Structural Regulation and Therapeutic Perspectives of JAK2 Kinase

Janus kinase 2 (JAK2) occupies a central position in cytokine signaling and plays essential roles in hematopoiesis, immune regulation, and cancer. Although recent advances in structural biology, cryo-EM, receptor modeling, and biophysical analysis have substantially expanded current views of JAK2 function, key mechanistic questions remain regarding how receptor geometry, JH2-mediated autoinhibition, and disease-associated mutations are structurally integrated. In this review, we discuss the multidomain organization of JAK2 and examine how the FERM–SH2 module, the pseudokinase domain (JH2), and the catalytic kinase domain (JH1) cooperate to govern receptor specificity, allosteric control, and cytokine-induced activation. We further analyze how pathogenic mutations rewire this regulatory system by weakening autoinhibitory contacts, altering linker-mediated communication, or stabilizing active dimeric conformations. Finally, we assess current and emerging therapeutic strategies, from ATP-competitive inhibitors to macrocyclic and JH2-selective allosteric modulators, with emphasis on how structural insight can guide next-generation drug design. These advances support a more integrated view of JAK2 regulation and define new opportunities for selective therapeutic intervention.