NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway.
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.
Division of Oncology Research, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester, Minnesota 55905, USA.
Daniel D
DD
Billadeau
Jadee L
JL
Upshaw
Renee A
RA
Schoon
Christopher J
CJ
Dick
Paul J
PJ
Leibson
D020816:Amino Acid Motifs / Q000276:immunology; D000818:Animals; D018797:Cell Cycle Proteins; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004792:Enzyme Precursors / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D055655:NK Cell Lectin-Like Receptor Subfamily K; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000276:immunology; D051567:Proto-Oncogene Proteins c-vav; D011971:Receptors, Immunologic / Q000276:immunology*; D055607:Receptors, Natural Killer Cell; D015398:Signal Transduction / Q000276:immunology; D000072377:Syk Kinase; D010738:Type C Phospholipases / Q000276:immunology; D020741:rho GTP-Binding Proteins / Q000276:immunology; D018909:src Homology Domains / Q000276:immunology
D018797:Cell Cycle Proteins; D004792:Enzyme Precursors; C120528:HCST protein, human; C492355:Hcst protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C496618:VAV1 protein, human; C496619:Vav1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D010738:Type C Phospholipases; D020741:rho GTP-Binding Proteins