title: Vav1 controls DAP10-mediated natural cytotoxicity by regulating actin and microtubule dynamics.
abstract: The NK cell-activating receptor NKG2D recognizes several MHC class I-related molecules expressed on virally infected and tumor cells. Human NKG2D transduces activation signals exclusively via an associated DAP10 adaptor containing a YxNM motif, whereas murine NKG2D can signal through either DAP10 or the DAP12 adaptor, which contains an ITAM sequence. DAP10 signaling is thought to be mediated, at least in part, by PI3K and is independent of Syk/Zap-70 kinases; however, the exact mechanism by which DAP10 induces natural cytotoxicity is incompletely understood. Herein, we identify Vav1, a Rho GTPase guanine nucleotide exchange factor, as a critical signaling mediator downstream of DAP10 in NK cells. Specifically, using mice deficient in Vav1 and DAP12, we demonstrate an essential role for Vav1 in DAP10-induced NK cell cytoskeletal polarization involving both actin and microtubule networks, maturation of the cytolytic synapse, and target cell lysis. Mechanistically, we show that Vav1 interacts with DAP10 YxNM motifs through the adaptor protein Grb2 and is required for activation of PI3K-dependent Akt signaling. Based on these findings, we propose a novel model of ITAM-independent signaling by Vav downstream of DAP10 in NK cells.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine and Siteman Cancer Center, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Graham
authors.forename: Marina
authors.initials: M
authors.lastname: Cella
authors.forename: Emanuele
authors.initials: E
authors.lastname: Giurisato
authors.forename: Keiko
authors.initials: K
authors.lastname: Fujikawa
authors.forename: Ana V
authors.initials: AV
authors.lastname: Miletic
authors.forename: Tracie
authors.initials: T
authors.lastname: Kloeppel
authors.forename: Karry
authors.initials: K
authors.lastname: Brim
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takai
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Shaw
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.forename: Wojciech
authors.initials: W
authors.lastname: Swat
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism*; D055655:NK Cell Lectin-Like Receptor Subfamily K; D051567:Proto-Oncogene Proteins c-vav / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D055607:Receptors, Natural Killer Cell; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000199:Actins; C492355:Hcst protein, mouse; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D051567:Proto-Oncogene Proteins c-vav; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C496619:Vav1 protein, mouse