title: Cutting edge: NKp80 uses an atypical hemi-ITAM to trigger NK cytotoxicity.
abstract: The human NK cell receptor NKp80 stimulates cytotoxicity upon engagement of its genetically linked ligand AICL. However, the mechanisms underlying NKp80-mediated signaling are unknown. In this study, we dissected NKp80 signaling using the NK cell line NK92MI. We demonstrated that NKp80, but not NKp80 mutated at tyrosine 7 (NKp80/Y7F), is tyrosine phosphorylated. Accordingly, NKp80/Y7F, but not NKp80/Y30F or NKp80/Y37F, failed to induce cytotoxicity. NKp80 phosphopeptides comprising the hemi-ITAM-like sequence surrounding tyrosine 7 bound Lck- and Syk-family kinases; accordingly, cross-linking of NKp80, but not NKp80/Y7F, induced Syk phosphorylation. Moreover, inhibition of Syk kinase, but not ZAP-70 kinase, impaired cytotoxic responses through NKp80. Atypical residues in the hemi-ITAM-like motif of NKp80 cause an altered stoichiometry of phosphorylation but did not substantially affect NK cytotoxicity. Altogether, these results show that NKp80 uses an atypical hemi-ITAM and Syk kinase to trigger cellular cytotoxicity.
authors.affiliation: Department of Immunology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Dennehy
authors.forename: Sascha N
authors.initials: SN
authors.lastname: Klimosch
authors.forename: Alexander
authors.initials: A
authors.lastname: Steinle
mesh_terms: D020816:Amino Acid Motifs / Q000276:immunology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D007694:Killer Cells, Natural / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D037181:Lectins, C-Type / Q000378:metabolism / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology; D010748:Phosphopeptides / Q000378:metabolism / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D055607:Receptors, Natural Killer Cell / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D000072377:Syk Kinase
chemical_list: C104778:CLEC2B protein, human; D047908:Intracellular Signaling Peptides and Proteins; C431711:KLRF1 protein, human; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D010748:Phosphopeptides; D055607:Receptors, Natural Killer Cell; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase