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.
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. 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 effect intracellular signaling. Cytokines including interleukins, interferons and hemopoietins activate the Janus kinases, which associate with their cognate receptors.
The mammalian JAK family has four members: JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). 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. 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 suffers from fatal, systemic autoimmune disease.
Tyk2 is activated by IL-10, and its deficiency affects the ability to generate and respond to IL-10. 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.
It is now widely accepted that atherosclerosis is a result of cellular and molecular events characteristic of inflammation. 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). 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. A role of Tyk2 in rheumatoid arthritis is directly observed in Tyk2-deficient mice that were resistant to experimental arthritis. 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. 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. 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. Development of a Tyk2 inhibitor appears to be a rational approach in the drug discovery.
^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. doi:10.1073/pnas.1930781100. PMC208803. PMID14500783.
^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". Immunity13 (4): 549–60. doi:10.1016/S1074-7613(00)00054-6. PMID11070173.
^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. PMC1636766. PMID16982690.
^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. PMID12679810.
^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. ISSN0006-291X. PMID9196040.
^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. ISSN0021-9258. PMID7629131.
^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. ISSN0021-9258. PMID9733772.
^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. ISSN0021-9258. PMC2441555. PMID18474601.
^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. ISSN0006-291X. PMID10673353.
^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. ISSN0022-1767. PMID12960323.
Colamonici O, Yan H, Domanski P, et al. (1994). "Direct binding to and tyrosine phosphorylation of the alpha subunit of the type I interferon receptor by p135tyk2 tyrosine kinase.". Mol. Cell. Biol.14 (12): 8133–42. PMC359352. PMID7526154.
Novak U, Harpur AG, Paradiso L, et al. (1995). "Colony-stimulating factor 1-induced STAT1 and STAT3 activation is accompanied by phosphorylation of Tyk2 in macrophages and Tyk2 and JAK1 in fibroblasts.". Blood86 (8): 2948–56. PMID7579387.
Domanski P, Yan H, Witte MM, et al. (1995). "Homodimerization and intermolecular tyrosine phosphorylation of the Tyk-2 tyrosine kinase.". FEBS Lett.374 (3): 317–22. doi:10.1016/0014-5793(95)01094-U. PMID7589562.
Yetter A, Uddin S, Krolewski JJ, et al. (1995). "Association of the interferon-dependent tyrosine kinase Tyk-2 with the hematopoietic cell phosphatase.". J. Biol. Chem.270 (31): 18179–82. doi:10.1074/jbc.270.31.18179. PMID7629131.
Trask B, Fertitta A, Christensen M, et al. (1993). "Fluorescence in situ hybridization mapping of human chromosome 19: cytogenetic band location of 540 cosmids and 70 genes or DNA markers.". Genomics15 (1): 133–45. doi:10.1006/geno.1993.1021. PMID8432525.
Platanias LC, Uddin S, Yetter A, et al. (1996). "The type I interferon receptor mediates tyrosine phosphorylation of insulin receptor substrate 2.". J. Biol. Chem.271 (1): 278–82. doi:10.1074/jbc.271.1.278. PMID8550573.
Gauzzi MC, Velazquez L, McKendry R, et al. (1996). "Interferon-alpha-dependent activation of Tyk2 requires phosphorylation of positive regulatory tyrosines by another kinase.". J. Biol. Chem.271 (34): 20494–500. doi:10.1074/jbc.271.34.20494. PMID8702790.
Uddin S, Gardziola C, Dangat A, et al. (1996). "Interaction of the c-cbl proto-oncogene product with the Tyk-2 protein tyrosine kinase.". Biochem. Biophys. Res. Commun.225 (3): 833–8. doi:10.1006/bbrc.1996.1259. PMID8780698.
Zou J, Presky DH, Wu CY, Gubler U (1997). "Differential associations between the cytoplasmic regions of the interleukin-12 receptor subunits beta1 and beta2 and JAK kinases.". J. Biol. Chem.272 (9): 6073–7. doi:10.1074/jbc.272.9.6073. PMID9038232.
Miyakawa Y, Oda A, Druker BJ, et al. (1997). "Thrombopoietin and thrombin induce tyrosine phosphorylation of Vav in human blood platelets.". Blood89 (8): 2789–98. PMID9108397.
Uddin S, Sher DA, Alsayed Y, et al. (1997). "Interaction of p59fyn with interferon-activated Jak kinases.". Biochem. Biophys. Res. Commun.235 (1): 83–8. doi:10.1006/bbrc.1997.6741. PMID9196040.
Burfoot MS, Rogers NC, Watling D, et al. (1997). "Janus kinase-dependent activation of insulin receptor substrate 1 in response to interleukin-4, oncostatin M, and the interferons.". J. Biol. Chem.272 (39): 24183–90. doi:10.1074/jbc.272.39.24183. PMID9305869.
Gauzzi MC, Barbieri G, Richter MF, et al. (1997). "The amino-terminal region of Tyk2 sustains the level of interferon alpha receptor 1, a component of the interferon alpha/beta receptor.". Proc. Natl. Acad. Sci. U.S.A.94 (22): 11839–44. doi:10.1073/pnas.94.22.11839. PMC23625. PMID9342324.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library.". Gene200 (1-2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Ahmad S, Alsayed YM, Druker BJ, Platanias LC (1997). "The type I interferon receptor mediates tyrosine phosphorylation of the CrkL adaptor protein.". J. Biol. Chem.272 (48): 29991–4. doi:10.1074/jbc.272.48.29991. PMID9374471.