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

The Janus kinase 2 (JAK2) V617F mutant pseudokinase domain (JH2) is a specific structural region of the JAK2 protein containing a somatic point mutation (Valine to Phenylalanine at position 617) (UniProt: O60674). JAK2 is a non-receptor tyrosine kinase that plays a pivotal role in the JAK-STAT signaling pathway, mediating signals from various cytokine and growth factor receptors essential for hematopoiesis (PMID: 15752413). The JH2 domain is a pseudokinase domain that normally functions as an auto-inhibitory regulator of the adjacent JH1 catalytic domain; however, the V617F mutation disrupts this regulation, leading to constitutive kinase activity (PMID: 24990443). This constitutive activation drives the overproduction of blood cells, characterizing myeloproliferative neoplasms (MPNs) such as polycythemia vera and essential thrombocythemia (PMID: 15752413). While current clinical inhibitors like ruxolitinib and fedratinib primarily target the JH1 domain, the JH2 domain is a focal point for developing next-generation allosteric inhibitors aimed at achieving higher selectivity for the mutant protein over wild-type JAK2 (PMID: 30635424). Targeting the JH2 domain offers a potential strategy to overcome the limitations of current therapies, such as off-target effects and incomplete suppression of the mutant clone (PMID: 30635424).

Other names

JAK2 V617FJanus kinase 2 JH2 domainJAK2 pseudokinase domain mutantJAK2-V617F

ATP-competitive inhibition of the JH1 catalytic domain or allosteric modulation of the JH2 pseudokinase domain to restore auto-inhibition.