Januskinases

Acronym for "Janus kinases - actually for"Just Another Kinase (JAK)". Janus kinases are cytoplasmically localized tyrosine kinases that occur, for example, in the chains of action of cytokine receptors. Janus kinases (JAKs) are intracellular enzymes that transduce cytokine and growth factor signals involved in a variety of cellular processes, including inflammatory responses, hematopoiesis, and immune surveillance.

In general, extracellular signaling peptides such as growth factors on target cells are bound by specific transmembrane receptors with their own tyrosine kinase activity.In contrast, most cytokine receptors of the JAK-STAT signaling pathway have no independent tyrosine kinase activity. This tyrosine kinase activity is provided by cytoplasmic proteins of the so-called Janus kinase family.

The JAK enzyme family comprises four members:

• JAK1
• JAK2
• JAK3 and
• TYK2

These phosphorylate and activate signal transducers and activators of transcription ( STATs) in pairs. When a cytokine binds to its cell surface receptor, receptor polymerization and autophosphorylation of the JAKs associated with the receptor occur. The activated JAKs phosphorylate another protein, thesignal transducer and activator of transcription(STAT). Through activation, STATs dimerize and promote gene transcription in the cell nucleus, for example of proinflammatory cytokines and chemokines, which in turn promote the production, differentiation, activity and recruitment of immune cells in the synovium.

JAK1 (Janus kinase 1) is important for signaling pathways of inflammatory cytokines.

JAK2 (Janus kinase 2) is important for the maturation of erythrocytes.

JAK3 signaling (Janus kinase 3) plays a role in immune surveillance and lymphocyte function.

In contrast to the extracellular inhibition of a single cytokine (principle of biologics), the signals of various cytokines can be modulated by inhibiting the JAK signaling pathway. Various Janus kinase inhibitors are currently in clinical use.

Inhibition of JAK 2 could play a role in the treatment of psoriasis vulgaris. Janus kinase inhibitors have been used successfully in the treatment of alopecia areata (experimental).

The recently successful specific inhibition of JAK3 promises selective immunosuppression, which has clinical significance for rheumatoid arthritis (Forster M 2016).

JAK mutations:

• Activating mutations of JAK1 have been reported primarily in prolymphocytic T-cell leukemia(Bellanger D et al. 2014) and acute lymphoblastic leukemia, where they have been shown to lead to a poorer prognosis.
• JAK2 mutations (JAK2V617 mutation) are highly associated with aquagenic pruritus associated with polycythaemia vera.
• Inactivating JAK3 mutations Mutations cause autosomal severe combined immunodeficiency disease(SCID).
• Activating JAK3 mutations are found in patients with T-cell acute lymphoblastic leukemia (T-ALL). Analysis of sequencing 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).
• Tyk2 mutations are associated with congenital immunodeficiency, which is considered a variant of hyper IgE syndrome(Immundefciency 35). Inhibition of Tyk2 appears to be successful in psoriasis .

They were named after the Roman god Janus. As it was initially unclear what function these kinases fulfilled, they were quickly given the name JAK: "Just Another Kinase". However, the name Janus kinase is now more commonly used. This name is derived from the Roman god Janus, the god with two faces. Janus kinases also have "two faces": one directed outwards and a second directed into the cell interior. Signals can be transmitted from the cell surface to the cell interior with the help of Janus kinases.

Ruxolitinib (Jakavi®), the first JAK inhibitor, was approved a few years ago.

1. Bellanger D et al.(2014) Recurrent JAK1 and JAK3 somatic mutations in T-cell prolymphocytic leukemia. Leukemia 28:417-419

2. Forster M et al.(2016) Selective JAK3 inhibitors with
   a covalent reversible binding mode targeting a new induced fit binding pocket. Cell Chem Biol 23:1335-1340.

3. Pieri L et al. (2009) The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils from patients with polycythemia vera. Haematologica 94:1537-1545

4. Xing L et al (2014) Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med 20:1043-1049