Janus family kinases

Yeh TC, Pellegrini S. 1999. The Janus Kinase family of protein tyrosine kinase and their ole in signaling. Cell Mol Life Sci. 55 1523-1534. 

The Ugand-occupied receptor dimer does not have inherent tyrosine kinase activity but, rather, provides docking sites for 2 molecules of JAK2, a cytoplasmic tyrosine kinase of the Janus kinase family. The juxtaposition of 2 JAK2 molecules leads to trani-phosphorylation and autoactivation of JAK2, with consequent tyrosine phosphorylation of cytoplasmic proteins that mediate downstream signahng events (Figure 55-2). 

Another family of protein kinases involved in signal transduction via cytokines includes the Janus kinases (Jak kinases). At least four different Jak kinases are known in mammals (Jakl, Jak2, Jak3 and Jak4). A characteristic feature of the structure of Jak kinases is the occurrence of two tyrosine kinase domains (Fig. 11.5). However, only... 

Fig. 11.5. Domain structure of the Jak kinases. JHl is the catalytic tyrosine kinase domain. JH2 shows similarity to a tyrosine kinase domain. The domains A—E are homologous elements of the Jak kinase family. JH Janus kinase homology region.

A variation on the basic theme of receptor Tyr kinases is seen in receptors that have no intrinsic protein kinase activity but, when occupied by their ligand, bind a soluble Tyr kinase. One example is the system that regulates the formation of erythrocytes in mammals. The cytokine (developmental signal) for this system is erythropoietin (EPO), a 165 amino acid protein produced in the kidneys. When EPO binds to its plasma membrane receptor (Fig. 12-9), the receptor dimerizes and can now bind the soluble protein kinase JAK (Janus kinase). This binding activates JAK, which phosphory-lates several Tyr residues in the cytoplasmic domain of the EPO receptor. A family of transcription factors, collectively called STATs (signal transducers and activators of transcription), are also targets of the JAK kinase activity. An SH2 domain in STATS binds (P)-Tyr residues in the EPO receptor, positioning it for this phosphorylation by JAK. When STATS is phosphorylated in re-... 

Four mammalian Janus kinase (JAK family members have been identified JAK1, JAK2, JAK3 and Tyk2 with molecular weights ranging from 120 to 140 kDa. 

The activation of cytokine receptors after ligands binding, provokes tyrosine phosphorylations by non-covalenty associated protein tyrosine kinases (PTKs) the Janus kinases (JAKs), a family that comprises JAKl, JAK 2, JAK 3 and TYR2. 

As a consequence of ligand binding to cytokine receptors, activation of a tyrosine kinase activity, which is not part of the receptor protein, is observed. In most cases this tyrosine kinase is permanently associated with one of the subunits ofthe receptor, and ligand-induced restructuring or hetero-oligomerization ofthe receptor induces activation of this tyrosine kinase. The tyrosine kinases most frequently associated with cytokine receptor subunits belong to the family of Janus kinases. However, protein tyrosine kinases ofthe Src family like Lck, Fyn and Tyk have also been shown to be direct downstream components of the cytokine receptors (see Section 11.2.2). 

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