Januskinase 2

JAK2 is the acronym for Janus kinase 2. Janus kinases belong to the tyrosine kinase family. Janus kinases play a key role in the JAK-STAT signaling pathway. The coding gene JAK2 is located on chromosome 9 gene locus 9p24.1.

JAK2 is a "non-receptor tyrosine kinase" involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, it plays a central role in signal transduction through its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and several interleukins.

After binding to the receptor, dimerization and activation of the receptor occurs. 2 JAK2 molecules phosphorylate each other (autophosphorylation), thereby increasing the activity of their kinase domains. The activated JAKs phosphorylate tyrosine residues at the receptor, to which Signal Transducer and Activator of Transcription (STAT) proteins can now bind.

Phosphorylated STATs then form homodimers or heterodimers and translocate to the nucleus to initiate transcription of several essential genes involved in the modulation of erythropoiesis. In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation.

Growth factors such as TGF-beta 1 also induce phosphorylation and activation of this kinase and translocation of downstream STAT proteins to the nucleus, where they influence gene transcription. Mutations in this gene are associated with numerous inflammatory diseases and malignancies.

JAK2 is involved in numerous processes of cell proliferation and differentiation. An important position is occupied by this kinase in the context of signal transduction of the immune system. Dysregulation of IL6/JAK2/STAT3 signaling pathways leads to increased cellular proliferation and myeloproliferative neoplasms of hematopoietic stem cells.

The JAK2-V617F point mutation occurs with variable frequency within myeloproliferative disorders. In particular, in polycythaemia vera, the JAK2 mutation is found in 95%, and in 50-60% of all patients with essential thrombocythaemia and primary myelofibrosis. Loss of JAK2 during embryogenesis is lethal.

Mutations in the JAK2 gene are associated with numerous inflammatory diseases as well as malignancies. The JAK2-V617F point mutation occurs in various myeloproliferative diseases. In 95 % of cases it is detectable in polycythaemia vera . In 50-60 % of all patients in essential thrombocythaemia and primary myelofibrosis.

Inflammatory bowel disease (IBD): Furthermore, JAK2- V617F point mutation is involved in the pathogenesis of IBD (Asadzadeh-Aghdaei H et al. 2019).

A non-synonymous mutation in the pseudokinase domain of the JAK2 gene disrupts the inhibitory action of the domain, leading to constitutive tyrosine phosphorylation activity and hypersensitivity to cytokine signaling pathways.

Evidence suggests an association between the JAK2 V617F mutation and various forms of thrombosis. This association is comparable to the association between inherited risk factors (factor V Leiden) and thrombotic events, but with a lower prevalence of the mutation (Zerjavic K et al. 2010).

Pharmacologically, JAK2 can be used as a target. The Janus kinase inhibitor ruxolitinib was already approved in 2012 for the treatment of polycythaemia vera and myelofibrosis. Another inhibitor of Janus kinase2 is baricitinib, which is used to treat rheumatoid arthritis.