Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells.
Natural killer (NK) cells express cell-surface receptors of the immunoglobulin and C-type lectin superfamilies that recognize major histocompatibility complex (MHC) class I peptides and inhibit NK-cell-mediated cytotoxicity. These inhibitory receptors possess ITIM sequences (for immunoreceptor tyrosine-based inhibitory motifs) in their cytoplasmic domains that recruit SH2-domain-containing protein tyrosine phosphatases, resulting in inactivation of NK cells. Certain isoforms of these NK-cell receptors lack ITIM sequences and it has been proposed that these 'non-inhibitory' receptors may activate, rather than inhibit, NK cells. Here we show that DAP12, a disulphide-bonded homodimer containing an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain, non-covalently associates with membrane glycoproteins of the killer-cell inhibitory receptor (KIR) family without an ITIM in their cytoplasmic domain. Crosslinking of KIR-DAP12 complexes results in cellular activation, as demonstrated by tyrosine phosphorylation of cellular proteins and upregulation of early-activation antigens. Phosphorylated DAP12 peptides bind ZAP-70 and Syk protein tyrosine kinases, suggesting that the activation pathway is similar to that of the T- and B-cell antigen receptors.
Lanier
L L
LL
DNAX Research Institute of Molecular and Cellular Biology, Department of Immunobiology, Palo Alto, California 94304, USA. lanier@dnax.org
Corliss
B C
BC
Wu
J
J
Leong
C
C
Phillips
J H
JH
D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002888:Chromosomes, Human, Pair 19; D016384:Consensus Sequence; D003432:Cross-Linking Reagents; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011946:Receptors, Antigen / Q000378:metabolism; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054340:Receptors, KIR; D013601:T-Lymphocytes / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism*; D051746:ZAP-70 Protein-Tyrosine Kinase
D003432:Cross-Linking Reagents; D018076:DNA, Complementary; D011946:Receptors, Antigen; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C497262:Zap70 protein, mouse