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Gene Review

JAK3  -  Janus kinase 3

Homo sapiens

Synonyms: JAK-3, JAK3_HUMAN, JAKL, L-JAK, LJAK, ...
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Disease relevance of JAK3

  • In XSCID and SCID resulting from mutations in JAK3, which encodes a Janus family tyrosine kinase that couples to gamma(c) and is required for gamma(c)-dependent signalling, T- and natural killer (NK)-cells are decreased but B-cell numbers are normal (T(-)B(+)NK(-)SCID) [1].
  • Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins [2].
  • Additionally, JAK3 was detected in lysates from bone marrow lymphoblasts of patients with B cell precursor acute lymphocytic leukemia and cell lines derived from human B cell lymphomas [3].
  • IL-4 also stimulated all three kinases and substrates, but unlike in immune cells, IL-4 did not involve JAK3 activation for its signaling in colon cancer cell lines [4].
  • In B cells isolated from PBMC of AD patients with high serum IgE levels, JAK3 was constitutively phosphorylated at the tyrosine residue, and its phosphorylation was enhanced by the treatment with CD40L and/or IL-4 as was that in splenic B cells of NC/Nga mice with dermatitis and high IgE levels [5].

High impact information on JAK3

  • Interaction of JAB with Jak1, Jak2 or Jak3 markedly reduces their tyrosine-kinase activity and suppresses the tyrosine-phosphorylation and activation of STATs [6].
  • An Epstein-Barr virus (EBV)-transformed cell line derived from her lymphocytes had normal gamma c expression but lacked Jak3 protein and had greatly diminished Jak3 messenger RNA [7].
  • The Janus family tyrosine kinase Jak3 is the only signaling molecule known to be associated with gamma c, so it was hypothesized that defects in Jak3 might cause an XSCID-like phenotype [7].
  • Jak1 and Jak3 were found to be selectively associated with the "serine-rich" region of IL-2R beta and the carboxyl-terminal region of IL-2R gamma, respectively [8].
  • Furthermore, Jak3-negative fibroblasts expressing reconstituted IL-2R became responsive to IL-2 after the additional expression of Jak3 complementary DNA [8].

Chemical compound and disease context of JAK3

  • Here, we show that the inhibition of IL-2R expression and proliferation induced by ligation of CD4 by HIV envelope glycoprotein, gp120, is correlated with inhibition of expression and activation of JAK3 [9].
  • While Jak3 SCID patients possess mature peripheral B cells, we demonstrate that the Jak3 tyrosine kinase is also expressed in human pre-B cells and can be activated by the pre-B cell growth factor IL-7 [10].

Biological context of JAK3


Anatomical context of JAK3

  • Recently, we have cloned a novel JAK family member, JAK3, that is expressed in natural killer and activated T cells and is coupled functionally and physically to the interleukin 2 (IL-2) receptor in these cells [11].
  • Here we report that JAK3 was expressed at low but detectable levels in human monocytes [11].
  • Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation [14].
  • The characterization of the genetic defects and biochemical abnormalities in these JAK3-deficient patients will help define the role of JAK3 in the ontogeny of a competent immune system and may lead to a better understanding of the JAK3 functional domains [15].
  • The discovery of these signaling pathways has led to important new insights into their role in lymphocyte maturation, as it has emerged that mutations in the genes encoding both gamma c and JAK3 result in similar forms of severe combined immunodeficiency (SCID) [16].

Associations of JAK3 with chemical compounds


Physical interactions of JAK3

  • Both IL-2 and IL-4 bind to receptors containing the common gamma chain and JAK3 [18].
  • As a result of this interaction, p12(I) increases signal transducers and activators of transcription 5 (STAT5) DNA binding and transcriptional activity and this effect depends on the presence of both IL-2R beta and gamma(c) chains and Jak3 [19].

Enzymatic interactions of JAK3

  • JAK1 was also phosphorylated in one of two cell lines while JAK3 was present but not phosphorylated in any of the cell lines studied [20].
  • Notably a polypeptide representing the kinase domain of Jak3 (Jak3-JH1) gained the ability to tyrosine phosphorylate STAT1, suggesting that the changes in substrate recognition may be influenced by domains outside the kinase domain [21].
  • Furthermore, Jak3 protein was phosphorylated upon treatment of these cells with interleukin-4 [22].
  • Neither Jak1 nor Jak3 was phosphorylated after IL-2 stimulation of an Epstein-Barr virus-transformed cell line (LCL) from an X-SCID patient with a gamma-c null mutation [23].
  • In order to study whether there was any correlation between SHP-1 protein expression and tyrosine phosphorylated state of JAK3, the state of phosphorylation of JAK3 was studied in the T cell line HUT-78, and found to be highly phosphorylated [24].

Regulatory relationships of JAK3


Other interactions of JAK3


Analytical, diagnostic and therapeutic context of JAK3


  1. Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. Puel, A., Ziegler, S.F., Buckley, R.H., Leonard, W.J. Nat. Genet. (1998) [Pubmed]
  2. Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins. Gires, O., Kohlhuber, F., Kilger, E., Baumann, M., Kieser, A., Kaiser, C., Zeidler, R., Scheffer, B., Ueffing, M., Hammerschmidt, W. EMBO J. (1999) [Pubmed]
  3. Regulation of JAK3 expression and activation in human B cells and B cell malignancies. Tortolani, P.J., Lal, B.K., Riva, A., Johnston, J.A., Chen, Y.Q., Reaman, G.H., Beckwith, M., Longo, D., Ortaldo, J.R., Bhatia, K., McGrath, I., Kehrl, J., Tuscano, J., McVicar, D.W., O'Shea, J.J. J. Immunol. (1995) [Pubmed]
  4. IL-13 induces phosphorylation and activation of JAK2 Janus kinase in human colon carcinoma cell lines: similarities between IL-4 and IL-13 signaling. Murata, T., Noguchi, P.D., Puri, R.K. J. Immunol. (1996) [Pubmed]
  5. IgE hyperproduction through enhanced tyrosine phosphorylation of Janus kinase 3 in NC/Nga mice, a model for human atopic dermatitis. Matsumoto, M., Ra, C., Kawamoto, K., Sato, H., Itakura, A., Sawada, J., Ushio, H., Suto, H., Mitsuishi, K., Hikasa, Y., Matsuda, H. J. Immunol. (1999) [Pubmed]
  6. A new protein containing an SH2 domain that inhibits JAK kinases. Endo, T.A., Masuhara, M., Yokouchi, M., Suzuki, R., Sakamoto, H., Mitsui, K., Matsumoto, A., Tanimura, S., Ohtsubo, M., Misawa, H., Miyazaki, T., Leonor, N., Taniguchi, T., Fujita, T., Kanakura, Y., Komiya, S., Yoshimura, A. Nature (1997) [Pubmed]
  7. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Russell, S.M., Tayebi, N., Nakajima, H., Riedy, M.C., Roberts, J.L., Aman, M.J., Migone, T.S., Noguchi, M., Markert, M.L., Buckley, R.H., O'Shea, J.J., Leonard, W.J. Science (1995) [Pubmed]
  8. Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Miyazaki, T., Kawahara, A., Fujii, H., Nakagawa, Y., Minami, Y., Liu, Z.J., Oishi, I., Silvennoinen, O., Witthuhn, B.A., Ihle, J.N. Science (1994) [Pubmed]
  9. Cutting edge: JAK3 activation and rescue of T cells from HIV gp120-induced unresponsiveness. Selliah, N., Finkel, T.H. J. Immunol. (1998) [Pubmed]
  10. Jak3 activation in human lymphocyte precursor cells. Sharfe, N., Dadi, H.K., O'Shea, J.J., Roifman, C.M. Clin. Exp. Immunol. (1997) [Pubmed]
  11. Regulation of JAK3 expression in human monocytes: phosphorylation in response to interleukins 2, 4, and 7. Musso, T., Johnston, J.A., Linnekin, D., Varesio, L., Rowe, T.K., O'Shea, J.J., McVicar, D.W. J. Exp. Med. (1995) [Pubmed]
  12. Downregulation of JAK3 protein levels in T lymphocytes by prostaglandin E2 and other cyclic adenosine monophosphate-elevating agents: impact on interleukin-2 receptor signaling pathway. Kolenko, V., Rayman, P., Roy, B., Cathcart, M.K., O'Shea, J., Tubbs, R., Rybicki, L., Bukowski, R., Finke, J. Blood (1999) [Pubmed]
  13. Inhibition of JAK3 induces apoptosis and decreases anaplastic lymphoma kinase activity in anaplastic large cell lymphoma. Amin, H.M., Medeiros, L.J., Ma, Y., Feretzaki, M., Das, P., Leventaki, V., Rassidakis, G.Z., O'Connor, S.L., McDonnell, T.J., Lai, R. Oncogene (2003) [Pubmed]
  14. Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation. Roberts, J.L., Lengi, A., Brown, S.M., Chen, M., Zhou, Y.J., O'Shea, J.J., Buckley, R.H. Blood (2004) [Pubmed]
  15. Structural and functional basis for JAK3-deficient severe combined immunodeficiency. Candotti, F., Oakes, S.A., Johnston, J.A., Giliani, S., Schumacher, R.F., Mella, P., Fiorini, M., Ugazio, A.G., Badolato, R., Notarangelo, L.D., Bozzi, F., Macchi, P., Strina, D., Vezzoni, P., Blaese, R.M., O'Shea, J.J., Villa, A. Blood (1997) [Pubmed]
  16. Signaling by IL-2 and related cytokines: JAKs, STATs, and relationship to immunodeficiency. Johnston, J.A., Bacon, C.M., Riedy, M.C., O'Shea, J.J. J. Leukoc. Biol. (1996) [Pubmed]
  17. JSI-124 (cucurbitacin I) inhibits Janus kinase-3/signal transducer and activator of transcription-3 signalling, downregulates nucleophosmin-anaplastic lymphoma kinase (ALK), and induces apoptosis in ALK-positive anaplastic large cell lymphoma cells. Shi, X., Franko, B., Frantz, C., Amin, H.M., Lai, R. Br. J. Haematol. (2006) [Pubmed]
  18. Signaling via IL-2 and IL-4 in JAK3-deficient severe combined immunodeficiency lymphocytes: JAK3-dependent and independent pathways. Oakes, S.A., Candotti, F., Johnston, J.A., Chen, Y.Q., Ryan, J.J., Taylor, N., Liu, X., Hennighausen, L., Notarangelo, L.D., Paul, W.E., Blaese, R.M., O'Shea, J.J. Immunity (1996) [Pubmed]
  19. HTLV-1 p12(I) protein enhances STAT5 activation and decreases the interleukin-2 requirement for proliferation of primary human peripheral blood mononuclear cells. Nicot, C., Mulloy, J.C., Ferrari, M.G., Johnson, J.M., Fu, K., Fukumoto, R., Trovato, R., Fullen, J., Leonard, W.J., Franchini, G. Blood (2001) [Pubmed]
  20. Two different IL-13 receptor chains are expressed in normal human skin fibroblasts, and IL-4 and IL-13 mediate signal transduction through a common pathway. Murata, T., Husain, S.R., Mohri, H., Puri, R.K. Int. Immunol. (1998) [Pubmed]
  21. Differential substrate recognition capabilities of Janus family protein tyrosine kinases within the interleukin 2 receptor (IL2R) system: Jak3 as a potential molecular target for treatment of leukemias with a hyperactive Jak-Stat signaling machinery. Witthuhn, B.A., Williams, M.D., Kerawalla, H., Uckun, F.M. Leuk. Lymphoma (1999) [Pubmed]
  22. Expression of Janus kinase 3 in human endothelial and other non-lymphoid and non-myeloid cells. Verbsky, J.W., Bach, E.A., Fang, Y.F., Yang, L., Randolph, D.A., Fields, L.E. J. Biol. Chem. (1996) [Pubmed]
  23. Correction of interleukin-2 receptor function in X-SCID lymphoblastoid cells by retrovirally mediated transfer of the gamma-c gene. Taylor, N., Uribe, L., Smith, S., Jahn, T., Kohn, D.B., Weinberg, K. Blood (1996) [Pubmed]
  24. SHP-1 expression in peripheral T cells from patients with Sezary syndrome and in the T cell line HUT-78: implications in JAK3-mediated signaling. León, F., Cespón, C., Franco, A., Lombardía, M., Roldán, E., Escribano, L., Harto, A., González-Porqué, P., Roy, G. Leukemia (2002) [Pubmed]
  25. Signal transduction pathway of interleukin-4 and interleukin-13 in human B cells derived from X-linked severe combined immunodeficiency patients. Izuhara, K., Heike, T., Otsuka, T., Yamaoka, K., Mayumi, M., Imamura, T., Niho, Y., Harada, N. J. Biol. Chem. (1996) [Pubmed]
  26. JAK3 associates with the human interleukin 4 receptor and is tyrosine phosphorylated following receptor triggering. Rolling, C., Treton, D., Beckmann, P., Galanaud, P., Richard, Y. Oncogene (1995) [Pubmed]
  27. Comparison of IL-13- and IL-4-induced signaling in EBV-immortalized human B cells. Murata, T., Puri, R.K. Cell. Immunol. (1997) [Pubmed]
  28. Borrelia burgdorferi-induced expression of matrix metalloproteinases from human chondrocytes requires mitogen-activated protein kinase and Janus kinase/signal transducer and activator of transcription signaling pathways. Behera, A.K., Thorpe, C.M., Kidder, J.M., Smith, W., Hildebrand, E., Hu, L.T. Infect. Immun. (2004) [Pubmed]
  29. Prevention of CD40-triggered dendritic cell maturation and induction of T-cell hyporeactivity by targeting of Janus kinase 3. Säemann, M.D., Diakos, C., Kelemen, P., Kriehuber, E., Zeyda, M., Böhmig, G.A., Hörl, W.H., Baumruker, T., Zlabinger, G.J. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. (2003) [Pubmed]
  30. Thrombopoietin induces tyrosine phosphorylation and activation of the Janus kinase, JAK2. Tortolani, P.J., Johnston, J.A., Bacon, C.M., McVicar, D.W., Shimosaka, A., Linnekin, D., Longo, D.L., O'Shea, J.J. Blood (1995) [Pubmed]
  31. Role of JAK3 in CD40-mediated signaling. Jabara, H.H., Buckley, R.H., Roberts, J.L., Lefranc, G., Loiselet, J., Khalil, G., Geha, R.S. Blood (1998) [Pubmed]
  32. Receptors for interleukin (IL)-4 do not associate with the common gamma chain, and IL-4 induces the phosphorylation of JAK2 tyrosine kinase in human colon carcinoma cells. Murata, T., Noguchi, P.D., Puri, R.K. J. Biol. Chem. (1995) [Pubmed]
  33. The interleukin-4 receptor activates STAT5 by a mechanism that relies upon common gamma-chain. Lischke, A., Moriggl, R., Brändlein, S., Berchtold, S., Kammer, W., Sebald, W., Groner, B., Liu, X., Hennighausen, L., Friedrich, K. J. Biol. Chem. (1998) [Pubmed]
  34. A kinase-deficient splice variant of the human JAK3 is expressed in hematopoietic and epithelial cancer cells. Lai, K.S., Jin, Y., Graham, D.K., Witthuhn, B.A., Ihle, J.N., Liu, E.T. J. Biol. Chem. (1995) [Pubmed]
  35. Ligation of RARgamma inhibits proliferation of phytohaemagglutinin-stimulated T-cells via down-regulating JAK3 protein levels. Ludányi, K., Nagy, Z.S., Alexa, M., Reichert, U., Michel, S., Fésüs, L., Szondy, Z. Immunol. Lett. (2005) [Pubmed]
  36. Ovarian carcinoma cells inhibit T cell proliferation: suppression of IL-2 receptor beta and gamma expression and their JAK-STAT signaling pathway. Wang, H., Xie, X., Lu, W.G., Ye, D.F., Chen, H.Z., Li, X., Cheng, Q. Life Sci. (2004) [Pubmed]
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