The Janus Kinases

In addition to the Lck kinase, other tyrosine kinases are activated on ligand binding to the IL-2 receptor. These are Fyn kinase and the Janus kinases Jakl and Jak3. 

Starting from the activated tyrosine kinase, the signal may be conducted along different signaling pathways depending on the receptor type. 

Cross-phosphorylation of the EGF receptor has also been observed dining the process of activation of cytokine receptors, whereby crosstalk with receptor tyrosine kinases is possible. 

The following signaling pathways are activated on ligand binding to cytokine receptors  

Cytokine signals may be conducted into the nucleus at the transcription level via these central signaling pathways. As a consequence, activation takes place of transcription factors with growth regulating and morphogenetic functions. 

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Figure 8.3 Schematic representation of the general domain structure of a STAT protein. A conserved ( C or con ) domain is located at the N-terminus, followed by the DNA-binding domain (D). Y represents a short se-guence that contains the tyrosine residue phosphorylated by the Janus kinase. The carboxy terminus domain (Tr) represents a transcriptional activation domain...

Uckun, F.M., Thoen, J., Chen, H., Sudbeck, E., Mao, C., Malaviya, R., Liu, X.-P. and Chen, C.-L. (2002) CYP1A-mediated metabolism of the janus kinase-3 inhibitor 4-(4 -hydroxyphenyl)-amino-6,7-dimethoxyquinazoline structural basis for inactivation by regioselective o-demethylation. Drug Metabolism and Disposition The Biological Fate of Chemicals, 30 (1), 74—85. 

These are indolent neoplasms characterised by uncontrolled expansion in the erythron where additional hazards are added by the thrombocytosis and, to a lesser extent, leucocytosis. There is a specific point mutation in the Janus Kinase 2 or JAK 2 gene that better defines these cases. 

Fig. 11.4. Model of signal transduction via the IL-2 receptor. Binding of IL-2 to the IL-2 receptor initiates activation of the Janus kinases Jakl and Jak3. These phosphorylate tyrosine residues in the P-chain of the IL-2 receptor and in the transcription factor StatS. SH2 domains or PTB domains of adaptor proteins can bind to the Tyr phosphate residues of the P-chain and, as shown in the figure for the Shc/Grb2/Sos complex, can transmit a signal in the direction of the Ras pathway. The phosphorylated transcription factor StatS is translocated into the nucleus and activates the transcription of corresponding gene sections. Another signaling pathway starting from the activated IL-2 receptor involves the Lck and Syk tyrosine kinases (see Chapter 8). The pathway leads to induction of genes for transcription factors such as c-Myc and c-Fos.

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... 

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. 

It is generally accepted that OBRb is the fully competent signal transduction isoform of the receptor, and that the short-form OBRs (a, c, d, f) while capable of signal transduction, do so to a lesser extent (Bjorbaek et al. 1997 Uotani et al. 1999). The major signaling pathway activated by leptin binding to OBRb is the Janus kinase... 

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway play a critical role in the signalling of a wide array of cytokines and growth factors, leading to various cellular functions, including proliferation, growth, haematopoiesis and immune response. 

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. 

Fig. 11.4 Schematic diagram ofthe 11-2 receptor complex. The II-2R is composed of three subunits, IL-2Ra, IL-2R/7 yc. The Box 1 and Box 2 domains are conserved among members ofthe cytokine receptor superfamily, and a variable spacer region V intervenes Boxl and Box2. The Boxl-V-Box2 regions encompass the sites of association with the Janus kinases (Jak). Jakl associates constitutively with IL-2R/> and Jak3 associates constitutively with yc. Both IL-2R/> and yc encode multiple cytoplasmic tyrosine residues with approximated locations shown. At least some of these tyrosines on both chains become phosphorylated following receptor activation whereupon they serve to recruit effector proteins to direct downstream signaling events.

For signaling pathways, recent years have seen an increasing number of studies of specific pathways where mathematical modeling is applied to infer systems properties from the models. These applications include the mitogen-activated protein (MAP)-kinase pathways [14-16], apoptotic pathways [17-19], the Wnt/j6-Catenin [20], and the Janus kinase-signal transduction and activator of transcription (JAK-STAT) pathway [21], A regulatory network that has been studied intensively is the cell cycle [7, 22, 23]. 

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). 

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