TYK2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTYK2, IMD35, JTK1, tyrosine kinase 2, Non-receptor tyrosine-protein kinase
External IDsOMIM: 176941 MGI: 1929470 HomoloGene: 20712 GeneCards: TYK2
Orthologs
SpeciesHumanMouse
Entrez

7297

54721

Ensembl

ENSG00000105397

ENSMUSG00000032175

UniProt

P29597

Q9R117

RefSeq (mRNA)

NM_003331

NM_001205312
NM_018793

RefSeq (protein)

NP_003322

NP_001192241
NP_061263

Location (UCSC)Chr 19: 10.35 – 10.38 MbChr 9: 21.02 – 21.04 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the TYK2 gene.[5][6]

TYK2 was the first member of the JAK family that was described (the other members are JAK1, JAK2, and JAK3).[7] 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.[6]

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.[8] 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.[9]

The mammalian JAK family has four members: JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2).[7] 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.[10] 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.[11] 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.[12]

Role in inflammation

It is now widely accepted that atherosclerosis is a result of cellular and molecular events characteristic of inflammation.[13] 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).[14] 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.[15] A role of TYK2 in rheumatoid arthritis is directly observed in TYK2-deficient mice that were resistant to experimental arthritis.[16] 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.[12][17] 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.[18] 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.[19] Development of a TYK2 inhibitor appears to be a rational approach in the drug discovery.[20]

Clinical significance

A mutation in this gene has been associated with hyperimmunoglobulin E syndrome (HIES), a primary immunodeficiency characterized by elevated serum immunoglobulin E.[21][22][23]

TYK2 appears to play a central role in the inflammatory cascade responses in the pathogenesis of immune-mediated inflammatory diseases such as psoriasis.[24] 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.[25]

Interactions

Tyrosine kinase 2 has been shown to interact with FYN,[26] PTPN6,[27] IFNAR1,[28][29] Ku80[30] and GNB2L1.[31]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000105397 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000032175 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Krolewski JJ, Lee R, Eddy R, Shows TB, Dalla-Favera R (March 1990). "Identification and chromosomal mapping of new human tyrosine kinase genes". Oncogene. 5 (3): 277–282. PMID 2156206.
  6. 1 2 "Entrez Gene: TYK2 tyrosine kinase 2".
  7. 1 2 Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD (1998). "How cells respond to interferons". Annual Review of Biochemistry. 67 (1): 227–264. doi:10.1146/annurev.biochem.67.1.227. PMID 9759489.
  8. ↑ Nicola N (1994). Guidebook to cytokines and their receptors. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-859947-1.
  9. ↑ Kubo M, Hanada T, Yoshimura A (December 2003). "Suppressors of cytokine signaling and immunity". Nature Immunology. 4 (12): 1169–1176. doi:10.1038/ni1012. PMID 14639467. S2CID 20626224.
  10. ↑ Velazquez L, Fellous M, Stark GR, Pellegrini S (July 1992). "A protein tyrosine kinase in the interferon alpha/beta signaling pathway". Cell. 70 (2): 313–322. doi:10.1016/0092-8674(92)90105-L. PMID 1386289. S2CID 140206909.
  11. ↑ Shaw MH, Freeman GJ, Scott MF, Fox BA, Bzik DJ, Belkaid Y, Yap GS (June 2006). "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. doi:10.4049/jimmunol.176.12.7263. PMID 16751369.
  12. 1 2 Shimoda K, Kato K, Aoki K, Matsuda T, Miyamoto A, Shibamori M, 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): 561–571. doi:10.1016/S1074-7613(00)00055-8. PMID 11070174.
  13. ↑ Ross R (January 1999). "Atherosclerosis--an inflammatory disease". The New England Journal of Medicine. 340 (2): 115–126. doi:10.1056/NEJM199901143400207. PMID 9887164.
  14. ↑ Brasier AR, Recinos A, Eledrisi MS (August 2002). "Vascular inflammation and the renin-angiotensin system". Arteriosclerosis, Thrombosis, and Vascular Biology. 22 (8): 1257–1266. doi:10.1161/01.ATV.0000021412.56621.A2. PMID 12171785.
  15. ↑ Wills-Karp M (July 2000). "Murine models of asthma in understanding immune dysregulation in human asthma". Immunopharmacology. 48 (3): 263–268. doi:10.1016/S0162-3109(00)00223-X. PMID 10960667.
  16. ↑ Shaw MH, Boyartchuk V, Wong S, Karaghiosoff M, Ragimbeau J, Pellegrini S, et al. (September 2003). "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. Bibcode:2003PNAS..10011594S. doi:10.1073/pnas.1930781100. PMC 208803. PMID 14500783.
  17. ↑ Karaghiosoff M, Neubauer H, Lassnig C, Kovarik P, Schindler H, Pircher H, et al. (October 2000). "Partial impairment of cytokine responses in Tyk2-deficient mice". Immunity. 13 (4): 549–560. doi:10.1016/S1074-7613(00)00054-6. PMID 11070173.
  18. ↑ Potla R, Koeck T, Wegrzyn J, Cherukuri S, Shimoda K, Baker DP, et al. (November 2006). "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. doi:10.1128/MCB.00497-06. PMC 1636766. PMID 16982690.
  19. ↑ Karaghiosoff M, Steinborn R, Kovarik P, Kriegshäuser G, Baccarini M, Donabauer B, et al. (May 2003). "Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock". Nature Immunology. 4 (5): 471–477. doi:10.1038/ni910. PMID 12679810. S2CID 19745533.
  20. ↑ Thompson JE (June 2005). "JAK protein kinase inhibitors". Drug News & Perspectives. 18 (5): 305–310. doi:10.1358/dnp.2005.18.5.904198. PMID 16193102.
  21. ↑ Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, et al. (November 2006). "Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity". Immunity. 25 (5): 745–755. doi:10.1016/j.immuni.2006.09.009. PMID 17088085.
  22. ↑ Watford WT, O'Shea JJ (November 2006). "Human tyk2 kinase deficiency: another primary immunodeficiency syndrome". Immunity. 25 (5): 695–697. doi:10.1016/j.immuni.2006.10.007. PMID 17098200.
  23. ↑ Minegishi Y, Karasuyama H (December 2007). "Hyperimmunoglobulin E syndrome and tyrosine kinase 2 deficiency". Current Opinion in Allergy and Clinical Immunology. 7 (6): 506–509. doi:10.1097/ACI.0b013e3282f1baea. PMID 17989526. S2CID 24042412.
  24. ↑ Shang L, Cao J, Zhao S, Zhang J, He Y (2022-09-16). "TYK2 in Immune Responses and Treatment of Psoriasis". Journal of Inflammation Research. 15: 5373–5385. doi:10.2147/JIR.S380686. PMC 9488612. PMID 36147687.
  25. ↑ Kerner G, Laval G, Patin E, Boisson-Dupuis S, Abel L, Casanova JL, Quintana-Murci L (March 2021). "Human ancient DNA analyses reveal the high burden of tuberculosis in Europeans over the last 2,000 years". American Journal of Human Genetics. 108 (3): 517–524. doi:10.1016/j.ajhg.2021.02.009. PMC 8008489. PMID 33667394.
  26. ↑ Uddin S, Sher DA, Alsayed Y, Pons S, Colamonici OR, Fish EN, et al. (June 1997). "Interaction of p59fyn with interferon-activated Jak kinases". Biochemical and Biophysical Research Communications. 235 (1): 83–88. doi:10.1006/bbrc.1997.6741. PMID 9196040.
  27. ↑ Yetter A, Uddin S, Krolewski JJ, Jiao H, Yi T, Platanias LC (August 1995). "Association of the interferon-dependent tyrosine kinase Tyk-2 with the hematopoietic cell phosphatase". The Journal of Biological Chemistry. 270 (31): 18179–18182. doi:10.1074/jbc.270.31.18179. PMID 7629131.
  28. ↑ Richter MF, 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". The Journal of Biological Chemistry. 273 (38): 24723–24729. doi:10.1074/jbc.273.38.24723. PMID 9733772.
  29. ↑ Kumar KG, Varghese B, Banerjee A, Baker DP, Constantinescu SN, Pellegrini S, Fuchs SY (July 2008). "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. doi:10.1074/jbc.M800991200. PMC 2441555. PMID 18474601.
  30. ↑ 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". Biochemical and Biophysical Research Communications. 267 (3): 692–696. doi:10.1006/bbrc.1999.1978. PMID 10673353.
  31. ↑ Usacheva A, Tian X, Sandoval R, Salvi D, Levy D, Colamonici OR (September 2003). "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. doi:10.4049/jimmunol.171.6.2989. PMID 12960323.

Further reading

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