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

The Janus kinase 2 (JAK2) V617F mutant JH2 pseudokinase domain is a key regulatory component of the JAK2 non-receptor tyrosine kinase, which plays a pivotal role in hematopoiesis and cytokine signaling (UniProt P29323). Under normal physiological conditions, the JH2 domain functions as an autoinhibitor, maintaining the catalytic JH1 domain in an inactive state in the absence of ligand binding (PubMed: 24550210). The V617F mutation, a somatic point mutation occurring in the JH2 domain, relieves this autoinhibition, resulting in the constitutive activation of the JAK-STAT pathway (PubMed: 15752421). This aberrant signaling is the primary driver of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera and primary myelofibrosis (NIH: NBK1116). Therapeutic strategies have historically focused on ATP-competitive inhibitors like ruxolitinib that target the JH1 domain, but these do not distinguish between wild-type and mutant JAK2 (PubMed: 20554977). Consequently, the JH2 domain has become a focal point for the development of allosteric inhibitors designed to stabilize the inactive conformation of the kinase (PubMed: 31152140). These JH2-targeted agents offer the potential for improved mutant-selectivity and reduced systemic toxicity compared to traditional kinase inhibitors (PubMed: 34161762).

Other names

JAK2 V617FJanus kinase 2 pseudokinase domainJH2 domain of JAK2JAK2-V617F

ATP-competitive inhibition of the JH1 domain and experimental allosteric modulation of the JH2 domain