TYK2

Official Full Name

tyrosine kinase 2

Organism

Homo sapiens

GeneID

7297

Background

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. A mutation in this gene has been associated with Immunodeficiency 35. [provided by RefSeq, Sep 2020]

Synonyms

JTK1; IMD35;

Bio Chemical Class

Kinase

Protein Sequence

MPLRHWGMARGSKPVGDGAQPMAAMGGLKVLLHWAGPGGGEPWVTFSESSLTAEEVCIHIAHKVGITPPCFNLFALFDAQAQVWLPPNHILEIPRDASLMLYFRIRFYFRNWHGMNPREPAVYRCGPPGTEASSDQTAQGMQLLDPASFEYLFEQGKHEFVNDVASLWELSTEEEIHHFKNESLGMAFLHLCHLALRHGIPLEEVAKKTSFKDCIPRSFRRHIRQHSALTRLRLRNVFRRFLRDFQPGRLSQQMVMVKYLATLERLAPRFGTERVPVCHLRLLAQAEGEPCYIRDSGVAPTDPGPESAAGPPTHEVLVTGTGGIQWWPVEEEVNKEEGSSGSSGRNPQASLFGKKAKAHKAVGQPADRPREPLWAYFCDFRDITHVVLKEHCVSIHRQDNKCLELSLPSRAAALSFVSLVDGYFRLTADSSHYLCHEVAPPRLVMSIRDGIHGPLLEPFVQAKLRPEDGLYLIHWSTSHPYRLILTVAQRSQAPDGMQSLRLRKFPIEQQDGAFVLEGWGRSFPSVRELGAALQGCLLRAGDDCFSLRRCCLPQPGETSNLIIMRGARASPRTLNLSQLSFHRVDQKEITQLSHLGQGTRTNVYEGRLRVEGSGDPEEGKMDDEDPLVPGRDRGQELRVVLKVLDPSHHDIALAFYETASLMSQVSHTHLAFVHGVCVRGPENIMVTEYVEHGPLDVWLRRERGHVPMAWKMVVAQQLASALSYLENKNLVHGNVCGRNILLARLGLAEGTSPFIKLSDPGVGLGALSREERVERIPWLAPECLPGGANSLSTAMDKWGFGATLLEICFDGEAPLQSRSPSEKEHFYQRQHRLPEPSCPQLATLTSQCLTYEPTQRPSFRTILRDLTRLQPHNLADVLTVNPDSPASDPTVFHKRYLKKIRDLGEGHFGKVSLYCYDPTNDGTGEMVAVKALKADCGPQHRSGWKQEIDILRTLYHEHIIKYKGCCEDQGEKSLQLVMEYVPLGSLRDYLPRHSIGLAQLLLFAQQICEGMAYLHAQHYIHRDLAARNVLLDNDRLVKIGDFGLAKAVPEGHEYYRVREDGDSPVFWYAPECLKEYKFYYASDVWSFGVTLYELLTHCDSSQSPPTKFLELIGIAQGQMTVLRLTELLERGERLPRPDKCPCEVYHLMKNCWETEASFRPTFENLIPILKTVHEKYQGQAPSVFSVC

Open

Disease

Asthma, Psoriasis, Psoriatic arthritis

Approved Drug

1 +

Clinical Trial Drug

4 +

Discontinued Drug

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Detailed Information

Tyrosine kinase 2 (TYK2) has been originally identified and cloned from a lymphoid cDNA screen by using the c-fms kinase domain as a probe. The involvement of TYK2 in cytokine signaling has been discovered by its ability to complement defects in a mutant human cell line that is unresponsive to interferon (IFN) alpha/beta. A similar method led to the identification of other Janus kinase (JAK) family members and the signal transducers and activators of transcription (STATs) as major components of signal transduction in response to many cytokines, and the JAK/STAT pathway as a paradigm for cytokine signaling. The JAKs are a family of four protein tyrosine kinases that associate with the intracellular domains of a wide range of cytokine and growth factor receptors that mediate inflammation and hematopoiesis. Each of the four Janus kinases (JAK1, JAK2, JAK3, and TYK2) associates with a distinct set of receptors and induces intracellular signaling upon ligand binding by phosphorylating the receptor intracellular domains to generate docking sites for signal transducers and activators of transcription (STAT) proteins. STAT proteins are subsequently phosphorylated by the JAKs, form homodimers and heterodimers, and mediate gene transcription upon translocation to the cell nucleus.

TYK2 in cytokines signaling.

The JAK family kinase TYK2 associates with several cytokine receptors, including those of the IL-6 family, the IL-12/IL-23 family, the IL-10 family, and the type I IFN family. Studies of TYK2- deficient mice and a human patient lacking TYK2 protein indicate that TYK2 protein is crucial for the signaling of IL-12 and IL-23, which are associated with T helper type 1 (Th1) and T helper type 17 (Th17) inflammation, respectively. In response to stimulation with IL-12 or IL-23, the TYK2 and JAK2 enzymes phosphorylate the intracellular domains of the cytokine receptors, which in turn serve as docking sites for STAT proteins. Subsequently, the TYK2 and JAK2 enzymes phosphorylate the STAT proteins, which then translocate into the nucleus where they regulate gene expression and transcription. Specifically, in the case of the IL-12 pathway, phosphorylation of STAT4 leads to expression of IFNγ while in the IL-23 pathway, phosphorylation of STAT3 leads to increased IL-17 levels.

TYK2 Figure 1. Cytokines and receptor complexes that engage TYK2 for signaling.

TYK2 in psoriasis and inflammatory bowel diseases

Th1 and Th17 immune responses and the IL-12/IL-23 pathways have been implicated in the pathogenesis of psoriasis and the inflammatory bowel diseases (IBD), which are chronic inflammatory disorders of the skin (psoriasis) and gastrointestinal tract and colon (IBD). There is a strong genetic association of the IL-12 and IL-23 pathways with psoriasis and IBD and substantial evidence for Th1 and Th17 inflammation in the skin and gut of patients with active disease. Neutralization or genetic deficiency of IL-12 and IL-23 is efficacious in mouse models of psoriasis and IBD. In addition, antibodies against the p40 subunit of IL-12 and IL-23 are highly efficacious and approved for the treatment of psoriasis, and have shown efficacy in clinical studies in Crohn’s disease. Therefore, inhibition of TYK2 kinase activity may be an effective therapeutic strategy for the treatment of psoriasis and IBD.

TYK2 and cancer

Over the last years, several reports on TYK2 and human cancer have emerged. Overexpression of TYK2 has been found in human breast cancer cell lines and in human tumors, such as prostate cancer and squamous cervical carcinoma. In these tissues, TYK2 protein levels seem to be specifically elevated in malignant cells compared to the non-transformed surrounding healthy tissue. Importantly, inhibition of TYK2-dependent signaling by siRNA or by employing a TYK2 inhibitor significantly reduced the invasiveness of prostate cancer cells in vitro. More recently it was reported that blocking TYK2 activity also inhibits the migration of a cell line originating from breast cancer. These data suggest that TYK2 has an important role in facilitating the invasion of malignant cells and that TYK2 inhibition might be a useful strategy to prevent metastatic tissue infiltration.

TYK2 has emerged as a crucial molecule in cytokine signaling and host immunity. Although thus far TYK2 is predominantly associated with IFNalpha/beta, IL-12 and more recently IL-23 signaling, several other less well-characterized cytokines can be predicted to rely at least partially on TYK2 for signal transduction. Moreover, TYK2-specific inhibitors are currently being developed and might be a useful strategy for the treatment of inflammatory and autoimmune diseases and to prevent tumor cell invasiveness.

References:

Liang J, et al. Lead identification of novel and selective TYK2 inhibitors. European Journal of Medicinal Chemistry, 2013, 67(17):175-187.
Strobl B, et al. Tyrosine kinase 2 (TYK2) in cytokine signalling and host immunity[J]. Front Biosci, 2011, 16: 3214-32.
Prchal-Murphy M, et al. TYK2 kinase activity is required for functional type I interferon responses in vivo. PLoS One, 2012, 7(6): e39141.

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