8.A.128.  The Signaling Adaptor Protein KARAP/DAP12/TYROBP (SAP-KDT) Family 

The signaling adaptor protein KARAP/DAP12/TYROBP (killer cell activating receptor-associated protein / DNAX activating protein of 12 kDa / tyrosine kinase binding protein) belongs to the family of transmembrane polypeptides bearing an intracytoplasmic immunoreceptor tyrosine-based activation motif (ITAM) (Tomasello and Vivier 2005). This adaptor, initially characterized in NK cells, is associated with multiple cell-surface activating receptors, including ionophoric receptors, expressed in both lymphoid and myeloid lineages. The main features of KARAP/DAP12 reveal its involvement in a broad array of biological functions. KARAP/DAP12 is a wiring component for NK cell anti-viral function (e.g. mouse cytomegalovirus via its association with mouse Ly49H) and NK cell anti-tumoral function (e.g. via its association with mouse NKG2D or human NKp44). KARAP/DAP12 is also involved in inflammatory reactions via its coupling to myeloid receptors, such as the triggering receptors expressed by myeloid cells (TREM) displayed by neutrophils, monocytes/macrophages and dendritic cells. Bone remodeling and brain function are also dependent upon the integrity of KARAP/DAP12 signals (Tomasello and Vivier 2005).

DAP12 (KARAP) amplifies inflammation and increases mortality from endotoxemia and septic peritonitis (Turnbull et al. 2005). Intrapulmonary, adenovirus-mediated overexpression of KARAP/DAP12 enhances fungal clearance during invasive aspergillosis (Carpenter et al. 2005). Mutations in KARAP/DAP12, a key protein of microglial activation, impacts synaptic functions in hippocampus, and synapses protein content (Bessis et al. 2007). Signal adaptor proteins, DAP10 and DAP12 associate with MDL-1 to trigger osteoclastogenesis (Inui et al. 2009). DAP12 impacts trafficking and surface stability of killer immunoglobulin-like receptors on natural killer cells (Mulrooney et al. 2013). As a microglial surface receptor, TREM2 interacts with DAP12 to initiate signal transduction pathways that promote microglial cell activation, phagocytosis, and microglial cell survival (Mecca et al. 2018). Defective TREM2-DAP12 functions play a central role in the pathogenesis of several diseases. The CX3CL1 (fractalkine)-CX3CR1 signaling represents the most important communication channel between neurons and microglia. The expression of CX3CL1 in neurons and of its receptor CX3CR1 in microglia determines a specific interaction, playing fundamental roles in the regulation of the maturation and function of these cells (Mecca et al. 2018).

As of 3/1/2020, subfamilies 2 and 4 are closely related, and 3 and 5 are closely related.  It is not certain that subfamilies 2 and 4 belong in this family.  However, it appears that all other subfamilies are likely to be members of this family. There is little evidence that subfamily 7 belongs to this family. Also, families 8.A.128, 8.A 23 are highly likely to be related, and possibly 8.A.24 is related as well.