Janus Kinase and Tyrosine Kinase Inhibitors in Dermatology

A Review of Their Utilization, Safety Profile and Future Applications

Mojahed M.K. Shalabi, BS; Benjamin Garcia, BS; Kendall Coleman, BS; Alfredo Siller Jr., MD; Austinn Miller, MD; Stephen K. Tyring, MD, PhD


Skin Therapy Letter. 2022;27(1):4-9. 

In This Article

JAK-STAT Signaling Pathway

The JAK-STAT pathway is activated by numerous different cytokines, which bind directly to the Janus kinase receptor and initiate transphosphorylation. This ligand-mediated receptor binding brings two JAKs in close proximity, allowing for its autophosphorylation and activation. The activated JAKs subsequently lead to the phosphorylation of the tyrosine residues on the receptor. The phosphorylation of the tyrosine residues on the receptor recruits STATs, inactive latent transcription factors in the cytoplasm. Using their SH2 domain, the STATs bind to the phosphorylated tyrosine residue on the receptor and are phosphorylated by JAKs. This causes the STATs to dissociate from the receptor, dimerize, and travel from the cytosol into the nucleus where they are able to modify gene transcription.[9] There are four members within the JAK family of kinases (JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]), and the STAT family has six proteins (STAT1, STAT2, STAT3, STAT5A/B and STAT6).[10]

One or more members of the JAK and STAT families may be recruited by any specific receptor influencing different aspects of immune cell development and function.[11] Various combinations of different types of JAK proteins can be associated with several receptors that have variable effects on specific signaling pathways of the immune system, such as the combination of JAK1 and JAK3 related to cytokine receptors fundamental for the function of lymphocytes or the TYK2/JAK2 combination that is essential for the signaling of interferon (IFN)-a, interleukin (IL)-12, and IL-23 receptors.[11] The varied distribution amongst different JAK/STAT proteins across distinct cell types shows how a genetic defect of JAKs or STATs might determine various clinical conditions, such as JAK3 deficiency in severe combined immunodeficiency syndrome.[11] Additionally, the modulation or inhibition of the activity of these intracellular pathways represents a potential target in immune mediated diseases such as psoriasis and atopic dermatitis.[11,12]

The mechanism of action of JAK inhibitors targets the kinase component of JAKs. This prevents the JAK protein from phosphorylating, thus halting the intracellular signaling transduction.[1] First generation JAK inhibitors, such as baricitinib, ruxolitinib, and tofacitinib, inhibit many JAKs. For example, tofacitinib, which is FDA-approved for psoriatic arthritis, inhibits JAK1 and JAK3 mainly, with some selectivity towards the JAK2 isoform.[13] The rationale behind the nonselective, multi-JAK inhibition is the notion that blocking multiple JAKs may enhance therapeutic efficacy.[14] On the other hand, the second generation JAK inhibitors are more selective to particular JAK isoforms to limit adverse effects and possibly maintain treatment efficacy. Deucravacitinib is a second generation JAK inhibitor that specifically targets TYK2.[13–15] This drug has shown efficacy in the treatment of systemic lupus erythematosus and is currently in a phase III trial for psoriasis.[1] Research into the efficacy of JAK inhibitors continues at a rapid pace as a host of new drug candidates are under development, thus shedding light on their mechanisms in treating rheumatological and dermatological diseases.

Figure 1.

The JAK-STAT signaling pathway using IL-4 and IL-2 as an example. The cytokine will attach to the membrane receptor, which causes the phosphorylation of JAK1/JAK3 residues; subsequently, STATs get recruited and are phosphorylated by JAK. This leads to dimerization of STATs, their translocation into the nucleus and finally their effects on the activation of various genes. Created with BioRender.com.