Understanding TYK2: An Intracellular Signaling Hub in Psoriasis

Explore where TYK2 fits within intracellular cytokine signaling, how it participates in JAK-STAT signaling, and its role in selected immune pathways relevant to psoriasis biology.

From Extracellular Signals to Intracellular Responses

The interleukin (IL)-23/IL-17 axis has a well-established central role in psoriasis pathogenesis.¹  IL-23 binds to receptors on T cells to promote the differentiation and maintenance of T helper 17 (Th17) cells, while IL-17 acts on keratinocytes to drive the inflammatory changes characteristic of psoriatic plaques.^2-4 IL-23 and several other cytokines implicated in psoriasis signal through intracellular Janus kinase-signal transducer and activator transcription (JAK-STAT) pathways, in which tyrosine kinase 2 (TYK2) participates as a receptor-associated JAK.^1,5

TYK2: A Member of the JAK Family

The JAK family consists of 4 members: JAK1, JAK2, JAK3, and TYK2. TYK2, like all JAK members, is a non-receptor tyrosine kinase that associates intracellularly with the cytoplasmic tails of type 1 and type 2 cytokine receptors, transducing extracellular signals into the cell.^1,6  JAK3 expression is largely limited to hemopoietic cells, whereas JAK1, JAK2, and TYK2 have a much broader distribution.¹ Different cytokine receptor complexes associate with distinct combinations of JAK family members. For example, depending on the receptor complex, TYK2 pairs with either JAK1 or JAK2.^1,7

Translating a Cytokine Signal Into a Cellular Response

The JAK-STAT signaling pathway begins when cytokines, such as IL-12, IL-23, and type I interferons (IFN-α and IFN-β), bind to their corresponding receptors on the cell surface.^1,6,7 This receptor activation brings together 2 associated JAK proteins, including TYK2, triggering their activation.¹ Depending on the receptor complex, TYK2 functions with another JAK family member, such as JAK1 or JAK2.^1,7 Once activated, the JAK pair phosphorylates STAT proteins, which then dimerize, translocate to the nucleus, and regulate gene transcription and expression.^1,7

From Cytokine Signal to Cellular Response

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TYK2 in Psoriasis-Relevant Immune Signaling

TYK2 participates in several cytokine signaling pathways relevant to psoriasis biology, with IL-23 signaling having a particularly well-established role in disease pathogenesis.² After IL-23 is released by activated dendritic cells, it binds to cytokine receptors expressed on T cells, triggering receptor-associated TYK2 and JAK2 and promoting Th17 differentiation and IL-17 production.^1,2,7 TYK2 and JAK2 also mediate signaling downstream of the IL-12 cytokine, supporting Th1 responses and the production of TNF- α and IFN-γ.^1,2,7 In addition, TYK2 pairs with JAK1 in type 1 interferon signaling, contributing to innate immune responses.^1,2,7

Defining the Boundaries of TYK2 Signaling

While TYK2 plays an important role in inflammatory signaling in psoriasis, its involvement is limited to select cytokine pathways rather than serving as a universal mediator of inflammation. One notable example of this is the IL-23/IL-17 axis. TYK2, together with JAK2, mediates signaling downstream of IL-23, whereas IL-17A/F signals through distinct intracellular pathways that are independent of TYK2 and JAK/STAT signaling.^1,3,8 Recognizing this distinction is important because although IL-23 and IL-17 are commonly described as part of the same inflammatory axis, they engage in different intracellular signaling pathways.

Clinical Takeaway

TYK2 is an intracellular JAK family member that participates in signaling downstream of selected cytokines involved in psoriasis. Its role is pathway-specific rather than universal, providing important context for understanding how extracellular inflammatory signals are translated into distinct cellular responses.

References

1. Krueger JG, McInnes IB, Blauvelt A. Tyrosine kinase 2 and Janus kinase–signal transducer and activator of transcription signaling and inhibition in plaque psoriasis. J Am Acad Dermatol. 2022;86(1):148-157. doi:10.1016/j.jaad.2021.06.869
2. Martin G. Novel therapies in plaque psoriasis: a review of tyrosine kinase 2 inhibitors. Dermatol Ther (Heidelb). 2023;13(2):417-435. doi:10.1007/s13555-022-00878-9
3. Brembilla NC, Boehncke, WH. Revisiting the interleukin 17 family of cytokines in psoriasis: pathogenesis and potentials targets for innovative therapies. Front Immunol. 2023;14:1186455. doi:10.3389/fimmu.2023.1186455 
4. Muromoto R, Oritani K, Matsuda T. Current understanding of the role of tyrosine kinase 2 signaling in immune responses. World J Biol Chem. 2022;13(1):1-14. doi:10.4331/wjbc.v13.i1.1
5. Guo J, Zhang H, Lin W, Lu L, Su J, Chen X. Signaling pathways and targeted therapies for psoriasis. Signal Transduct Target Ther. 2023;8(1):437. doi:10.1038/s41392-023-01655-6
6. Li B, Song X, Shan C, et al. JAK-STAT pathway-associated skin diseases: a refined functional framework for inflammatory skin diseases. Front Immunol. 2026;17:1851255. doi:10.3389/fimmu.2026.1851255
7. Rusiñol L, Puig L. Tyk2 targeting in immune-mediated inflammatory diseases. Int J Mol Sci. 2023;24(4):3391. doi:10.3390/ijms24043391
8. Shang L, Cao J, Zhao S, Zhang J, He Y. TYK2 in immune responses and treatment of psoriasis. J Inflamm Res. 2022;15:5373-5385. doi:10.2147/JIR.S380686