Tyrosine kinase 2
Encyclopedia
Non-receptor tyrosine-protein kinase TYK2 is an enzyme
that in humans is encoded by the TYK2 gene
.
Tyk2 was the first member of the JAK
family that was described (the other members are JAK1
, JAK2
, and JAK3
). It has been implicated in IFN-α
, IL-6
, IL-10
and IL-12
signaling.
and, to be more specific, the Janus kinase
s (JAKs) protein families. This protein associates with the cytoplasmic domain of type I and type II cytokine receptor
s 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 receptor
s. 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.
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.
(HIES) - a primary immunodeficiency characterized by elevated serum immunoglobulin E
.
with FYN
, PTPN6
, IFNAR1
, Ku80 and GNB2L1
.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that in humans is encoded by the TYK2 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Tyk2 was the first member of the JAK
Janus kinase
Janus kinase is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 & 2 , but were ultimately published as "Janus kinase"...
family that was described (the other members are JAK1
Janus kinase 1
JAK1 is a human tyrosine kinase protein essential for signaling for certain type I and type II cytokines. It interacts with the common gamma chain of type I cytokine receptors, to elicit signals from the IL-2 receptor family , the IL-4 receptor family , the gp130 receptor family JAK1 is a human...
, JAK2
Janus kinase 2
Janus kinase 2 is a human protein that has been implicated in signaling by members of the type II cytokine receptor family , the GM-CSF receptor family , the gp130 receptor family , and the single chain receptors...
, and JAK3
Janus kinase 3
Tyrosine-protein kinase JAK3 is an enzyme that in humans is encoded by the JAK3 gene.Since JAK3 expression is restricted mostly to hematopoietic cells, its role in cytokine signaling is thought to be more restricted than other JAKs. It is most commonly expressed in T cells and NK cells, but has...
). It has been implicated in IFN-α
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
, IL-6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
, IL-10
Interleukin 10
Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....
and IL-12
Interleukin 12
Interleukin 12 is an interleukin that is naturally produced by dendritic cells, macrophages and human B-lymphoblastoid cells in response to antigenic stimulation.-Gene and structure:...
signaling.
Function
This gene encodes a member of the tyrosine kinaseTyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
and, to be more specific, the Janus kinase
Janus kinase
Janus kinase is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 & 2 , but were ultimately published as "Janus kinase"...
s (JAKs) protein families. This protein associates with the cytoplasmic domain of type I and type II cytokine receptor
Cytokine receptor
Cytokine receptors are receptors that bind cytokines.In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics, and partly because a deficiency of cytokine receptors has now been...
s and promulgate cytokine signals by phosphorylating receptor subunits. It is also component of both the type I and type III interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
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
Interferon type I
Human type I interferons comprise a vast and growing group of IFN proteins.All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α receptor that consists of IFNAR1 and IFNAR2 chains....
(IFN-1) signaling identified Tyk2 as an essential element, which is activated by an array of cytokine receptor
Cytokine receptor
Cytokine receptors are receptors that bind cytokines.In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics, and partly because a deficiency of cytokine receptors has now been...
s. 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
Interleukin 12
Interleukin 12 is an interleukin that is naturally produced by dendritic cells, macrophages and human B-lymphoblastoid cells in response to antigenic stimulation.-Gene and structure:...
signaling, Tyk2 has major effects on the transduction of [IL-23
Interleukin 23
Interleukin-23 subunit alpha is a protein that in humans is encoded by the IL23A gene. IL-23 is produced by dendritic cells and macrophages...
, IL-10
Interleukin 10
Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....
, and IL-6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
signals. Since, IL-6 signals through the gp-130 receptor
Glycoprotein 130
Glycoprotein 130 is a transmembrane protein which is the founding member of the class of all cytokine receptors. It forms one subunit of type I cytokine receptors within the IL-6 receptor family...
-chain that is common to a large family of cytokines, including IL-6, IL-11
Interleukin 11
Interleukin 11 is a protein that in humans is encoded by the IL11 gene.IL-11 is a multifunctional cytokine first isolated in 1990 from bone marrow-derived stromal cells. It is a key regulator of multiple events in hematopoiesis, most notably the stimulation of megakaryocyte maturation...
, IL-27
Interleukin 27
Interleukin-27 is a heterodimeric cytokine belonging to the IL-12 family that is composed of two subunits, Epstein-Barr virus -induced gene 3 and IL27-p28 ....
, IL-31
Interleukin 31
Interleukin-31 also known as IL-31 is a protein that in humans is encoded by the IL31 gene.- Function :IL-31 is a cytokine with a four-helix bundle structure, which is preferentially produced by type 2 helper T cells . The structure of IL-31 places it in the IL-6 family of cytokines...
, oncostatin M
Oncostatin M
Oncostatin M, also known as OSM, is a protein that in humans is encoded by the OSM gene.OSM is a pleiotropic cytokine that belongs to the interleukin 6 group of cytokines. Of these cytokines it most closely resembles leukemia inhibitory factor in both structure and function...
(OSM), ciliary neurotrophic factor
Ciliary neurotrophic factor
Ciliary neurotrophic factor is a protein that in humans is encoded by the CNTF gene.CNTF has also been shown to be expressed by cells on the bone surface, and to reduce the activity of bone forming cells, osteoblasts.- Satiety effects :...
, cardiotrophin 1
Cardiotrophin 1
Cardiotrophin-1 is a cytokine. It is a cardiac hypertrophic factor of 21.5 kDa and a protein member of the IL-6 cytokine family. CT-1 is associated with the pathophysiology of heart diseases, including hypertension, myocardial infarction, valvular heart disease, and congestive heart failure...
, cardiotrophin-like cytokine
CLCF1
Cardiotrophin-like cytokine factor 1 , also known as Novel Neurotrophin-1 or B cell-stimulating factor-3 , is a protein that in humans is encoded by the CLCF1 gene.- Function :...
, and LIF
Leukemia inhibitory factor
Leukemia inhibitory factor, or LIF, an interleukin 6 class cytokine, is a protein in cells that affects cell growth and development.-Function:LIF derives its name from its ability to induce the terminal differentiation of myeloid leukemic cells...
, 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
Interleukin 10
Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....
, 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.
Role in inflammation
It is now widely accepted that atherosclerosisAtherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
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
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
, a cytokine responsible for induction of angiotensinogen synthesis in liver through JAK/STAT3
STAT3
Signal transducer and activator of transcription 3 also known as STAT3 is a transcription factor which in humans is encoded by the STAT3 gene.- Function :The protein encoded by this gene is a member of the STAT protein family...
pathway, which gets activated through high affinity membrane protein receptors on target cells, termed IL-6R
Interleukin-6 receptor
Interleukin 6 receptor also known as CD126 is a type I cytokine receptor....
-chain recruiting gp-130
Glycoprotein 130
Glycoprotein 130 is a transmembrane protein which is the founding member of the class of all cytokine receptors. It forms one subunit of type I cytokine receptors within the IL-6 receptor family...
that is associated with tyrosine kinases (Jaks 1/2, and Tyk2 kinase). Cytokines IL-4
Interleukin 4
Interleukin-4, abbreviated IL-4, is a cytokine that induces differentiation of naive helper T cells to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4. The cell that initially produces IL-4, thus inducing Th0 differentiation, has not been identified, but recent...
and IL-13
Interleukin 13
Interleukin 13 is a protein that in humans is encoded by the IL13 gene. IL-13 is cytokine secreted by many cell types, but especially T helper type 2 cells, that is a mediator of allergic inflammation and disease.-Functions:...
gets elevated in lungs of chronically suffered asthmatics. Signalling through IL-4/IL-13 complexes is thought to occur through IL-4Rα
Interleukin-4 receptor
Interleukin 4 receptor is a type I cytokine receptor. IL4R is its human gene.-Interactions:Interleukin-4 receptor has been shown to interact with SHC1.-Further reading:-External links:...
-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
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
. Further elucidation of molecular mechanisms of LPS signaling, showed that Tyk2 and IFN-β deficiency leads resistance to LPS-induced endotoxin
Endotoxin
Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...
shock, whereas STAT1
STAT1
STAT1 is a member of the Signal Transducers and Activators of Transcription family of transcription factors. STAT1 is involved in upregulating genes due to a signal by either type I, type II or type III interferons...
-deficient mice are susceptible. Development of a Tyk2 inhibitor appears to be a rational approach in the drug discovery.
Clinical significance
A mutation in this gene has been associated with hyperimmunoglobulin E syndromeHyper-IgE syndrome
Hyperimmunoglobulin E syndrome , also called Job's syndrome and Buckley syndrome, is a heterogeneous group of immune disorders.-Presentation:...
(HIES) - a primary immunodeficiency characterized by elevated serum immunoglobulin E
Immunoglobulin E
Immunoglobulin E is a class of antibody that has been found only in mammals. IgE is a monomeric antibody with 4 Ig-like domains...
.
Interactions
Tyrosine kinase 2 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with FYN
FYN
Proto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.This gene is a member of the protein-tyrosine kinase oncogene family. It encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth...
, PTPN6
PTPN6
Tyrosine-protein phosphatase non-receptor type 6 is an enzyme that in humans is encoded by the PTPN6 gene.Also known as Src homology region 2 domain-containing phosphatase-1 .-Interactions:...
, IFNAR1
IFNAR1
Interferon-alpha/beta receptor alpha chain is a protein that in humans is encoded by the IFNAR1 gene.-Interactions:IFNAR1 has been shown to interact with STAT2, Tyrosine kinase 2 and PRMT1.-Further reading:...
, Ku80 and GNB2L1
GNB2L1
Guanine nucleotide-binding protein subunit beta-2-like 1 is a protein that in humans is encoded by the GNB2L1 gene.-Interactions:GNB2L1 has been shown to interact with PDE4D, STAT1, Tyrosine kinase 2, Src, Androgen receptor, AGTRAP, Janus kinase 1, FYN, Cyclin A1, IFNAR2, PRKCE, P73, RAS p21...
.