Abstract
The immune recognition receptor complex NKG2D-DAP10 on natural killer cells is stimulated by specific ligands carried on virus-infected and malignant cells. Because DAP10 does not have an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic tail, its ability to trigger killing has been debated. Here we show that a crucial Tyr-Ile-Asn-Met amino acid motif in the cytoplasmic tail of DAP10 couples receptor stimulation to the downstream activation of phosphatidylinositol 3-kinase, Vav1, Rho family GTPases and phospholipase C. Unlike that of ITAM-containing receptors, the activation of NKG2D-DAP10 proceeds independently of Syk family protein tyrosine kinases. Yet the signals initiated by NKG2D-DAP10 are fully capable of inducing killing. Our findings identify a previously unknown mechanism by which receptor complexes that lack ITAM motifs can trigger lymphocyte activation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Motifs / immunology
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Animals
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Cell Cycle Proteins*
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Cytotoxicity, Immunologic / immunology
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Enzyme Precursors / immunology*
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Enzyme Precursors / metabolism
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Humans
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Immunoblotting
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Intracellular Signaling Peptides and Proteins
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Jurkat Cells
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Killer Cells, Natural / immunology*
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Membrane Proteins / immunology*
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Mice
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NK Cell Lectin-Like Receptor Subfamily K
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Phosphatidylinositol 3-Kinases / immunology
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Protein-Tyrosine Kinases / immunology*
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins / immunology
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Proto-Oncogene Proteins c-vav
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Receptors, Immunologic / immunology*
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Receptors, Natural Killer Cell
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Signal Transduction / immunology
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Syk Kinase
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Type C Phospholipases / immunology
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rho GTP-Binding Proteins / immunology
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src Homology Domains / immunology
Substances
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Cell Cycle Proteins
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Enzyme Precursors
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HCST protein, human
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Hcst protein, mouse
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Intracellular Signaling Peptides and Proteins
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KLRK1 protein, human
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Klrk1 protein, mouse
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Membrane Proteins
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NK Cell Lectin-Like Receptor Subfamily K
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-vav
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Receptors, Immunologic
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Receptors, Natural Killer Cell
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VAV1 protein, human
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Vav1 protein, mouse
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Phosphatidylinositol 3-Kinases
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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Syk protein, mouse
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Type C Phospholipases
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rho GTP-Binding Proteins