Janus kinase 2 pseudokinase domain (JAK2 JH2)

The **Janus kinase 2 pseudokinase domain** (*JAK2 JH2*) is a structural regulatory region within the non-receptor tyrosine kinase JAK2. It is termed a *pseudokinase* because, despite having a canonical kinase domain fold and weak catalytic activity, it lacks key residues for efficient phosphotransfer and primarily regulates the activity of the adjacent JAK2 tyrosine kinase (JH1) domain by autoinhibition[1][2][3]. The *V617F mutation* within this domain disrupts the autoinhibitory function, leading to constitutive JAK2 activation, uncontrolled signaling through cytokine receptors (especially erythropoietin and others), and is found in over 95% of polycythemia vera cases and in other myeloproliferative neoplasms[1][3]. JAK2 inhibitors targeting this mutant are in clinical use for these blood cancers. The JH2 domain binds ATP in a noncanonical manner and can autophosphorylate at low efficiency; its ability to bind ATP is critical for the pathogenic effects of the V617F mutation[3]. Detection of the JAK2 V617F mutation is a key diagnostic and prognostic marker in hematologic malignancies[3].

Other names

JAK2 JH2 domainJak2 pseudokinase domainJanus kinase 2 JH2JAK2 V617F (for the pathogenic mutant form)

Inhibition of JAK2 kinase activity (via targeting ATP-binding site or allosteric inhibition) Reduction of abnormal JAK-STAT signaling driven by V617F mutation Blockade of cytokine-dependent cell proliferation