JAK1

JAK1, or Janus kinase 1, is a cytoplasmic non-receptor protein tyrosine kinase in the JAK family that transduces signals from many cytokine and growth factor receptors. It functions as part of the JAK-STAT signaling pathway, phosphorylating receptor tails and STAT transcription factors after cytokine binding, which leads to gene expression changes that regulate immune responses, cell growth, and differentiation.

Structurally, JAK1 contains the typical JAK receptor-associated module: an N-terminal FERM domain for receptor engagement, an SH2-like domain, a pseudokinase domain (JH2) that modulates activity, and a catalytic kinase domain (JH1). Activation occurs through receptor dimerization and trans-phosphorylation, after which JAK1 phosphorylates itself and the receptor, enabling STAT recruitment and activation.

JAK1 participates in signaling for a broad set of cytokines important for hematopoiesis and immune function, including interleukins such as IL-2, IL-4, IL-6, IL-7, IL-9, IL-15, and IL-21, as well as type I and II interferons. For several receptors, JAK1 pairs with other JAK family members, such as JAK2 or TYK2, to propagate signals.

Clinical relevance includes the consequences of aberrant JAK1 signaling, which can contribute to immunodeficiency, autoinflammation, and cancer. Pharmacologic inhibition of JAK1 (often with broader JAK inhibitors) is employed in autoimmune and inflammatory diseases, with potential side effects including infection risk and cytopenias. Regulation of JAK1 activity is maintained by cellular feedback mechanisms, including SOCS proteins.