JAKSTATpathways

JAK-STAT pathways, often described as JAK-STAT or JAKSTAT pathways, are a family of signaling cascades activated by cytokine receptors that rely on Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). These pathways regulate immune responses, hematopoiesis, development, and cell proliferation, and are conserved across vertebrates.

Activation begins when a cytokine binds its receptor, causing receptor dimerization and juxtaposition of JAKs bound to the cytoplasmic tails. JAKs trans-phosphorylate each other and the receptor, creating phosphotyrosine docking sites. STAT proteins are recruited, phosphorylated on a key tyrosine, dimerize via SH2 domains, and translocate to the nucleus to regulate transcription.

Principal components include JAK1, JAK2, JAK3, and TYK2, and the STAT family (STAT1–STAT6). Receptor families include type I and type II cytokine receptors, which respond to interferons, interleukins, erythropoietin, prolactin, and growth hormone. Gene targets vary but commonly include interferon-stimulated genes and regulators of the cell cycle, differentiation, and survival.

Negative regulation is provided by SOCS proteins (SOCS1–SOCS3), phosphatases such as SHP-1 and SHP-2, and PIAS proteins. These mechanisms limit signaling duration and prevent inappropriate activation. Cross-talk with other pathways and post-translational modifications shape the response and specificity of signaling outcomes.

Clinical significance includes activating mutations in JAK2 (notably JAK2 V617F) in myeloproliferative neoplasms, leading to constitutive signaling. JAK inhibitors such as ruxolitinib treat certain myeloproliferative disorders and inflammatory diseases but may cause anemia, thrombocytopenia, or infection.