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.
© 2015 Zhang et al.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / immunology
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Actins / metabolism
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Amino Acid Motifs / genetics
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Amino Acid Motifs / immunology*
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Animals
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Antigens, Differentiation, T-Lymphocyte / genetics
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Antigens, Differentiation, T-Lymphocyte / immunology*
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Antigens, Differentiation, T-Lymphocyte / metabolism
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Calcium / immunology
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Calcium / metabolism
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Cell Line
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Cell Line, Tumor
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Cell Survival / genetics
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Cell Survival / immunology
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Cytokines / immunology
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Cytokines / metabolism
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Enzyme Activation / immunology
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Extracellular Signal-Regulated MAP Kinases / immunology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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GRB2 Adaptor Protein / genetics
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GRB2 Adaptor Protein / immunology
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GRB2 Adaptor Protein / metabolism
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Humans
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Immunoblotting
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology*
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Mice, Inbred C57BL
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Mice, Knockout
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Microscopy, Confocal
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Polymerization
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Protein Binding / immunology
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Proto-Oncogene Proteins c-akt / immunology
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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Signal Transduction / genetics
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Signal Transduction / immunology
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T Lineage-Specific Activation Antigen 1
Substances
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Actins
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Antigens, Differentiation, T-Lymphocyte
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T Lineage-Specific Activation Antigen 1
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Cytokines
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GRB2 Adaptor Protein
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Grb2 protein, mouse
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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Calcium