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Gene Review

Tyk2  -  tyrosine kinase 2

Mus musculus

Synonyms: JTK1, Non-receptor tyrosine-protein kinase TYK2
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Disease relevance of Tyk2

  • Tyk2-/- mice are unable to clear vaccinia virus and show a reduced T cell response after LCMV challenge [1].
  • In wild type mice infected with lymphocytic choriomeningitis virus, there is a greater loss of B cells in the bone marrow and spleen than in Tyk2(-/-) mice infected with the virus, suggesting that the expression of this kinase plays an in vivo role in IFNalpha/beta-mediated PCD [2].
  • An additional implication of our findings is that naturally occurring mutations in the Tyk2 gene may underlie altered susceptibilities to infectious or autoimmune diseases in human and animal populations [3].
  • To elucidate potential roles of Tyk2 in generation and maintenance of Ag-specific CD8(+) T cells, we followed the fate of OVA-specific CD8(+) T cells in Tyk2-deficient (-/-) mice after infection with recombinant Listeria monocytogenes expressing OVA (rLM-OVA) [4].
  • Mice deficient in Tyk2 function have been previously shown to be resistant to autoimmune arthritis and septic shock but are acutely susceptible to opportunistic pathogens such as Toxoplasma gondii [5].

High impact information on Tyk2

  • Previous studies using cell lines selected for their inability to respond to IFN-alpha (ref. 4) have shown that the protein kinase Tyk2 plays a central role in the IFN alpha/beta response [6].
  • Activation of Tyk2 in NK cells by IFN-alpha/beta also required NOS2 [7].
  • Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed with hyper-IgE syndrome [8].
  • Thus, the Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired T helper 1 (Th1) differentiation and accelerated Th2 differentiation [8].
  • Tyk2 is a Janus kinase, and we developed tyk2-deficient mice to study the requirement for tyk2 in vivo [9].

Biological context of Tyk2


Anatomical context of Tyk2

  • Our in vitro studies demonstrate that MCMV replicates to dramatically higher titers in Tyk2-deficient macrophages compared with wild-type cells [12].
  • Suppression of B-cell growth by limitin, however, is severely impaired in the absence of Tyk2, whereas it is unaffected by the absence of Stat1 [10].
  • We evaluated the role of Tyk2 and Stat1 in the IFN-mediated inhibition of haematopoietic progenitor cell growth [13].
  • High levels of IFN-alpha (10,000 U/ml) suppressed the CFU-GM or BFU-E obtained from Stat1-deficient mice, but did not suppress this growth in cells from Tyk2-deficient mice [13].
  • In addition, Tyk2 induces plasma membrane relocalization of the R2 subunit of the interleukin-10 receptor [11].

Associations of Tyk2 with chemical compounds


Enzymatic interactions of Tyk2

  • Stat1 was phosphorylated by IFN-alpha in Tyk2-deficient cells, although the level of phosphorylation was weaker than that observed in wild type mice [13].

Regulatory relationships of Tyk2

  • We further demonstrate that Tyk2 indirectly controls CD4 IL-10 reactivation by signaling for maximal IFN-gamma secretion [5].
  • The IL-12-induced production of IFN-gamma by NK cells and CD8(+) T cells was strongly suppressed in Tyk2(-/-) mice at day 1 of infection, but partly regained during the late phase of infection [19].
  • Taken together, these results indicate that the expression of Tyk2 in DCs is crucial for the production of Th1-promoting cytokines such as IL-12 and IFN-gamma from DCs and thereby for the induction of antigen-specific Th1-cell differentiation [20].

Other interactions of Tyk2

  • The absence of Tyk2 abrogates this induction of Daxx expression and nuclear translocation [10].
  • Interestingly, Tyk2-deficient mice had higher resistance to LPS challenge than mice lacking either Stat1 or Stat4 [21].
  • Interestingly, the induction of both IFN-beta and IFN-gamma by LPS was severely reduced in Tyk2-deficient mice [21].
  • Jak2 and Tyk2 are necessary for lineage-specific differentiation, but not for the maintenance of self-renewal of mouse embryonic stem cells [22].
  • Here we report that mice devoid of the JAK protein tyrosine kinase family member, Tyk2, were resistant to shock induced by high doses of LPS [15].

Analytical, diagnostic and therapeutic context of Tyk2


  1. Partial impairment of cytokine responses in Tyk2-deficient mice. Karaghiosoff, M., Neubauer, H., Lassnig, C., Kovarik, P., Schindler, H., Pircher, H., McCoy, B., Bogdan, C., Decker, T., Brem, G., Pfeffer, K., Müller, M. Immunity (2000) [Pubmed]
  2. Activation of Tyk2 and Stat3 is required for the apoptotic actions of interferon-beta in primary pro-B cells. Gamero, A.M., Potla, R., Wegrzyn, J., Szelag, M., Edling, A.E., Shimoda, K., Link, D.C., Dulak, J., Baker, D.P., Tanabe, Y., Grayson, J.M., Larner, A.C. J. Biol. Chem. (2006) [Pubmed]
  3. A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infection and autoimmunity. Shaw, M.H., Boyartchuk, V., Wong, S., Karaghiosoff, M., Ragimbeau, J., Pellegrini, S., Muller, M., Dietrich, W.F., Yap, G.S. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  4. Tyk2 Signaling in Host Environment Plays an Important Role in Contraction of Antigen-Specific CD8+ T Cells following a Microbial Infection. Li, W., Yamada, H., Yajima, T., Nakagawa, R., Shimoda, K., Nakayama, K., Yoshikai, Y. J. Immunol. (2007) [Pubmed]
  5. Tyk2 negatively regulates adaptive Th1 immunity by mediating IL-10 signaling and promoting IFN-gamma-dependent IL-10 reactivation. Shaw, M.H., Freeman, G.J., Scott, M.F., Fox, B.A., Bzik, D.J., Belkaid, Y., Yap, G.S. J. Immunol. (2006) [Pubmed]
  6. Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway. Watling, D., Guschin, D., Müller, M., Silvennoinen, O., Witthuhn, B.A., Quelle, F.W., Rogers, N.C., Schindler, C., Stark, G.R., Ihle, J.N. Nature (1993) [Pubmed]
  7. Requirement for type 2 NO synthase for IL-12 signaling in innate immunity. Diefenbach, A., Schindler, H., Röllinghoff, M., Yokoyama, W.M., Bogdan, C. Science (1999) [Pubmed]
  8. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Minegishi, Y., Saito, M., Morio, T., Watanabe, K., Agematsu, K., Tsuchiya, S., Takada, H., Hara, T., Kawamura, N., Ariga, T., Kaneko, H., Kondo, N., Tsuge, I., Yachie, A., Sakiyama, Y., Iwata, T., Bessho, F., Ohishi, T., Joh, K., Imai, K., Kogawa, K., Shinohara, M., Fujieda, M., Wakiguchi, H., Pasic, S., Abinun, M., Ochs, H.D., Renner, E.D., Jansson, A., Belohradsky, B.H., Metin, A., Shimizu, N., Mizutani, S., Miyawaki, T., Nonoyama, S., Karasuyama, H. Immunity (2006) [Pubmed]
  9. Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function. Shimoda, K., Kato, K., Aoki, K., Matsuda, T., Miyamoto, A., Shibamori, M., Yamashita, M., Numata, A., Takase, K., Kobayashi, S., Shibata, S., Asano, Y., Gondo, H., Sekiguchi, K., Nakayama, K., Nakayama, T., Okamura, T., Okamura, S., Niho, Y., Nakayama, K. Immunity (2000) [Pubmed]
  10. Limitin, an interferon-like cytokine, transduces inhibitory signals on B-cell growth through activation of Tyk2, but not Stat1, followed by induction and nuclear translocation of Daxx. Aoki, K., Shimoda, K., Oritani, K., Matsuda, T., Kamezaki, K., Muromoto, R., Numata, A., Tamiya, S., Haro, T., Ishikawa, F., Takase, K., Yamamoto, T., Yumioka, T., Miyamoto, T., Nagafuji, K., Gondo, H., Nagafuchi, S., Nakayama, K., Harada, M. Exp. Hematol. (2003) [Pubmed]
  11. The tyrosine kinase Tyk2 controls IFNAR1 cell surface expression. Ragimbeau, J., Dondi, E., Alcover, A., Eid, P., Uzé, G., Pellegrini, S. EMBO J. (2003) [Pubmed]
  12. Novel functions of tyrosine kinase 2 in the antiviral defense against murine cytomegalovirus. Strobl, B., Bubic, I., Bruns, U., Steinborn, R., Lajko, R., Kolbe, T., Karaghiosoff, M., Kalinke, U., Jonjic, S., Müller, M. J. Immunol. (2005) [Pubmed]
  13. Intracellular signal transduction of interferon on the suppression of haematopoietic progenitor cell growth. Kato, K., Kamezaki, K., Shimoda, K., Numata, A., Haro, T., Aoki, K., Ishikawa, F., Takase, K., Ariyama, H., Matsuda, T., Miyamoto, T., Nagafuji, K., Gondo, H., Nakayama, K., Harada, M. Br. J. Haematol. (2003) [Pubmed]
  14. Regulation of Lipopolysaccharide-Induced Inducible Nitric-Oxide Synthase Expression through the Nuclear Factor-{kappa}B Pathway and Interferon-beta/Tyrosine Kinase 2/Janus Tyrosine Kinase 2-Signal Transducer and Activator of Transcription-1 Signaling Cascades by 2-Naphthylethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (THI 53), a New Synthetic Isoquinoline Alkaloid. Kim, H.J., Tsoyi, K., Heo, J.M., Kang, Y.J., Park, M.K., Lee, Y.S., Lee, J.H., Seo, H.G., Yun-Choi, H.S., Chang, K.C. J. Pharmacol. Exp. Ther. (2007) [Pubmed]
  15. Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock. Karaghiosoff, M., Steinborn, R., Kovarik, P., Kriegshäuser, G., Baccarini, M., Donabauer, B., Reichart, U., Kolbe, T., Bogdan, C., Leanderson, T., Levy, D., Decker, T., Müller, M. Nat. Immunol. (2003) [Pubmed]
  16. Mechanical stretch activates the JAK/STAT pathway in rat cardiomyocytes. Pan, J., Fukuda, K., Saito, M., Matsuzaki, J., Kodama, H., Sano, M., Takahashi, T., Kato, T., Ogawa, S. Circ. Res. (1999) [Pubmed]
  17. Conditional activation of Janus kinase (JAK) confers factor independence upon interleukin-3-dependent cells. Essential role of Ras in JAK-triggered mitogenesis. Mizuguchi, R., Hatakeyama, M. J. Biol. Chem. (1998) [Pubmed]
  18. 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]
  19. Control of Leishmania major in the absence of Tyk2 kinase. Schleicher, U., Mattner, J., Blos, M., Schindler, H., Röllinghoff, M., Karaghiosoff, M., Müller, M., Werner-Felmayer, G., Bogdan, C. Eur. J. Immunol. (2004) [Pubmed]
  20. Expression of Tyk2 in dendritic cells is required for IL-12, IL-23, and IFN-gamma production and the induction of Th1 cell differentiation. Tokumasa, N., Suto, A., Kagami, S., Furuta, S., Hirose, K., Watanabe, N., Saito, Y., Shimoda, K., Iwamoto, I., Nakajima, H. Blood (2007) [Pubmed]
  21. The role of Tyk2, Stat1 and Stat4 in LPS-induced endotoxin signals. Kamezaki, K., Shimoda, K., Numata, A., Matsuda, T., Nakayama, K., Harada, M. Int. Immunol. (2004) [Pubmed]
  22. Jak2 and Tyk2 are necessary for lineage-specific differentiation, but not for the maintenance of self-renewal of mouse embryonic stem cells. Chung, B.M., Kang, H.C., Han, S.Y., Heo, H.S., Lee, J.J., Jeon, J., Lim, J.Y., Shin, I., Hong, S.H., Cho, Y.S., Kim, C.G. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  23. Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice. Seto, Y., Nakajima, H., Suto, A., Shimoda, K., Saito, Y., Nakayama, K.I., Iwamoto, I. J. Immunol. (2003) [Pubmed]
  24. Tyk2 is dispensable for induction of myeloproliferative disease by mutant FLT3. Nakajima, H., Shibata, F., Kumagai, H., Shimoda, K., Kitamura, T. Int. J. Hematol. (2006) [Pubmed]
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