EGF receptor kinase

Out of those PTKs involved in pathophysiological states a relatively small number show up in cancers and other proliferative states. For example, overexpression of the EGF receptor kinase is the hallmark of most, if not all,... 

Two of the small molecule inhibitors, gefitinib (166, EGF receptor kinase inhibitor) and imat-inib (167, Bcr-Abl receptor kinase inhibitor), have reached the market. Although many of the starting leads for kinase inhibitors were obtained by random screening approaches, further medicinal chemistry was aided by the availability of a number of crystal structures and other modelling approaches The design of irreversible... 

Tauroacidins A (194) and B (195) from an Okinawan sponge Hymeniacidon sp. exhibit inhibitory activity against EGF receptor kinase and c-erbB-2 kinase (IC50 20 pg/ml each) [155]. 

Yaish, P., Gazit, A., Gilon, C., Levitzki, A. Blocking of EGF-Dependent Cell Proliferation by EGF Receptor Kinase Inhibitors. Science. 1998, 242, 933-935. 

There is recent data to suggest that there may in fact be a biological role for the internalized insulin and EGF receptors (both of which are themselves tyrosine kinases). Thus, microinjection of insulin-occupied insulin receptors into Xenopus oocytes causes the increased phosphorylation of ribosomal protein S6 (a known substrate for the insulin receptor/kinase) [62] and the EGF receptor in endocytic vesicles has been shown to retain its kinase activity [63]. Whether the internalized insulin receptor/kinase or EGF receptor/kinase has a physiological role or not is as yet unknown. Clearly, though, these data suggest that there is much more to be learned about the role of internalized hormone-receptor complexes, especially those where the receptor possesses intrinsic enzymatic activity. 

Treatment of NIH3T3 cells with 15 or 20 pM curcumin for 15 min inhibited TPA-induced PKC activity in particulate fraction by 26 or 60% and did not affect the level of PKC protein. Curcumin (10 pM) inhibits EGF receptor kinase activity up to 90% in a dose- and time-dependent manner and also inhibits EGF-induced tyrosine phosphorylation of EGF receptors in A431 cells. ... 

We have shown that the inhibitory effect of GM3 on EGF receptor Tyr kinase of A431 cells is greatly enhanced in the presence of lyso-phosphatidylcho-line (lyso-PC), but not lyso-phosphatidylethanolamine, lyso-phosphatidylserine, or lyso-phosphatidylinositol (Igarashi et ai, 1990). In an in vitro assay system, lyso-PC (but not the other compounds listed above) greatly stimulated EGF-dependent Tyr phosphorylation of EGF receptor. It is therefore assumed that lyso-PC promotes the inhibitory effect of GM3 in modulation of EGF receptor kinase (RK). Figure 1 illustrates the possible cooperative effect between lyso-PC and GM3, and specificities of ganglioside effects on various growth factor and hormone receptors. 

In the continuing paper, Kreuter et al. reported the inhibition of intrinsic protein tyrosine kinase activity of the EGF-receptor kinase complex from human breast cancer cells by (-l-)-aeroplysinin-l (14) (273). Aeroplysinin-1, which possesses a close structure-relationship to tyrosine, blocks the epidermal growth factor (EGF) dependent proliferation of both MCF-7 and ZR-75-1 hmnan breast cancer cells, and inhibited the ligand-induced endocytosis of the EGF receptor in vitro. Aeroplysinin-1 was foimd to inhibit the tyrosine-specific phosphorylation of lipocortin-like proteins, which have been established as major substrates of the EGF receptor-associated protein-tyrosine kinase... 

The growth requirement for EGF is a good example in this regard. EGF stimulates the growth of many different types of animal cells in culture. In order to initiate the growth response, EGF interacts with specific EGF receptors localized in the plasma membrane, activating a tyrosine-specific protein kinase, which is an intrinsic part of the receptor (Figure 12). As a consequence, specific proteins are phosphorylated at tyrosine residues, and some of these proteins (which are also... 

Single protein kinases such as PKA, PKC, and Ca +-calmodulin (CaM)-kinases, which result in the phosphorylation of serine and threonine residues in target proteins, play a very important role in hormone action. The discovery that the EGF receptor contains an intrinsic tyrosine kinase activity that is activated by the binding of the hgand EGF was an important breakthrough. The insuhn and IGF-I receptors also contain intrinsic... 

LiNASSiER c, PIERRE M, LE PECQ J B and PIERRE J (1990) Mechanism of action in NIH-3T3 cells of genistein, an inhibitor of EGF receptor tyrosine kinase activity. Biochem Pharmacol. 39 (1) 187-93. 

App, H., Hazan, R., Zilberstein, A., Ullrich, A., Schlessinger, J., and Rapp, U. (1991). Epidermanl growth factor (EGF) stimulates association and kinase activity of raf-1 with the EGF receptor. Mol. Cell. Biol. 11 913-919. 

All RTKs contain between one and three tyrosines in the kinase activation loop, which is composed of subdomains VII and VIII of the protein kinase catalytic core. Phosphorylation of these tyrosines has been shown to be critical for stimulation of catalytic activity and biological function for a number of RTKs, including insulin receptor, FGF receptor, VEGF receptor, PDGF receptor, Met (hepatocyte growth factor receptor), and TrkA (NGF receptor). A major exception is the EGF receptor, for which autophosphorylation of a conserved tyrosine in the activation loop does not seem to be involved in signaling. Substitution of tyrosine with phenylalanine has no effect on RTK activity or downstream signals. 

The oncogene v-erbB, unlike c-erbB, codes for a shortened form of the EGF receptor protein. Usually the binding of EGF is required to turn on the tyrosine kinase activity of the EGF receptor protein, the one coded by c-erbB. However, the tyrosine kinase activity of the receptor derived from v-erbB is switched on permanently, even in the absence of EGF. The uncontrolled grqwth characteristic of cancer cells results. 

Figure 10.7 The EGF receptor. The N-terminal, extracellular region of the receptor contains 622 amino acids. It displays two cysteine-rich regions, between which the ligand-binding domain is located. A 23 amino acid hydrophobic domain spans the plasma membrane. The receptor cytoplasmic region contains some 542 amino acids. It displays a tyrosine kinase domain, which includes several tyrosine autophosphorylation sites, and an actin-binding domain that may facilitate interaction with the cell cytoskeleton...

Neuregulins bind to a family of receptor tyrosine kinases that are homologous to the EGF receptor, termed... 

ErbB (or HER in the human). There are four ErbB receptors that form homo- or heterodimers in various combinations upon ligand binding. Specific NRG isoforms preferentially interact with different ErbB dimers. The ErbB receptors are ligand-activated tyrosine kinases structurally similar to the EGF receptor. 

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