JAKs

Janus kinases (JAKs) are a family of cytoplasmic tyrosine kinases that associate with type I and type II cytokine receptors to transduce signals from extracellular cytokines to the nucleus via the JAK-STAT pathway. The human JAK family consists of four members: JAK1, JAK2, JAK3, and TYK2. Each plays overlapping but distinct roles in hematopoiesis and immune signaling. JAK2 is essential for signaling by erythropoietin and thrombopoietin receptors; JAK3 is primarily used by the common gamma chain cytokines in immune cells; JAK1 and TYK2 participate in signaling by multiple interleukin receptors and interferons.

Structure and activation: JAKs are non-receptor protein tyrosine kinases with several domains: an N-terminal FERM domain for receptor binding, a SH2-like domain, a catalytically inactive pseudokinase JH2 domain that modulates activity, and the JH1 kinase domain. Cytokine binding induces receptor dimerization, bringing JAKs into proximity, enabling transphosphorylation and activation of JH2 and JH1. Activated JAKs phosphorylate specific tyrosine residues on the receptor, creating docking sites for STAT proteins, which are themselves phosphorylated, dimerize, and move to the nucleus to regulate gene expression.

Biological role: The JAK-STAT pathway regulates cell proliferation, differentiation, survival, and immune responses. Proper JAK signaling is essential for hematopoiesis and for responses to a wide range of cytokines, interferons, and growth factors. Dysregulation by mutation, overexpression, or constitutive activation contributes to immune disorders and malignancies.

Clinical relevance: JAK inhibitors have been developed to treat myeloproliferative neoplasms and inflammatory diseases. Examples include ruxolitinib (JAK1/2 inhibitor), baricitinib (JAK1/2), tofacitinib (JAK1/3), and fedratinib (JAK2). Therapy can reduce splenomegaly, control symptoms, and lower inflammatory activity, but may cause anemia, thrombocytopenia, infections, and lipid abnormalities. Long-term safety and monitoring are important.