NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway

Nat Immunol. 2003 Jun;4(6):557-64. doi: 10.1038/ni929. Epub 2003 May 11.


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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs / immunology
  • Animals
  • Cell Cycle Proteins*
  • Cytotoxicity, Immunologic / immunology
  • Enzyme Precursors / immunology*
  • Enzyme Precursors / metabolism
  • Humans
  • Immunoblotting
  • Intracellular Signaling Peptides and Proteins
  • Jurkat Cells
  • Killer Cells, Natural / immunology*
  • Membrane Proteins / immunology*
  • Mice
  • NK Cell Lectin-Like Receptor Subfamily K
  • Phosphatidylinositol 3-Kinases / immunology
  • Protein-Tyrosine Kinases / immunology*
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / immunology
  • Proto-Oncogene Proteins c-vav
  • Receptors, Immunologic / immunology*
  • Receptors, Natural Killer Cell
  • Signal Transduction / immunology
  • Syk Kinase
  • Type C Phospholipases / immunology
  • rho GTP-Binding Proteins / immunology
  • src Homology Domains / immunology


  • Cell Cycle Proteins
  • Enzyme Precursors
  • HCST protein, human
  • Hcst protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • KLRK1 protein, human
  • Klrk1 protein, mouse
  • Membrane Proteins
  • NK Cell Lectin-Like Receptor Subfamily K
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-vav
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell
  • VAV1 protein, human
  • Vav1 protein, mouse
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • Syk protein, mouse
  • Type C Phospholipases
  • rho GTP-Binding Proteins