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Key Event Title
|Level of Biological Organization|
Key Event Components
|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
Key Event Description
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
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
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).
Evidence for Perturbation by Stressor
Overview for Molecular Initiating Event
EGFR activation in lung epithelial cells can be triggered by exposure to H2O2 (Goldkorn et al., 1998; Takeyama et al., 2000), naphthalene (Van Winkle et al., 1997), cigarette smoke (Takeyama et al., 2001; de Boer et al., 2006; Marinaş et al., 2011; Yu et al., 2011; Yu et al., 2015), acrolein (Deshmukh et al., 2008), and TCDD (Lee et al., 2011). 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., 2004; 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).
EGFR phosphorylation increased in lungs of Sprague-Dawley rats that were whole-body exposed (inExpose smoking system; SCIREQ, Montreal, Canada) at a total particulate matter (TPM) concentration of 2000 mg/m3 for 1 h (20 cigarettes) daily for 56 days (Chen et al., 2020); in lungs of Sprague-Dawley rats exposed to 12 cigarettes daily for 40 days (Nie et al., 2012); inlungs of Sprague-Dawley rats that were whole body-exposed to six nonfiltered cigarettes per day, 5 d/wk, for 2 to 28 days (Hegab et al., 2007); in lungs of Sprague-Dawley rats exposed to 10 cigarettes per h, 6 h per day for 60 days (Wu et al., 2011); in lungs of C57Bl6/J mice exposed to cigarette smoke at a TPM concentration of 100 mg/m3 (Teague Enterprises, Davis, CA) for 6 h a day, 5 days a week for two weeks (Mishra et al., 2016); in lungs of A/J mice that were exposed to cigarette smoke at a TPM concentration of 80 mg/m3 (Teague Enterprises, Davis, CA) for 4 h a day, 5 days per week for 1 year (Geraghty et al., 2014); in lungs of Balb/c mice exposed to mainstream cigarette smoke for 2 h twice daily, 6 days per week for 4 weeks (Wang et al., 2018); in primary human bronchial epithelial cells and NuLi-1 bronchial epithelial cell monolayers following exposure to cigarette smoke (Mishra et al., 2016); in primary bronchial epithelial cell monolayers following treatment with cigarette smoke extract (Zhang et al., 2012); in primary human airway epithelial cells differentiated at the air-liquid interface following treatment with cigarette smoke extract (Zhang et al., 2013; Hussain et al., 2018; Cortijo et al., 2011; Chen et al., 2010) or exposure to whole mainstream cigarette smoke (Amatngalim et al., 2016); in human small airway epithelial cell monolayers following treatment with cigarette smoke extract (Geraghty et al., 2014; Agraval and Yadav, 2019); in human NCI-H292 lung cancer cells following treatment with cigarette smoke extract (Takeyama et al., 2001; Shao et al., 2004; Lee et al., 2006; Yang et al., 2012; Wang et al., 2018); in human A549 lung cancer cells following treatment with cigarette smoke extract for 15 min (Dey et al., 2011) or 3 h (Agraval and Yadav, 2019); in immortalized human bronchial epithelial 1HAEo cells following exposure to cigarette smoke (Zhang et al., 2005); human immortalized 16HBE bronchial epithelial cells following treatment with 10% cigarette smoke extract for 24 h (Yu et al., 2015) or 5% cigarette smoke extract for up to 6 h (Heihjink et al., 2012); A549 lung adenocarcinoma and HBE1 papilloma virus-immortalized human bronchial epithelial cells following exposure to cigarette smoke (Khan et al., 2008).
EGFR phosphorylation was approx. two-fold higher in lung tissues, alveolar type II and bronchial epithelial cells of healthy smokers compared to non-smokers and was also elevated in the lungs and lung epithelial cells of COPD smokers (Mishra et al., 2016).
EGFR activation was seen in human NCI-H292 lung cancer cells following treatment with 0.03 µM acrolein for 1 h (Deshmukh et al., 2005; Deshmukh et al., 2008).
Treatment of human normal oral keratinocytes with 5 µM acrolein for 3 h also increased EGFR phosphorylation (Tsou et al., 2021).
H2O2 treatment increased EGFR tyrosine phosphorylation in NCI-H292 lung cancer cells (Takeyama et al., 2000) and in normal human nasal epithelial cells (Kim et al., 2008; Kim et al., 2010).
Phosphorylation of EGFR was significantly increased in normal human bronchial epithelial cells differentiated at the air-liquid interface following treatment with 10 nM TCDD for 0.5, 3, 4, and 6 h (Lee et al., 2011).
Increased EGFR phosphorylation was seen in normal human bronchial epithelial cells following treatment with 500 μM nicotine for 1 h (Martínez-García et al., 2008) or with 1 nM nicotine for 48 h (Lupacchini et al., 2021). EGFR activation is also seen in human lung cancer cells (A549, H1975) following treatment with 100 nM nicotine (Wang et al., 2020), human dysplastic oral keratinocytes following treatment with up to 10 µM nicotine (Wisniewski et al., 2018).
EGFR phosphorylation increased in A549 lung cancer cells treated with 1 µM benzo[a]pyrene for 4 or 2 weeks (Kometani et al., 2009).
Treatment of immortalized human bronchial epithelial HBEC-2 and BEAS-2B cells with BPDE for 2 h increased EGFR activation in a dose-dependent manner (Xu et al., 2012).
Intratracheal instillation of PM 2.5 (collected at a major city of central China; 4 mg/kg body weight) in Balb/c mice once a day for 5 consecutive days induced phosphorylation of EGFR (Tyr1068) in lung tissues (Jin et al., 2016).
Intratracheal instillation of PM 2.5 (collected at Seoul, Korea), either as an aqueous extract or a dichloromethane extract at high concentrations (164 µg/50 µL), in Balb/c mice once a week for 4 weeks induced phosphorylation of EGFR (Tyr1068) in lung tissues (Jeong et al., 2017).
Treatment of human immortalized bronchial epithelial BEAS-2B cells with with 0, 20, 50, 100 and 150 μg/mL PM 2.5 (collected on the roof of Science and Technology Building on the campus of Xinxiang Medical University, China) for 6 h increased EGFR Y1068 phosphorylation in a concentration-dependent manner (Wang et al., 2020).
EGFR activation (increased phospho-EGFR (Y1068)) was seen in primary human lobar bronchial epithelial cells incubated with 20 µg/cm2 pine wood smoke particulate matter (WSPM) for 6 h, but not at 2 h (Memon et al., 2020).
In NCI-H292 lung cancer cells stimulated with WSPM2.5 (8 μg/mL), EGFR phosphorylation increased continuously over time, with a significant increase observed at 60 min (Huang et al., 2017).
EGFR phosphorylation increased in H292 lung cancer cells following treatment with diacetyl (2,3-butanedione) (Kelly et al., 2019).
Treatment of rat RLE-6TN lung epithelial cells with 10 µg/cm2 carbon nanoparticles (CNP Printex 90, Degussa, Essen, Germany) for 5 min significantly increased EGFR Tyr845 phosphorylation (Stöckmann et al., 2018).
Exposure to O3 (0.25–1.0 ppm) concentration- and time-dependently increased EGFR Y1068 and Y845 phosphorylation in human immortalized bronchial epithelial BEAS-2B cells (Wu et al., 2015).
Exposure of Balb/c mice to 0.25, 0.5, or 1.0 ppm ozone for 3 h a day, for 7 days increased EGFR Y1068 phosphorylation in the bronchial epithelium in a concentration-dependent manner (Feng et al., 2016).
EGFR phosphorylation increased significantly in human immortalized bronchial epithelial BEAS-2B cells following exposure to 10 μg/mL hexabromocyclodecane for 15 min (Koike et al., 2016).
EGFR phosphorylation increased significantly in human immortalized bronchial epithelial BEAS-2B cells following exposure to 10 μg/mL tetrabromobisphenol A for 15 min (Koike et al., 2016).
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