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Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells

Nature volume 391, pages 703–707 (1998)Cite this article

Abstract

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 cytotoxicity1. 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 cells2,3,4. 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 cells4,5,6. 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.

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Figure 1: DAP12 cDNA and gene.
Figure 2: DAP12 gene and expression.
Figure 3: Coimmunoprecipitation of DAP12 and KIR2DS2 proteins and association of DAP12 phosphopeptide with ZAP-70.
Figure 4: Cellular activation of transfectants expressing KIR2DS2 and DAP12.

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Acknowledgements

We thank F. Bazan and J. Bolen for helpful discussion, C. Saraiya for expert technical assistance, C. Turck and A. Weiss for phosphopeptides and antibodies, J. Ford, T. McClanahan and K.Bacon for cDNA libraries, J. A. Katheiser, G. Burget and M. Andonian for graphics, J. Cupp, E. Callas, E.Murphy and D. Polakoff for flow cytometry, D. Gorman for DNA sequencing and D. Liggett for oligonucleotides. DNAX Research Institute is supported by Schering Plough Corporation.

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  1. Department of Immunobiology, DNAX Research Institute of Molecular and Cellular Biology, 901 California Avenue, Palo Alto, 94304, California, USA

    Lewis L. Lanier, Brian C. Corliss, Jun Wu, Clement Leong & Joseph H. Phillips

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  1. Lewis L. Lanier
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Correspondence to Lewis L. Lanier.

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Lanier, L., Corliss, B., Wu, J. et al. Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature 391, 703–707 (1998). https://doi.org/10.1038/35642

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