Associated tyrosine kinase

Tyrosine Kinase Inhibitors/Receptor Associated Tyrosine Kinase Inhibitors (RTK-I)... 

Uckun, F.M. et al. (1995) Biotherapy of B-Cell precursor leukemia by targeting genistein to CD19-associated tyrosine kinases. Science 267, 886-891. 

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. 

Figure 7.3. Structure of PD 153035, a tyrosine kinase inhibitor that may be of therapeutic use in the treatment of cancers caused by inappropriate overexpression of EGF-associated tyrosine kinase activity...

Tyrosine kinase inhibitors may represent effective chemotherapeutic agents for such cancers. Potentially attractive candidates include the inhibitor known as PD 153035 (Figure 7.3) which, even at picomolar (pM) concentrations, inhibits EGF-associated tyrosine kinase activity. While PD 153035 also inhibits additional cellular tyrosine kinases, it does so only at concentrations in the micromolar (/ M) range. 

Phospholipase C, which occurs in different subtypes in the cell, is a key enzyme of phosphatide inositol metabohsm (for cleavage specificity, see Fig. 5.24). Two central signaling pathways regulate phosphohpase C activity of the cell in a positive way (Fig. 6.4). Phospholipases of type CP (PL-CP) are activated by G-proteins and are thus linked into signal pathways starting from G-protein-coupled receptors. Phosphohpases of type Y (PL-Cy), in contrast, are activated by transmembrane receptors with intrinsic or associated tyrosine kinase activity (see Chapter 8, Chapter 10). The nature of the extracellular stimuli activated by the two major reaction pathways is very diverse (see Fig 6.4), which is why the phosphohpase C activity of the cell is subject to multiple regulation. 

Fig. 6.4. Formation and function of diacylglycerol and Ins(l,4,5)P3. Formation of diacylglycerol (DAG) and Ins(l,4,5)P3 is subject to regulation by two central signaling pathways, which start from transmembrane receptors with intrinsic or associated tyrosine kinase activity (see Chapters 8 11) or from G-protein-coupled receptors. DAG activates protein kinase C (PKC, see Chapter 7), which has a regulatory effect on ceU proliferation, via phosphorylation of substrate proteins. Ins(l,4,5)P3 binds to corresponding receptors (InsPs-R) and induces release of Ca from internal stores. The membrane association of DAG, PtdIns(3,4)P2 and PL-C is not shown here, for clarity.

Transmembrane Receptors with Associated Tyrosine Kinase Activity... 

Granulocyte colony stimulating factor, G-CSF 24 kD 150 kD, G-CSF-R, receptor with associated tyrosine kinase... 

Erythropoietin Epo-R, receptor with associated tyrosine kinase... 

Interferon a, P, y INF-Ra, INF-RP, INF-Ry, receptors with associated tyrosine kinase... 

The T cell receptors (see Chapter 11) are an example of receptors composed of several subimits. Ligand binding to the receptor activates an associated tyrosine kinase which phosphorylates Tyr residues in the cytoplasmic region of the receptor and thus creates binding sites for SH2 domains of effector molecules downstream. 

Intracellular signal transduction employs central switching stations that receive, modulate and transmit signals further. The Ras proteins (also known as p2T proteins) make up a switching station of particular importance for growth and differentiation processes. The Ras proteins process signals received by receptor tyrosine kinases, by receptors with associated tyrosine kinase activity and by G-protein-coupled receptors, and transmit these into the cell interior (Fig. 9.1). 

Fig. 9.1. The Ras protein as a central switching station of signaling pathways. A main pathway for Ras activation is via receptor tyrosine kinases, which pass the signal on via adaptor proteins and guanine nucleotide exchange factors to the Ras protein. Activation ofRas protein can also be initiated via G-protein-coupled receptors and via transmembrane receptors with associated tyrosine kinase activity. The membrane association of the Ras protein (see Fig. 9.6) is not shown for clarity. In addition, not aU signahng pathways that contribute to activation of the Ras protein are shown, nor are all effector reactions. Py omplex of the heterotrimeric G proteins GAP GTPase activating protein GEF guanine nucleotide exchange factor.

Fig. 9.12. Overview of the Ras signaling pathway. Signals from at least three major signaling pathways meet at the Ras protein. Activation of the Ras protein may be initiated by receptor tyrosine kinases, by G-protein-coupled receptors and by receptors with associated tyrosine kinases. The nature of the communication between the Ras protein and receptors with associated tyrosine kinase or G-protein-coupled receptors is mostly unknown. From the activated Ras protein, the signal is passed to various effector molecules including members of the MEK kinases, PI3-kinase, pl20 GAP and Ral-GEFs. The best understood is the effector function of Raf kinase, which passes a signal to the transcription level via the MAP kinase pathway.

Examples of receptor-associated tyrosine kinases are given in Table 8.1. Most of the associated protein tyrosine kinases belong to the family of Src kinases (see 8.3) and the Jak kinases (see 11.1.3). 

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