The Janus kinase (Jak) family is one of the ten recognized families of non-receptor tyrosine kinases. Mammals have four members of this family, JAK1, JAK2, JAK3 and tyrosine kinase 2 (Tyk2). Birds, fish and insects also have Jaks. Each protein has a kinase domain and a catalytically inactivated pseudokinase domain, each of which binds to a cytokine receptor via an amino terminal FERM (Band-4.1, ezrin, radixin, moesin) domain. Upon binding of a cytokine to its receptor, Jaks is activated and phosphorylates the receptor, resulting in a docking site for signaling molecules, particularly members of the signal transduction and transcriptional activator (Stat) family. Mutations in Drosophila Jak (Hopscotch) reveal developmental defects, and constitutive activation of Jaks in Drosophila and humans is associated with leukemia-like syndrome. The basic non-redundant function of Jaks in cytokine signaling has been established by generating Jak-deficient cell lines and gene-targeting mice. Importantly, JAK3 deficiency is the basis of human autosomal recessive severe combined immunodeficiency (SCID); therefore, a selective JAK3 inhibitor has been developed to form a new class of immunosuppressive drugs.
Classification and functions
In mammals, JAK1, JAK2, and Tyk2 are three common types. In contrast, the expression of JAK3 is more restricted; it is predominantly expressed in hematopoietic cells and is highly regulated with cell development and activation. At the cellular level, Jaks can be found in the cytosol when they are experimentally expressed in the absence of cytokine receptors, but, because of their intimate association with cytokine receptors, they ordinarily localize to endosomes and the plasma membrane, along with their cognate receptors. The link between Jaks and cytokine signaling was first made using mutant cell lines that lacked responsiveness to interferon (IFN). One such cell line was shown to lack Tyk2, and adding back this kinase restored IFN signaling. Shortly thereafter other Jaks were shown to be associated with various cytokine receptors, and subsequently Jak knockout mice have illustrated their essential and specific functions (see Table 1)
Table1. Functions of Jaks
|Gene||Phenotype of mouse knockout||Cytokines whose signaling requires this Jak|
|JAK1||Viable but early postnatal lethal owing to neurological deficits; SCID||Families of receptor with the shared subunits γc or gp130; IFNs|
|JAK2||Embryonic lethal owing to a defect of erythropoiesis||IL-3; family of receptors with the shared subunit gp130; IFN-γ; hormone-like cytokines (EPO, GH, PRL, TPO)|
|JAK3||SCID, viable and fertile||Family of receptor with the shared subunit γc|
|Tyk2||Viable and fertile; susceptible to parasite infection; resistant to LPS||IL-12; LPS|
Characteristic structural features
The three-dimensional structure of Jaks is still unclear. This is undoubtedly partly due to the fact that they are relatively large proteins of more than 1,100 amino acids with an apparent molecular weight of 120-140 kDa; they have been problematic to express and purify them. From the primary structure, it has been recognized that the putative domain structure is conserved between mammals, birds, bony fish and insect Jaks. Seven Jak homology (JH) domains have been identified, numbered from carboxyl to amino terminus (Figure 1). The carboxy-terminal JH1 domain has all the features of a typical eukaryotic tyrosine kinase domain. Interestingly, this domain is most closely related to the kinase domain of the epidermal growth factor family of receptor tyrosine kinases, suggesting that the Jak family may be derived from this larger family of protein kinases. Adjacent to the JH1 domain is a catalytically inactive pseudokinase or kinase-like domain (JH2) that is remotely related to other tyrosine kinase domains. The tandem structure of this kinase domain is a hallmark of Jak kinase and names them; like the Roman god Janus, they are two-faced in these areas. Although the pseudokinase domain lacks catalytic activity, it has the necessary regulatory functions. Many patient-derived and artificial mutations in this field eliminate kinase activity and underscore its key functions. In contrast, mutations within this domain in Drosophila Hop activate kinases and result in transformation (discussed below). In mammalian Jak2, mutations introduced experimentally in this domain can also increase basal activity, but they eliminate ligand-dependent activation.
Figure 1. A schematic representation of the primary structure of Janus kinases (Jaks), which are made up of FERM, SH2-like, pseudokinase and kinase domains. An alternative nomenclature for the putative domains is as a series of Janus homology (JH) domains. The FERM domain mediates binding to cytokine receptors. Both the FERM and the pseudokinase domains regulate catalytic activity and appear to interact with the kinase domain. Jaks autophosphorylate at multiple sites (P), including two in the activation loop of the kinase domain, but the precise function of these modifications is just beginning to be understood. (Kunihiro Y.; et al. 2004)
1. Kunihiro Y.; et al. The Janus kinases (Jaks). Genome Biology. 2004, 5:253.