| DAP12 (TYROBP/KARAP) is a disulfide‑linked homodimeric transmembrane adaptor protein expressed in NK cells, myeloid cells, and other hematopoietic lineages, where it provides immunoreceptor tyrosine‑based activation motif (ITAM)–dependent signaling capacity to a broad set of ligand‑binding receptors. Each DAP12 chain contains a short extracellular region, a transmembrane segment with a negatively charged aspartate that pairs with basic residues in partner receptor transmembrane domains, and a cytoplasmic tail with a dual‑tyrosine ITAM that becomes phosphorylated by Src family kinases when associated receptors engage their ligands. Phosphorylated ITAM tyrosines recruit Syk (and ZAP‑70 in NK cells), which then autophosphorylates and phosphorylates scaffold proteins such as LAT and SLP‑76, leading to assembly of signaling complexes that include PI3K, PLCγ, Vav, Grb2–SOS, and Gads and propagate signals to AKT, ERK, PKC, calcium mobilization, and actin cytoskeleton rearrangement. DAP12 associates with multiple activating receptors, including TREM‑1 and TREM‑2 on myeloid cells, certain killer cell activating receptors on NK cells, MDL‑1, and SIRPβ1, so the same ITAM‑based module can couple diverse pattern‑recognition or immunoregulatory inputs to a conserved activation cascade. Ligation of TREM‑1–DAP12 on monocytes and neutrophils induces robust production of pro‑inflammatory cytokines and chemokines, generation of reactive oxygen species, degranulation, and phagocytosis, and TREM‑1–DAP12 blockade in experimental sepsis models reduces inflammatory mediator production and improves survival, highlighting this axis as an amplifier of innate inflammatory responses. TREM‑2–DAP12 signaling in macrophages, dendritic cells, osteoclasts, and microglia promotes phagocytosis of bacteria and cell debris, supports differentiation and function of osteoclasts, and can inhibit TLR‑driven inflammatory signaling, indicating context‑dependent roles that range from activation to negative feedback on inflammation. Mutations in DAP12 and TREM-2 are associated with distinct bone and neurological phenotypes, such as those seen in Nasu–Hakola disease, and influence microglial responses during neurodegeneration, as impaired DAP12-dependent signaling disrupts osteoclast-driven bone remodeling and alters microglial phagocytic and inflammatory activities. |
