Fig. 1.

Model of mammalian natural killer receptor (NKR) signaling. NK cells display both inhibitory and activating NKRs along with adaptor proteins (e.g. DAP12 dimer). Ligand recognition by a mammalian activating NKR will induce the ITAM in DAP12 to be tyrosine-phosphorylated, leading to the recruitment of the tyrosine kinases Syk and ZAP70, which in turn activates a signaling cascade that stimulates the production of cytokines and chemokines and the release of the cytolytic granules. In contrast to activating NKRs, ligand recognition by an inhibitory NKR induces its ITIM to be tyrosine-phosphorylated that in turn leads to the recruitment of the tyrosine-specific SHP phosphatases: SHP-1 and SHP-2, or the phospholipid-specific phosphatase: SHIP. In mammalian NK cells, the recruitment and activation of SHP-1 and SHP-2 by inhibitory NKRs can result in decreased phosphorylation of numerous intracellular signaling proteins, including Syk and ZAP-70. Activating NKRs typically bind nonpolymorphic MHC I or MHC I related stress-induced molecules and inhibitory NKRs typically bind polymorphic MHC I. Not all activating NKRs partner with DAP12 (Fig. 2)