TYK2

TYK2, or tyrosine kinase 2, is a non-receptor tyrosine kinase involved in the signal transduction of numerous cytokines and interferons that regulate cell growth, development, cell migration, and innate and adaptive immunity. The coding gene TYK2 gene is located on chromosome 19p13.2.

Tyrosine kinase 2 plays both a structural and a catalytic role in the signaling of numerous interleukins and interferons (IFN-alpha/beta). It associates with heterodimeric cytokine receptor complexes and activates STAT family members such as STAT1, STAT3, STAT4, or STAT6. The heterodimeric cytokine receptor complexes consist of (1) a TYK2-associated receptor chain (IFNAR1, IL12RB1, IL10RB, or IL13RA1) and (2) a second receptor chain associated with either JAK1 or JAK2. In response to cytokine binding to receptors, the receptors (IFNAR1, IL12RB1, IL10RB, or IL13RA1) are phosphorylated and activated, creating docking sites for STAT members . The recruited STATs are in turn phosphorylated by TYK2 (or JAK1/JAK2 at the second receptor chain), form homodimers and heterodimers, migrate to the nucleus, and regulate cytokine/growth factor responsive genes. TYK2 negatively regulates STAT3 activity by promoting phosphorylation at a specific tyrosine distinct from the site used for signaling.

Genetic TYK2 inhibition is associated with a lower risk of a variety of autoimmune diseases. Associations with hypothyroidism and psoriasis were confirmed in MR analysis of tissue-specific TYK2 gene expression, and associations with systemic lupus erythematosus, psoriasis, and rheumatoid arthritis were observed in colocalization analysis. There are nominal associations between genetic TYK2 inhibition and increased risk of prostate and breast cancer, but not in tissue-specific MR expression or colocalization analyses.

The efficacy of TYK2 inhibitors in plaque psoriasis has been confirmed by numerous RCTs (Yuan S et al. 2023). Fifteen studies reported data on the efficacy of treatment with TYK2 inhibitors in versch. Target diseases. In plaque psoriasis, all studies (n = 7) found improvement in disease activity, as measured by the Psoriasis Area and Severity Index(PASI), in the intervention groups at different doses compared with the control group. Similarly, disease activity improved in the intervention group compared with the control group in patients with psoriatic arthritis (n = 2), alopecia areata (n = 2), atopic dermatitis (n = 1), or active nonsegmental vitiligo (n = 1), although few studies have been conducted on these diseases.

TYK2 inhibitors improved certain clinical measures of ulcerative colitis severity, such as improvement in the modified endoscopic Mayo score and Mayo sub-score for rectal bleeding in the intervention group; however, there was no clear evidence of an effect on clinical remission.

Potential Adverse Effects of TYK2 Inhibitors: The most common complaints in individuals treated with TYK2 inhibitors are headache, upper respiratory tract infections, nausea, diarrhea, and elevated blood creatinine and liver enzyme levels. Two RCTs reported carcinoma formation (prostate and breast carcinoma) as a possible adverse effect of TYK2 inhibitors (Yuan S et al 2023). Deucravacitinib is a selective tyrosine kinase 2 (TYK2) inhibitor that interrupts JAK-STAT signaling pathways involved in proinflammatory responses. By specifically inhibiting TYK2, deucravacitinib can alleviate inflammatory processes. Deucravacitinib is approved for the treatment of psoriasis.

1. Müller M et al (1993) The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature 366:129-135
2. Rani MR et al (1999) Catalytically active TYK2 is essential for interferon-beta-mediated phosphorylation of STAT3 and interferon-alpha receptor-1 (IFNAR-1) but not for activation of phosphoinositol 3-kinase. J Biol Chem 274:32507-32511
3. Yuan S et al (2023) Mendelian randomization and clinical trial evidence supports TYK2 inhibition as a therapeutic target for autoimmune diseases. EBioMedicine 89:104488.