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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 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
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
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).
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.
BARBIER, D., GARCIA-VERDUGO, I., POTHLICHET, J., KHAZEN, R., DESCAMPS, D., ROUSSEAU, K., THORNTON, D., SI-TAHAR, M., TOUQUI, L., CHIGNARD, M. & SALLENAVE, J. M. 2012. Influenza A induces the major secreted airway mucin MUC5AC in a protease-EGFR-extracellular regulated kinase-Sp1-dependent pathway. Am J Respir Cell Mol Biol, 47, 149-57.
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.
BOGDAN, S. & KLÄMBT, C. 2001. Epidermal growth factor receptor signaling. Curr Biol, 11, R292-5.
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.
DESHMUKH, H. S., CASE, L. M., WESSELKAMPER, S. C., BORCHERS, M. T., MARTIN, L. D., SHERTZER, H. G., NADEL, J. A. & LEIKAUF, G. D. 2005. Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation. American Journal of Respiratory and Critical Care Medicine, 171, 305-314.
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.
GOFFIN, J. R. & ZBUK, K. 2013. Epidermal growth factor receptor: pathway, therapies, and pipeline. Clin Ther, 35, 1282-303.
GOLDKORN, T., BALABAN, N., MATSUKUMA, K., CHEA, V., GOULD, R., LAST, J., CHAN, C. & CHAVEZ, C. 1998. EGF-receptor phosphorylation and signaling are targeted by H2O2 redox stress. American Journal of Respiratory Cell and Molecular Biology, 19, 786-798.
GRESIK, E. W., KASHIMATA, M., KADOYA, Y. & YAMASHINA, S. 1998. The EGF system in fetal development. Eur J Morphol, 36 Suppl, 92-7.
GUPTA, C. 1996. The role of epidermal growth factor receptor (EGFR) in male reproductive tract differentiation: stimulation of EGFR expression and inhibition of Wolffian duct differentiation with anti-EGFR antibody. Endocrinology, 137, 905-10.
HACKEL, P. O., ZWICK, E., PRENZEL, N. & ULLRICH, A. 1999. Epidermal growth factor receptors: critical mediators of multiple receptor pathways. Current Opinion in Cell Biology, 11, 184-189.
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.
HIGASHIYAMA, S., IWABUKI, H., MORIMOTO, C., HIEDA, M., INOUE, H. & MATSUSHITA, N. 2008. Membrane-anchored growth factors, the epidermal growth factor family: Beyond receptor ligands. Cancer Science, 99, 214-220.
HUANG, L., PU, J., HE, F., LIAO, B., HAO, B., HONG, W., YE, X., CHEN, J., ZHAO, J. & LIU, S. 2017. Positive feedback of the amphiregulin-EGFR-ERK pathway mediates PM2. 5 from wood smoke-induced MUC5AC expression in epithelial cells. Scientific reports, 7, 1-12.
JEONG, S. C., CHO, Y., SONG, M. K., LEE, E. & 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. Environmental toxicology, 32, 1628-1636.
JIAO, J., HU, P., LI, Y., CAI, C., WANG, X. & ZHANG, L. 2022. PM2. 5 Upregulates the Expression of MUC5AC via the EGFR-PI3K Pathway in Human Sinonasal Epithelial Cells. International Archives of Allergy and Immunology, 183, 361-374.
JIN, Y., WU, W., ZHANG, W., ZHAO, Y., WU, Y., GE, G., BA, Y., GUO, Q., GAO, T. & CHI, X. 2017. Involvement of EGF receptor signaling and NLRP12 inflammasome in fine particulate matter‐induced lung inflammation in mice. Environmental toxicology, 32, 1121-1134.
KELLY, F. L., WEINBERG, K. E., NAGLER, A. E., NIXON, A. B., STAR, M. D., TODD, J. L., BRASS, D. M. & PALMER, S. M. 2019. EGFR-dependent IL8 production by airway epithelial cells after exposure to the food flavoring chemical 2, 3-butanedione. Toxicological Sciences, 169, 534-542.
KILEY, S. C. & CHEVALIER, R. L. 2007. Species differences in renal Src activity direct EGF receptor regulation in life or death response to EGF. American Journal of Physiology-Renal Physiology, 293, F895-F903.
KIM, C. E., LEE, S. J., SEO, K. W., PARK, H. M., YUN, J. W., BAE, J. U., BAE, S. S. & KIM, C. D. 2010a. Acrolein increases 5-lipoxygenase expression in murine macrophages through activation of ERK pathway. Toxicology and applied pharmacology, 245, 76-82.
KIM, H. J., PARK, Y.-D., MOON, U. Y., KIM, J.-H., JEON, J. H., LEE, J.-G., BAE, Y. S. & YOON, J.-H. 2008. The role of Nox4 in oxidative stress–induced MUC5AC overexpression in human airway epithelial cells. American Journal of Respiratory Cell and Molecular Biology, 39, 598-609.
KIM, H. J., RYU, J.-H., KIM, C.-H., LIM, J. W., MOON, U. Y., LEE, G. H., LEE, J.-G., BAEK, S. J. & YOON, J.-H. 2010b. Epicatechin gallate suppresses oxidative stress–induced MUC5AC overexpression by interaction with epidermal growth factor receptor. American Journal of Respiratory Cell and Molecular Biology, 43, 349-357.
KNUDSEN, S. L., MAC, A. S., HENRIKSEN, L., VAN DEURS, B. & GRØVDAL, L. M. 2014. EGFR signaling patterns are regulated by its different ligands. Growth Factors, 32, 155-63.
KOHRI, K., UEKI, I. F. & NADEL, J. A. 2002. Neutrophil elastase induces mucin production by ligand-dependent epidermal growth factor receptor activation. American Journal of Physiology - Lung Cellular and Molecular Physiology, 283, L531-40.
KOIKE, E., YANAGISAWA, R. & TAKANO, H. 2016. Brominated flame retardants, hexabromocyclododecane and tetrabromobisphenol A, affect proinflammatory protein expression in human bronchial epithelial cells via disruption of intracellular signaling. Toxicology In Vitro, 32, 212-219.
KOMETANI, T., YOSHINO, I., MIURA, N., OKAZAKI, H., OHBA, T., TAKENAKA, T., SHOJI, F., YANO, T. & MAEHARA, Y. 2009. Benzo [a] pyrene promotes proliferation of human lung cancer cells by accelerating the epidermal growth factor receptor signaling pathway. Cancer letters, 278, 27-33.
LEE, Y. C., OSLUND, K. L., THAI, P., VELICHKO, S., FUJISAWA, T., DUONG, T., DENISON, M. S. & WU, R. 2011. 2,3,7,8-Tetrachlorodibenzo-p-dioxin–induced MUC5AC expression aryl hydrocarbon receptor-independent/EGFR/ERK/p38-dependent SP1-based transcription. American Journal of Respiratory Cell and Molecular Biology, 45, 270-276.
LEMJABBAR, H., LI, D., GALLUP, M., SIDHU, S., DRORI, E. & BASBAUM, C. 2003. Tobacco smoke-induced lung cell proliferation mediated by tumor necrosis factor alpha-converting enzyme and amphiregulin. Journal of Biological Chemistry, 278, 26202-7.
LIU, Z., TIAN, F., FENG, X., HE, Y., JIANG, P., LI, J., GUO, F., ZHAO, X., CHANG, H. & WANG, S. 2013. LPS increases MUC5AC by TACE/TGF-α/EGFR pathway in human intrahepatic biliary epithelial cell. Biomed Res Int, 2013, 165715.
LU, N., WANG, L., CAO, H., LIU, L., VAN KAER, L., WASHINGTON, M. K., ROSEN, M. J., DUBÉ, P. E., WILSON, K. T., REN, X., HAO, X., POLK, D. B. & YAN, F. 2014. Activation of the epidermal growth factor receptor in macrophages regulates cytokine production and experimental colitis. J Immunol, 192, 1013-23.
MARINAŞ, A., CIUREA, P., MĂRGĂRITESCU, C. & COTOI, O. 2011. Expression of epidermal growth factor (EGF) and its receptors (EGFR1 and EGFR2) in chronic bronchitis. Romanian Journal of Morphology and Embryology, 53, 957-966.
MARTÍNEZ-GARCÍA, E., IRIGOYEN, M., ANSÓ, E., MARTÍNEZ-IRUJO, J. J. & ROUZAUT, A. 2008. Recurrent exposure to nicotine differentiates human bronchial epithelial cells via epidermal growth factor receptor activation. Toxicology and applied pharmacology, 228, 334-342.
MCCULLOUGH, S. D., DUNCAN, K. E., SWANTON, S. M., DAILEY, L. A., DIAZ-SANCHEZ, D. & DEVLIN, R. B. 2014. Ozone induces a proinflammatory response in primary human bronchial epithelial cells through mitogen-activated protein kinase activation without nuclear factor-κB activation. American journal of respiratory cell and molecular biology, 51, 426-435.
MCELROY, S. J., HOBBS, S., KALLEN, M., TEJERA, N., ROSEN, M. J., GRISHIN, A., MATTA, P., SCHNEIDER, C., UPPERMAN, J., FORD, H., POLK, D. B. & WEITKAMP, J. H. 2012. Transactivation of EGFR by LPS induces COX-2 expression in enterocytes. PLoS One, 7, e38373.
MEMON, T. A., NGUYEN, N. D., BURRELL, K. L., SCOTT, A. F., ALMESTICA-ROBERTS, M., RAPP, E., DEERING-RICE, C. E. & REILLY, C. A. 2020. Wood smoke particles stimulate MUC5AC overproduction by human bronchial epithelial cells through TRPA1 and EGFR signaling. Toxicological Sciences, 174, 278-290.
MOSCATELLO, C., DI MARCANTONIO, M. C., SAVINO, L., D’AMICO, E., SPACCO, G., SIMEONE, P., LANUTI, P., MURARO, R., MINCIONE, G. & COTELLESE, R. 2022. Emerging Role of Oxidative Stress on EGFR and OGG1-BER Cross-Regulation: Implications in Thyroid Physiopathology. Cells, 11, 822.
NEXØ, E. & HANSEN, H. F. 1985. Binding of epidermal growth factor from man, rat and mouse to the human epidermal growth factor receptor. Biochimica et Biophysica Acta (BBA)-General Subjects, 843, 101-106.
NISHIOKA, T., KIM, H. S., LUO, L. Y., HUANG, Y., GUO, J. & CHEN, C. Y. 2011. Sensitization of epithelial growth factor receptors by nicotine exposure to promote breast cancer cell growth. Breast Cancer Res, 13, R113.
O’DONNELL, R., RICHTER, A., WARD, J., ANGCO, G., MEHTA, A., ROUSSEAU, K., SWALLOW, D., HOLGATE, S., DJUKANOVIC, R. & DAVIES, D. 2004. Expression of ErbB receptors and mucins in the airways of long term current smokers. Thorax, 59, 1032-1040.
PAULSEN, C. E., TRUONG, T. H., GARCIA, F. J., HOMANN, A., GUPTA, V., LEONARD, S. E. & CARROLL, K. S. 2011. Peroxide-dependent sulfenylation of the EGFR catalytic site enhances kinase activity. Nature Chemical Biology, 8, 57-64.
PERRAIS, M., PIGNY, P., COPIN, M. C., AUBERT, J. P. & VAN SEUNINGEN, I. 2002. Induction of MUC2 and MUC5AC mucins by factors of the epidermal growth factor (EGF) family is mediated by EGF receptor/Ras/Raf/extracellular signal-regulated kinase cascade and Sp1. J Biol Chem, 277, 32258-67.
POLOSA, R., PROSPERINI, G., LEIR, S.-H., HOLGATE, S. T., LACKIE, P. M. & DAVIES, D. E. 1999. Expression of c-erbB receptors and ligands in human bronchial mucosa. American Journal of Respiratory Cell and Molecular Biology, 20, 914-923.
RAJARAM, P., CHANDRA, P., TICKU, S., PALLAVI, B. K., RUDRESH, K. B. & MANSABDAR, P. 2017. Epidermal growth factor receptor: Role in human cancer. Indian J Dent Res, 28, 687-694.
RICHANI, D. & GILCHRIST, R. B. 2018. The epidermal growth factor network: role in oocyte growth, maturation and developmental competence. Hum Reprod Update, 24, 1-14.
RUMELHARD, M., RAMGOLAM, K., HAMEL, R., MARANO, F. & BAEZA-SQUIBAN, A. 2007. Expression and role of EGFR ligands induced in airway cells by PM2.5 and its components. European Respiratory Journal, 30, 1064-1073.
SHANG, D., SUN, D., SHI, C., XU, J., SHEN, M., HU, X., LIU, H. & TU, Z. 2020. Activation of epidermal growth factor receptor signaling mediates cellular senescence induced by certain pro-inflammatory cytokines. Aging Cell, 19, e13145.
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.
SHIM, J. J., DABBAGH, K., UEKI, I. F., DAO-PICK, T., BURGEL, P. R., TAKEYAMA, K., TAM, D. C. W. & NADEL, J. A. 2001. IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils. American Journal of Physiology - Lung Cellular and Molecular Physiology, 280, L134-40.
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.
TAKEYAMA, K., DABBAGH, K., SHIM, J. J., DAO-PICK, T., UEKI, I. F. & NADEL, J. A. 2000. Oxidative stress causes mucin synthesis via transactivation of epidermal growth factor receptor: role of neutrophils. Journal of Immunology, 164, 1546-1552.
TAKEYAMA, K., JUNG, B., SHIM, J. J., BURGEL, P.-R., DAO-PICK, T., UEKI, I. F., PROTIN, U., KROSCHEL, P. & NADEL, J. A. 2001. Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke. American Journal of Physiology - Lung Cellular and Molecular Physiology, 280, L165-L172.
TAKEZAWA, K., OGAWA, T., SHIMIZU, S. & SHIMIZU, T. 2016. Epidermal growth factor receptor inhibitor AG1478 inhibits mucus hypersecretion in airway epithelium. Am J Rhinol Allergy, 30, 1-6.
TRUONG, T. H. & CARROLL, K. S. 2012. Redox regulation of EGFR signaling through cysteine oxidation. Biochemistry, 51, 9954-9965.
TRUONG, T. H., UNG, P. M.-U., PALDE, P. B., PAULSEN, C. E., SCHLESSINGER, A. & CARROLL, K. S. 2016. Molecular basis for redox activation of epidermal growth factor receptor kinase. Cell Chemical Biology, 23, 837-848.
TSOU, H.-H., TSAI, H.-C., CHU, C.-T., CHENG, H.-W., LIU, C.-J., LEE, C.-H., LIU, T.-Y. & WANG, H.-T. 2021. Cigarette smoke containing acrolein upregulates EGFR signaling contributing to oral tumorigenesis in vitro and in vivo. Cancers, 13, 3544.
TUNG, N. T., HO, K.-F., NIU, X., SUN, J., SHEN, Z., WU, F., CAO, J., DUNG, H. B., THUY, T. P. C. & HSIAO, T.-C. 2021. Loss of E-cadherin due to road dust PM2. 5 activates the EGFR in human pharyngeal epithelial cells. Environmental Science and Pollution Research, 28, 53872-53887.
VAL, S., BELADE, E., GEORGE, I., BOCZKOWSKI, J. & BAEZA-SQUIBAN, A. 2012. Fine PM induce airway MUC5AC expression through the autocrine effect of amphiregulin. Archives of Toxicology, 86, 1851-1859.
VAN WINKLE, L. S., ISAAC, J. M. & PLOPPER, C. G. 1997. Distribution of epidermal growth factor receptor and ligands during bronchiolar epithelial repair from naphthalene-induced Clara cell injury in the mouse. American Journal of Pathology, 151, 443.
WANG, G., ZHANG, G., GAO, X., ZHANG, Y., FAN, W., JIANG, J., AN, Z., LI, J., SONG, J. & WU, W. 2020a. Oxidative stress-mediated epidermal growth factor receptor activation regulates PM2. 5-induced over-secretion of pro-inflammatory mediators from human bronchial epithelial cells. Biochimica et Biophysica Acta (BBA)-General Subjects, 1864, 129672.
WANG, J., ZHU, M., WANG, L., CHEN, C. & SONG, Y. 2019. Amphiregulin potentiates airway inflammation and mucus hypersecretion induced by urban particulate matter via the EGFR-PI3Kα-AKT/ERK pathway. Cell Signal, 53, 122-131.
WANG, M.-L., HSU, Y.-F., LIU, C.-H., KUO, Y.-L., CHEN, Y.-C., YEH, Y.-C., HO, H.-L., WU, Y.-C., CHOU, T.-Y. & WU, C.-W. 2020b. Low-dose nicotine activates EGFR signaling via α5-nAChR and promotes lung adenocarcinoma progression. International journal of molecular sciences, 21, 6829.
WISNIEWSKI, D. J., MA, T. & SCHNEIDER, A. 2018. Nicotine induces oral dysplastic keratinocyte migration via fatty acid synthase-dependent epidermal growth factor receptor activation. Experimental cell research, 370, 343-352.
WONG, R. W. 2003. Transgenic and knock-out mice for deciphering the roles of EGFR ligands. Cell Mol Life Sci, 60, 113-8.
WU, W., WAGES, P. A., DEVLIN, R. B., DIAZ-SANCHEZ, D., PEDEN, D. B. & SAMET, J. M. 2015. SRC-mediated EGF receptor activation regulates ozone-induced interleukin 8 expression in human bronchial epithelial cells. Environmental health perspectives, 123, 231-236.
XU, X., BAI, L., CHEN, W., PADILLA, M. T., LIU, Y., KIM, K. C., BELINSKY, S. A. & LIN, Y. 2012. MUC1 contributes to BPDE-induced human bronchial epithelial cell transformation through facilitating EGFR activation. PloS one, 7, e33846.
YANO, S., KONDO, K., YAMAGUCHI, M., RICHMOND, G., HUTCHISON, M., WAKELING, A., AVERBUCH, S. & WADSWORTH, P. 2003. Distribution and function of EGFR in human tissue and the effect of EGFR tyrosine kinase inhibition. Anticancer Res, 23, 3639-50.
YARDEN, Y. & SLIWKOWSKI, M. X. 2001. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol, 2, 127-37.
YOSHISUE, H. & HASEGAWA, K. 2004. Effect of MMP/ADAM inhibitors on goblet cell hyperplasia in cultured human bronchial epithelial cells. Bioscience, Biotechnology, and Biochemistry 68, 2024-2031.
YU, H., LI, Q., KOLOSOV, V. P., PERELMAN, J. M. & ZHOU, X. 2012a. Regulation of cigarette smoke‐mediated mucin expression by hypoxia‐inducible factor‐1α via epidermal growth factor receptor‐mediated signaling pathways. Journal of Applied Toxicology, 32, 282-292.
YU, H., ZHOU, X., WEN, S. & XIAO, Q. 2012b. Flagellin/TLR5 responses induce mucus hypersecretion by activating EGFR via an epithelial cell signaling cascades. Exp Cell Res, 318, 723-31.