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.
References:
Berger, V., L. Gabriel, E. Lilliu, B. Hackl, J. Marksteiner, K. Hilber, X. Koenig, P. Uhrin, and H. Todt. (2023). Modulation of cardiac ventricular conduction: Impact on QRS duration, amplitude and dispersion. Eur J Pharmacol 941: 175495.
Bessis, A., C. Béchade, D. Bernard, and A. Roumier. (2007). Microglial control of neuronal death and synaptic properties. Glia 55: 233-238.
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.
Charbonneau, H., N.K. Tonks, K.A. Walsh, and E.H. Fischer. (1988). The leukocyte common antigen (CD45): a putative receptor-linked protein tyrosine phosphatase. Proc. Natl. Acad. Sci. USA 85: 7182-7186.
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.
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.
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.
Kim, D.K., J. Kabat, F. Borrego, T.B. Sanni, C.H. You, and J.E. Coligan. (2004). Human NKG2F is expressed and can associate with DAP12. Mol Immunol 41: 53-62.
Kountikov, E., M. Wilson, N. Miller, W. Clem, and E. Bengtén. (2004). Organization and expression of thirteen alternatively spliced exons in catfish CD45 homologs. Dev Comp Immunol 28: 1023-1035.
Ma, T., B. Yang, M.A. Matthay, and A.S. Verkman. (1998). Evidence against a role of mouse, rat, and two cloned human t1alpha isoforms as a water channel or a regulator of aquaporin-type water channels. Am J Respir Cell Mol Biol 19: 143-149.
Marchelletta, R.R., M. Krishnan, M.R. Spalinger, T.W. Placone, R. Alvarez, A. Sayoc-Becerra, V. Canale, A. Shawki, Y.S. Park, L.H. Bernts, S. Myers, M.L. Tremblay, K.E. Barrett, E. Krystofiak, B. Kachar, D.P. McGovern, C.R. Weber, E.M. Hanson, L. Eckmann, and D.F. McCole. (2021). T cell protein tyrosine phosphatase protects intestinal barrier function by restricting epithelial tight junction remodeling. J Clin Invest 131:.
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:.
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.
Sengelaub, C.A., K. Navrazhina, J.B. Ross, N. Halberg, and S.F. Tavazoie. (2016). PTPRN2 and PLCβ1 promote metastatic breast cancer cell migration through PI(4,5)P2-dependent actin remodeling. EMBO. J. 35: 62-76.
Tomasello, E. and E. Vivier. (2005). KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions. Eur J Immunol 35: 1670-1677.
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.
Wu, L., J. Fu, and S.H. Shen. (2002). SKAP55 coupled with CD45 positively regulates T-cell receptor-mediated gene transcription. Mol. Cell Biol. 22: 2673-2686.
Examples:
TC#	Name	Organismal Type	Example
8.A.128.1.1	Signal adaptor protein and TYRO protein tyrosine kinase-binding protein, KARAP/DAP12/TYROBP, of 113 aas and 2 N-terminal TMSs. It is an adapter protein which non-covalently associates with activating receptors found on the surface of a variety of immune cells to mediate signaling and cell activation following ligand binding by the receptors (Dietrich et al. 2000). See family description and UniProt (O43914) for more information. Human NKG2F can associate with DAP12 (Kim et al. 2004).		KARAP of Homo sapiens

8.A.128.1.10	T-cell surface glycoprotein CD3, epsilon chain, CD3e, of 207 aas and 1 TMS.		CD3e of Homo sapiens

8.A.128.1.11	Receptor-type tyrosine-protein phosphatase C, PTPRC, LCA or CD45, of 1306 aas and 2 TMSs, one N-terminal and one centrally located. It is a tyrosine-protein phosphatase required for T-cell activation through the antigen receptor (Charbonneau et al. 1988). It acts as a positive regulator of T-cell coactivation upon binding to DPP4. The first PTPase domain has enzymatic activity, while the second one seems to affect the substrate specificity of the first one (Wu et al. 2002). A prominent CD45 feature is alternative splicing of exons encoding the N-terminus, resulting in the generation of several isoforms (Kountikov et al. 2004). The C-terminal half of the protein has two 300 aa repeats, homologous to a 300 aa segment in the protein with TC# 8.A.128.1.7 (residues 450 to 750).		CD45 of Homo sapiens

8.A.128.1.12	*Phogrin, a receptor-type tyrosine-protein phosphatase N2, PTPRN2, of 1015 aas and 2 - 4 TMSs. It plays a role in vesicle-mediated secretory processes (Sengelaub et al.* 2016).**		Phogrin of Homo sapiens

8.A.128.1.13	Tyrosine-protein phosphatase non-receptor type 2, PTPT or PTPN2 of 415 aas and 1 C-terminal TMS. It protects intestinal barrier function by restricting epithelial tight junction remodeling (Marchelletta et al. 2021). It plays also an important role in glucose homeostasis.		PTPN2 of Homo saiens

8.A.128.1.2	DAP10 precursor of 81 aas and 1 TMS.		*DAP10 of Ictalurus punctatus* (channel catfish)**

8.A.128.1.3	Uncharacterized protein of 159 aas and 1 TMS		*UP of Marmota monax* (woodchuck)**

8.A.128.1.4	Uncharacterized protein of 589 aas and 1 C-terminal TMS. Only the C-terminal residues show sequence similarity with TYROBP.		*UP of Chiloscyllium punctatum* (brownbanded bambooshark)**

8.A.128.1.5	T-cell surface glycoprotein CD3 delta chain of174 aas and 2 TM		*CD3 of Mesitornis unicolor* (brown roatelo)**

8.A.128.1.6	T-cell surface glycoprotein CD3 gamma chain-like isoform X1 of 183 aas and 2 TMSs, one N-terminal and one near the C-terminus.		*CD3 of Paralichthys olivaceus* (Japanese flounder)**

8.A.128.1.7	Receptor-type tyrosine-protein phosphatase H of 788 aas and 2 closely spaced TMSs near the middle of the protein.		PPH of Propithecus coquereli (Coquerel's sifaka)

8.A.128.1.8	Uncharacterized protein of 104 aas and 2 N-terminal TMSs		UP of Takifugu bimaculatus

8.A.128.1.9	Uncharacterized protein of 118 aas and 2 N-terminal TMSs		*UP of Cyprinus carpio* (common carp)**

Examples:
TC#	Name	Organismal Type	Example
8.A.128.2.1	Periaxin of 262 aas and 2 N-terminal TM		*Periaxin of Toxocara canis* (dog roundworm)**

8.A.128.2.2	Uncharacterized protein of 1516 aas and 1 N-terminal TMS, the region of homology with TC# 8.A.128.2.1.		UP of Spodoptera litura

8.A.128.2.3	Periaxin isoform X1 of 1365 aas and 1 N-terminal TMS, the region of homology with TC# 8.A.128.2.1.		Periaxin of Mus musculus

8.A.128.2.4	Uncharacterized protein of 679 aas and 1 N-terminal TMS.		UP of Leucothrix mucor

Examples:
TC#	Name	Organismal Type	Example
8.A.128.3.1	Uncharacterized protein of 550 aas and 1 TMS towards the C-terminus, and possibly 1 - 3 TMSs at the N-terminus.		UP of Pyricularia oryzae

8.A.128.3.10	Uncharacterized protein of 356 aas and 1 TMS		UP of Fomitiporia mediterranea

8.A.128.3.11	Uncharacterized protein of 404 aas and 1 TMS		UP of Alternaria alternata

8.A.128.3.2	Uncharacterized protein of 256 aas and 1 or 2 TMSs.		UP of Coprinopsis marcescibilis

8.A.128.3.3	Uncharacterized protein of 269 aas and 1 TMS		UP of Tolypocladium ophioglossoides CBS 100239 (Elaphocordyceps ophioglossoides CBS 100239)

8.A.128.3.4	Uncharacterized protein of 594 aas and 1 - 2 TMSs.		UP of Exophiala aquamarina

8.A.128.3.5	Uncharacterized protein of 237 aas and 1 TMS		UP of Lizonia empirigonia

8.A.128.3.6	Uncharacterized protein of 266 aas and 1 TMS		UP of Epicoccum nigrum

8.A.128.3.7	Uncharacterized protein of 883 aas and 1 TMS		UP of Crucibulum laeve

8.A.128.3.8	Uncharacterized protein of 276 aas and 1 TMS at aas 160 - 180.		UP of Setomelanomma holmii

8.A.128.3.9	Uncharacterized protein of 317 aas and 1 TMS		UP of Trematosphaeria pertusa

Examples:
TC#	Name	Organismal Type	Example
8.A.128.4.1	Uncharacterized protein of 240 aas and 1 TMS		*UP of Tenacibaculum* sp.**

8.A.128.4.2	Uncharacterized protein of s189 aas and 1 N-terminal TMS		UP of Thiothrix caldifontis

8.A.128.4.3	Uncharacterized protein of 275 aas and 1 N-terminal TMS		UP of Candidatus Bathyarchaeota archaeon (marine sediment metagenome)

8.A.128.4.4	Uncharacterized protein of 242 aas and 3 TMSs in a 2 (N-terminal) + 1 (near the c-terminus) TMS arrangement.		UP of Candidatus Thermofonsia Clade 2 bacterium (hot springs metagenome)

8.A.128.4.5	Uncharacterized protein of 221 aas and 1 TMS		UP of Rudanella lutea

Examples:
TC#	Name	Organismal Type	Example
8.A.128.5.1	Uncharacterized protein of 300 aas and 1 TMS		UP of Amniculicola lignicola

8.A.128.5.2	Uncharacterized protein of 326 aas and 2 TMSs, N-terminal and towards the C-terminus.		*UP of Tuber borchii* (whitish truffle)**

8.A.128.5.3	Uncharacterized protein of 314 aas and 2 TMSs. This protein shows sequence similarity not only with other members of 8.A.128.5, but also 8.A.128.1 and 8.A.23.1.		UP of Rhizopus microsporus

8.A.128.5.4	Uncharacterized protein of 271 aas and 1 TMS		UP of Colletotrichum chlorophyti

8.A.128.5.5	Uncharacterized protein of 534 aas and 1 TMS		UP of Dothistroma septosporum

8.A.128.5.6	Uncharacterized protein of 372 aas and 2 TMSs		UP of Viridothelium virens

8.A.128.5.7	Uncharacterized protein of 439 aas and 1 TMS		UP of Aaosphaeria arxii

8.A.128.5.8	Uncharacterized protein of 323 aas and 1 TMS		UP of Bipolaris oryzae

Examples:
TC#	Name	Organismal Type	Example
8.A.128.6.1	Uncharacterized protein of 92 aas and 1 TMS		*UP of Enterobacter cloacae* complex**

8.A.128.6.2	Uncharacterized protein of 89 aas and 1 TMS.		UP of Cronobacter malonaticus

8.A.128.6.3	Uncharacterized protein of 77 aas and 1 TMS		UP of Candidatus Sodalis pierantonius

8.A.128.6.4	Uncharacterized protein of 84 aas and 1 TMS		UP of Ensifer adhaerens (Sinorhizobium morelense = Ensifer morelensis)

8.A.128.6.5	Uncharacterized protein of 94 aas and 1 TMS		UP of Kalamiella piersonii

Examples:
TC#	Name	Organismal Type	Example
8.A.128.7.1	T-cell surface glycoprotein CD3 zeta chain, CD247, of 164 aas and 1 TMS. Plays important roles in intrathymic T-cell differentiation and activity-dependent synapse formation of retinal ganglion cells in both the retina and dorsal lateral geniculate nucleus. It is phosphorylated by the ZAP70 protein kinase (Dong et al. 2017).

8.A.128.7.2	High affinity immunoglobulin epsilon receptor subunit gamma of 91 aas and 1 TM		*Receptor of Terrapene carolina* triunguis (Three-toed box turtle)**

8.A.128.7.3	T-cell surface glycoprotein CD3 zeta chain-like isoform X1 of 156 aas and 1 TMS		*CD3 of Esox lucius* (northern pike)**

8.A.128.7.4	Uncharacterized protein of 187 aas and 2 TMSs		*UP of Perca fluviatilis* (European perch)**

8.A.128.7.5	Uncharacterized protein of 138 aas and 1 TMS		UP of Danionella translucida

8.A.128.7.6	Uncharacterized protein of 114 aas and 1 TMS		UP of Planctomycetes bacterium

8.A.128.7.7	Uncharacterized protein of 132 aas and 1 TMS		*UP of Oryzias javanicus* (javanese ricefish)**

Examples:
TC#	Name	Organismal Type	Example
8.A.128.8.1	Podoplanin, APDPN, of 162 aas with one C-terminal TMS (Berger et al. 2023). It does not function as a water channel or as a regulator of aquaporin-type water channels, and does not have any effect on folic acid or amino acid transport (Ma et al. 1998).		Podoplanin of Homo sapiens