Research Progress on NK Cell Receptors and Their Signaling Pathways

Figure 4

Signaling pathways of 2B4 and DNAM-1. Binding of 2B4 to CD48 promotes ITSM phosphorylation and recruits the adaptor SAP. SAP combines with ITSM to recruit Fyn, and Fyn phosphorylates the downstream proteins PLCγ and Vav1 to activate NK cells. 2B4 can also recruit the phosphatases SHP-1/SHP-2 in the absence of SAP, transmitting inhibitory signals. The 2B4-EAT2 complex may have opposite functions in NK cells. DNAM-1 binds to its ligand, and it is phosphorylated by PKC and Fyn, which promotes the interaction between DNAM-1 and LFA-1. Eventually, DNAM-1 is recruited to the lipid raft and binds to the adaptor Grb2. Binding of DNAM-1 to Grb2 enables PI3K, Vav1, SLP76, and PLCγ1/2 to be recruited and then activates the AKT and ERK signaling pathways, thus triggering degranulation and calcium mobilization. In addition, activated AKT catalyzes FOXO1 phosphorylation. Phosphorylated FOXO1 is transferred from the nucleus to the intracellular space, where it is inactivated and degraded, regulating NK cell cytotoxicity and exerting antitumor effects.