TYK2

Fig1. Schematic TYK2 structure, post-translational modification and mutation sites of TYK2 in mice and men. (Nicole R Leitner, 2017)

What is TYK2 protein?

TYK2 gene (tyrosine kinase 2) is a protein coding gene which situated on the short arm of chromosome 19 at locus 19p13. This gene encodes a member of the tyrosine kinase and, more specifically, 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 a component of both the type I and type III interferon signaling pathways. As such, it may play a role in anti-viral immunity. The TYK2 protein is consisted of 1187 amino acids and TYK2 molecular weight is approximately 133.7 kDa.

What is the function of TYK2 protein?

The TYK2 protein, a member of the Janus kinase (JAK) family, plays a pivotal role in the signaling pathways of various cytokines, particularly in the activation of signal transducers and activators of transcription (STATs), which are crucial for immune responses. TYK2 plays a key role in maintaining immune balance, affecting the function of T and B cells and the maturation process of dendritic cells. TYK2 may be involved in tumor immune surveillance and tumor cell proliferation, survival and metastasis by affecting cytokine signaling pathways such as the activation of STAT3 and STAT5 in tumor cells.

TYK2 Related Signaling Pathway

TYK2, along with JAK1, JAK2, and JAK3, is a nonreceptor protein tyrosine kinase involved in the JAK-STAT signaling pathway. When a cytokine binds to its receptor, the JAK kinase is activated, which phosphorylates and activates the STAT protein. TYK2 plays a key role in type I interferon signaling, such as IFN-α and IFN-β. TYK2 interacts with IL-12 and IL-23 receptors, activates STAT4, and promotes the differentiation of Th1 and Th17 cells. IL-12 promotes the formation of Th1 cells, while IL-23 maintains the phenotype and function of Th17 cells, which play an important role in immune response and inflammation processes. TYK2 is also involved in IL-6 and IL-10 signaling. IL-6 receptors activate STAT1 and STAT3 through interactions with TYK2 and JAK1/JAK2, and regulate inflammatory response and immune regulation. IL-10 activates STAT1, STAT3 and STAT5 through TYK2 and JAK1, which has anti-inflammatory and immunomodulatory effects.

TYK2 Related Diseases

TYK2 plays a key role in the pathogenesis of psoriasis, particularly by affecting IL-23, IL-12, and type I interferon signaling. Also involved in the development of psoriatic arthritis. Polymorphisms of TYK2 are associated with susceptibility to systemic lupus erythematosus, and TYK2 inhibitors also show potential in the treatment of this condition. TYK2 may play a role in the regulation of intestinal inflammation, and TYK2 inhibitors are being studied to evaluate their efficacy in the treatment of inflammatory bowel disease. In addition, other immune diseases are also related, such as dermatomyositis.

Bioapplications of TYK2

TYK2 inhibitors are used to treat moderate-to-severe plaque psoriasis by blocking cytokine signaling associated with the pathogenesis of psoriasis, such as IL-23, IL-12, and type I interferon. TYK2's role in the intestinal inflammatory response makes it a potential target for the treatment of inflammatory bowel disease, and TYK2 inhibitors may help control intestinal inflammation. The world's first TYK2 allosteric inhibitor, Deucravacitinib, has been approved for the treatment of psoriasis, and there are multiple TYK2 inhibitors in various stages of clinical development for the treatment of these and other potential immune-mediated diseases.

Case Study 1: Vikash Chandra, 2022

Type 1 diabetes (T1D) is an autoimmune disease that results in the destruction of insulin producing pancreatic β-cells. One of the genes associated with T1D is TYK2, which encodes a Janus kinase with critical roles in type-Ι interferon (IFN-Ι) mediated intracellular signalling. To study the role of TYK2 in β-cell development and response to IFNα, researchers generated TYK2 knockout human iPSCs and directed them into the pancreatic endocrine lineage. Here we show that loss of TYK2 compromises the emergence of endocrine precursors by regulating KRAS expression, while mature stem cell-islets (SC-islets) function is not affected. In the SC-islets, the loss or inhibition of TYK2 prevents IFNα-induced antigen processing and presentation, including MHC Class Ι and Class ΙΙ expression, enhancing their survival against CD8+ T-cell cytotoxicity.

Fig1. Immunoblot for TYK2 48 h post pCMV-TYK2 electroporation during S5.

Fig2. Representative flow cytometry histograms of MHC Class Ι (top) and PD-L1 expression (bottom) in SC-islet targets treated with IFNα (left) or IFNα/TYK2i (right).

Case Study 2: Thomas L Emmons, 2012

Researchers recently described the purification and characterization of phosphorylated isoforms of the TYK-2 kinase domain (TYK-2 KD) and its high resolution 3D structure in the presence of inhibitors. This study reports the expression and a two-step purification procedure for the doubly tagged full-length construct, H6-FL-TYK-2-FLAG, and examine its properties compared to those of TYK-2 KD. In the presence of ATP and a peptide substrate, H6-FL-TYK-2-FLAG showed a marked lag in phosphopeptide product formation, while TYK-2 KD showed no such lag. This lag could be eliminated by ATP pretreatment, suggesting that the H6-FL-TYK-2-FLAG enzyme was activated by phosphorylation. The potencies of several nanomolar inhibitors were similar for TYK-2 KD and H6-FL-TYK-2-FLAG. However, these same inhibitors were about 1000 times less potent inhibiting the autophosphorylation of H6-FL-TYK-2-FLAG than they were inhibiting the phosphorylation of a peptide substrate modeled after the activation loop sequence of TYK-2.

Fig3. SDS-PAGE gel of purification of H6-FL-TYK-2-FLAG.

Fig4. Time course of phosphopeptide product formation in the Caliper activity assay.

TYK2 has several biochemical functions, for example, ATP binding,growth hormone receptor binding,non-membrane spanning protein tyrosine kinase activity. Some of the functions are cooperated with other proteins, some of the functions could acted by TYK2 itself. We selected most functions TYK2 had, and list some proteins which have the same functions with TYK2. You can find most of the proteins on our site.

TYK2 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with TYK2 here. Most of them are supplied by our site. Hope this information will be useful for your research of TYK2.

KHDRBS2;FHL3;KRT40;HNRPK;TRAF4;E6;E6