Janus kinase 2 (JAK2) V617F mutant pseudokinase domain (JAK2 V617F JH2)

Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase that plays a pivotal role in the signal transduction of cytokine receptors involved in hematopoiesis, such as the erythropoietin receptor (UniProt P23458). The protein structure includes a catalytic JH1 domain and a regulatory pseudokinase JH2 domain, the latter of which acts as a molecular switch to inhibit the catalytic activity of JH1 in the absence of ligand binding (Nature Chemical Biology, PMID: 24441560). The V617F mutation is a somatic point mutation located in the JH2 domain that is found in nearly all patients with polycythemia vera and approximately half of those with essential thrombocythemia or primary myelofibrosis (Nature, PMID: 15752413). This mutation impairs the autoinhibitory function of the JH2 domain, resulting in constitutive activation of the JAK-STAT pathway and driving the overproduction of blood cells (Blood, PMID: 28356245). Current therapeutic strategies primarily involve Type I inhibitors that target the JH1 domain, but the JH2 domain is a major focus for the development of next-generation allosteric inhibitors aimed at achieving mutant-specific targeting (Blood, PMID: 28356245).

Other names

JAK2 V617FJanus kinase 2 pseudokinase domainJH2 domain of JAK2JAK2 V617F mutantJanus kinase 2 V617F

Inhibition of the JAK-STAT signaling pathway through competitive inhibition of the ATP-binding site in the catalytic JH1 domain or through allosteric modulation of the JH2 pseudokinase domain to stabilize the autoinhibited state of the kinase (Nature Chemical Biology, PMID: 24441560; Blood, PMID: 28356245).