Biology:Tyrosine kinase 2

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Short description: Enzyme and coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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]

TYK2 appears to play a central role in the inflammatory cascade responses in the pathogenesis of immune-mediated inflammatory diseases such as psoriasis.[20] The drug deucravacitinib (marketed as Sotyktu), a small-molecule TYK2 inhibitor, was approved for moderate-to-severe plaque psoriasis in 2022.

The P1104A allele of TYK2 has been shown to increase risk of tuberculosis when carried as a homozygote; population genetic analyses suggest that the arrival of tuberculosis in Europe drove the frequency of that allele down three-fold about 2,000 years before present.[21]

Interactions

Tyrosine kinase 2 has been shown to interact with FYN,[22] PTPN6,[23] IFNAR1,[24][25] Ku80[26] and GNB2L1.[27]

References

  1. ↑ "Identification and chromosomal mapping of new human tyrosine kinase genes". Oncogene 5 (3): 277–282. March 1990. PMID 2156206. 
  2. ↑ 2.0 2.1 "Entrez Gene: TYK2 tyrosine kinase 2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7297. 
  3. ↑ 3.0 3.1 "How cells respond to interferons". Annual Review of Biochemistry 67 (1): 227–264. 1998. doi:10.1146/annurev.biochem.67.1.227. PMID 9759489. 
  4. ↑ Guidebook to cytokines and their receptors. Oxford [Oxfordshire]: Oxford University Press. 1994. ISBN 0-19-859947-1. 
  5. ↑ "Suppressors of cytokine signaling and immunity". Nature Immunology 4 (12): 1169–1176. December 2003. doi:10.1038/ni1012. PMID 14639467. 
  6. ↑ "A protein tyrosine kinase in the interferon alpha/beta signaling pathway". Cell 70 (2): 313–322. July 1992. doi:10.1016/0092-8674(92)90105-L. PMID 1386289. 
  7. ↑ "Tyk2 negatively regulates adaptive Th1 immunity by mediating IL-10 signaling and promoting IFN-gamma-dependent IL-10 reactivation". Journal of Immunology 176 (12): 7263–7271. June 2006. doi:10.4049/jimmunol.176.12.7263. PMID 16751369. 
  8. ↑ 8.0 8.1 "Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function". Immunity 13 (4): 561–571. October 2000. doi:10.1016/S1074-7613(00)00055-8. PMID 11070174. 
  9. ↑ "Atherosclerosis--an inflammatory disease". The New England Journal of Medicine 340 (2): 115–126. January 1999. doi:10.1056/NEJM199901143400207. PMID 9887164. 
  10. ↑ "Vascular inflammation and the renin-angiotensin system". Arteriosclerosis, Thrombosis, and Vascular Biology 22 (8): 1257–1266. August 2002. doi:10.1161/01.ATV.0000021412.56621.A2. PMID 12171785. 
  11. ↑ "Murine models of asthma in understanding immune dysregulation in human asthma". Immunopharmacology 48 (3): 263–268. July 2000. doi:10.1016/S0162-3109(00)00223-X. PMID 10960667. 
  12. ↑ "A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infection and autoimmunity". Proceedings of the National Academy of Sciences of the United States of America 100 (20): 11594–11599. September 2003. doi:10.1073/pnas.1930781100. PMID 14500783. Bibcode: 2003PNAS..10011594S. 
  13. ↑ "Partial impairment of cytokine responses in Tyk2-deficient mice". Immunity 13 (4): 549–560. October 2000. doi:10.1016/S1074-7613(00)00054-6. PMID 11070173. 
  14. ↑ "Tyk2 tyrosine kinase expression is required for the maintenance of mitochondrial respiration in primary pro-B lymphocytes". Molecular and Cellular Biology 26 (22): 8562–8571. November 2006. doi:10.1128/MCB.00497-06. PMID 16982690. 
  15. ↑ "Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock". Nature Immunology 4 (5): 471–477. May 2003. doi:10.1038/ni910. PMID 12679810. 
  16. ↑ "JAK protein kinase inhibitors". Drug News & Perspectives 18 (5): 305–310. June 2005. doi:10.1358/dnp.2005.18.5.904198. PMID 16193102. 
  17. ↑ "Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity". Immunity 25 (5): 745–755. November 2006. doi:10.1016/j.immuni.2006.09.009. PMID 17088085. 
  18. ↑ "Human tyk2 kinase deficiency: another primary immunodeficiency syndrome". Immunity 25 (5): 695–697. November 2006. doi:10.1016/j.immuni.2006.10.007. PMID 17098200. 
  19. ↑ "Hyperimmunoglobulin E syndrome and tyrosine kinase 2 deficiency". Current Opinion in Allergy and Clinical Immunology 7 (6): 506–509. December 2007. doi:10.1097/ACI.0b013e3282f1baea. PMID 17989526. 
  20. ↑ "TYK2 in Immune Responses and Treatment of Psoriasis" (in English). Journal of Inflammation Research 15: 5373–5385. 2022-09-16. doi:10.2147/JIR.S380686. PMID 36147687. 
  21. ↑ "Human ancient DNA analyses reveal the high burden of tuberculosis in Europeans over the last 2,000 years" (in English). American Journal of Human Genetics 108 (3): 517–524. March 2021. doi:10.1016/j.ajhg.2021.02.009. PMID 33667394. 
  22. ↑ "Interaction of p59fyn with interferon-activated Jak kinases". Biochemical and Biophysical Research Communications 235 (1): 83–88. June 1997. doi:10.1006/bbrc.1997.6741. PMID 9196040. 
  23. ↑ "Association of the interferon-dependent tyrosine kinase Tyk-2 with the hematopoietic cell phosphatase". The Journal of Biological Chemistry 270 (31): 18179–18182. August 1995. doi:10.1074/jbc.270.31.18179. PMID 7629131. 
  24. ↑ "Specific contribution of Tyk2 JH regions to the binding and the expression of the interferon alpha/beta receptor component IFNAR1". The Journal of Biological Chemistry 273 (38): 24723–24729. September 1998. doi:10.1074/jbc.273.38.24723. PMID 9733772. 
  25. ↑ "Basal ubiquitin-independent internalization of interferon alpha receptor is prevented by Tyk2-mediated masking of a linear endocytic motif". The Journal of Biological Chemistry 283 (27): 18566–18572. July 2008. doi:10.1074/jbc.M800991200. PMID 18474601. 
  26. ↑ "Interferon-alpha signaling promotes nucleus-to-cytoplasmic redistribution of p95Vav, and formation of a multisubunit complex involving Vav, Ku80, and Tyk2". Biochemical and Biophysical Research Communications 267 (3): 692–696. January 2000. doi:10.1006/bbrc.1999.1978. PMID 10673353. 
  27. ↑ "The WD motif-containing protein RACK-1 functions as a scaffold protein within the type I IFN receptor-signaling complex". Journal of Immunology 171 (6): 2989–2994. September 2003. doi:10.4049/jimmunol.171.6.2989. 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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