cd05081: PTKc_Jak2_Jak3_rpt2 (this model, PSSM-Id:133212 is obsolete and has been replaced by 270665)
Catalytic (repeat 2) domain of the Protein Tyrosine Kinases, Janus kinases 2 and 3
Protein Tyrosine Kinase (PTK) family; Janus kinase 2 (Jak2) and Jak3; catalytic (c) domain (repeat 2). The PTKc family is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, and phosphoinositide 3-kinase (PI3K). PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Jak2 and Jak3 are members of the Janus kinase (Jak) subfamily of proteins, which are cytoplasmic (or nonreceptor) tyr kinases containing an N-terminal FERM domain, followed by a Src homology 2 (SH2) domain, a pseudokinase domain, and a C-terminal catalytic tyr kinase domain. Jaks are crucial for cytokine receptor signaling. They 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). Jak2 is widely expressed in many tissues while Jak3 is expressed only in hematopoietic cells. Jak2 is essential for the signaling of hormone-like cytokines such as growth hormone, erythropoietin, thrombopoietin, and prolactin, as well as some IFNs and cytokines that signal through the IL-3 and gp130 receptors. Jak3 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. Disruption of Jak2 in mice results in an embryonic lethal phenotype with multiple defects including erythropoietic and cardiac abnormalities. It is the only Jak gene that results in a lethal phenotype when disrupted in mice. A mutation in the pseudokinase domain of Jak2, V617F, is present in many myeloproliferative diseases, including almost all patients with polycythemia vera, and 50% of patients with essential thrombocytosis and myelofibrosis. Jak3 is important in lymphoid development and myeloid cell differentiation. Inactivating mutations in Jak3 have been reported in humans with severe combined immunodeficiency (SCID).
Comment:Based on the structures of other PTK family members bound to substrate peptides and ATP analogs as well as, the structures of human Jak2 bound with a pan-Jak inhibitor , and human Jak3 tyr kinase bound with an analog of the inhibitor, staurosporine (1YVJ_A and 2B7A_B respectively).
Lu S et al.(2020). "CDD/SPARCLE: the conserved domain database in 2020.",