Abstract
JAK2 is a member of the Janus kinase (JAKs) family of non-receptor protein tyrosine kinases, which includes JAK1–3 and TYK2. JAKs serve as the cytoplasmic signaling components of cytokine receptors and are activated through cytokine-mediated trans-phosphorylation, which leads to receptor phosphorylation and recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins. JAKs are unique among tyrosine kinases in that they possess a pseudokinase domain, which is just upstream of the C-terminal tyrosine kinase domain. A wealth of biochemical and clinical data have established that the pseudokinase domain of JAKs is crucial for maintaining a low basal (absence of cytokine) level of tyrosine kinase activity. In particular, gain-of-function mutations in the JAK genes, most frequently, V617F in the pseudokinase domain of JAK2, have been mapped in patients with blood disorders, including myeloproliferative neoplasms and leukemias. Recent structural and biochemical studies have begun to decipher the molecular mechanisms that maintain the basal, low-activity state of JAKs and that, via mutation, lead to constitutive activity and disease. This review will examine these mechanisms and describe how this knowledge could potentially inform drug development efforts aimed at obtaining a mutant (V617F)-selective inhibitor of JAK2.
Highlights
Janus kinases (JAKs) are non-receptor protein tyrosine kinases that serve as the catalytic signaling components for a wide range of cytokine receptors, including the receptors for interleukins, interferons, growth hormone, erythropoietin, and leptin [1]
There are four mammalian members of the JAK family: JAK1-3 and TYK2, which are constitutively bound to the cytoplasmic region of cytokine receptors
Cytokine receptors belonging to a subclass that includes erythropoietin receptor (EpoR) and growth hormone receptor (GHR) are homodimeric and bind JAK2 exclusively
Summary
Janus kinases (JAKs) are non-receptor protein tyrosine kinases that serve as the catalytic signaling components for a wide range of cytokine receptors, including the receptors for interleukins, interferons, growth hormone, erythropoietin, and leptin [1]. JH1 catalyzes trans-phosphorylation of two tyrosine residues in the kinase activation loop (Tyr1007 and Tyr1008 in JAK2), which stabilizes the active state. The activated kinase domain phosphorylates specific tyrosine residues in the associated cytokine receptor and in the recruited STAT molecules, as well as other tyrosines in the JAK molecule (Figure 1A). Biochemical studies, in addition to sequencing data from MPN patients mentioned above, have implicated the pseudokinase domain (JH2) of JAKs as a negative regulator of the tyrosine kinase activity of JH1 [16,17,18] [reviewed in Ref. In addition to functioning sterically as a negative regulator of JH1, JAK2 JH2 was shown to possess weak catalytic activity [21], phosphorylating two sites, Ser523 and Tyr570, which had previously been identified as negative-regulatory phosphorylation sites [22,23,24,25]. For JAKs, the β2–β3 loop of JH2, where pTyr570 in JAK2 resides, is negatively charged, and the N lobe of JH1 (interaction site for pTyr570) is positively charged, suggesting that a favorable charge interaction between these two regions stabilizes the JH2–JH1 autoinhibitory interaction for all JAKs
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