Tyk2-KO Mouse

Tyk2, short for Tyrosine kinase 2, is a member of the Janus kinase (Jak) family of intracellular signalling molecules. It participates in the Jak/signal transducer and activating protein (STAT) pathways, mediating the intracellular signaling of cytokines in numerous cellular processes, and is crucial for physiologic and inflammatory cascades [1,3]. Gene-targeted mice and hereditary defects of Tyk2 in humans have helped establish its biological and pathological functions in innate and adaptive immune responses to infection, cancer, and (auto-)inflammation [4].

Genetic linkage has associated Tyk2 dysfunction with protection from psoriasis and other immune-mediated inflammatory diseases (IMIDs) without increasing the risk of serious infections [1]. A loss-of-function missense variant in the Tyk2 gene has been used as a genetic instrument in Mendelian randomization studies, which found that genetically-proxied Tyk2 inhibition is associated with a lower risk of various autoimmune diseases [2]. In NF1-associated malignant peripheral nerve sheath tumors, overexpression of Tyk2 occurs, and pharmacologic Tyk2 inhibition dose-dependently decreases cell proliferation and induces apoptosis [5].

In conclusion, Tyk2 is essential for cytokine-mediated intracellular signaling and immune-related processes. Studies using gene-targeted mice and genetic variants as tools have revealed its role in autoimmune diseases, psoriasis, and certain tumors. These findings suggest Tyk2 as a promising therapeutic target for these disease areas.

References:

1. Rusiñol, Lluís, Puig, Luis. 2023. Tyk2 Targeting in Immune-Mediated Inflammatory Diseases. In International journal of molecular sciences, 24, . doi:10.3390/ijms24043391. https://pubmed.ncbi.nlm.nih.gov/36834806/

2. Yuan, Shuai, Wang, Lijuan, Zhang, Han, Larsson, Susanna C, Li, Xue. 2023. Mendelian randomization and clinical trial evidence supports TYK2 inhibition as a therapeutic target for autoimmune diseases. In EBioMedicine, 89, 104488. doi:10.1016/j.ebiom.2023.104488. https://pubmed.ncbi.nlm.nih.gov/36842216/

3. Morand, Eric, Merola, Joseph F, Tanaka, Yoshiya, Gladman, Dafna, Fleischmann, Roy. 2024. TYK2: an emerging therapeutic target in rheumatic disease. In Nature reviews. Rheumatology, 20, 232-240. doi:10.1038/s41584-024-01093-w. https://pubmed.ncbi.nlm.nih.gov/38467779/

4. Karjalainen, Anzhelika, Shoebridge, Stephen, Krunic, Milica, Strobl, Birgit, Müller, Mathias. 2020. TYK2 in Tumor Immunosurveillance. In Cancers, 12, . doi:10.3390/cancers12010150. https://pubmed.ncbi.nlm.nih.gov/31936322/

5. Borcherding, Dana C, Amin, Neha V, He, Kevin, Widemann, Brigitte C, Hirbe, Angela C. . MEK Inhibition Synergizes with TYK2 Inhibitors in NF1-Associated Malignant Peripheral Nerve Sheath Tumors. In Clinical cancer research : an official journal of the American Association for Cancer Research, 29, 1592-1604. doi:10.1158/1078-0432.CCR-22-3722. https://pubmed.ncbi.nlm.nih.gov/36799629/