title: DNAM-1 controls NK cell activation via an ITT-like motif.
abstract: DNAM-1 (CD226) is an activating receptor expressed on natural killer (NK) cells, CD8(+) T cells, and other immune cells. Upon recognition of its ligands, CD155 and CD112, DNAM-1 promotes NK cell-mediated elimination of transformed and virus-infected cells. It also has a key role in expansion and maintenance of virus-specific memory NK cells. Herein, the mechanism by which DNAM-1 controls NK cell-mediated cytotoxicity and cytokine production was elucidated. Cytotoxicity and cytokine production triggered by DNAM-1 were mediated via a conserved tyrosine- and asparagine-based motif in the cytoplasmic domain of DNAM-1. Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3' kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization. We propose that DNAM-1 promotes NK cell activation via an immunoreceptor tyrosine tail (ITT)-like motif coupling DNAM-1 to Grb2 and other downstream effectors.
authors.affiliation: Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec H2W 1R7, Canada Department of Medicine, McGill University, Montréal, Québec H3G 1Y6, Canada.
authors.forename: Zhanguang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
authors.forename: Ning
authors.initials: N
authors.lastname: Wu
authors.affiliation: Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
authors.forename: Dominique
authors.initials: D
authors.lastname: Davidson
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.affiliation: Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec H2W 1R7, Canada Department of Medicine, McGill University, Montréal, Québec H3G 1Y6, Canada Department of Medicine, University of Montréal, Montréal, Québec H3T 1J4, Canada veillea@ircm.qc.ca.
authors.forename: André
authors.initials: A
authors.lastname: Veillette
mesh_terms: D000199:Actins / Q000276:immunology / Q000378:metabolism; D020816:Amino Acid Motifs / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D058105:Polymerization; D011485:Protein Binding / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000199:Actins; D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D016207:Cytokines; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium