Disease relevance of Tyrobp

• KARAP/DAP12 loss-of-function mutant mice also exhibit a dramatic accumulation of dendritic cells in muco-cutaneous epithelia, associated with an impaired hapten-specific contact sensitivity [1].
• DAP12-deficient mice were more susceptible to endotoxic shock and had enhanced resistance to infection by the intracellular bacterium Listeria monocytogenes [2].
• These mononuclear cells are functional osteoclast-like cells because, by RT-PCR, they express other osteoclast markers and generate resorption pits on dentine slices, although quantitative assessment of bone resorption shows decreased resorption by DAP12 -/- osteoclasts compared with C57BL/6 osteoclasts [3].
• To analyze the consequences of DAP12 deficiency in vivo, we examined the susceptibility of DAP12-/- mice to experimental autoimmune encephalomyelitis (EAE) [4].
• These data demonstrate that, during sepsis, DAP12 signaling augments the response to microbial products, amplifying inflammation and contributing to mortality [5].

Psychiatry related information on Tyrobp

• Deletions in the DAP12 gene in humans result in Nasu-Hakola disease, characterized by a combination of bone fractures and psychotic symptoms similar to schizophrenia, rapidly progressing to presenile dementia [6].

High impact information on Tyrobp

• Thus, despite its homology with CD3zeta and FcRgamma, KARAP/DAP12 plays a specific role in innate immunity, emphasizing the nonredundancy of these ITAM-bearing polypeptides in hematopoietic cells [1].
• Combined natural killer cell and dendritic cell functional deficiency in KARAP/DAP12 loss-of-function mutant mice [1].
• DAP12 is an ITAM-bearing membrane adaptor molecule implicated in the activation of NK and myeloid cells [4].
• DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming [4].
• These data suggest that DAP12 signaling may be required for optimal antigen-presenting cell (APC) function or inflammation [4].

Chemical compound and disease context of Tyrobp

• In cells isolated after sepsis and stimulated ex vivo, DAP12 signaling augments lipopolysaccharide-mediated cytokine production [5].

Biological context of Tyrobp

• Down-modulation of Tyrobp involved IFN consensus sequence binding protein (ICSBP), a transcription factor also known as IRF-8 [7].
• Bone density of DAP12 -/- and control mice were analyzed by microcomputed tomography [3].
• TREM2 stimulation induced DAP12 phosphorylation, extracellular signal-regulated kinase phosphorylation, and cytoskeleton reorganization and increased phagocytosis [8].
• Gene targeting of the adaptor molecule DAP12 in mice caused abnormal distribution and impaired antigen presentation capacity of dendritic cells (DCs) [9].
• Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis [10].

Anatomical context of Tyrobp

• Natural killer (NK) cells express multiple activating receptors that initiate signaling cascades through DAP10- or immunoreceptor tyrosine-based activation motif-containing adapters, including DAP12 and FcRgamma [11].
• Unexpectedly, DAP12-deficient macrophages produced higher concentrations of inflammatory cytokines in response to a variety of pathogenic stimuli [2].
• DAP12 is a signaling adaptor containing an immunoreceptor tyrosine-based activation motif (ITAM) that pairs with receptors on myeloid cells and natural killer cells [2].
• The aim of this study was to clarify the role of DAP12 signaling during osteoclast development [3].
• In addition, we identify microglial cells and oligodendrocytes as the major Dap12/Trem2-producing cells in the CNS and, consequently, as the predominant cell types involved in PLOSL pathogenesis [12].

Associations of Tyrobp with chemical compounds

• Ten other transcripts elevated in both mouse models are associated with macrophage functions, including complement C4, the three subunits of complement C1q, lysozyme M, cathepsins S and Z, cytochrome b558 small subunit, macrophage-specific protein 1, and DAP12 [13].

Physical interactions of Tyrobp

• Attesting to the importance of the Dap12/Syk complex, Syk deficient macrophages do not undergo normal osteoclastogenesis [14].
• In this study, we show that in contrast to C57BL/6 NK cells, cross-linking of DAP12-coupled receptors in 129/J mice induces phosphorylation of DAP12 but not calcium mobilization or cytokine production [15].

Regulatory relationships of Tyrobp

• NKG2D triggers cytotoxicity in mouse NK cells lacking DAP12 or Syk family kinases [16].
• In adoptive transfer experiments, T-DAP12 cells enhanced the survival of NK cell-depleted RAG-1-deficient mice inoculated with RMA-S-Rae-1beta but not parental RMA-S tumors [17].
• Importantly, following a period of proliferation through endogenous T cell receptor ligation, OT-1-DAP12 cells retained specificity against NKG2D-L expressing major histocompatibility complex class I-deficient tumor [17].

Other interactions of Tyrobp

• Mice lacking two ITAM-bearing adapters, DAP12 and the Fc receptor gamma-chain (FcRgamma), are severely osteopetrotic [18].
• IL-4 confers NK stimulatory capacity to murine dendritic cells: a signaling pathway involving KARAP/DAP12-triggering receptor expressed on myeloid cell 2 molecules [19].
• Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12 [2].
• Two mCD200 receptor-like family members, designated mCD200RLa and mCD200RLb, were shown to pair with the activatory adaptor protein, DAP12, suggesting that these receptors would transmit strong activating signals in contrast to the apparent inhibitory signal delivered by triggering the CD200R [20].
• In contrast to NK cells, T cells fail to express the activation-signaling molecule DAP12 even when activated and, therefore, ligation of NKG2D alone is insufficient to induce T cell cytolytic function [17].

Analytical, diagnostic and therapeutic context of Tyrobp

• We show that DAP12-/- mice have improved survival from both endotoxemia and cecal ligation and puncture-induced septic shock [5].
• Sequence analysis of receptors and DAP12 suggests no structural basis for inactivity, and both the 129/J and C57BL/6 receptors demonstrate normal function in a reconstituted receptor system [15].

References