The cytokine receptor superfamily has expanded to more than 40 members and the receptor chains function to transmit the signal of around 50 cytokines. Composed of transmembrane type I transmembrane proteins without intrinsic kinase activity, most chains associate in their intracellular domain with members of the Janus kinase family, either JAK1, JAK2, JAK3 or TYK2. When bound by their ligands, the receptors adopt homodimeric or heterodimeric or heteromeric conformations that allows the kinase domains of the associated JAKs to phosphorylate each other on their activation loops, which in turn initiates JAK activation. The result is rapid tyrosine phosphorylation of JAK themselves and of cytosolic receptor tails, which all become docking sites for signaling molecules that once attracted become themselves substrates of the JAKs. Prominent among those are the 7 members of the Signal Transducer and Activator of Transcription family (STATs), which once activated translocate to the nucleus and regulate gene expression. But cytokine receptor signaling involves also activation of ras-MAP-kinase and phosphatydylinositol-3'-kinase:AKT pathways, as well as induction and function of several negative regulators like Suppressors of Cytokine Signaling and Protein Inhibitors of Activated STATs. Altogether cytokines control basic organismal processed such as blood formation, immune response, inflammation, epithelial healing and others. recent structural insights in the extracellular and intracellular cytokine receptor domains, the relationship between orientation and signaling open the possibility to manipulate such receptors pharmacologically. Further interest has been raised by the discovery that activating mutations in JAKs (such as JAK2V617F in myeloid cancers), in receptors and in STATs are associated with acquired and hereditary diseases. Altogether the field of cytokine receptor -JAK-STAT signaling is ripe for therapeutic exploitation. More so, very recent structural advances unveil the long-waited structures of intracellular key regions and their binding to JAKs.

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