Non-receptor tyrosine-protein kinase TYK2 is an
enzyme that in humans is encoded by the TYK2gene.[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]
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]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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.
PMID2156206.
^Ross R (January 1999). "Atherosclerosis--an inflammatory disease". The New England Journal of Medicine. 340 (2): 115–126.
doi:
10.1056/NEJM199901143400207.
PMID9887164.
^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.
PMID10960667.
^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.
PMID12679810.
S2CID19745533.
^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.
PMID17989526.
S2CID24042412.
^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.
PMID9196040.
^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.
PMID10673353.
Firmbach-Kraft I, Byers M, Shows T, Dalla-Favera R, Krolewski JJ (September 1990). "tyk2, prototype of a novel class of non-receptor tyrosine kinase genes". Oncogene. 5 (9): 1329–1336.
PMID2216457.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174.
doi:
10.1016/0378-1119(94)90802-8.
PMID8125298.
Uddin S, Gardziola C, Dangat A, Yi T, Platanias LC (August 1996). "Interaction of the c-cbl proto-oncogene product with the Tyk-2 protein tyrosine kinase". Biochemical and Biophysical Research Communications. 225 (3): 833–838.
doi:
10.1006/bbrc.1996.1259.
PMID8780698.
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.
PMID9196040.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156.
doi:
10.1016/S0378-1119(97)00411-3.
PMID9373149.