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How NF-\u03baB 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-\u03baB activation. Rather, cooperation between these receptors is required at the level of Vav1 for synergistic NF-\u03baB activation. Vav1-dependent synergistic signalling requires a separate PI3K-Akt signal, primarily mediated by NKG2D or DNAM-1, for optimal p65 phosphorylation and NF-\u03baB activation. Vav1 controls downstream p65 phosphorylation and NF-\u03baB 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-\u03baB activation. Thus, our study provides a framework explaining how signals from different activating receptors are coordinated to determine specificity and magnitude of NF-\u03baB activation and NK cell responses.<\/jats:p>","DOI":"10.1038\/ncomms11686","type":"journal-article","created":{"date-parts":[[2016,5,25]],"date-time":"2016-05-25T10:52:24Z","timestamp":1464173544000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":146,"title":["Stepwise phosphorylation of p65 promotes NF-\u03baB activation and NK cell responses during target cell recognition"],"prefix":"10.1038","volume":"7","author":[{"given":"Hyung-Joon","family":"Kwon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Go-Eun","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangryeol","family":"Ryu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soon Jae","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun Chang","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Booth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim E.","family":"Nichols","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hun Sik","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,5,25]]},"reference":[{"key":"BFncomms11686_CR1","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1146\/annurev-immunol-020711-075005","volume":"31","author":"EO Long","year":"2013","unstructured":"Long, E. 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