Receptor tyrosine kinase Effector proteins

FIGURE 8.3 Domain organization of proteins that associate with phosphorylated tyrosine kinase (PTK)-containing receptors. Proteins that associate with tyrosine-phosphorylated receptors contain SH2 or PTB domains, which recognize specific amino-acid stretches in the vicinity of phosphorylated tyrosine residues. Unlike the enzymes, the adaptors lack intrinsic catalytic activity but serve to link phosphorylated receptors with other effector proteins. Some of the proteins presented in this figure are discussed in this chapter. 

All steps of the Ras pathway from ligand binding to receptor tyrosine kinases, down to activation of effectors like Raf kinase, occur at the plasma membrane. However, most biophysical studies on protein/protein interactions involved in this scenario have been carried out with bacterially synthesized proteins lacking... 

Fig. 8.6. Functions of autophosphorylation of receptor tyrosine kinases. Autophosphorylation of receptor tyrosine kinases takes place in trans, i.e., between neighboring protomers of the receptor. The catalytic domain of the receptor is shown as a shaded segment. As a consequence of autophosphorylation, the intrinsic tyrosine kinase activity of the receptor is stimulated. Effector proteins can also bind to the activated receptor. Binding takes place with specific phosphotyrosine binding domains (SH2 or PTB domains) at phosphotyrosine residues of the activated receptor. A critical factor for further signal transduction is the membrane association of the effector proteins that enter into binding with the activated receptor. Details of the effector proteins can be found as follows phospholipase Cy 5.6.2 Src kinase 8.3.2 pl20 GAP 9.4 Grb2, She, IRS 8.5 PI3-kinase 6.6.1 Syp tyrosine phosphatase 8.4.

Starting from an activated receptor tyrosine kinase, further conduction of the signal takes place with the help of specific protein-protein interactions between the activated receptor and one or more effector proteins next in the sequence. In many cases, the effector molecules pass the signal on to other proteins of the signaling pathway, forming chains of signal proteins in sequence. Specific protein-protein interactions are the... 

Cytoplasmically localized protein tyrosine phosphatases have a catalytic domain and other structural elements that specify the subcellular localization and association with effector molecules. These structural elements contain sequence signals for nuclear localization, for membrane association and for association with the cytoskeleton (see Fig. 8.16). The presence of SH2 domains suggests that these molecules might interact with signaling pathways involving growth hormones and receptor tyrosine kinases. 

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.

Figure 1 Ras GTPases function as regulated GDP/GTP molecular switches. Diverse extracellular signals, for example those received by membrane-bound receptors such as G-protein coupled receptors and receptor tyrosine kinases, can cause Ras GTPase activation at the plasma membrane and endomembranes. Receptor-mediated activation of Ras most commonly involves the activation of RasGEFs, which then cause transient activation of Ras. Activated Ras-GTP adopts a conformation that enhances its affinity for transient binding to and activation of downstream effectors (E).A The activated effectors then regulate distinct cytoplasmic signaling networks that control cellular proliferation, differentiation, and survival. Ras signaling is terminated by RasGAP-mediated stimulation of hydrolysis of bound GTP to GDP, which precludes further Ras-effector interaction. Tumor-associated Ras mutant proteins are insensitive to GAP stimulation.

Although the phospholipases of type Cfi and Cy catalyze the same biochemical reaction, they are activated via different signaling pathways. The Cfi subfamily participates in G protein signaling while the members of the Cy subfamily function as effectors of receptor tyrosine kinases (see Chapter 8). 

Activated receptor tyrosine kinases transduce signals to a variety of central intracellular signaling pathways. A multitude of effector proteins are recruited into signaling by receptor tyrosine kinases. Important examples are... 

---