JAK-3

Non-receptor tyrosine kinase involved in various processes such as cell growth, development or differentiation. It belongs to the Janus family of kinases. Other members of the Janus family are JAK1, JAK2 and TYK2.

All Janus kinases are cytosolic tyrosine kinases specifically associated with cytokine receptors. Since cytokine receptor proteins lack enzymatic activity, they rely on JAKs to initiate signal transduction after binding their ligands (e.g. cytokines) (Musumeci F et al. 2019).

Cytokine receptors can be divided into five major subgroups based on their distinct domains and activation motifs. JAK3 is required for signaling of type I receptors that use the common gamma chain (γc) such as IL2R, IL4R, IL7R, IL9R, IL15R, and IL21R.

JAK3 mediates essential signaling events in both innate and adaptive immunity and plays a critical role in hematopoiesis during T cell development.

Following ligand binding to cell surface receptors, JAK 3 phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STAT proteins. Subsequently, JAK3 phosphorylates STAT proteins once they are recruited to the receptor.

Phosphorylated STATs then form homodimers or heterodimers and translocate to the nucleus to activate gene transcription. For example, JAK1 and JAK3 molecules bind to the IL2R beta (IL2RB) and gamma chain (IL2RG) subunits after IL2R activation by IL2, inducing tyrosine phosphorylation of both receptor subunits at their cytoplasmic domain. Subsequently, STAT5A and STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes transcription of specific target genes in a cytokine-specific manner.

Epithelial Jak3 is important for the regulation of epithelial-mesenchymal transition, cell survival, cell growth, development and differentiation. Growth factors and cytokines produced by cells of hematopoietic origin utilize Jak kinases for signal transduction in both immune and non-immune cells.

Among JAKs, JAK3 is expressed in both human immune cells and intestinal epithelial cells (IECs).

Mutations that abrogate JAK3 functions cause autosomal severe combined immunodeficiency disease (SCID), while activating Jak3 mutations lead to the development of hematologic and epithelial cancers.

ActivatingJAK3 mutations are found in patients with T-cell acute lymphoblastic leukemia (T-ALL). Analysis of sequence data from 419 cases of T-cell acute lymphoblastic leukemia (T-ALL) showed a significant association between SUZ12 and JAK3 mutations (Broux M et al. (2019).

In addition, activating (oncogenic) JAK3 mutations can be detected in megakaryoblastic acute leukemia, prolymphocytic T-cell leukemia , juvenile myelomonocytic leukemia, natural killer T-cell lymphoma (NK/T-lymphoma), and extranodal nasal-type NK/T-cell lymphoma (Sim SH et al. 2017).

Most mutations are located in the pseudokinase and kinase domains of the JAK3 protein.

Inactivating mutations of JAK3 are known causes of immunodeficiency. Mutations in the common gamma chain (γc) lead to X-linked severe combined immunodeficiency (X-SCID). Since γc specifically associates with JAK3, mutations in JAK3 also lead to SCID.

Deficiency of JAK3 blocks the signaling of the following cytokines and their actions:

• IL-2 - T cell proliferation and maintenance of peripheral tolerance.
• IL-4 - differentiation of Th2 cells
• IL-7 - thymocyte development in the thymus
• IL-9 - survival signal for various hematopoietic cells
• IL-15 - development of NK cells
• IL-21 - regulation of immunoglobulin class switching in B cells

Overall, JAK3 deficiency leads to the phenotype of SCID characterized by T-B+NK-, indicating the absence of T cells and NK cells. Although B cells are present, they are non-functional due to defective B cell activation and impaired antibody class switching.

A JAK3 inhibitor called CP-690550(tofacitinib ) has been developed and approved in the EU since March 2017 for the treatment of moderate to severe active rheumatoid arthritis. Furthermore, for the treatment of ulcerative colitis. However, the active substance may only be prescribed if therapy with other long-acting antirheumatic drugs (DMARDs) has not been sufficiently successful or has not been tolerated. In addition, tofacitinib may only be given as monotherapy if treatment with methotrexate is not possible. The recommended dose is 5 mg twice daily.

Furthermore, tofacitinib is indicated in adult patients in combination with methotrexate for the treatment of active psoriatic arthritis (PsA) who have had an inadequate response to or have been intolerant of prior disease-modifying antirheumatic (DMARD) therapy .

Combination therapy with tofacitinib and ruxolitinib (JAK1/2 inhibitor) has been successfully used in refractory "T-cell prolymphocytic leukemia" (Gomez-Arteaga A et al. 2019).

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