the activation of Tpl-2, and a catalytically inactive Tpl-2 mutant suppresses LMP1-induced NF-kappaB signaling. In colocalization and coimmunoprecipitation experiments, Tpl-2 and TRAF2 were found to interact with Tpl-2 functioning downstream of TRAF2. Consistent with this observation, catalytically inactive Tpl-2 also blocked CD40-mediated NF-kappaB activation, which largely depends on TRAF2. The ability of Tpl-2 to influence LMP1-induced NF-kappaB occurs through modulation of both IkappaBalpha and p105 functions. Furthermore, Tpl-2 was found to influence the expression of angiogenic mediators, such as COX-2 in LMP1-transfected cells. These data identify Tpl-2 as a component of LMP1 signaling downstream of TRAF2 and as a modulator of LMP1-mediated effects.
authors.affiliation: The Cancer Research UK Institute for Cancer Studies, The University of Birmingham Medical School, Birmingham B15 2TA, England. A.G.Eliopoulos@bham.ac.uk
authors.forename: Aristides G
authors.initials: AG
authors.lastname: Eliopoulos
authors.forename: Clare
authors.initials: C
authors.lastname: Davies
authors.forename: Sarah S M
authors.initials: SS
authors.lastname: Blake
authors.forename: Paul
authors.initials: P
authors.lastname: Murray
authors.forename: Sohrab
authors.initials: S
authors.lastname: Najafipour
authors.forename: Philip N
authors.initials: PN
authors.lastname: Tsichlis
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Young
mesh_terms: D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002277:Carcinoma / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D051546:Cyclooxygenase 2; D003598:Cytoskeletal Proteins; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism; D006689:Hodgkin Disease / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism; D060588:LIM Domain Proteins; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism* / Q000494:pharmacology; D008565:Membrane Proteins; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism* / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism; D012269:Ribosomal Proteins; D015398:Signal Transduction / Q000187:drug effects; D047992:TNF Receptor-Associated Factor 2; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; C484380:PDLIM7 protein, human; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins; C489369:Rpl22 protein, rat; D047992:TNF Receptor-Associated Factor 2; C067169:RPL22 protein, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; C489843:Map3k8 protein, mouse