SLAM-SAP intracellular signaling. On SLAM-R engagement (usually through homotypic interactions on an adjacent cell), SAP binds as an SH2-domain adaptor protein to ITSMs found in the cytoplasmic tail of SLAM-Rs. This interaction facilitates further recruitment of Src-family kinases, such as FYN (via its SH3 domain) and LCK (via its kinase domain), which further phosphorylate ITSM tyrosines in the SLAM-R as well as other downstream substrates.^15,17  In docking to SLAM receptors, SAP may simultaneously displace phosphatases, such as SHP1/SHP2, which bind to SLAM-Rs before engagement, which potentiates cytotoxic function and TCR signal transduction by removing these inhibitory molecules. SAP can also associate directly with DOK1 and other SH3-containing proteins, such as NCK and PIX, which facilitates their activation and involvement in TCR-induced extracellular signal-regulated kinase and nuclear factor of activated T-cell activation, respectively.^18-21  These molecular interactions allow SAP to regulate NK- and CTL-cell cytotoxicity and regulate several signaling outcomes entrained to the TCR, some of which are dependent on FYN binding (eg, Th2 cytokine secretion) and others that do not require FYN (eg, RICD).^14,22