The Janus kinases or JAKs are a family of tyrosine kinases known to mediate signal transduction events mediated by cytokine receptors that lack intrinsic tyrosine kinase activity. The JAK family of kinases include JAK1, JAK2, JAK3 and Tyk2 (Tyrosine kinase 2). Tyk2 was one of the first member to be identified by using a low stringency hybridization screening of a T cell cDNA library with the c-fms catalytic domain, while JAK1, JAK2 and JAK3 were cloned using a PCR-based strategy using degenerate primers spanning the conserved domains within the catalytic domains of tyrosine kinases. Among the JAKs, JAK1, JAK2 and Tyk2 are ubiquitously expressed while JAK3 has more restricted and regulated tissue ex
The JAK protein kinases have tandem kinase and pseudokinase domains, a feature which gives them their name, Janus Kinases, named after the two-faced Roman god of gates and doorways. The structural domains of JAKs comprise of the JAK homology (JH) domains 1 through 7 (JH1 to JH7). The Janus kinases do not have Src homology domains like SH2 and SH3. The JH1 or the kinase domain is located at the most carboxy terminus of the protein and next to this kinase domain is the pseudo kinase domain, JH2 followed by JH3 through JH7. The JH1 is the functional kinase domain. The function of the pseudokinase domain and that of JH3 to JH7 is still unclear, however recent studies have suggested that the pseudokinase domain regulates the activity of the JAK kinase activity. It was shown that mutation of the JH2 and not JH3 to JH7 domains negatively regulated the tyrosine kinase activity of JAK2. The JH3-JH7 domains have been implicated in associating with the cytokine receptors and other mediators of signal transduction.
A number of studies have demonstrated the activation of JAK kinases in the signal transduction events by cytokines including IL-3, IL-5, GM-CSF, IL-2, IL-4, IL-7, IL-9 and IL-15. JAKs are also activated by G-CSF, growth hormone, prolactin and Epo. The Interferons also transmit their signaling through activation of JAK kinases, including JAK1, JAK2 and Tyk2.
A role for JAK kinases in interferon signaling was established by using cell lines unable to respond to interferons. Cell lines like U1A, U4A and gamma 2A which were deficient in Tyk2, JAK1 and JAK2 respectively were found to be unable to respond to interferons. However, upon introduction of functional Tyk2, JAK1 and JAK2 into these cell lines, interferon signaling was restored in these cells. JAK kinases associate with the cytokine receptors and are known to mediate receptor phosphorylation upon ligand binding. Mutational analysis of JAK2 demonstrated that the amino terminus of JAK2 is required for its binding to the GM-CSF receptor and the amino termini of JAK1 and JAK2 are required for association with the IFN-y receptor subunit.
JAK2 is activated by various cytokines including IL-3/IL-5/GM-CSF, in the hematopoietic cells. The amino terminus of JAK2 is shown to associate with the membrane proximal region of the IL-3R βc chain, and deletion of this region in the IL-3R Pc chain results in loss in JAK2 activation. In addition, the cytoplasmic portion of the a chains of IL-3, GM-CSF and IL-5 receptors also appear to be involved in the activation of JAK2 kinase. Activation of JAK2 leads to phosphorylation of the IL-3R Pc chain on multiple tyrosine residues (Y577, Y612, Y695 and Y750) which in turn serve as docking sites for other signal transducing proteins, the most important of which are the STATs. IL-3 activation of hematopoietic cells appears to lead to the activation of multiple STATs, which include STAT-1, STAT-3, STAT-5 and STAT-6. The nature of STATs that are activated appear to be more dependent of the cell line that is used in the study, rather than the cytokine or the nature of JAK activated by cytokine/receptor interactions. This observation suggests that neither the cytokine receptors nor the JAKs by themselves dictate the nature of the STATs that are activated by a given cytokine. It is also interesting to note that ex