TYK2

TYK2, or tyrosine kinase 2, is a cytoplasmic non-receptor protein tyrosine kinase of the JAK family that participates in signaling pathways activated by a subset of cytokine receptors. It couples receptor engagement to the activation of the JAK-STAT signaling cascade, influencing gene transcription programs involved in immune responses. The TYK2 protein has the typical four-domain architecture of JAK family kinases, including an N-terminal FERM domain, a SH2-like domain, a pseudokinase (JH2) domain, and a C-terminal kinase (JH1) domain.

The TYK2 gene in humans is located on chromosome 19p13.2 and is expressed broadly, with notable activity in immune tissues such as leukocytes and the spleen. In signaling, TYK2 associates with receptors for type I interferons and several cytokines from the IL-12/23 axis and certain IL-6 family cytokines. It is activated by receptor-associated JAK kinases and phosphorylates downstream STAT transcription factors, leading to expression of genes involved in inflammation, antimicrobial defense, and adaptive immune responses.

Genetic variation in TYK2 has been linked to susceptibility to autoimmune and inflammatory diseases, while TYK2 deficiency in model systems reveals impaired IL-12/23 and interferon signaling. On the therapeutic front, selective TYK2 inhibitors have been developed and approved for inflammatory conditions. Deucravacitinib, a selective TYK2 inhibitor, has approval for plaque psoriasis and is being explored for additional indications. Overall, TYK2 plays a nuanced role in host defense and inflammatory regulation, making it a focus of both basic and clinical research.