NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells

Nat Immunol. 2006 May;7(5):524-32. doi: 10.1038/ni1325. Epub 2006 Apr 2.


NKG2D is an important immunosurveillance receptor that responds to stress-induced ligand expression on tumors and virus-infected cells. Human natural killer cells express NKG2D and require the transmembrane adaptor DAP10 to initiate their full cytotoxic activation. However, DAP10 has no immunoreceptor tyrosine-based activation motif and thus the mechanism of recruiting 'downstream' effector proteins is unclear. We show here that binding of the p85 subunit of phosphatidylinositol-3- kinase to DAP10 could not by itself trigger cell-mediated cytotoxicity and that binding of an intermediate consisting of the DAP10 binding partner Grb2 and the effector molecule Vav1 (Grb2-Vav1) to DAP10 was sufficient to initiate tyrosine-phosphorylation events. For full calcium release and cytotoxicity to occur, both Grb2-Vav1 and p85 had to bind to DAP10. These findings identify a previously unknown mechanism by which NKG2D-DAP10 mediates cytotoxicity and provides a framework for evaluating activation by other receptor complexes that lack immunoreceptor tyrosine-based activation motifs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Differentiation, T-Lymphocyte / metabolism*
  • Calcium / metabolism
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic
  • GRB2 Adaptor Protein / metabolism*
  • Humans
  • Killer Cells, Natural / metabolism*
  • Membrane Proteins / metabolism*
  • Models, Biological
  • NK Cell Lectin-Like Receptor Subfamily K
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-vav / metabolism*
  • Receptors, Immunologic / metabolism*
  • Receptors, Natural Killer Cell
  • Signal Transduction / immunology


  • Antigens, Differentiation, T-Lymphocyte
  • GNLY protein, human
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • HCST protein, human
  • KLRK1 protein, human
  • Membrane Proteins
  • NK Cell Lectin-Like Receptor Subfamily K
  • Proto-Oncogene Proteins c-vav
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell
  • VAV1 protein, human
  • Phosphatidylinositol 3-Kinases
  • Calcium