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.
Billadeau
Daniel D
DD
Division of Oncology Research, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester, Minnesota 55905, USA.
Upshaw
Jadee L
JL
Schoon
Renee A
RA
Dick
Christopher J
CJ
Leibson
Paul J
PJ
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