Schematic of JAK2 activation. (Top) In the basal state, 2 JAK2 molecules associate via their N-terminal band 4.1, ezrin, radixin, moesin (FERM or F) and SH2 (S) domains with predimerized type I cytokine receptors. The autoinhibitory interaction between JH2 (2) and JH1 (1) sequesters JH1 from each other and stabilizes an inactive state of JH1 (dark cyan) (left). This is in equilibrium with a state (right) in which JH1 is disengaged from JH2 (JH1 cyan, higher activity), which increases the probability of trans-phosphorylation (orange arrows) on the activation loop of JH1. By destabilizing the autoinhibitory interaction, pathogenic mutations, such as V617F and R683S, shift the equilibrium to the partially active state. (Bottom) Cytokine binding to the extracellular region of the cytokine receptors induces a structural rearrangement in the cytoplasmic region (possibly through rotation of the transmembrane helices), which greatly facilitates (red arrows) JH1 trans-phosphorylation. JH2 is also necessary for cytokine-induced JAK2 activation, but the molecular interaction(s) responsible for this is not known (and not shown). As indicated, in addition to destabilizing the autoinhibitory interaction, V617F might promote the JH2-mediated positive interaction normally induced by cytokine (or possibly promote an interaction distinct from the cytokine-mediated one).