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TYROBP  -  TYRO protein tyrosine kinase binding protein

Homo sapiens

Synonyms: DAP12, DNAX-activation protein 12, KAR-associated protein, KARAP, Killer-activating receptor-associated protein, ...
 
 
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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

 

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

 

Associations of TYROBP with chemical compounds

 

Physical interactions of TYROBP

 

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

References

  1. Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Paloneva, J., Kestilä, M., Wu, J., Salminen, A., Böhling, T., Ruotsalainen, V., Hakola, P., Bakker, A.B., Phillips, J.H., Pekkarinen, P., Lanier, L.L., Timonen, T., Peltonen, L. Nat. Genet. (2000) [Pubmed]
  2. Modulation of hepatic granulomatous responses by transgene expression of DAP12 or TREM-1-Ig molecules. Nochi, H., Aoki, N., Oikawa, K., Yanai, M., Takiyama, Y., Atsuta, Y., Kobayashi, H., Sato, K., Tateno, M., Matsuno, T., Katagiri, M., Xing, Z., Kimura, S. Am. J. Pathol. (2003) [Pubmed]
  3. DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features. Paloneva, J., Mandelin, J., Kiialainen, A., Bohling, T., Prudlo, J., Hakola, P., Haltia, M., Konttinen, Y.T., Peltonen, L. J. Exp. Med. (2003) [Pubmed]
  4. Massive inflammatory syndrome and lymphocytic immunodeficiency in KARAP/DAP12-transgenic mice. Lucas, M., Daniel, L., Tomasello, E., Guia, S., Horschowski, N., Aoki, N., Figarella-Branger, D., Gomez, S., Vivier, E. Eur. J. Immunol. (2002) [Pubmed]
  5. Enhanced tryptophan catabolism in the absence of the molecular adapter DAP12. Orabona, C., Tomasello, E., Fallarino, F., Bianchi, R., Volpi, C., Bellocchio, S., Romani, L., Fioretti, M.C., Vivier, E., Puccetti, P., Grohmann, U. Eur. J. Immunol. (2005) [Pubmed]
  6. Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia. Sessa, G., Podini, P., Mariani, M., Meroni, A., Spreafico, R., Sinigaglia, F., Colonna, M., Panina, P., Meldolesi, J. Eur. J. Neurosci. (2004) [Pubmed]
  7. Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Lanier, L.L., Corliss, B.C., Wu, J., Leong, C., Phillips, J.H. Nature (1998) [Pubmed]
  8. Association of DAP12 with activating CD94/NKG2C NK cell receptors. Lanier, L.L., Corliss, B., Wu, J., Phillips, J.H. Immunity (1998) [Pubmed]
  9. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Paloneva, J., Manninen, T., Christman, G., Hovanes, K., Mandelin, J., Adolfsson, R., Bianchin, M., Bird, T., Miranda, R., Salmaggi, A., Tranebjaerg, L., Konttinen, Y., Peltonen, L. Am. J. Hum. Genet. (2002) [Pubmed]
  10. 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. Snyder, M.R., Lucas, M., Vivier, E., Weyand, C.M., Goronzy, J.J. J. Exp. Med. (2003) [Pubmed]
  11. Cutting edge: signal-regulatory protein beta 1 is a DAP12-associated activating receptor expressed in myeloid cells. Dietrich, J., Cella, M., Seiffert, M., Bühring, H.J., Colonna, M. J. Immunol. (2000) [Pubmed]
  12. Syk regulation of phosphoinositide 3-kinase-dependent NK cell function. Jiang, K., Zhong, B., Gilvary, D.L., Corliss, B.C., Vivier, E., Hong-Geller, E., Wei, S., Djeu, J.Y. J. Immunol. (2002) [Pubmed]
  13. Association of signal-regulatory proteins beta with KARAP/DAP-12. Tomasello, E., Cant, C., Bühring, H.J., Vély, F., André, P., Seiffert, M., Ullrich, A., Vivier, E. Eur. J. Immunol. (2000) [Pubmed]
  14. Contrasting roles of DAP10 and KARAP/DAP12 signaling adaptors in activation of the RBL-2H3 leukemic mast cell line. Anfossi, N., Lucas, M., Diefenbach, A., Bühring, H.J., Raulet, D., Tomasello, E., Vivier, E. Eur. J. Immunol. (2003) [Pubmed]
  15. The assembly of diverse immune receptors is focused on a polar membrane-embedded interaction site. Feng, J., Call, M.E., Wucherpfennig, K.W. PLoS Biol. (2006) [Pubmed]
  16. NKp44 triggers NK cell activation through DAP12 association that is not influenced by a putative cytoplasmic inhibitory sequence. Campbell, K.S., Yusa, S., Kikuchi-Maki, A., Catina, T.L. J. Immunol. (2004) [Pubmed]
  17. TREMs in the immune system and beyond. Colonna, M. Nat. Rev. Immunol. (2003) [Pubmed]
  18. Negative regulation of leucocyte functions by CD33-related siglecs. Avril, T., Attrill, H., Zhang, J., Raper, A., Crocker, P.R. Biochem. Soc. Trans. (2006) [Pubmed]
  19. Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy--PLOSL): a dementia associated with bone cystic lesions. From clinical to genetic and molecular aspects. Bianchin, M.M., Capella, H.M., Chaves, D.L., Steindel, M., Grisard, E.C., Ganev, G.G., da Silva Júnior, J.P., Neto Evaldo, S., Poffo, M.A., Walz, R., Carlotti Júnior, C.G., Sakamoto, A.C. Cell. Mol. Neurobiol. (2004) [Pubmed]
  20. Stimulatory killer Ig-like receptors modulate T cell activation through DAP12-dependent and DAP12-independent mechanisms. Snyder, M.R., Nakajima, T., Leibson, P.J., Weyand, C.M., Goronzy, J.J. J. Immunol. (2004) [Pubmed]
  21. Silencing human NKG2D, DAP10, and DAP12 reduces cytotoxicity of activated CD8+ T cells and NK cells. Karimi, M., Cao, T.M., Baker, J.A., Verneris, M.R., Soares, L., Negrin, R.S. J. Immunol. (2005) [Pubmed]
  22. Decreased DAP12 expression in natural killer lymphocytes from patients with systemic lupus erythematosus is associated with increased transcript mutations. Toyabe, S., Kaneko, U., Uchiyama, M. J. Autoimmun. (2004) [Pubmed]
  23. Myeloid DAP12-associating lectin (MDL)-1 is a cell surface receptor involved in the activation of myeloid cells. Bakker, A.B., Baker, E., Sutherland, G.R., Phillips, J.H., Lanier, L.L. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  24. Cloning and characterization of a novel activating Ly49 closely related to Ly49A. Makrigiannis, A.P., Gosselin, P., Mason, L.H., Taylor, L.S., McVicar, D.W., Ortaldo, J.R., Anderson, S.K. J. Immunol. (1999) [Pubmed]
 
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