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.


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 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]


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


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  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.
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Further reading

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