Figure 1

The domains of JAK2 illustrating binding to the receptor and changes consequent to receptor binding and mutation in the JH2 domain. The V617F mutation of the JH2 domain of JAK2 results in constitutive kinase activation. Panel A: When no ligand in bound to the EPO, TPO, G-CSF or GM-CSF receptors, the kinase activity of the JH1 domain is inhibited by the JH2 domain and JAK2 is inactive. Panel B: When EPO binding to it receptor, the two strands of the receptor come closer together, JAK2 changes conformation, the JH1 kinase activity in no longer inhibited by JH2. Panel C: The JAK2 V617F mutation prevents JH2 from inhibiting JH1 and the kinase is active even when no ligand is bound by the receptor.