Janus kinase, phosphorylation

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...

Leptin signalling is via monomeric receptors in the brain. A short-form of the leptin receptor (Lep-R) is required to transport the hormone across the blood-brain barrier and a long-form Lep-R is located in the hypothalamus. The long-form is functionally linked with a particular type of receptor-associated tyrosine kinase called Janus kinase (JAK, see Section 4.7) whose function is to phosphorylate a STAT (signal transducer and activator of transcription) protein a similar mechanism to that often associated with signalling by inflammatory cytokines. 

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.

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... 

Cytokines all function using a group of transmembrane receptors embedded in the plasma membranes of target cells. The receptors have no tyrosine kinase activity but associate with and activate kinases known as Janus kinases (JAKs). These kinases phosphory-late tyrosine side chains in their receptors, and the phosphorylated receptors activate transcription factors of the STAT (signal transducer-activators of transcription) group.186-195 The specificity of cytokine action results from a combination of receptor recognition and recognition of the various STAT molecules by different JAKs.111 Cytokines have a variety of structures. Many are helix bundles or have (3 sheet structures (Fig. 30-6). 

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)...

Incorporation of cytokine in a naive Th lymphocyte receptor activates the route of Janus kinases (JAK1, JAK2, JAK3), transmission proteins for intracellular signals, and activating transcriptions—Signal Transducer and Activator Transcription (STAT)—consequently phosphorylation of receptor tyrosine results. 

Mellado, M., Rodriguez-Frade, J. M., Aragay, A., del Real, G., Martin, A. M., Vila-Coro, A. J., Serrano, A., Mayor, F., Jr., and Martinez, A. C. (1998). The chemokine monocyte chemotactic protein 1 triggers Janus kinase 2 activation and tyrosine phosphorylation of the CCR2B receptor./. Immunol. 161, 805-813. 

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. 

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. 

Receptor coupling mechanisms. A number are G-protein coupled (Gi/o), but others involve JAK/STAT, l.e. signalling depends upon receptor association with Janus kinases OAKs), which couple ligand binding to tyrosine phosphorylation of signalling proteins recruited to the receptor complex. 

IL-2 often synergizes with other cytokines (notably IL-12) to induce IFNy production by NK cells and to increase cytotoxicity by NK and LAK cells. The expression of the receptor for this cytokine on NK cells is, however, continuous in character, but only a very small percentage of these cells have receptors of great affinity. The study of differential use of Janus kinase-signal transducer activator of transcription signaling pathways in the stimulation of human NK cells by IL-2, IL-12, and IFNa has demonstrated a differential phosphorylation and consequent differential activation of both separate and overlapping STAT proteins by IL-2, IL-12, and IFNa. This may provide a molecular basis for the similarities and differences in the actions of these cytokines on NK cells. ... 

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,... 

JAK2 Janus kinase 2 an enzyme that will phosphorylate tyrosine residues on target proteins. JAK2 is bound to the growth hormone receptor but is inactive until the receptor binds the hormone. When hormone binds the receptor, it triggers dimerization and activates JAK2. 

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