Inhibitory receptor signaling via tyrosine phosphorylation of the adaptor Crk.
Many cellular responses, such as autoimmunity and cytotoxicity, are controlled by receptors with cytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs). Here, we showed that binding of inhibitory natural killer (NK) cell receptors to human leukocyte antigen (HLA) class I on target cells induced tyrosine phosphorylation of the adaptor Crk, concomitant with dephosphorylation of the guanine exchange factor Vav1. Furthermore, Crk dissociated from the guanine exchange factor C3G and bound to the tyrosine kinase c-Abl during inhibition. Membrane targeting of a tyrosine-mutated form of Crk could overcome inhibition of NK cell cytotoxicity, providing functional evidence that Crk phosphorylation contributes to inhibition. The specific phosphorylation of Crk and its dissociation from a signaling complex, observed here with two types of inhibitory receptors, expands the signaling potential of the large ITIM-receptor family and reveals an unsuspected component of the inhibitory mechanism.
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
Mary E
ME
Peterson
Eric O
EO
Long
D020816:Amino Acid Motifs / Q000276:immunology; D000818:Animals; D050719:Crk-Associated Substrate Protein / Q000276:immunology / Q000378:metabolism; D020735:Guanine Nucleotide-Releasing Factor 2 / Q000276:immunology / Q000378:metabolism; D006680:HLA Antigens / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000276:immunology / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000276:immunology / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000276:immunology / Q000378:metabolism; D050737:Proto-Oncogene Proteins c-crk / Q000276:immunology / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000276:immunology / Q000378:metabolism; D051381:Rats; D054340:Receptors, KIR / Q000276:immunology / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell / Q000276:immunology / Q000378:metabolism; D000097625:HLA-E Antigens
D050719:Crk-Associated Substrate Protein; D020735:Guanine Nucleotide-Releasing Factor 2; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D051920:NK Cell Lectin-Like Receptor Subfamily D; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D016315:Proto-Oncogene Proteins c-abl; D050721:Proto-Oncogene Proteins c-cbl; D050737:Proto-Oncogene Proteins c-crk; D051567:Proto-Oncogene Proteins c-vav; D054340:Receptors, KIR; D055607:Receptors, Natural Killer Cell; D000097625:HLA-E Antigens; C493841:BCAR1 protein, human; C496618:VAV1 protein, human; C509249:PTPN6 protein, human