Activation loop tyrosines allow the JAK2(V617F) mutant to attain hyperactivation

Abstract

A gain-of-function mutation (V617F) in the pseudokinase domain of JAK2 is frequently present in patients with myeloproliferative disorders such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis. This mutation might serve as an important diagnostic biomarker for these uncommon diseases and may represent a target for novel therapy. It is imperative that a well-defined molecular mechanism be provided to account for the gain of function. This manuscript focuses on whether the V617F mutation is sufficient to cause constitutive activation of the enzyme. The evidence presented suggests that the V617F mutation would not cause constitutive activation because its hyperactivating effect is not observed when the mutation is combined with the YY1007,1008FF mutations. The phosphorylation of these two tyrosines within the activation loop is generally accepted as an essential step in the enzyme's normal transition from a basal state of activity to a fully active catalytic state following cytokine receptor stimulation. These observations are consistent with an interpretation that V617F-induced hyperactivation does not supersede the requirement for receptor-mediated activation, as others have shown by combining the V617F mutation with critical mutations in the enzyme's FERM domain. Thus, JAK2(V617F) should be considered as a hyperactive kinase rather than a constitutively active kinase.