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 signal 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 pathway do not possess an 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). Upon activation, STATs dimerize and promote gene transcription in the nucleus, including, for example, proinflammatory cytokines and chemokines, which in turn promote immune cell production, differentiation, activity, and recruitment 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 (Janus kinase 3) signaling plays a role in immune surveillance and lymphocyte function.

In contrast to extracellular inhibition of a single cytokine (the principle of biologics), inhibition of the JAK pathway can modulate the signals of multiple cytokines. Currently, several JAK inhibitors are in clinical use.

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

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

JAK mutations:

• Activating mutations of JAK1 have been reported mainly in prolymphocytic T-cell leukemia(Bellanger D et al 2014) and acute lymphoblastic leukemia, where they have been shown to lead to a worse prognosis.
• JAK2 mut ations(JAK2V617 mutation) are highly associated in aquagenic pruritus associated with polycythaemia vera.
• Inactivating JAK3 mutations mutations cause autosomal severe combined immunodeficiency disease(SCID).
• Activating JAK3 mut ations 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).
• 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. Since it was initially unclear what function these kinases fulfilled, they were given the name JAK: "Just Another Kinase". In the meantime, however, the name Janus kinase has become more common. This name is derived from the Roman god Janus, the god with two faces. Janus kinases also have "two faces": one directed outward and a second directed inward. Signals can be transmitted from the cell surface to the cell interior with the help of the Janus kinases.

A few years ago, the first JAK kinase inhibitor, ruxolitinib (Jakavi®), was approved.

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