Pseudokinase (repeat 1) domain of the Protein Tyrosine Kinase, Janus kinase 3
Jak3 is expressed only in hematopoietic cells. It binds the shared receptor subunit, common gamma chain and thus, is essential in the signaling of cytokines that use it such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Jak3 is important in lymphoid development and myeloid cell differentiation. Inactivating mutations in Jak3 have been reported in humans with severe combined immunodeficiency (SCID). Jak3 is a cytoplasmic (or nonreceptor) PTK containing an N-terminal FERM domain, followed by a Src homology 2 (SH2) domain, a pseudokinase domain, and a C-terminal tyr kinase domain. The pseudokinase domain shows similarity to tyr kinases but lacks crucial residues for catalytic activity and ATP binding. It modulates the kinase activity of the C-terminal catalytic domain. Jaks are activated by autophosphorylation upon cytokine-induced receptor aggregation, and subsequently trigger downstream signaling events such as the phosphorylation of signal transducers and activators of transcription (STATs). The Jak3 subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.
Comment:The Jak2 V617F mutation is found in many myeloproliferative diseases. It is present in almost all patients with polycythemia vera, 50% of patients with essential thrombocytosis and myelofibrosis, and less commonly in chronic myelomonocytic leukemia (CMML), myelodysplasia, and acute myeloid leukemia.
Jiyao W et al.(2023). "The conserved domain database in 2023.",