JAK

JAK refers to the Janus kinase family, a group of cytoplasmic non-receptor protein tyrosine kinases that play a central role in transmitting signals from many cytokine receptors to the cell nucleus. The family comprises four members in humans: JAK1, JAK2, JAK3, and TYK2. They are closely associated with type I and type II cytokine receptors and are essential for the activation of the JAK-STAT signaling pathway, which governs processes such as hematopoiesis, immune function, and cell growth.

Structurally, JAK proteins feature multiple domains that enable receptor binding and signaling. An N-terminal FERM domain mediates association with cytokine receptors, followed by an SH2-like domain. The catalytic activity resides in the C-terminal kinase domain, JH1, while a nearby pseudokinase domain, JH2, regulates kinase activity. Upon cytokine binding, receptors dimerize and JAKs cross-phosphorylate each other and the receptor. This creates phosphotyrosine docking sites for STAT transcription factors, which are then phosphorylated, dimerize, and translocate to the nucleus to regulate gene expression.

Functionally, JAK-STAT signaling integrates signals from a wide range of cytokines and growth factors, influencing hematopoiesis, immune responses, inflammation, and development. Dysregulation of the pathway—via mutations, overexpression, or constitutive activation—can contribute to autoimmune diseases and malignancies. The best-known mutation is JAK2 V617F, associated with myeloproliferative neoplasms such as polycythemia vera.

Therapeutically, JAK inhibitors (jakinibs) target this pathway and are used to treat inflammatory and hematologic diseases. Examples include ruxolitinib (JAK1/2 inhibitor), baricitinib (JAK1/2 inhibitor), tofacitinib (JAK1/3 inhibitor), and select JAK1- or JAK2-specific inhibitors. Adverse effects can include infections, anemia, thrombocytopenia, and lipid or liver enzyme changes, reflecting the pathway’s broad role in physiology.