Disease relevance of TYROBP

• Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts [1].
• However, an anti-FLAG monoclonal antibody used to potentiate the signaling of adenoviral-derived DAP12, enhanced granuloma formation at day 7 [2].
• Here we show that loss of function mutations in DAP12 and TREM2 result in an inefficient and delayed differentiation of osteoclasts with a remarkably reduced bone resorption capability in vitro [3].
• KARAP/DAP12-transgenic mice present, in a transgene dose-dependent manner, a complex phenotype characterized by two independent and spontaneous hematological abnormalities: (i) a severe lymphopenia and (ii) a massive inflammatory syndrome associated with neutrophilia and lung infiltration by multinucleated macrophages [4].
• Increased resistance to experimental encephalomyelitis is observed in DAP12 knockin mice, which is dependent on IDO expression [5].

Psychiatry related information on TYROBP

• Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia [6].

High impact information on TYROBP

• On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class I molecules [1].
• TYROBP is a transmembrane protein that has been recognized as a key activating signal transduction element in natural killer (NK) cells [1].
• Phosphorylated DAP12 peptides bind ZAP-70 and Syk protein tyrosine kinases, suggesting that the activation pathway is similar to that of the T- and B-cell antigen receptors [7].
• Crosslinking of KIR-DAP12 complexes results in cellular activation, as demonstrated by tyrosine phosphorylation of cellular proteins and upregulation of early-activation antigens [7].
• Association of DAP12 with activating CD94/NKG2C NK cell receptors [8].

Biological context of TYROBP

• Our data imply that the TYROBP-mediated signaling pathway plays a significant role in human brain and bone tissue and provide an interesting example of how mutations in two different subunits of a multisubunit receptor complex result in an identical human disease phenotype [9].
• Patients with PLOSL have no defects in cell-mediated immunity, suggesting a remarkable capacity of the human immune system to compensate for the inactive TYROBP-mediated activation pathway [9].
• Modulation of hepatic granulomatous responses by transgene expression of DAP12 or TREM-1-Ig molecules [2].
• We have earlier characterized the molecular genetic background of PLOSL by identifying mutations in two genes, DAP12 and TREM2 [3].
• Elsewhere, we have identified PLOSL mutations in TYROBP (DAP12), which codes for a membrane receptor component in natural-killer and myeloid cells, and also have identified genetic heterogeneity in PLOSL, with some patients carrying no mutations in TYROBP [9].

Anatomical context of TYROBP

• TREM2 forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells [9].
• The DAP12-TREM2 complex is involved in the maturation of dendritic cells [3].
• However, the majority of CD4(+)CD28(null) T cell clones lacked the expression of KARAP/DAP12 [10].
• DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features [3].
• Using a SIRP-specific mAb, we show that SIRP beta 1 is expressed in monocytes and dendritic cells and associates with the signal transduction molecule DAP12 [11].

Associations of TYROBP with chemical compounds

• Selective activation of the c-Jun NH2-terminal protein kinase signaling pathway by stimulatory KIR in the absence of KARAP/DAP12 in CD4+ T cells [10].
• Tumor cell ligation stimulated DAP12 tyrosine phosphorylation and its association with Syk in NK92 cells; Syk tyrosine phosphorylation and activation were also observed [12].
• The physical association between SIRPbeta1 and KARAP/DAP-12 results in the functional coupling of SIRPbeta1 engagement to the recruitment of the protein tyrosine kinase Syk and to serotonin release in RBL cell transfectants [13].
• In association with KARAP/DAP12, SIRPbeta1 complexes are capable of inducing serotonin release and tumor necrosis factor (TNF) secretion [14].
• In contrast, a high degree of specificity for the basic side chain could be observed because the KIR-DAP12 and FcalphaRI-Fcgamma interactions favored lysine or arginine, respectively [15].

Physical interactions of TYROBP

• SIRP beta 1/DAP12 complex formation was required for efficient cell-surface expression of SIRP beta 1 [11].

Regulatory relationships of TYROBP

• NKp44 triggers NK cell activation through DAP12 association that is not influenced by a putative cytoplasmic inhibitory sequence [16].
• TREM1 and TREM2 activate myeloid cells by signalling through the adaptor protein DAP12 [17].
• Siglec-H depends on DAP12 (DNAX-activating protein of 12 kDa) for surface expression and cross-linking with anti-siglec-H antibodies can selectively inhibit interferon-alpha production by PDCs following TLR9 (Toll-like receptor 9) ligation [18].

Other interactions of TYROBP

• Recently, molecular analysis of affected families revealed mutations in the DAP12 (TYROBP) or TREM2 genes, providing an interesting example how mutations in two different subunits of a multi-subunit receptor complex result in an identical human disease phenotype [19].
• In sharp contrast to the effect by Ad-FDAP12, transgene expression in the liver of soluble form of extracellular domain of TREM-1 as an antagonist of DAP12 signaling, remarkably inhibited zymosan A-induced granuloma formation at all time points examined [2].
• Physical linkage to DAP12 requires lysine-183 in the NKp44 transmembrane domain [16].
• In clones that lacked expression of KARAP/DAP12, stimulation of KIR2DS2 did not induce cytotoxicity [20].
• Silencing human NKG2D, DAP10, and DAP12 reduces cytotoxicity of activated CD8+ T cells and NK cells [21].

Analytical, diagnostic and therapeutic context of TYROBP

• By flow cytometry, we demonstrated that CD4+CD28null T cells heterogeneously express KIRs and/or KARAP/DAP12 [20].
• By confocal immunocytochemistry we demonstrate that, in both human and mouse cerebral cortex, TREM2/DAP12, strongly expressed by microglia, is also present in a fraction of neurons but not in astrocytes and oligodendrocytes [6].
• Sequence analysis of DAP12 cDNA showed increased nucleotide mutations, including both nucleotide substitutions and deletions [22].
• In the present study, we report the molecular cloning of the myeloid DAP12-associating lectin-1 (MDL-1), a DAP12-associating membrane receptor expressed exclusively in monocytes and macrophages [23].
• Furthermore, immunoprecipitation of 129/J NK cell lysates with YE1/32 and YE1/48, Abs specific for the inhibitory Ly49A in B6, resulted in detection of the activation-associated DAP12 molecule [24].

References