Key Event Overview
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AOPs Including This Key Event
|AOP Name||Event Type||Essentiality|
|EGFR Activation Leading to Decreased Lung Function||MIE||Strong|
The following are chemical initiators that operate directly through this Event:
Level of Biological Organization
How this Key Event works
EGFR activation occurs via ligand dependent tyrosine phosphorylation where EGFR ligands such as EGF, HB-EGF, amphiregulin and TGFA bind to EGFR receptors, or ligand independent tyrosine phosphorylation, where oxidative stress from cigarette smoke or activated neutrophils can activate EGFR (Burgel and Nadel, 2004). A combination of these two pathways can occur where cigarette smoke induces shedding of EGFR proligands, such as TNF-alpha-converting enzyme (TACE), resulting in ligand dependent EGFR activation (Shao et al., 2004). Hydrogen peroxide activates EGFR tyrosine phosphorylation (Goldkorn et al., 1998) and is required for EGF-induced tyrosine phosphorylation activity of EGFR (Bae et al., 1997). Neutrophils promote ligand independent EGFR activation by release oxygen free radicals. Eosinophils and macrophages express EGFR ligands that can result in ligand dependent activation of EGFR. Other ligand dependent activators include phorbol 12-myristate 13-acetate (PMA), which activates TACE, and bacteria, where Gram positive and negative bacterial products can lead to shedding of EGFR proligands and autocrine activation. This can also occur by neutrophil proteases such as elastase which cleaves proTGFA, releasing mature TGFA which binds to EGFR (Kohri et al., 2002).
Activation of EGFR can lead to the activation of many downstream pathways including Ras/MAPK, PI3K, and JAK/STAT pathways resulting in cell proliferation, cell migration, and mucus hypersecretion (Jorissen et al., 2003), (Burgel and Nadel, 2004).
How it is Measured or Detected
Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?
EGFR activation is measured by tyrosine phosphorylation using immunoprecipitation and immunoblotting. EGFR activation is blocked by EGFR inhibitors such as AG1478 and BIBX1522.
Evidence Supporting Taxonomic Applicability
EGFR activation in human, mouse and rat is well documented, and EGF ligands and EGFR are orthologous within these species. EGFR is a driver of human cancer in various tissues and numerous drugs are approved that inhibit EGFR activation (Ciardiello and Tortora, 2008). Although EGFR and its ligands are expressed in human, mouse and rat (Chen et al., 2007), species differences have been noted in binding and structure (Nexø and Hansen, 1985), and even can have opposite downstream effects in mouse and rat (Kiley and Chevalier, 2007).
1. Bae, Y., Kang, S., Seo, M., Baines, I., Tekle, E., Chock, P., and Rhee, S. (1997). Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. Role in EGF receptor-mediated tyrosine phosphorylation. J Biol Chem 272, 217–221.
2. Burgel, P., and Nadel, J. (2004). Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium. Thorax 59, 992–996.
3. Chen, H., Liu, B., and Neufeld, A.H. (2007). Epidermal growth factor receptor in adult retinal neurons of rat, mouse, and human. J. Comp. Neurol. 500, 299–310.
4. Ciardiello, F., and Tortora, G. (2008). EGFR antagonists in cancer treatment. N. Engl. J. Med. 358, 1160–1174.
5. Goldkorn, T., Balaban, N., Matsukuma, K., Chea, V., Gould, R., Last, J., Chan, C., and Chavez, C. (1998). EGF-Receptor Phosphorylation and Signaling Are Targeted by H2O2 Redox Stress. Am. J. Respir. Cell Mol. Biol. 19, 786–798.
6. Jorissen, R.N., Walker, F., Pouliot, N., Garrett, T.P.J., Ward, C.W., and Burgess, A.W. (2003). Epidermal growth factor receptor: mechanisms of activation and signalling. Exp. Cell Res. 284, 31–53.
7. Kiley, S.C., and Chevalier, R.L. (2007). Species differences in renal Src activity direct EGF receptor regulation in life or death response to EGF. Am. J. Physiol. Renal Physiol. 293, F895–F903.
8. Kohri, K., Ueki, I., and Nadel, J. (2002). Neutrophil elastase induces mucin production by ligand-dependent epidermal growth factor receptor activation. Am J Physiol Lung Cell Mol Physiol 283, L531–L540.
9. Nexø, E., and Hansen, H.F. (1985). Binding of epidermal growth factor from man, rat and mouse to the human epidermal growth factor receptor. Biochim. Biophys. Acta 843, 101–106.
10. Shao, M.X.G., Nakanaga, T., and Nadel, J.A. (2004). Cigarette smoke induces MUC5AC mucin overproduction via tumor necrosis factor-alpha-converting enzyme in human airway epithelial (NCI-H292) cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 287, L420–L427.