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Gene Review

TYK2  -  tyrosine kinase 2

Homo sapiens

Synonyms: IMD35, JTK1, Non-receptor tyrosine-protein kinase TYK2
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Disease relevance of TYK2

  • The increased rate of leukemia/lymphoma formation was linked to a decreased in vitro cytotoxic capacity of TYK2(-/-) NK and NKT cells toward tumor-derived cells [1].
  • Moreover, IFN does not promote NF-kappaB activation in TYK2-deficient mutant fibrosarcoma cells [2].
  • Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed with hyper-IgE syndrome [3].
  • We suggest that mutations in the JAK1 and Tyk2 genes may be identified as initial molecular defects in human cancers and autoimmune diseases [4].
  • The JAKs and STATs (with the exception of Jak3 and Tyk2) were present both in the dura and in the meningiomas studied [5].

High impact information on TYK2


Chemical compound and disease context of TYK2


Biological context of TYK2

  • Molecular characterization of an alpha interferon receptor 1 subunit (IFNaR1) domain required for TYK2 binding and signal transduction [10].
  • TYK2 amino acids 1-601 act in a dominant manner to inhibit the transcription of an interferon-alpha-dependent reporter gene, presumably by displacing endogenous TYK2 from the receptor [11].
  • Urokinase stimulates human vascular smooth muscle cell migration via a phosphatidylinositol 3-kinase-Tyk2 interaction [12].
  • We have generated a line of U937 promonocytes expressing a tyk2 transgene [13].
  • Catalytic TYK2 is the first identified component in an accessory signaling pathway that supplements ISGF3/interferon-stimulated response element signaling for gene induction by type I IFNs [14].

Anatomical context of TYK2

  • We now report IFN-beta-mediated activation of STATs and other components in U1 (TYK2-null) cell lines that were complemented with kinase-negative (U1.KR930) or wild-type TYK2 (U1.wt) [15].
  • Constitutive STAT1 tyrosine phosphorylation in U937 monocytes overexpressing the TYK2 protein tyrosine kinase does not induce gene transcription [13].
  • These findings suggest that in EBV-immortalized B cells JAK3 and Tyk2 proteins were constitutively phosphorylated but STAT6 protein was not constitutively phosphorylated [16].
  • In MonoMac-1 cells, STAT1 and STAT3 translocated to the nucleus following PAF stimulation, and their translocation in transiently transfected COS-7 cells was shown to be dependent on the presence of Tyk2 [17].
  • MAIN OUTCOME MEASURE(S): Cell lysates prepared from sperm and Jurkat T-cell line were resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the expression of JAKs (1-3 and TYK 2) and STATs (1-6) was examined by Western blot analysis [18].

Associations of TYK2 with chemical compounds


Physical interactions of TYK2

  • Tyk2 directly binds to either of the two Src homology 2(SH2)p85 domains in a uPA-dependent fashion [12].
  • Specific contribution of Tyk2 JH regions to the binding and the expression of the interferon alpha/beta receptor component IFNAR1 [22].
  • Rack-1 interacts weakly with the kinase domain and interacts strongly with the pseudokinase domain of Tyk2 [23].

Enzymatic interactions of TYK2

  • Mechanical stimulation (MS) resulted in an IL4R-dependent increase in phosphorylated Tyk2 in normal chondrocytes, which could be abolished by IL1beta preincubation [24].
  • In IGROV-1 cells, Tyk2 was constitutively phosphorylated and this phosphorylation was augmented by IL-4 or IL-13 [25].
  • Using these, we have identified tyk2 as a 134-kDa protein which is rapidly and transiently phosphorylated on tyrosine in response to IFN-alpha/beta and possesses an inducible kinase activity when tested in vitro [26].
  • Studies of mutant Tyk2 forms deleted at the N terminus indicated that the integrity of the N-terminal region is required to sustain IFNAR1 [27].

Regulatory relationships of TYK2

  • No migratory effect of uPA was observed in VSMC expressing the dominant negative form of Tyk2 [12].
  • In this study, we demonstrate that expression of the JEV nonstructural protein NS5 readily blocked IFN-stimulated Jak-Stat signaling events such as Stat1 nuclear translocation and tyrosine phosphorylation of Tyk2 and Stat1 [9].

Other interactions of TYK2

  • Here we show that the homologous mutations in JAK1 (V658F) and in Tyk2 (V678F) lead to constitutive activation of these kinases [4].
  • In both model systems, titration of the Tyk2 kinase away from the Ifnar1 receptor chain accounts for the observed cross-interference [28].
  • Catalytically active TYK2 is essential for interferon-beta-mediated phosphorylation of STAT3 and interferon-alpha receptor-1 (IFNAR-1) but not for activation of phosphoinositol 3-kinase [15].
  • This same fragment inhibits interferon-alpha-dependent tyrosine phosphorylation of TYK2, STAT1, and STAT2 [11].
  • Coprecipitation experiments demonstrated an association of constitutively tyrosine-phosphorylated TYK2 with the IFN-alpha receptor 1 chain [13].

Analytical, diagnostic and therapeutic context of TYK2


  1. TYK2 is a key regulator of the surveillance of B lymphoid tumors. Stoiber, D., Kovacic, B., Schuster, C., Schellack, C., Karaghiosoff, M., Kreibich, R., Weisz, E., Artwohl, M., Kleine, O.C., Muller, M., Baumgartner-Parzer, S., Ghysdael, J., Freissmuth, M., Sexl, V. J. Clin. Invest. (2004) [Pubmed]
  2. Interferon alpha activates NF-kappaB in JAK1-deficient cells through a TYK2-dependent pathway. Yang, C.H., Murti, A., Valentine, W.J., Du, Z., Pfeffer, L.M. J. Biol. Chem. (2005) [Pubmed]
  3. 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]
  4. JAK1 and Tyk2 activation by the homologous polycythemia vera JAK2 V617F mutation: cross-talk with IGF1 receptor. Staerk, J., Kallin, A., Demoulin, J.B., Vainchenker, W., Constantinescu, S.N. J. Biol. Chem. (2005) [Pubmed]
  5. Expression of the JAK and STAT superfamilies in human meningiomas. Magrassi, L., De-Fraja, C., Conti, L., Butti, G., Infuso, L., Govoni, S., Cattaneo, E. J. Neurosurg. (1999) [Pubmed]
  6. A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Velazquez, L., Fellous, M., Stark, G.R., Pellegrini, S. Cell (1992) [Pubmed]
  7. Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Marrero, M.B., Schieffer, B., Paxton, W.G., Heerdt, L., Berk, B.C., Delafontaine, P., Bernstein, K.E. Nature (1995) [Pubmed]
  8. Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12. Bacon, C.M., McVicar, D.W., Ortaldo, J.R., Rees, R.C., O'Shea, J.J., Johnston, J.A. J. Exp. Med. (1995) [Pubmed]
  9. Blocking of interferon-induced Jak-Stat signaling by Japanese encephalitis virus NS5 through a protein tyrosine phosphatase-mediated mechanism. Lin, R.J., Chang, B.L., Yu, H.P., Liao, C.L., Lin, Y.L. J. Virol. (2006) [Pubmed]
  10. Molecular characterization of an alpha interferon receptor 1 subunit (IFNaR1) domain required for TYK2 binding and signal transduction. Yan, H., Krishnan, K., Lim, J.T., Contillo, L.G., Krolewski, J.J. Mol. Cell. Biol. (1996) [Pubmed]
  11. Definition of the interferon-alpha receptor-binding domain on the TYK2 kinase. Yan, H., Piazza, F., Krishnan, K., Pine, R., Krolewski, J.J. J. Biol. Chem. (1998) [Pubmed]
  12. Urokinase stimulates human vascular smooth muscle cell migration via a phosphatidylinositol 3-kinase-Tyk2 interaction. Kusch, A., Tkachuk, S., Haller, H., Dietz, R., Gulba, D.C., Lipp, M., Dumler, I. J. Biol. Chem. (2000) [Pubmed]
  13. Constitutive STAT1 tyrosine phosphorylation in U937 monocytes overexpressing the TYK2 protein tyrosine kinase does not induce gene transcription. Eilers, A., Kanda, K., Klose, B., Krolewski, J., Decker, T. Cell Growth Differ. (1996) [Pubmed]
  14. Induction of beta-R1/I-TAC by interferon-beta requires catalytically active TYK2. Rani, M.R., Gauzzi, C., Pellegrini, S., Fish, E.N., Wei, T., Ransohoff, R.M. J. Biol. Chem. (1999) [Pubmed]
  15. Catalytically active TYK2 is essential for interferon-beta-mediated phosphorylation of STAT3 and interferon-alpha receptor-1 (IFNAR-1) but not for activation of phosphoinositol 3-kinase. Rani, M.R., Leaman, D.W., Han, Y., Leung, S., Croze, E., Fish, E.N., Wolfman, A., Ransohoff, R.M. J. Biol. Chem. (1999) [Pubmed]
  16. Comparison of IL-13- and IL-4-induced signaling in EBV-immortalized human B cells. Murata, T., Puri, R.K. Cell. Immunol. (1997) [Pubmed]
  17. G-protein-independent activation of Tyk2 by the platelet-activating factor receptor. Lukashova, V., Asselin, C., Krolewski, J.J., Rola-Pleszczynski, M., Stanková, J. J. Biol. Chem. (2001) [Pubmed]
  18. Members of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway are present and active in human sperm. D'Cruz, O.J., Vassilev, A.O., Uckun, F.M. Fertil. Steril. (2001) [Pubmed]
  19. TYK2 activity promotes ligand-induced IFNAR1 proteolysis. Marijanovic, Z., Ragimbeau, J., Kumar, K.G., Fuchs, S.Y., Pellegrini, S. Biochem. J. (2006) [Pubmed]
  20. Combining multiple structure and sequence alignments to improve sequence detection and alignment: application to the SH2 domains of Janus kinases. Al-Lazikani, B., Sheinerman, F.B., Honig, B. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  21. Linkage between alpha(1) adrenergic receptor and the Jak/STAT signaling pathway in vascular smooth muscle cells. Sasaguri, T., Teruya, H., Ishida, A., Abumiya, T., Ogata, J. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  22. Specific contribution of Tyk2 JH regions to the binding and the expression of the interferon alpha/beta receptor component IFNAR1. Richter, M.F., Duménil, G., Uzé, G., Fellous, M., Pellegrini, S. J. Biol. Chem. (1998) [Pubmed]
  23. Tyrosine kinase 2 interacts with and phosphorylates receptor for activated C kinase-1, a WD motif-containing protein. Haro, T., Shimoda, K., Kakumitsu, H., Kamezaki, K., Numata, A., Ishikawa, F., Sekine, Y., Muromoto, R., Matsuda, T., Harada, M. J. Immunol. (2004) [Pubmed]
  24. Roles for the interleukin-4 receptor and associated JAK/STAT proteins in human articular chondrocyte mechanotransduction. Millward-Sadler, S.J., Khan, N.S., Bracher, M.G., Wright, M.O., Salter, D.M. Osteoarthr. Cartil. (2006) [Pubmed]
  25. Human ovarian-carcinoma cell lines express IL-4 and IL-13 receptors: comparison between IL-4- and IL-13-induced signal transduction. Murata, T., Obiri, N.I., Puri, R.K. Int. J. Cancer (1997) [Pubmed]
  26. Activation of the protein tyrosine kinase tyk2 by interferon alpha/beta. Barbieri, G., Velazquez, L., Scrobogna, M., Fellous, M., Pellegrini, S. Eur. J. Biochem. (1994) [Pubmed]
  27. The amino-terminal region of Tyk2 sustains the level of interferon alpha receptor 1, a component of the interferon alpha/beta receptor. Gauzzi, M.C., Barbieri, G., Richter, M.F., Uzé, G., Ling, L., Fellous, M., Pellegrini, S. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  28. Down-modulation of type 1 interferon responses by receptor cross-competition for a shared Jak kinase. Dondi, E., Pattyn, E., Lutfalla, G., Van Ostade, X., Uzé, G., Pellegrini, S., Tavernier, J. J. Biol. Chem. (2001) [Pubmed]
  29. 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]
  30. The Jak/Stat pathway and urokinase receptor signaling in human aortic vascular smooth muscle cells. Dumler, I., Weis, A., Mayboroda, O.A., Maasch, C., Jerke, U., Haller, H., Gulba, D.C. J. Biol. Chem. (1998) [Pubmed]
  31. 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]
  32. Direct binding to and tyrosine phosphorylation of the alpha subunit of the type I interferon receptor by p135tyk2 tyrosine kinase. Colamonici, O., Yan, H., Domanski, P., Handa, R., Smalley, D., Mullersman, J., Witte, M., Krishnan, K., Krolewski, J. Mol. Cell. Biol. (1994) [Pubmed]
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