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

References associated with 8.A.128 family:

Bessis, A., C. Béchade, D. Bernard, and A. Roumier. (2007). Microglial control of neuronal death and synaptic properties. Glia 55: 233-238. 17106878
Carpenter, K.J., K.F. Buckland, Z. Xing, and C.M. Hogaboam. (2005). Intrapulmonary, adenovirus-mediated overexpression of KARAP/DAP12 enhances fungal clearance during invasive aspergillosis. Infect. Immun. 73: 8402-8406. 16299339
Dietrich, J., M. Cella, M. Seiffert, H.J. Bühring, and M. Colonna. (2000). Cutting edge: signal-regulatory protein beta 1 is a DAP12-associated activating receptor expressed in myeloid cells. J Immunol 164: 9-12. 10604985
Dong, G., R. Kalifa, P.R. Nath, Y. Babichev, S. Gelkop, and N. Isakov. (2017). Crk adaptor proteins regulate CD3ζ chain phosphorylation and TCR/CD3 down-modulation in activated T cells. Cell Signal 36: 117-126. 28465009
Inui, M., Y. Kikuchi, N. Aoki, S. Endo, T. Maeda, A. Sugahara-Tobinai, S. Fujimura, A. Nakamura, A. Kumanogoh, M. Colonna, and T. Takai. (2009). Signal adaptor DAP10 associates with MDL-1 and triggers osteoclastogenesis in cooperation with DAP12. Proc. Natl. Acad. Sci. USA 106: 4816-4821. 19251634
Mecca, C., I. Giambanco, R. Donato, and C. Arcuri. (2018). Microglia and Aging: The Role of the TREM2-DAP12 and CX3CL1-CX3CR1 Axes. Int J Mol Sci 19:. 29361745
Mulrooney, T.J., P.E. Posch, and C.K. Hurley. (2013). DAP12 impacts trafficking and surface stability of killer immunoglobulin-like receptors on natural killer cells. J Leukoc Biol 94: 301-313. 23715743
Tomasello, E. and E. Vivier. (2005). KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions. Eur J Immunol 35: 1670-1677. 15884055
Turnbull, I.R., J.E. McDunn, T. Takai, R.R. Townsend, J.P. Cobb, and M. Colonna. (2005). DAP12 (KARAP) amplifies inflammation and increases mortality from endotoxemia and septic peritonitis. J Exp Med 202: 363-369. 16061725