Disease relevance of TYK2

• The increased rate of leukemia/lymphoma formation was linked to a decreased in vitro cytotoxic capacity of TYK2(-/-) NK and NKT cells toward tumor-derived cells [1].
• Moreover, IFN does not promote NF-kappaB activation in TYK2-deficient mutant fibrosarcoma cells [2].
• Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed with hyper-IgE syndrome [3].
• We suggest that mutations in the JAK1 and Tyk2 genes may be identified as initial molecular defects in human cancers and autoimmune diseases [4].
• The JAKs and STATs (with the exception of Jak3 and Tyk2) were present both in the dura and in the meningiomas studied [5].

High impact information on TYK2

• Complementary DNAs were cloned and found to be virtually identical to tyk2, a human mRNA encoding a non-receptor protein tyrosine kinase of previously unknown function [6].
• We show here that angiotensin II induces the rapid phosphorylation of tyrosine in the intracellular kinases Jak2 and Tyk2 in rat aortic smooth-muscle cells and that this phosphorylation is associated with increased activity of Jak2 [7].
• Thus, the Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired T helper 1 (Th1) differentiation and accelerated Th2 differentiation [3].
• Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12 [8].
• RAG2/TYK2 double-knockout mice succumbed to A-MuLV-induced leukemia/lymphoma faster than RAG2(-/-)TYK2(+/-) mice [1].

Chemical compound and disease context of TYK2

• Japanese encephalitis virus (JEV), a mosquito-borne flavivirus that causes severe human disease, has been shown to block the interferon (IFN)-induced Janus kinase signal transducer and activation of transcription (Jak-Stat) signaling cascade by preventing Tyk2 tyrosine phosphorylation and Stat activation [9].

Biological context of TYK2

• Molecular characterization of an alpha interferon receptor 1 subunit (IFNaR1) domain required for TYK2 binding and signal transduction [10].
• TYK2 amino acids 1-601 act in a dominant manner to inhibit the transcription of an interferon-alpha-dependent reporter gene, presumably by displacing endogenous TYK2 from the receptor [11].
• Urokinase stimulates human vascular smooth muscle cell migration via a phosphatidylinositol 3-kinase-Tyk2 interaction [12].
• We have generated a line of U937 promonocytes expressing a tyk2 transgene [13].
• Catalytic TYK2 is the first identified component in an accessory signaling pathway that supplements ISGF3/interferon-stimulated response element signaling for gene induction by type I IFNs [14].

Anatomical context of TYK2

• We now report IFN-beta-mediated activation of STATs and other components in U1 (TYK2-null) cell lines that were complemented with kinase-negative (U1.KR930) or wild-type TYK2 (U1.wt) [15].
• Constitutive STAT1 tyrosine phosphorylation in U937 monocytes overexpressing the TYK2 protein tyrosine kinase does not induce gene transcription [13].
• These findings suggest that in EBV-immortalized B cells JAK3 and Tyk2 proteins were constitutively phosphorylated but STAT6 protein was not constitutively phosphorylated [16].
• In MonoMac-1 cells, STAT1 and STAT3 translocated to the nucleus following PAF stimulation, and their translocation in transiently transfected COS-7 cells was shown to be dependent on the presence of Tyk2 [17].
• MAIN OUTCOME MEASURE(S): Cell lysates prepared from sperm and Jurkat T-cell line were resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the expression of JAKs (1-3 and TYK 2) and STATs (1-6) was examined by Western blot analysis [18].

Associations of TYK2 with chemical compounds

• Further, introduction of dimerized glutathione S-transferase-IFNaR1 fusion proteins into permeabilized cells is sufficient to induce phosphorylation of TYK2 and the receptor, confirming the role of the binding domain in IFNalpha signal transduction [10].
• In the present study, we show that catalytic activation of Tyk2 is not essential for IFNAR1 internalization, but is required for ligand-induced IFNAR1 serine phosphorylation, ubiquitination and efficient lysosomal proteolysis [19].
• One of the Janus kinases, human TYK2, has an SH2 domain that contains a histidine instead of the conserved arginine at the key phosphotyrosine-binding position, betaB5 [20].
• Calculations of the pK(a) values of the betaB5 arginines in a number of SH2 domains and of the betaB5 histidine in a homology model of TYK2 suggest that this histidine is likely to be neutral around pH 7, thus indicating that it may have lost the ability to bind phosphotyrosine [20].
• The alpha(1) agonist phenylephrine induced tyrosine phosphorylation of Jak2, Tyk2, and STAT1 in vascular smooth muscle cells [21].

Physical interactions of TYK2

• Tyk2 directly binds to either of the two Src homology 2(SH2)p85 domains in a uPA-dependent fashion [12].
• Specific contribution of Tyk2 JH regions to the binding and the expression of the interferon alpha/beta receptor component IFNAR1 [22].
• Rack-1 interacts weakly with the kinase domain and interacts strongly with the pseudokinase domain of Tyk2 [23].

Enzymatic interactions of TYK2

• Mechanical stimulation (MS) resulted in an IL4R-dependent increase in phosphorylated Tyk2 in normal chondrocytes, which could be abolished by IL1beta preincubation [24].
• In IGROV-1 cells, Tyk2 was constitutively phosphorylated and this phosphorylation was augmented by IL-4 or IL-13 [25].
• Using these, we have identified tyk2 as a 134-kDa protein which is rapidly and transiently phosphorylated on tyrosine in response to IFN-alpha/beta and possesses an inducible kinase activity when tested in vitro [26].
• Studies of mutant Tyk2 forms deleted at the N terminus indicated that the integrity of the N-terminal region is required to sustain IFNAR1 [27].

Regulatory relationships of TYK2

• No migratory effect of uPA was observed in VSMC expressing the dominant negative form of Tyk2 [12].
• In this study, we demonstrate that expression of the JEV nonstructural protein NS5 readily blocked IFN-stimulated Jak-Stat signaling events such as Stat1 nuclear translocation and tyrosine phosphorylation of Tyk2 and Stat1 [9].

Other interactions of TYK2

• Here we show that the homologous mutations in JAK1 (V658F) and in Tyk2 (V678F) lead to constitutive activation of these kinases [4].
• In both model systems, titration of the Tyk2 kinase away from the Ifnar1 receptor chain accounts for the observed cross-interference [28].
• Catalytically active TYK2 is essential for interferon-beta-mediated phosphorylation of STAT3 and interferon-alpha receptor-1 (IFNAR-1) but not for activation of phosphoinositol 3-kinase [15].
• This same fragment inhibits interferon-alpha-dependent tyrosine phosphorylation of TYK2, STAT1, and STAT2 [11].
• Coprecipitation experiments demonstrated an association of constitutively tyrosine-phosphorylated TYK2 with the IFN-alpha receptor 1 chain [13].

Analytical, diagnostic and therapeutic context of TYK2

• LPS activated phosphorylations of tyrosine kinases, especially tyrosine kinase 2 (Tyk2) and signal transducer and activator of transcription-1 (STAT-1); these were reduced by THI 53 [29].
• Migration experiments with double immunofluorescence staining revealed polarization of uPAR, and colocalization with Jak1 and Tyk2 to the leading edge of the migrating cells [30].
• In addition, by immunoprecipitation assay, three other phosphorylated bands were identified as JAK1, JAK2, and Tyk2 tyrosine kinases [31].
• By confocal microscopy, antibodies to TYK 2 reacted with the sperm tail as well as the apical region of sperm head, whereas antibodies to STAT 1 and STAT 4 reacted with the apical region of the sperm head [18].
• The association between the alpha subunit and Tyk2 was demonstrated by immunoblotting with anti-Tyk2 and antiphosphotyrosine antibodies and by using an in vitro kinase assay [32].

References