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Jak3  -  Janus kinase 3

Mus musculus

Synonyms: JAK-3, Tyrosine-protein kinase JAK3, fae, wil
 
 
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Disease relevance of Jak3

 

High impact information on Jak3

  • Analysis for vector copy number in lymphoid and myeloid populations showed a large in vivo selective advantage for Jak3-expressing lymphoid cells [5].
  • We used a mouse model of Jak3-deficient SCID to test a gene therapy approach for treatment of this disease [5].
  • Jak-3 activation requires the serine-rich, membrane-proximal domain of the interleukin-2 receptor beta-chain, but does not require the acidic domain that is required for association and activation of Src family kinases [6].
  • Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells [6].
  • Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3 [7].
 

Chemical compound and disease context of Jak3

 

Biological context of Jak3

 

Anatomical context of Jak3

 

Associations of Jak3 with chemical compounds

 

Physical interactions of Jak3

  • The amino terminus of JAK3 is necessary and sufficient for binding to the common gamma chain and confers the ability to transmit interleukin 2-mediated signals [18].
 

Regulatory relationships of Jak3

 

Other interactions of Jak3

  • In response to mitogenic signals, peripheral T cells in Jak3-deficient mice did not proliferate and secreted small amounts of IL-2 [7].
  • However, the effects of IL-4 and IL-9 were absent in BMMCs from gamma(c)(-) and Jak3(-) mice [12].
  • However, Bax loss failed to restore proper ratios of peripheral CD4/CD8 T cells, which are abnormally high in Jak3-null mice [4].
  • In addition, IL-4Ralpha, gamma(c), and Jak3, but not IL-2Rbeta or IL-7Ralpha, were expressed in BMMCs [12].
  • However, when Jak3-/- mice are crossed with RAG-1-deficient animals, no splenomegaly or myeloid expansion is apparent [3].
 

Analytical, diagnostic and therapeutic context of Jak3

  • Homozygous mutant mice in which the Jak3 gene had been disrupted were generated by gene targeting [1].
  • The exon-intron sequences provided in this report can be used to facilitate the identification of new Jak3-deficient SCID patients, including prenatal diagnosis [22].
  • Moreover, AG-490 markedly inhibited IL-4 activation of JAK3 and blocked the downstream activation of signal transducer and activator of transcription 6, as judged by tyrosine phosphorylation, DNA binding, and transcription assays [23].
  • More extensive Southern blot, polymerase chain reaction and sequencing analyses showed that the published mouse sequence for exon 23 of the JAK3 gene in fact comprises two exons, 23A and 23B, separated by an additional novel intron of 2.2 kb, and that within this intron the promoter and exon 1 of the mouse RLF gene are encoded [24].
  • Prevention of islet allograft rejection in diabetic mice by targeting Janus Kinase 3 with 4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (JANEX-1) [25].

References

  1. Defective lymphoid development in mice lacking Jak3. Nosaka, T., van Deursen, J.M., Tripp, R.A., Thierfelder, W.E., Witthuhn, B.A., McMickle, A.P., Doherty, P.C., Grosveld, G.C., Ihle, J.N. Science (1995) [Pubmed]
  2. Absence of an essential role for thymic stromal lymphopoietin receptor in murine B-cell development. Carpino, N., Thierfelder, W.E., Chang, M.S., Saris, C., Turner, S.J., Ziegler, S.F., Ihle, J.N. Mol. Cell. Biol. (2004) [Pubmed]
  3. Dysregulated myelopoiesis in mice lacking Jak3. Grossman, W.J., Verbsky, J.W., Yang, L., Berg, L.J., Fields, L.E., Chaplin, D.D., Ratner, L. Blood (1999) [Pubmed]
  4. Jak3 selectively regulates Bax and Bcl-2 expression to promote T-cell development. Wen, R., Wang, D., McKay, C., Bunting, K.D., Marine, J.C., Vanin, E.F., Zambetti, G.P., Korsmeyer, S.J., Ihle, J.N., Cleveland, J.L. Mol. Cell. Biol. (2001) [Pubmed]
  5. Restoration of lymphocyte function in Janus kinase 3-deficient mice by retroviral-mediated gene transfer. Bunting, K.D., Sangster, M.Y., Ihle, J.N., Sorrentino, B.P. Nat. Med. (1998) [Pubmed]
  6. Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Witthuhn, B.A., Silvennoinen, O., Miura, O., Lai, K.S., Cwik, C., Liu, E.T., Ihle, J.N. Nature (1994) [Pubmed]
  7. Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Thomis, D.C., Gurniak, C.B., Tivol, E., Sharpe, A.H., Berg, L.J. Science (1995) [Pubmed]
  8. Development of autologous, oligoclonal, poorly functioning T lymphocytes in a patient with autosomal recessive severe combined immunodeficiency caused by defects of the Jak3 tyrosine kinase. Brugnoni, D., Notarangelo, L.D., Sottini, A., Airò, P., Pennacchio, M., Mazzolari, E., Signorini, S., Candotti, F., Villa, A., Mella, P., Vezzoni, P., Cattaneo, R., Ugazio, A.G., Imberti, L. Blood (1998) [Pubmed]
  9. Differential requirement of the cytoplasmic subregions of gamma c chain in T cell development and function. Tsujino, S., Di Santo, J.P., Takaoka, A., McKernan, T.L., Noguchi, S., Taya, C., Yonekawa, H., Saito, T., Taniguchi, T., Fujii, H. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  10. Reconstitution of early lymphoid proliferation and immune function in Jak3-deficient mice by interleukin-3. Brown, M.P., Nosaka, T., Tripp, R.A., Brooks, J., van Deursen, J.M., Brenner, M.K., Doherty, P.C., Ihle, J.N. Blood (1999) [Pubmed]
  11. IFN-gamma suppresses STAT6 phosphorylation by inhibiting its recruitment to the IL-4 receptor. Huang, Z., Xin, J., Coleman, J., Huang, H. J. Immunol. (2005) [Pubmed]
  12. Role of common cytokine receptor gamma chain (gamma(c))- and Jak3-dependent signaling in the proliferation and survival of murine mast cells. Suzuki, K., Nakajima, H., Watanabe, N., Kagami, S., Suto, A., Saito, Y., Saito, T., Iwamoto, I. Blood (2000) [Pubmed]
  13. Jak3 negatively regulates dendritic-cell cytokine production and survival. Yamaoka, K., Min, B., Zhou, Y.J., Paul, W.E., O'shea, J.J. Blood (2005) [Pubmed]
  14. Thymic stromal lymphopoietin: a cytokine that promotes the development of IgM+ B cells in vitro and signals via a novel mechanism. Levin, S.D., Koelling, R.M., Friend, S.L., Isaksen, D.E., Ziegler, S.F., Perlmutter, R.M., Farr, A.G. J. Immunol. (1999) [Pubmed]
  15. Photochemical preparation of a pyridone containing tetracycle: a Jak protein kinase inhibitor. Thompson, J.E., Cubbon, R.M., Cummings, R.T., Wicker, L.S., Frankshun, R., Cunningham, B.R., Cameron, P.M., Meinke, P.T., Liverton, N., Weng, Y., DeMartino, J.A. Bioorg. Med. Chem. Lett. (2002) [Pubmed]
  16. The role of Jak3 in lymphoid development, activation, and signaling. Thomis, D.C., Berg, L.J. Curr. Opin. Immunol. (1997) [Pubmed]
  17. Inhibition of JAK3 and STAT6 tyrosine phosphorylation by the immunosuppressive drug leflunomide leads to a block in IgG1 production. Siemasko, K., Chong, A.S., Jäck, H.M., Gong, H., Williams, J.W., Finnegan, A. J. Immunol. (1998) [Pubmed]
  18. The amino terminus of JAK3 is necessary and sufficient for binding to the common gamma chain and confers the ability to transmit interleukin 2-mediated signals. Chen, M., Cheng, A., Chen, Y.Q., Hymel, A., Hanson, E.P., Kimmel, L., Minami, Y., Taniguchi, T., Changelian, P.S., O'Shea, J.J. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  19. Possible mechanism for the alpha subunit of the interleukin-2 receptor (CD25) to influence interleukin-2 receptor signal transduction. Ellery, J.M., Nicholls, P.J. Immunol. Cell Biol. (2002) [Pubmed]
  20. Cutting edge: an alternative pathway of CD4+ T cell differentiation is induced following activation in the absence of gamma-chain-dependent cytokine signals. Mayack, S.R., Berg, L.J. J. Immunol. (2006) [Pubmed]
  21. Impaired chemokine-induced migration during T-cell development in the absence of Jak 3. Soldevila, G., Licona, I., Salgado, A., Ramírez, M., Chávez, R., García-Zepeda, E. Immunology (2004) [Pubmed]
  22. Revised exon-intron structure of human JAK3 locus. Brooimans, R.A., van der Slot, A.J., van den Berg, A.J., Zegers, B.J. Eur. J. Hum. Genet. (1999) [Pubmed]
  23. Selective disruption of interleukin 4 autocrine-regulated loop by a tyrosine kinase inhibitor restricts activity of T-helper 2 cells. Wang, L.H., Kirken, R.A., Yang, X.Y., Erwin, R.A., DaSilva, L., Yu, C.R., Farrar, W.L. Blood (2000) [Pubmed]
  24. The mouse relaxin-like factor gene and its promoter are located within the 3' region of the JAK3 genomic sequence. Koskimies, P., Spiess, A.N., Lahti, P., Huhtaniemi, I., Ivell, R. FEBS Lett. (1997) [Pubmed]
  25. Prevention of islet allograft rejection in diabetic mice by targeting Janus Kinase 3 with 4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (JANEX-1). Cetkovic-Cvrlje, M., Dragt, A.L., Uckun, F.M. Arzneimittel-Forschung. (2003) [Pubmed]
 
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