Tyrosine kinase 2

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Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the TYK2 gene.[1][2]

Tyk2 was the first member of the JAK family that was described (the other members are JAK1, JAK2, and JAK3).[3] It has been implicated in IFN-α, IL-6, IL-10 and IL-12 signaling.

Function

This gene encodes a member of the tyrosine kinase and, to be more specific, the Janus kinases (JAKs) protein families. This protein associates with the cytoplasmic domain of type I and type II cytokine receptors and promulgate cytokine signals by phosphorylating receptor subunits. It is also component of both the type I and type III interferon signaling pathways. As such, it may play a role in anti-viral immunity.[2]

Cytokines play pivotal roles in immunity and inflammation by regulating the survival, proliferation, differentiation, and function of immune cells, as well as cells from other organ systems.[4] Hence, targeting cytokines and their receptors is an effective means of treating such disorders. Type I and II cytokine receptors associate with Janus family kinases (JAKs) to affect intracellular signaling. Cytokines including interleukins, interferons and hemopoietins activate the Janus kinases, which associate with their cognate receptors.[5]

The mammalian JAK family has four members: JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2).[3] The connection between Jaks and cytokine signaling was first revealed when a screen for genes involved in interferon type I (IFN-1) signaling identified Tyk2 as an essential element, which is activated by an array of cytokine receptors.[6] Tyk2 has broader and profound functions in humans than previously appreciated on the basis of analysis of murine models, which indicate that Tyk2 functions primarily in IL-12 and type I-IFN signaling. Tyk2 deficiency has more dramatic effects in human cells than in mouse cells. However, in addition to IFN-α and -β and IL-12 signaling, Tyk2 has major effects on the transduction of IL-23, IL-10, and IL-6 signals. Since, IL-6 signals through the gp-130 receptor-chain that is common to a large family of cytokines, including IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF, Tyk2 might also affect signaling through these cytokines. Recently, it has been recognized that IL-12 and IL-23 share ligand and receptor subunits that activate Tyk2. IL-10 is a critical anti-inflammatory cytokine, and IL-10−/− mice suffer from fatal, systemic autoimmune disease.

Tyk2 is activated by IL-10, and its deficiency affects the ability to generate and respond to IL-10.[7] Under physiological conditions, immune cells are, in general, regulated by the action of many cytokines and it has become clear that cross-talk between different cytokine-signalling pathways is involved in the regulation of the JAK–STAT pathway.[8]

Role in inflammation

It is now widely accepted that atherosclerosis is a result of cellular and molecular events characteristic of inflammation.[9] Vascular inflammation can be caused by upregulation of Ang-II, which is produced locally by inflamed vessels and induces synthesis and secretion of IL-6, a cytokine responsible for induction of angiotensinogen synthesis in liver through JAK/STAT3 pathway, which gets activated through high affinity membrane protein receptors on target cells, termed IL-6R-chain recruiting gp-130 that is associated with tyrosine kinases (Jaks 1/2, and Tyk2 kinase).[10] Cytokines IL-4 and IL-13 gets elevated in lungs of chronically suffered asthmatics. Signalling through IL-4/IL-13 complexes is thought to occur through IL-4Rα-chain, which is responsible for activation of JAK-1 and Tyk2 kinases.[11] A role of Tyk2 in rheumatoid arthritis is directly observed in Tyk2-deficient mice that were resistant to experimental arthritis.[12] Tyk2−/− mice displayed a lack of responsiveness to a small amount of IFN-α, but they respond normally to a high concentration of IFN-α/β.[8][13] In addition, these mice respond normally to IL-6 and IL-10, suggesting that Tyk2 is dispensable for mediating for IL-6 and IL-10 signaling and does not play a major role in IFN-α signaling. Although Tyk2−/− mice are phenotypically normal, they exhibit abnormal responses to inflammatory challenges in a variety of cells isolated from Tyk2−/− mice.[14] The most remarkable phenotype observed in Tyk2-deficient macrophages was lack of nitric oxide production upon stimulation with LPS. Further elucidation of molecular mechanisms of LPS signaling, showed that Tyk2 and IFN-β deficiency leads resistance to LPS-induced endotoxin shock, whereas STAT1-deficient mice are susceptible.[15] Development of a Tyk2 inhibitor appears to be a rational approach in the drug discovery.[16]

Clinical significance

A mutation in this gene has been associated with hyperimmunoglobulin E syndrome (HIES) - a primary immunodeficiency characterized by elevated serum immunoglobulin E.[17][18][19]

Interactions

Tyrosine kinase 2 has been shown to interact with FYN,[20] PTPN6,[21] IFNAR1,[22][23] Ku80[24] and GNB2L1.[25]

References

  1. ↑ Krolewski JJ, Lee R, Eddy R, Shows TB, Dalla-Favera R (April 1990). "Identification and chromosomal mapping of new human tyrosine kinase genes". Oncogene. 5 (3): 277–82. PMID 2156206.
  2. ↑ 2.0 2.1 "Entrez Gene: TYK2 tyrosine kinase 2".
  3. ↑ 3.0 3.1 Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD (1998). "How cells respond to interferons". Annu. Rev. Biochem. 67 (1): 227–64. doi:10.1146/annurev.biochem.67.1.227. PMID 9759489.
  4. ↑ Nicola, Nicos (1994). Guidebook to cytokines and their receptors. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-859947-1.
  5. ↑ Kubo M, Hanada T, Yoshimura A (December 2003). "Suppressors of cytokine signaling and immunity". Nat. Immunol. 4 (12): 1169–76. doi:10.1038/ni1012. PMID 14639467.
  6. ↑ Velazquez L, Fellous M, Stark GR, Pellegrini S (July 1992). "A protein tyrosine kinase in the interferon alpha/beta signaling pathway". Cell. 70 (2): 313–22. doi:10.1016/0092-8674(92)90105-L. PMID 1386289.
  7. ↑ Shaw MH, Freeman GJ, Scott MF, et al. (June 2006). "Tyk2 negatively regulates adaptive Th1 immunity by mediating IL-10 signaling and promoting IFN-γ-dependent IL-10 reactivation". J. Immunol. 176 (12): 7263–71. doi:10.4049/jimmunol.176.12.7263. PMID 16751369.
  8. ↑ 8.0 8.1 Shimoda K, Kato K, Aoki K, et al. (October 2000). "Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function". Immunity. 13 (4): 561–71. doi:10.1016/S1074-7613(00)00055-8. PMID 11070174.
  9. ↑ Ross R; Ross, Russell (January 1999). "Atherosclerosis--an inflammatory disease". N. Engl. J. Med. 340 (2): 115–26. doi:10.1056/NEJM199901143400207. PMID 9887164.
  10. ↑ Brasier AR, Recinos A, Eledrisi MS (August 2002). "Vascular inflammation and the renin-angiotensin system". Arterioscler. Thromb. Vasc. Biol. 22 (8): 1257–66. doi:10.1161/01.ATV.0000021412.56621.A2. PMID 12171785.
  11. ↑ Wills-Karp M (July 2000). "Murine models of asthma in understanding immune dysregulation in human asthma". Immunopharmacology. 48 (3): 263–8. doi:10.1016/S0162-3109(00)00223-X. PMID 10960667.
  12. ↑ Shaw MH, Boyartchuk V, Wong S, Karaghiosoff M, Ragimbeau J, Pellegrini S, Muller M, Dietrich WF, Yap GS (September 2003). "A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infection and autoimmunity". Proc. Natl. Acad. Sci. U.S.A. 100 (20): 11594–9. Bibcode:2003PNAS..10011594S. doi:10.1073/pnas.1930781100. PMC 208803. PMID 14500783.
  13. ↑ Karaghiosoff M, Neubauer H, Lassnig C, Kovarik P, Schindler H, Pircher H, McCoy B, Bogdan C, Decker T, Brem G, Pfeffer K, Müller M (October 2000). "Partial impairment of cytokine responses in Tyk2-deficient mice". Immunity. 13 (4): 549–60. doi:10.1016/S1074-7613(00)00054-6. PMID 11070173.
  14. ↑ Potla R, Koeck T, Wegrzyn J, Cherukuri S, Shimoda K, Baker DP, Wolfman J, Planchon SM, Esposito C, Hoit B, Dulak J, Wolfman A, Stuehr D, Larner AC (November 2006). "Tyk2 tyrosine kinase expression is required for the maintenance of mitochondrial respiration in primary pro-B lymphocytes". Mol. Cell. Biol. 26 (22): 8562–71. doi:10.1128/MCB.00497-06. PMC 1636766. PMID 16982690.
  15. ↑ 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 (May 2003). "Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock". Nat. Immunol. 4 (5): 471–7. doi:10.1038/ni910. PMID 12679810.
  16. ↑ Thompson JE (June 2005). "JAK protein kinase inhibitors". Drug News Perspect. 18 (5): 305–10. doi:10.1358/dnp.2005.18.5.904198. PMID 16193102.
  17. ↑ 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 HD, Renner ED, Jansson A, Belohradsky BH, Metin A, Shimizu N, Mizutani S, Miyawaki T, Nonoyama S, Karasuyama H (November 2006). "Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity". Immunity. 25 (5): 745–55. doi:10.1016/j.immuni.2006.09.009. PMID 17088085.
  18. ↑ Watford WT, O'Shea JJ (November 2006). "Human tyk2 kinase deficiency: another primary immunodeficiency syndrome". Immunity. 25 (5): 695–7. doi:10.1016/j.immuni.2006.10.007. PMID 17098200.
  19. ↑ Minegishi Y, Karasuyama H (December 2007). "Hyperimmunoglobulin E syndrome and tyrosine kinase 2 deficiency". Curr Opin Allergy Clin Immunol. 7 (6): 506–9. doi:10.1097/ACI.0b013e3282f1baea. PMID 17989526.
  20. ↑ Uddin, S; Sher D A; Alsayed Y; Pons S; Colamonici O R; Fish E N; White M F; Platanias L C (June 1997). "Interaction of p59fyn with interferon-activated Jak kinases". Biochem. Biophys. Res. Commun. United States. 235 (1): 83–8. doi:10.1006/bbrc.1997.6741. ISSN 0006-291X. PMID 9196040.
  21. ↑ Yetter, A; Uddin S; Krolewski J J; Jiao H; Yi T; Platanias L C (August 1995). "Association of the interferon-dependent tyrosine kinase Tyk-2 with the hematopoietic cell phosphatase". J. Biol. Chem. United States. 270 (31): 18179–82. doi:10.1074/jbc.270.31.18179. ISSN 0021-9258. PMID 7629131.
  22. ↑ Richter, M F; Duménil G; Uzé G; Fellous M; Pellegrini S (September 1998). "Specific contribution of Tyk2 JH regions to the binding and the expression of the interferon alpha/beta receptor component IFNAR1". J. Biol. Chem. United States. 273 (38): 24723–9. doi:10.1074/jbc.273.38.24723. ISSN 0021-9258. PMID 9733772.
  23. ↑ Kumar, K G Suresh; Varghese Bentley; Banerjee Anamika; Baker Darren P; Constantinescu Stefan N; Pellegrini Sandra; Fuchs Serge Y (July 2008). "Basal ubiquitin-independent internalization of interferon alpha receptor is prevented by Tyk2-mediated masking of a linear endocytic motif". J. Biol. Chem. United States. 283 (27): 18566–72. doi:10.1074/jbc.M800991200. ISSN 0021-9258. PMC 2441555. PMID 18474601.
  24. ↑ Adam, L; Bandyopadhyay D; Kumar R (January 2000). "Interferon-alpha signaling promotes nucleus-to-cytoplasmic redistribution of p95Vav, and formation of a multisubunit complex involving Vav, Ku80, and Tyk2". Biochem. Biophys. Res. Commun. United States. 267 (3): 692–6. doi:10.1006/bbrc.1999.1978. ISSN 0006-291X. PMID 10673353.
  25. ↑ Usacheva, Anna; Tian Xinyong; Sandoval Raudel; Salvi Debra; Levy David; Colamonici Oscar R (September 2003). "The WD motif-containing protein RACK-1 functions as a scaffold protein within the type I IFN receptor-signaling complex". J. Immunol. United States. 171 (6): 2989–94. doi:10.4049/jimmunol.171.6.2989. ISSN 0022-1767. PMID 12960323.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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