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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

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

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	Karsta Luettich (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 epidermal growth factor receptor (EGFR, also referred to as ERBB1/HER1) is part of the ERBB family of receptor tyrosine kinases comprising another three distinct receptors, ERBB2/NEU/HER2, ERBB3/HER3 and ERBB4/HER4 (Yarden and Sliwkowski, 2001), 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).

ERBB family of receptors are expressed in tissues of epithelial, mesenchymal and neuronal origin, and EGFR pathway is involved in wide range of processes such as reproduction, growth and development (Wong, 2003, Yano et al., 2003). EGFR signaling is central to airway epithelial maintenance and mucin production (Burgel and Nadel, 2008), 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, Polosa et al., 1999, O’donnell et al., 2004). 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 (Marinaş et al., 2011) and in the presence of neutrophils or neutrophil elastase (Kohri et al., 2002, 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) and cigarette smoke exposure (Blanchet et al., 2004, Lemjabbar et al., 2003, Rumelhard et al., 2007). Mechanistically, this process is dependent on 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., 2005, 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, partly also through inhibition of EGFR phosphatase PTP1B (DeYulia et al., 2005, DeYulia Jr. and Cárcamo, 2005, Truong and Carroll, 2012). In addition, 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, Truong and Carroll, 2012, Truong et al., 2016).

Classical EGFR downstream signaling involves activation of RAS which subsequently initiates signal transduction through the RAF1/MEK/ERK cascade (Hackel et al., 1999). The activation of this pathway promotes airway epithelial cell proliferation and differentiation, and facilitates epithelial wound repair (Chambard et al., 2007, Berlanga-Acosta et al., 2009). Another principal signaling cascade downstream of EGFR is phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathway, which promotes cell proliferation and inhibits apoptosis (Goffin and Zbuk, 2013).

Evidence for Perturbation by Stressor

EGFR activation in respiratory tract epithelial cells can be triggered by exposure to hydrogen peroxide (Goldkorn et al., 1998, Takeyama et al., 2000, Kim et al., 2008, Kim et al., 2010b), ozone (Wu et al., 2015, McCullough et al., 2014, Feng et al., 2016), naphthalene (Van Winkle et al., 1997), cigarette smoke (Takeyama et al., 2001, Yu et al., 2012a), nicotine (Wang et al., 2020b, Martínez-García et al., 2008), benzo[a]pyrene and its diol epoxide metabolite (Kometani et al., 2009, Xu et al., 2012), acrolein (Deshmukh et al., 2008), fine particulate matter (PM 2.5) (Jin et al., 2017, Jeong et al., 2017, Huang et al., 2017, Jiao et al., 2022, Tung et al., 2021, Wang et al., 2020a), carbon nanoparticles (Stöckmann et al., 2018), (Shang et al., 2020), bacterial lipopolysaccharide (LPS) (Takezawa et al., 2016), 2,3-butanedione (Kelly et al., 2019), and other chemical stressors such as hexabromocyclododecane and tetrabromobisphenol A (Koike et al., 2016), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Lee et al., 2011). Some of these stressors induce EGFR pathway activation also in other cell models. In addition to respiratory epithelium, acrolein activated EGFR in human normal oral keratinocytes (Takeuchi et al., 2001, Tsou et al., 2021) as well as in mouse J774A.1 macrophage cell line (Kim et al., 2010a), PM 2.5 induced EGFR activation in human thyroid follicular epithelial Nthy-ori 3-1 cells (Moscatello et al., 2022). Following nicotine treatment EGFR was shown to be activated in MCF10A and MDA-MB-231 breast cancer cells (Nishioka et al., 2011) and in human dysplastic oral keratinocytes (Wisniewski et al., 2018). LPS activates EGFR in several different model systems such as intestinal epithelial cells, RAW 264.7 macrophages, mammary epithelial cells, human intrahepatic biliary epithelial cells (HIBECs), etc (McElroy et al., 2012, Lu et al., 2014, De et al., 2015, Liu et al., 2013). Pro-inflammatory cytokines (e.g. SDF-1α) induce EGFR activity in IMR90 cells and human umbilical vein endothelial cells (HUVECs) (Shang et al., 2020).

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 protein-analytical techniques such as Western blots of e.g. untreated and treated cell or tissue lysates using specific antibodies targeting the phosphorylated EGFR epitopes (Casalino-Matsuda et al., 2006, Hao et al., 2014).
Phosphorylated, hence active EGFR can be detected and quantified also by Enzyme-Linked Immunosorbent Assay (ELISA) (Barbier et al., 2012, Knudsen et al., 2014). Detailed method description and different types of ELISA can be found in Tabatabaei and Ahmed research method article (Tabatabaei and Ahmed, 2022).
Suppression of EGFR activity with EGFR inhibitors such as AG1478 and BIBX 1522 or neutralizing antibodies is well suited to demonstrate EGFR’s involvement in signaling (Memon et al., 2020, Perrais et al., 2002, Val et al., 2012, Wang et al., 2019, Yu et al., 2012b).

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

AIDA, S., TAMAI, S., SEKIGUCHI, S. & 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.

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BERLANGA-ACOSTA, J., GAVILONDO-COWLEY, J., LÓPEZ-SAURA, P., GONZÁLEZ-LÓPEZ, T., CASTRO-SANTANA, M. D., LÓPEZ-MOLA, E., GUILLÉN-NIETO, G. & HERRERA-MARTINEZ, L. 2009. Epidermal growth factor in clinical practice - a review of its biological actions, clinical indications and safety implications. Int Wound J, 6, 331-46.

BLANCHET, S., RAMGOLAM, K., BAULIG, A., MARANO, F. & BAEZA-SQUIBAN, A. 2004. Fine particulate matter induces amphiregulin secretion by bronchial epithelial cells. American Journal of Respiratory Cell and Molecular Biology, 30, 421-427.

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BURGEL, P.-R. & NADEL, J. A. 2008. Epidermal growth factor receptor-mediated innate immune responses and their roles in airway diseases. European Respiratory Journal, 32, 1068-1081.

CASALINO-MATSUDA, S. M., MONZON, M. E., CONNER, G. E., SALATHE, M. & FORTEZA, R. M. 2004. Role of hyaluronan and reactive oxygen species in tissue kallikrein-mediated epidermal growth factor receptor activation in human airways. Journal of Biological Chemistry, 279, 21606-21616.

CASALINO-MATSUDA, S. M., MONZÓN, M. E. & 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, 581-91.

CHAMBARD, J. C., LEFLOCH, R., POUYSSÉGUR, J. & LENORMAND, P. 2007. ERK implication in cell cycle regulation. Biochim Biophys Acta, 1773, 1299-310.

DE, S., ZHOU, H., DESANTIS, D., CRONIGER, C. M., LI, X. & STARK, G. R. 2015. Erlotinib protects against LPS-induced endotoxicity because TLR4 needs EGFR to signal. Proc Natl Acad Sci U S A, 112, 9680-5.

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DESHMUKH, H. S., SHAVER, C., CASE, L. M., DIETSCH, M., WESSELKAMPER, S. C., HARDIE, W. D., KORFHAGEN, T. R., CORRADI, M., NADEL, J. A. & BORCHERS, M. T. 2008. Acrolein-activated matrix metalloproteinase 9 contributes to persistent mucin production. American journal of respiratory cell and molecular biology, 38, 446-454.

DEYULIA, G. J., CÁRCAMO, J. M., BÓRQUEZ-OJEDA, O., SHELTON, C. C. & GOLDE, D. W. 2005. Hydrogen peroxide generated extracellularly by receptor–ligand interaction facilitates cell signaling. Proceedings of the National Academy of Sciences of the United States of America, 102, 5044-5049.

DEYULIA JR., G. J. & CÁRCAMO, J. M. 2005. EGF receptor-ligand interaction generates extracellular hydrogen peroxide that inhibits EGFR-associated protein tyrosine phosphatases. Biochemical and Biophysical Research Communications, 334, 38-42.

FENG, F., JIN, Y., DUAN, L., YAN, Z., WANG, S., LI, F., LIU, Y., SAMET, J. M. & WU, W. 2016. Regulation of ozone‐induced lung inflammation by the epidermal growth factor receptor in mice. Environmental toxicology, 31, 2016-2027.

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HAO, Y., KUANG, Z., JING, J., MIAO, J., MEI, L. Y., LEE, R. J., KIM, S., CHOE, S., KRAUSE, D. C. & LAU, G. W. 2014. Mycoplasma pneumoniae modulates STAT3-STAT6/EGFR-FOXA2 signaling to induce overexpression of airway mucins. Infect Immun, 82, 5246-55.

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SHAO, M. X. G. & 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. Journal of Immunology, 175, 4009-4016.

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STÖCKMANN, D., SPANNBRUCKER, T., ALE-AGHA, N., JAKOBS, P., GOY, C., DYBALLA-RUKES, N., HORNSTEIN, T., KÜMPER, A., KRAEGELOH, A. & HAENDELER, J. 2018. Non-Canonical activation of the epidermal growth factor receptor by carbon nanoparticles. Nanomaterials, 8, 267.

TABATABAEI, M. S. & AHMED, M. 2022. Enzyme-Linked Immunosorbent Assay (ELISA). Methods Mol Biol, 2508, 115-134.

TAKEUCHI, K., KATO, M., SUZUKI, H., AKHAND, A. A., WU, J., HOSSAIN, K., MIYATA, T., MATSUMOTO, Y., NIMURA, Y. & NAKASHIMA, I. 2001. Acrolein induces activation of the epidermal growth factor receptor of human keratinocytes for cell death. Journal of cellular biochemistry, 81, 679-688.

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