JAK2 structure and signaling. (A) Domain structure of JAK2. JAK2 contains a tyrosine kinase domain (JH1), a pseudokinase domain (JH2), an SH2-like domain, and a FERM domain that is responsible for attachment to the intracellular domain of cytokine receptors. (B) Model for JAK2 activation at the cytokine receptor. Left, Intermolecular JH1–JH2 interactions keeps JAK2 in an inactive state. Center, Ligand binding induces increased separation of cytokine receptors and movement of JAK2 dimers leads to apposition of kinase domains of the 2 JAK2 molecules and facilitates mutual phosphorylation of specific tyrosine residues in trans. Right, Consequences of the JAK2V617F mutation on the “sliding model” of JAK2 activation remains unclear, but is likely to involve diminished repression of the catalytic activity of the JH1 domain due to decreased stability of JH1–JH2 interaction.