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