Janus kinases domain

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...

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... 

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-... 

The leptin signal is transduced by a mechanism also used by receptors for interferon and growth factors, the JAIC-STAT system (Fig. 23-34 see Fig. 12-9). The leptin receptor, which has a single transmembrane segment, dimerizes when leptin binds to the extracellular domain of two monomers. Both monomers are phos-phorylated on a Tyr residue of the intracellular domain by a Janus kinase (JAK). The -Tyr residues become docking sites for three proteins that are signal transducers and activators of transcription (STATs 3, 5, and 6, sometimes called fat-STATS). The docked STATs are then phosphorylated on Tyr residues by the... 

Fig. 3.2 The JAK/STAT signaling pathway after cytokine binds to its receptors, the associated Janus kinase (JAK) is induced. This results in the phosphorylation of the receptor s cytoplasmic domain. STAT is recruited after the phosphorylation of the receptor s cytoplasmic domain, which after phosphorylation dimerizes and migrates into the nucleus. In the nucleus, STAT binds to its niche in the DNA and induces gene expression see Color Insert)...

This process takes place outside the cell. Dimerization of the extracellular domains of the receptor brings together the intracellular domains as well. Associated with each intracellular domain is a molecule of a protein kinase termed Janus kinase 2 (JAK2) in an unactivated form. Janus kinases have modular structures consisting of four previously described domains (Figure 15.26). 

Figure 15.26. Janus Kiuase Domaiu Structure. A Janus kinase (JAK) includes four recognized domains an ERM domain that favors interactions with membranes, an SH2 domain that binds phosphotyrosine-containing peptides, and two domains homologous to protein kinases. Only the second protein kinase domain appears to be enzymatically functional.

Some ligands induce dimerization of the receptors to which they bind. Such a receptor contains an extracellular domain that binds the ligand, a transmembrane region, and a cytosolic domain that either binds or contains a protein kinase. The growth-hormone receptor participates in an example of this type of signal-transduction pathway. Dimerization of the receptor activates Janus kinase 2, a protein kinase associated with the intracellular part of the receptor. The kinase, in turn, phosphorylates and activates a transcription factor called STAT5. 

Mechanism of prolactin receptor activation. Activation of prolactin receptor consists of ligand-induced sequential receptor homodimerization driven by the two binding sites of prolactin. In the intracellular domain of the homodimer of the ligand-receptor complex, a tyrosine kinase [known as Janus kinase 2 (Jak-2)] is activated. Jak-2 kinase causes autophosphorylation and phosphorylation of the receptor. [Reproduced with permi,ssion from M. E. Freeman,... 

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.

The cytoplasmic domains of cytokine receptors contain binding sites for protein tyrosine kinases called JAKs. Janus kinase). In the absence of a bound cytokine, the JAKs have low catalytic activity but they become highly active following cytokine binding. 

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