Janus kinase 2 (JAK2) is a protein tyrosine kinase central to a multitude of cellular processes. Here, a novel model of JAK2 regulation and activation is proposed. In the JAK2 dimer, instead of being auto-inhibited by its own JH2 domain, inhibition comes from the JH2 domain of the partnering JAK2 monomer. Upon ligand binding, the receptor undergoes a conformational rotation that is passed to its dimeric partner. The activation is achieved by the rotation of two JAK2 molecules, which relieves

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... JH1/JH2 inhibitory interface and brings two JH1 domains in proximity for the subsequent trans-phosphorylation event. This hypothetical model is consistent with most of the currently available experimental evidence and warrants further tests. Based on the proposed model, it is possible to rationalize the differential responses of JAK2 signaling involving various receptors and ligands. Implications: The proposed model of JAK2 regulation and activation is poised to suggest potential alternative drug-discovery strategies that could impact a number of relevant diseases.