title: Stepwise phosphorylation of p65 promotes NF-κB activation and NK cell responses during target cell recognition.
abstract: NF-κB is a key transcription factor that dictates the outcome of diverse immune responses. How NF-κB is regulated by multiple activating receptors that are engaged during natural killer (NK)-target cell contact remains undefined. Here we show that sole engagement of NKG2D, 2B4 or DNAM-1 is insufficient for NF-κB activation. Rather, cooperation between these receptors is required at the level of Vav1 for synergistic NF-κB activation. Vav1-dependent synergistic signalling requires a separate PI3K-Akt signal, primarily mediated by NKG2D or DNAM-1, for optimal p65 phosphorylation and NF-κB activation. Vav1 controls downstream p65 phosphorylation and NF-κB activation. Synergistic signalling is defective in X-linked lymphoproliferative disease (XLP1) NK cells entailing 2B4 dysfunction and required for p65 phosphorylation by PI3K-Akt signal, suggesting stepwise signalling checkpoint for NF-κB activation. Thus, our study provides a framework explaining how signals from different activating receptors are coordinated to determine specificity and magnitude of NF-κB activation and NK cell responses.
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, 86 Asanbyeongwon-Gil, Seoul 138-735, Korea.
authors.forename: Hyung-Joon
authors.initials: HJ
authors.lastname: Kwon
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, 86 Asanbyeongwon-Gil, Seoul 138-735, Korea.|Institute of Convergence Bio-Health, Dong-A University, Busan, Korea.
authors.forename: Go-Eun
authors.initials: GE
authors.lastname: Choi
authors.affiliation: Department of Food and Animal Biotechnology, Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Korea.
authors.forename: Sangryeol
authors.initials: S
authors.lastname: Ryu
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, 86 Asanbyeongwon-Gil, Seoul 138-735, Korea.
authors.forename: Soon Jae
authors.initials: SJ
authors.lastname: Kwon
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Sun Chang
authors.initials: SC
authors.lastname: Kim
authors.affiliation: Molecular Immunology Unit, Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Booth
authors.affiliation: Department of Oncology, Division of Cancer Predisposition, St Jude Children's Research Hospital, Memphis, Tennessee 38105-3678, USA.
authors.forename: Kim E
authors.initials: KE
authors.lastname: Nichols
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, 86 Asanbyeongwon-Gil, Seoul 138-735, Korea.|Department of Microbiology, University of Ulsan College of Medicine, Seoul 138-735, Korea.|Cellular Dysfunction Research Center, University of Ulsan College of Medicine, Seoul 138-735, Korea.
authors.forename: Hun Sik
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism*; D008232:Lymphoproliferative Disorders / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D000071176:Signaling Lymphocytic Activation Molecule Family / Q000378:metabolism*; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; C084093:CD244 protein, human; C527085:KLRK1 protein, human; D016328:NF-kappa B; D055655:NK Cell Lectin-Like Receptor Subfamily K; D051567:Proto-Oncogene Proteins c-vav; D000071176:Signaling Lymphocytic Activation Molecule Family; C496618:VAV1 protein, human