Janus kinase family (JAK) (JAK)

The Janus kinase (JAK) family consists of four intracellular non-receptor tyrosine kinases—JAK1, JAK2, JAK3, and TYK2—that are essential components of the JAK-STAT signaling pathway (UniProt P23458, O60674). These kinases associate with the cytoplasmic tails of cytokine receptors; upon ligand binding, they become activated and phosphorylate both the receptor and downstream Signal Transducer and Activator of Transcription (STAT) proteins (Rawlings et al., 2004, J Cell Sci). The ATP-binding pocket, located in the highly conserved catalytic JH1 domain, serves as the primary target for most first- and second-generation JAK inhibitors (JAKis). By blocking ATP binding, these therapeutic agents prevent the phosphorylation events necessary for signal transduction, thereby dampening the production of pro-inflammatory cytokines and modulating hematopoietic activity (PubMed: 28848215). Consequently, the JAK family is a pivotal target for treating a wide range of conditions, including rheumatoid arthritis, myelofibrosis, and various dermatological and gastrointestinal inflammatory diseases (StatPearls: Janus Kinase Inhibitors). However, targeting the ATP-binding pocket often presents challenges regarding isoform selectivity, as the pocket is highly conserved across the four family members, leading to potential off-target effects related to JAK2 or JAK3 inhibition.

Other names

Janus kinasesJAKsJAK family kinasesNon-receptor tyrosine-protein kinase JAK familyJanus-activated kinases

Competitive inhibition of adenosine triphosphate (ATP) binding within the catalytic JH1 domain of Janus kinases, preventing the phosphorylation of STAT proteins and subsequent downstream gene transcription (Schwartz et al., 2017, Nat Rev Drug Discov).