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Event: 941

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Activation, EGFR

Short name

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Activation, EGFR

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
epithelial cell

Organ term

Organ term
lung

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
epidermal growth factor-activated receptor activity	epidermal growth factor receptor	occurrence
phosphorylation	epidermal growth factor receptor	increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Decreased lung function	MolecularInitiatingEvent	Cataia Ives (send email)	Under development: Not open for comment. Do not cite	Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens	High	NCBI
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Adult	High

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Mixed	Moderate

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

The EGF receptor family comprises 4 members, EGFR (also referred to as ErbB1/HER1), ErbB2/Neu/HER2, ErbB3/HER3 and ErbB4/HER4, all of which are transmembrane glycoproteins with an extracellular ligand binding site and an intracellular tyrosine kinase domain. Receptor-ligand binding induces dimerization and internalization, subsequently leading to activation of the receptor through autophosphorylation (Higashiyama et al., 2008).

EGFR signaling is central to airway epithelial maintenance and mucin production (Burgel and Nadel, 2004), and EGFR expression has been demonstrated in lung epithelial cells under physiological (albeit weakly) as well as pathological conditions in vitro and in vivo (Aida et al., 1994; Burgel and Nadel, 2008; O’Donnell et al., 2004; Polosa et al., 1999). Of note, lung epithelial cell EGFR phosphorylation (i.e., activation) was increased under conditions of oxidative stress including exposure to H₂O₂ (Goldkorn et al., 1998), naphthalene (Van Winkle et al., 1997), cigarette smoke (de Boer et al., 2006; Marinaş et al., 2011) and in the presence of neutrophils or neutrophil elastase (Kohri et al., 2002; Shao et al., 2004; Shao and Nadel, 2005; Shim et al., 2001; Takeyama et al., 2000). EGFR activation by oxidative stress may have a number of root causes: ROS were shown to increase production of EGF, the prime EGFR ligand, by lung epithelial cells (Casalino-Matsuda et al., 2004). Similarly, expression and secretion of TGF-α and AREG, also EGFR ligands, were elevated in human bronchial epithelial cells in response to fine particulate matter (PM2.5), diesel particulate matter and cigarette smoke exposure (Blanchet et al., 2004; Lemjabbar et al., 2003; Rumelhard et al., 2007). Mechanistically, this process is dependent on ROS-mediated activation of metalloproteinases or ADAMs which cleave membrane-bound EGFR ligand precursors, making them locally available to bind to and transactivate EGFR in an autocrine manner (Deshmukh et al., 2009; Kim et al., 2004b; Val et al., 2012; Yoshisue and Hasegawa, 2004). Furthermore, ligand binding to EGFR itself was shown to lead to H₂O₂ production, thereby facilitating receptor activation and downstream signaling (DeYulia et al., 2005; DeYulia and Cárcamo, 2005; Truong and Carroll, 2012). While it is tempting to speculate that the increase in H₂O₂ would perpetuate EGFR activation via the continuous proteolytic shedding of pro-ligands in an autocrine loop, multiple lines of evidence suggest that oxidative modification, specifically EGFR sulfenylation, contributes to enhanced tyrosine phosphorylation of the receptor and downstream signaling (Paulsen et al., 2011; Ravid et al., 2002; Truong and Carroll, 2012; Truong et al., 2016).

Classical EGFR downstream signaling involves activation of Ras which subsequently initiates signal transduction through the Raf-1/MEK/ERK pathway. MAP kinase activation in turn promotes airway epithelial cell proliferation and differentiation (Hackel et al., 1999; Kim et al., 2005; Lemjabbar et al., 2003) and facilitates epithelial wound repair (Allahverdian et al., 2010; Burgel and Nadel, 2004; Van Winkle et al., 1997).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Proof of EGFR activation can be derived from Western blots of e.g. untreated and treated cell or tissue lysates using specific antibodies targeting the phosphorylated EGFR epitopes. Densitometric evaluation of the colorimetrically stained, chemiluminescent or radioactive bands on the blot then permit a (semi-)quantitative measure of activation. Moreover, the addition of EGFR inhibitors such as AG1478 and BIBX 1522 or neutralizing antibodies is well suited to demonstrate causality.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

EGFR activation in human, mouse and rat is well documented, and EGF ligands and EGFR are orthologous in 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, 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).

References

List of the literature that was cited for this KE description. More help

Agraval, H., and Yadav, U.C. (2019). MMP-2 and MMP-9 mediate cigarette smoke extract-induced epithelial-mesenchymal transition in airway epithelial cells via EGFR/Akt/GSK3β/β-catenin pathway: Amelioration by fisetin. Chem. Biol. Interact. 314, 108846.

Aida, S., Tamai, S., Sekiguchi, S., and Shimizu, N. (1994). Distribution of epidermal growth factor and epidermal growth factor receptor in human lung: immunohistochemical and immunoelectron-microscopic studies. Respiration 61, 161-166.

Allahverdian, S., Wang, A., Singhera, G.K., Wong, B.W., and Dorscheid, D.R. (2010). Sialyl Lewis X modification of the epidermal growth factor receptor regulates receptor function during airway epithelial wound repair. Clin. Exp. Allergy 40, 607-618.

Amatngalim, G.D., Broekman, W., Daniel, N.M., van der Vlugt, L.E., van Schadewijk, A., Taube, C., et al. (2016). Cigarette Smoke Modulates Repair and Innate Immunity following Injury to Airway Epithelial Cells. PLoS One 11, e0166255.

Blanchet, S., Ramgolam, K., Baulig, A., Marano, F., and Baeza-Squiban, A. (2004). Fine particulate matter induces amphiregulin secretion by bronchial epithelial cells. Am. J. Respir. Cell .Mol. Biol. 30, 421-427.

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.

Burgel, P.-R., and Nadel, J.A. (2008). Epidermal growth factor receptor-mediated innate immune responses and their roles in airway diseases. Eur. Respir. J. 32, 1068-1081.

Casalino-Matsuda, S.M., Monzón, M.E., and Forteza, R.M. (2006). Epidermal growth factor receptor activation by epidermal growth factor mediates oxidant-induced goblet cell metaplasia in human airway epithelium. Am. J. Respir. Cell .Mol. Biol 34, 581-591.

Chen, H., et al., Epidermal growth factor receptor in adult retinal neurons of rat, mouse, and human. J Comp Neurol 2007. 500(2):299-310.

Chen, R., Liang, Y., Ip, M.S.M., Zhang, K.Y., and Mak, J.C.W. (2020). Amelioration of Cigarette Smoke-Induced Mucus Hypersecretion and Viscosity by Dendrobium officinale Polysaccharides In Vitro and In Vivo. Oxid. Med. Cell Longev. 2020, 8217642-8217642.

Chen, Y.-T., Gallup, M., Nikulina, K., Lazarev, S., Zlock, L., Finkbeiner, W., et al. (2010). Cigarette smoke induces epidermal growth factor receptor-dependent redistribution of apical MUC1 and junctional beta-catenin in polarized human airway epithelial cells. Am. J. Pathol. 177, 1255-1264.

Ciardiello, F., and Tortora, G. (2008). EGFR antagonists in cancer treatment. N. Engl. J. Med. 358, 1160-1174.

Cortijo, J., Mata, M., Milara, J., Donet, E., Gavaldà, A., Miralpeix, M., et al. (2011). Aclidinium inhibits cholinergic and tobacco smoke-induced MUC5AC in human airways. Eur. Respir. J. 37, 244-254.

de Boer, W.I., Hau, C.M., van Schadewijk, A., Stolk, J., van Krieken, J.H.J.M., and Hiemstra, P.S. (2006). Expression of epidermal growth factors and their receptors in the bronchial epithelium of subjects with chronic obstructive pulmonary disease. Am. J. Clin. Pathol. 125, 184-192.

Deshmukh, H.S., Case, L.M., Wesselkamper, S.C., Borchers, M.T., Martin, L.D., Shertzer, H.G., et al. (2005). Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation. Am. J. Respir. Crit. Care Med. 171, 305-314.

Deshmukh, H.S., McLachlan, A., Atkinson, J.J., Hardie, W.D., Korfhagen, T.R., Dietsch, M., et al. (2009). Matrix metalloproteinase-14 mediates a phenotypic shift in the airways to increase mucin production. Am. J. Respir. Crit. Care Med. 180, 834-845.

Deshmukh, H.S., Shaver, C., Case, L.M., Dietsch, M., Wesselkamper, S.C., Hardie, W.D., et al. (2008). Acrolein-activated matrix metalloproteinase 9 contributes to persistent mucin production. Am. J. Respir. Cell Mol. Biol. 38, 446-454.

Dey, N., Chattopadhyay, D.J., and Chatterjee, I.B. (2011). Molecular mechanisms of cigarette smoke-induced proliferation of lung cells and prevention by vitamin C. J. Oncol. 2011, 561862.

DeYulia, G.J., Cárcamo, J.M., Bórquez-Ojeda, O., Shelton, C.C., and Golde, D.W. (2005). Hydrogen peroxide generated extracellularly by receptor–ligand interaction facilitates cell signaling. Proc. Nat. Acad. Sci. U. S. A. 102(14), 5044-5049.

DeYulia Jr., G.J., and Cárcamo, J.M. (2005). EGF receptor-ligand interaction generates extracellular hydrogen peroxide that inhibits EGFR-associated protein tyrosine phosphatases. Biochem. Biophys. Res. Comm. 334, 38-42.

Feng, F., Jin, Y., Duan, L., Yan, Z., Wang, S., Li, F., et al. (2016). Regulation of ozone-induced lung inflammation by the epidermal growth factor receptor in mice. Environ. Toxicol. 31, 2016-2027.

Geraghty, P., Hardigan, A., and Foronjy, R.F. (2014). Cigarette smoke activates the proto-oncogene c-src to promote airway inflammation and lung tissue destruction. Am. J. Respir. Cell Mol. Biol. 50, 559-570.

Goldkorn, T., Balaban, N., Matsukuma, K., Chea, V., Gould, R., Last, J., et al. (1998). EGF-receptor phosphorylation and signaling are targeted by H2O2 redox stress. Am. J. Respir. Cell Mol. Biol. 19, 786-798.

Hackel, P.O., Zwick, E., Prenzel, N., and Ullrich, A. (1999). Epidermal growth factor receptors: critical mediators of multiple receptor pathways. Curr. Opin. Cell Biol. 11, 184-189.

Higashiyama, S., Iwabuki, H., Morimoto, C., Hieda, M., Inoue, H., and Matsushita, N. (2008). Membrane-anchored growth factors, the epidermal growth factor family: Beyond receptor ligands. Cancer Sci. 99, 214-220.

Huang, L., Pu, J., He, F., Liao, B., Hao, B., Hong, W., et al. (2017). Positive feedback of the amphiregulin-EGFR-ERK pathway mediates PM2.5 from wood smoke-induced MUC5AC expression in epithelial cells. Sci. Rep. 7, 11084.

Hussain, S.S., George, S., Singh, S., Jayant, R., Hu, C.-A., Sopori, M., et al. (2018). A Small Molecule BH3-mimetic Suppresses Cigarette Smoke-Induced Mucous Expression in Airway Epithelial Cells. Sci. Rep. 8, 13796-13796.

Jeong, S.C., Cho, Y., Song, M.K., Lee, E., and Ryu, J.C. (2017). Epidermal growth factor receptor (EGFR)—MAPK—nuclear factor (NF)‐κB—IL8: A possible mechanism of particulate matter (PM) 2.5‐induced lung toxicity. Environ. Toxicol. 32, 1628-1636.

Jin, Y., Wu, W., Zhang, W., Zhao, Y., Wu, Y., Ge, G., et al. (2017). Involvement of EGF receptor signaling and NLRP12 inflammasome in fine particulate matter‐induced lung inflammation in mice. Environm. Toxicol. 32, 1121-1134.

Kelly, F.L., Weinberg, K.E., Nagler, A.E., Nixon, A.B., Star, M.D., Todd, J.L., et al. (2019). EGFR-Dependent IL8 Production by Airway Epithelial Cells After Exposure to the Food Flavoring Chemical 2,3-Butanedione. Toxicol. Sci. 169, 534-542.

Khan, E.M., Lanir, R., Danielson, A.R., and Goldkorn, T. (2008). Epidermal growth factor receptor exposed to cigarette smoke is aberrantly activated and undergoes perinuclear trafficking. FASEB J. 22, 910-917.

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.

Kim, H.J., Park, Y.-D., Moon, U.Y., Kim, J.-H., Jeon, J.H., Lee, J.-G., et al. (2008). The role of Nox4 in oxidative stress–induced MUC5AC overexpression in human airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 39, 598-609.

Kim, H.J., Ryu, J.-H., Kim, C.-H., Lim, J.W., Moon, U.Y., Lee, G.H., et al. (2010). Epicatechin gallate suppresses oxidative stress–induced MUC5AC overexpression by interaction with epidermal growth factor receptor. Am. J. Respir. Cell Mol. Biol. 43, 349-357.

Kim, S., Schein, A.J., and Nadel, J.A. (2005). E-cadherin promotes EGFR-mediated cell differentiation and MUC5AC mucin expression in cultured human airway epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 289, L1049-L1060.

Kim, J.-H., Jung, K.-H., Han, J.-H., Shim, J.-J., In, K.-H., Kang, K.-H., et al. (2004). Relation of epidermal growth factor receptor expression to mucus hypersecretion in diffuse panbronchiolitis. Chest 126, 888-895.

Kohri, K., Ueki, I.F., and Nadel, J.A. (2002). Neutrophil elastase induces mucin production by ligand-dependent epidermal growth factor receptor activation. Am. J. Physiol. Lung Cell. Mol. Physiol. 283(3), L531-540.

Koike, E., Yanagisawa, R., and Takano, H. (2016). Brominated flame retardants, hexabromocyclododecane and tetrabromobisphenol A, affect proinflammatory protein expression in human bronchial epithelial cells via disruption of intracellular signaling. Toxicol. In Vitro 32, 212-219.

Kometani, T., Yoshino, I., Miura, N., Okazaki, H., Ohba, T., Takenaka, T., et al. (2009). Benzo[a]pyrene promotes proliferation of human lung cancer cells by accelerating the epidermal growth factor receptor signaling pathway. Cancer Lett. 278, 27-33.

Lee, S.Y., Kang, E.J., Hur, G.Y., Jung, K.H., Jung, H.C., Lee, S.Y., et al. (2006). The inhibitory effects of rebamipide on cigarette smoke-induced airway mucin production. Respir. Med. 100, 503-511.

Lee, Y.C., Oslund, K.L., Thai, P., Velichko, S., Fujisawa, T., Duong, T., et al. (2011). 2,3,7,8-Tetrachlorodibenzo-p-dioxin–induced MUC5AC expression aryl hydrocarbon receptor-independent/EGFR/ERK/p38-dependent SP1-based transcription. Am. J. Respir. Cell Mol. Biol. 45, 270-276.

Lemjabbar, H., Li, D., Gallup, M., Sidhu, S., Drori, E., and Basbaum, C. (2003). Tobacco smoke-induced lung cell proliferation mediated by tumor necrosis factor alpha-converting enzyme and amphiregulin. J. Biol. Chem. 278, 26202-26207.

Lupacchini, L., Maggi, F., Tomino, C., De Dominicis, C., Mollinari, C., Fini, M., et al. (2020). Nicotine Changes Airway Epithelial Phenotype and May Increase the SARS-COV-2 Infection Severity. Molecules 26, 101.

Marinaş, A., Ciurea, P., Mărgăritescu, C., and Cotoi, O. (2011). Expression of epidermal growth factor (EGF) and its receptors (EGFR1 and EGFR2) in chronic bronchitis. Rom. J. Morphol. Embryol. 53, 957-966.

Martínez-García, E., Irigoyen, M., Ansó, E., Martínez-Irujo, J.J., and Rouzaut, A. (2008). Recurrent exposure to nicotine differentiates human bronchial epithelial cells via epidermal growth factor receptor activation. Toxicol. Appl. Pharmacol. 228, 334-342.

Memon, T.A., Nguyen, N.D., Burrell, K.L., Scott, A.F., Almestica-Roberts, M., Rapp, E., et al. (2020). Wood Smoke Particles Stimulate MUC5AC Overproduction by Human Bronchial Epithelial Cells Through TRPA1 and EGFR Signaling. Toxicol. Sci. 174, 278-290.

Mishra, R., Foster, D., Vasu, V.T., Thaikoottathil, J.V., Kosmider, B., Chu, H.W., et al. (2016). Cigarette Smoke Induces Human Epidermal Receptor 2-Dependent Changes in Epithelial Permeability. Am. J. Respir. Cell Mol. Biol. 54, 853-864.

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(1-2):101–106.

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Paulsen, C.E., Truong, T.H., Garcia, F.J., Homann, A., Gupta, V., Leonard, S.E., et al. (2011). Peroxide-dependent sulfenylation of the EGFR catalytic site enhances kinase activity. Nat. Chem. Biol. 8, 57-64.

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Rumelhard, M., Ramgolam, K., Hamel, R., Marano, F., and Baeza-Squiban, A. (2007). Expression and role of EGFR ligands induced in airway cells by PM2.5 and its components. Eur. Respir. J. 30, 1064-1073.

Shao, M.X.G., and Nadel, J.A. (2005). Neutrophil elastase induces MUC5AC mucin production in human airway epithelial cells via a cascade involving protein kinase C, reactive oxygen species, and TNF-α-converting enzyme. J. Immunol. 175, 4009-4016.

Shao, M.X.G., Nakanaga, T., and Nadel, J.A. (2004). Cigarette smoke induces MUC5AC mucin overproduction via tumor necrosis factor-α-converting enzyme in human airway epithelial (NCI-H292) cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 287, L420-L427.

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Yoshisue, H., and Hasegawa, K. (2004). Effect of MMP/ADAM inhibitors on goblet cell hyperplasia in cultured human bronchial epithelial cells. Biosci. Biotechnol. Biochem. 68, 2024-2031.

Yu, H., Li, Q., Kolosov, V.P., Perelman, J.M., and Zhou, X. (2011). Regulation of cigarette smoke-induced mucin expression by neuregulin1β/ErbB3 signalling in human airway epithelial cells. Basic Clin. Pharmacol. Toxicol. 109, 63-72.

Yu, Q., Chen, X., Fang, X., Chen, Q., and Hu, C. (2015). Caveolin-1 aggravates cigarette smoke extract-induced MUC5AC secretion in human airway epithelial cells. Int. J. Mol. Med. 35, 1435-1442.

Zhang, L., Gallup, M., Zlock, L., Basbaum, C., Finkbeiner, W.E., and McNamara, N.A. (2013). Cigarette smoke disrupts the integrity of airway adherens junctions through the aberrant interaction of p120-catenin with the cytoplasmic tail of MUC1. J Pathol. 229, 74-86.

Zhang, L., Gallup, M., Zlock, L., Finkbeiner, W., and McNamara, N.A. (2012). p120-catenin modulates airway epithelial cell migration induced by cigarette smoke. Biochem. Biophys. Res. Commun. 417, 49-55.

Zhang, Q., Adiseshaiah, P., and Reddy, S.P. (2005). Matrix metalloproteinase/epidermal growth factor receptor/mitogen-activated protein kinase signaling regulate fra-1 induction by cigarette smoke in lung epithelial cells. Am. J. Respir. Cell Mol. Biol. 32, 72-81.