The regulation of JAKs in cytokine signaling and its breakdown in disease

The JAK-STAT signal transduction pathway is responsible for mediating signals of over fifty cytokines, growth factors and hormones. Signaling through the JAK-STAT pathway is regulated on multiple levels, including intramolecular regulation by the JAK pseudokinase domain, and intermolecular regulation by a host of regulatory proteins. The advent of accessible genomic tools have provided a wealth of information on disease-associated mutations in the JAK-STAT pathway and its regulatory components. The vast number of these mutations in diseases ranging from immunodeficiencies and obesity to many cancers highlight the importance of correct regulation of JAK-STAT signaling for biological processes such as hematopoiesis, regulation of the immune system, metabolism, and growth. Simultaneously, JAK inhibitors are gaining traction in clinical use, both for treatment of diseases driven by JAK mutations, and for a host of inflammatory disorders, in which proinflammatory cytokine signaling through the JAK-STAT pathway is an integral part of pathogenesis. The elucidation of molecular mechanisms in the pathogenesis of complex diseases has also, however, brought the limitations of our current understanding on the regulation of cytokine signaling to the foreground. Indeed, deeper understanding of these regulatory mechanisms are a prerequisite for the development of the next generation of pharmacological modulators of the JAK-STAT pathway. In this review we discuss the current state of knowledge of the intra- and intermolecular regulation of the JAK-STAT pathway, with a focus on diseases arising from disruptions in the regulatory apparatus.