NKp8, also known as KLRF1, is an activating homodimeric C-type lectin-like receptor which is expressed on nearly all natural killer cells and stimulates their cytoxicity and cytokine release. NKp8 stimulates cytotoxicity upon engagement of its genetically linked ligand: myeloid-specific CTLR activation-induced C-type lectin (AICL). NKp8, but not NKp8 mutated at tyrosine 7 (NKp8/Y7F), is tyrosine phosphorylated. Accordingly, NKp8/Y7F, but not NKp8/Y3F or NKp8/Y37F, failed to induce cytotoxicity. NKp8 phosphopeptides comprising the hemi-ITAM-like sequence surrounding tyrosine 7 bound Lck- and Syk-family kinases; accordingly, cross-linking of NKp8, but not NKp8/Y7F, induced Syk phosphorylation. Moreover, inhibition of Syk kinase, but not ZAP-7 kinase, impaired cytotoxic responses through NKp8. Atypical residues in the hemi-ITAM-like motif of NKp8 cause an altered stoichiometry of phosphorylation but did not substantially affect NK cytotoxicity. Altogether, these results show that NKp8 uses an atypical hemi-ITAM and Syk kinase to trigger cellular cytotoxicity.
killer cell lectin like receptor F1
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