JAKSTAT

JAK-STAT is a signaling pathway used by many cytokine receptors to transmit information from extracellular ligands to the cell nucleus, resulting in gene expression changes. It centrally involves the Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs).

In the resting state, JAK kinases are bound to receptor cytoplasmic domains. Ligand binding induces receptor dimerization and activation of JAKs, which phosphorylate themselves and the receptor. This creates docking sites for STAT proteins, which are recruited via their SH2 domains and phosphorylated by JAKs. Phosphorylated STATs dimerize and translocate to the nucleus where they regulate target gene transcription.

The JAK family includes JAK1, JAK2, JAK3 and TYK2, while the STAT family comprises STAT1 through STAT6. Cytokine receptors often utilize shared subunits such as the common gamma chain or gp130. Negative regulators include SOCS proteins, PIAS proteins, and protein tyrosine phosphatases that limit signaling to prevent excessive responses.

Physiological roles of the JAK-STAT pathway span hematopoiesis, immune responses, growth, and development. Dysregulation is linked to myeloproliferative neoplasms (notably JAK2 V617F), autoimmune and inflammatory diseases, and some cancers. Because of its central role in cytokine signaling, the pathway is a target for therapy.

Pharmacological inhibitors of JAKs, such as tofacitinib, ruxolitinib, baricitinib, and fedratinib, are used to treat diseases including myelofibrosis, rheumatoid arthritis, and certain inflammatory conditions. Side effects can include immunosuppression, infections, and metabolic disturbances. The pathway has been widely studied to understand immune regulation and signal integration.