Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Epidermal Growth Factor Receptor

  • Brian P. CeresaEmail author
  • Julie A. Gosney
  • Nicole M. Jackson
  • Jamie S. Rush
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101589


Historical Background

The epidermal growth factor receptor (EGFR, also known as ErbB1) is the first of four members of the ErbB lineage of receptor tyrosine kinases. The ErbB family members are cell surface receptors that are expressed in most tissues throughout the body and form both homo- and heterodimers to generate signals. Heterodimers form with the other ErbB family members. For example, ErbB2 (which lacks endogenous ligands) and ErbB3 (known to have reduced kinase activity) heterodimers provide a foundation for the most robust signaling network of the ErbB family. ErbB4 is structurally similar to ErbB1 and ErbB3, but is unique in that it is the only ErbB family member capable of signaling directly from within the nucleus. EGFR is one of the most well-studied cell surface receptor tyrosine kinases and has established roles in cell growth, development, migration, and tissue homeostasis (Roskoski 2014).

Our understanding of the EGFR started with the discovery of its principal ligand, the epidermal growth factor (EGF). In the early 1960s Stanley Cohen reported that he had isolated a 53 amino acid residue polypeptide, containing three internal disulfide bonds, using ion exchange chromatography. Injecting the purified peptide into newborn mice stimulated growth of embryonic neurons and induced precocious eyelid opening. Subsequent studies in the 1970s using A-431 cells, a human epidermoid carcinoma cell line that is responsive to EGF, led to the discovery of the EGFR, a 170-kilodalton cell surface glycoprotein. Later studies using 32P-ATP revealed that the receptor is both a phosphoprotein and has intrinsic kinase activity (Carpenter and Cohen 1990). These findings helped establish the EGFR as the prototypical receptor tyrosine kinase (RTK). In addition to crucial biological roles and a clear association with cancer, the EGFR has been central in establishing the paradigm for many molecular and cellular events in biology. The basic concepts of ligand binding, receptor activation, receptor-effector communication, and molecular regulation for many other RTKs were built upon the initial discoveries made with the EGFR. Although most closely related to its ErbB family members – ErbB2, ErbB3, and ErbB4 –, the EGFR is structurally and functionally similar to other RTKs, such as the insulin-like growth factor-1 receptor, platelet-derived growth factor receptor, and colony-stimulating growth factor receptor, among others.

Physiological Role

EGFR has many physiological roles in mammalian biology, including tissue development, maintenance, and homeostasis. EGFR plays a critical role in neonatal development that is most evident in EGFR null mice that have nonviable embryos or postnatal pups that die within 3 weeks after birth. While EGFR knockout is catastrophic to most embryos, the surviving pups have EGFR knockout-specific defects in skin, hair, lungs, and brain (Chen et al. 2016). EGFR knockout mice expose the physiological roles of the receptor in development but are limited in furthering our understanding of the receptor’s role in tissue homeostasis and the specific roles of the protein.

Administration of EGFR ligands is the principal way EGFR functions have been understood in tissue homeostasis. Newborn mice injected with EGF had early teeth emergence and opened their eyes unusually early through receptor stimulation and increased proliferation of epithelial cells (Carpenter and Cohen 1990). Lambs born prematurely when treated with EGF not only have an increase in respiratory competence but also hypertrophy of the skin, thyroid, liver, kidney, and wool follicles. Enhanced wound healing is seen in tissues such as skin, cornea, and the gastrointestinal tract following treatment with EGF or transforming growth factor-α (TGF-α). EGFR activation in the brain has been associated with brain axonal branching, neurogenesis, and gliogenesis (Chen et al. 2016). Functional inhibition or activation of EGFR through its ligands reveals the importance of the receptor-specific ligands in activation and signaling of the receptor and the physiological consequences of that action.

In addition, our understanding of EGFR signaling has also been advanced by systematic whole animal knockout of the individual EGFR ligands. Although many studies of the EGFR use EGF, there are six other endogenous ligands [transforming growth factor-α (TGF-α), betacellulin (BTC), heparin-binding epidermal growth factor receptor (HB-EGF), amphiregulin (AREG), epigen (EPGN), and epiregulin (EREG)], all ligands appear to activate the receptor through a similar mechanism and differ in their tissue distribution and local concentrations. Mice with individual ligand knockouts produce viable pups indicating no obvious defect in embryo development (Luetteke et al. 1999). Most ligand knock out mice had no obvious phenotype, with two exceptions: HB-EGF and EREG. When HB-EGF was knocked-out, there was impaired corneal wound healing and increased liver fibrosis. Weaned HB-EGF knockout mice had increased mortality attributed to heart dysfunction (Taylor et al. 2014; Chen et al. 2016). EREG knockout mice were viable and fertile but were stricken with chronic dermatitis. Greater insight into EGFR physiology was provided when mice were crossed to ablate expression of multiple ligands; several abnormalities were found in hair, skin and mammary gland development, which mimic phenotypes observed with EGFR mutations (Chen et al. 2016).

Spontaneously arising mutations in the EGFR or one of its endogenous ligands have provided valuable insight into the receptor’s role in tissue homeostasis. Waved-1 (wa-1) mice have a spontaneous mutation on chromosome 11 which causes a deficiency in TGFα, and waved-2 (wa-2) mice have a point mutation within the tyrosine kinase domain (Chen et al. 2016). Both of these spontaneous mutations result in similar phenotypes: smaller size, short/curly vibrissae, wavy/curly hair, hair follicle reduction, small/null salivary glands, reduction in mammary gland tissue, corneal opacity, and abrasions. These mutant mice have severe phenotypes that produce viable animals while exposing physiological roles of the receptor. One exception to this are the mice born to homozygous wa-2 mothers which die of malnutrition due to impaired maternal lactation attributed to undeveloped mammary glands (Fowler et al. 1995). These spontaneous EGFR mutations present themselves as changes in the hair, skin, and teeth, providing more evidence that EGFR has a critical role in epithelial development and homeostasis.

EGFR expression and activation has been reported in a variety of tissues (Table 1); however, expression can decrease in some tissues during animal maturation (Estrada and Villalobo 2006). This change could reflect a shift from a critical role in development to a less significant role in tissue maintenance and homeostasis during the aging process. EGFR has also been associated with the development and regeneration of the gastrointestinal system, homeostasis of corneal epithelium, and development and homeostasis of mammary tissue (Luetteke et al. 1999; Ceresa and Peterson 2014). Locating EGFR in multiple epithelial tissues supports the receptor as a ubiquitous epithelium modulator.
Epidermal Growth Factor Receptor, Table 1

The roles of EGFR signaling in various tissues.

Activated receptor

Inhibited receptor


Brain: SVZ (niches), midbrain, cerebellum, pituitary gland, hypothalamus

Stimulate proliferation of multipotent progenitors and astrocytes and enhance neuron survival, ↑ axonal branching

↓ Proliferation, ↓ new neurons reaching olfactory bulb, ↓ neural cell migration

Pituitary macroadenomas, glioblastomas, Alzheimer’s disease, Parkinson’s disease, schizophrenia


Hypertrophy of the skin/follicles

Dermatitis, ↓hair follicles, randomized direction of follicles, curly hair, shortened and curly vibrissae

Squamous cell carcinoma

Endocrine tissues: Thyroid, parathyroid, adrenal gland

↑ Organ weight


Papillary carcinomas

Bone/marrow and immune system: Appendix, bone marrow, lymph node, tonsil, spleen


Enlarged hypertrophic chondrocyte zone, delayed primary endochondral ossification

Chronic myelogenous leukemia

Muscle tissues/tendon: Heart, skeletal, smooth, tendons

↑ Growth of vascular smooth muscle, cardiac hypertrophy

Defective valvulogenesis, ↓ neuroectoderm specification, ↑ cardiac fibrosis

Hypertension, abdominal aortic aneurysms

Lung: Nasopharynx, bronchus

↑ Respiratory competence

Pulmonary toxicity, interstitial lung disease, type II pneumocyte immaturity, thickened alveolar septae, ↓ pulmonary fibrosis

NSCLC, lung adenocarcinoma, asthma, chronic obstructive pulmonary disease, cystic fibrosis


Acinar cell proliferation, acinar-to-ductal metaplasia and fibrogenesis, ↑ insulin secretion

Impaired pancreatic islet development

Pancreatic cancer

Gastrointestinal tract: Oral mucosa, salivary gland, esophagus, stomach, duodenum, small intestine, colon, rectum

↑ Proliferation of epithelium, enhanced wound healing, ↑ mucous, enhanced cell growth

Intestinal wall abrasions, diarrhea, increased stomach acid

Intestinal adenocarcinoma, gastroesophageal cancer, inflammatory bowel disease, necrotizing enterocolitis,

Liver and gallbladder

↑ Weight, ↓ in hemopoietic tissue, ↑ liver regeneration

Thickened hepatocyte cords, distorted sinusoidal anatomy, abnormally vacuolized nuclei, ↓ hepatocyte proliferation

Hepatocellular carcinogenesis

Kidney and bladder

↑ Renal regeneration and recovery following acute kidney injury

Renal damage, attenuates diabetic nephropathy

Renal interstitial fibrosis, glomerular diseases, kidney cancer, ↑ fibrotic lesion, bladder cancer

Male tissues: Testis, epididymis, prostate, seminal vesicle

Impaired testicular descent (TGF-α), induces hyperspermatogenesis (EGF)

↑ Testicular apoptosis, ↓ epididymal-spermatozoa total motile count, ↑ division frequency of germline stem cells

Prostate basal cell carcinoma

Female tissues: Breast, vagina, cervix, uterus, endometrium, fallopian tube, ovary

↑ Embryogenesis or implantation

Undeveloped mammary glands, impaired ovulation

Breast, cervical, uterine, fallopian and ovarian cancer

The role of EGFR in tissue homeostasis is highlighted by the side effects of EGFR inhibitors used therapeutically. Patients taking inhibitors for cancer therapy (e.g., cetuximab, gefitinib) often have short-lived improved prognoses and can experience colitis, diarrhea, dermatitis, and persistent corneal erosions associated with the treatments that limit the function of EGFR (Kohler and Schuler 2013). The adverse events associated with treatment often become too painful or detrimental to the patients’ overall health to continue the EGFR inhibiting therapy. EGFR has been shown to be critical in development, maintenance, and homeostasis in a variety of epithelial tissues in experiments that span five decades. Often it is not known if the dysregulation or mutation of EGFR is the cause of the disease or a result of the disease. Therefore, more specific treatments, disease analysis, and better knowledge of EGFR and its effectors is needed to make drugs more effective in treating ailments without the negative consequences of inhibiting critical EGFR function.

Molecular Biology/Biochemistry

In 1984, Ullrich and colleagues used the newly developed tools in molecular biology to clone the human EGFR cDNA and generated a model of the functional domains of the receptor (Ullrich et al. 1984). Although the model has been refined over the years, the basic structure remains consistent. The EGFR is comprised of four major domains: (1) an extracellular, ligand-binding domain with cysteine-rich regions, (2) a single-pass transmembrane domain, (3) a cytosolic, intrinsic kinase domain, and (4) a cytosolic domain containing tyrosine residues. The functional ligand-binding domains were further defined, utilizing 125 I-labeled EGF to label the EGFR binding sites and cyanogen bromide (CNBr) cleavage. Site-specific antibodies were then used to identify certain residues (294 and 543) that are critical for the ligand-binding function of the receptor. The 644 amino acids making up the extracellular domain have since been divided into 4 subdomains (Fig. 1a). Domains I and III are weakly homologous (37%) ligand-binding regions and Domains II and IV are cysteine-rich sections that interface with other ErbB receptors for dimerization (Ceresa and Peterson 2014).
Epidermal Growth Factor Receptor, Fig. 1

Schematic representation of the EGFR. (a) Secondary structure highlighting the major functional domains of the EGFR with the corresponding amino acid number. (b) Schematic representation of the monomeric EGFR in its closed/unliganded conformation (left), open/liganded conformation (center), and a liganded EGFR homodimer (right).

The model of how these domains come together is based on crystal structures. In the unliganded state, the cysteine-rich domains of a monomeric receptor bind to one another through an intramolecular interaction. Upon the introduction of ligand, the receptor undergoes a ligand-induced conformational change such that both ligand-binding domains bind the ligand and disrupt the interaction between the two cysteine-rich domains (Fig. 1b). The exposure of cysteine-rich domain II then can interact with the corresponding domain on another receptor to form a dimer pair. Additionally, the conformational change at the ligand-biding domain activates the intrinsic kinase domain and elicits auto-transphosphorylation of the cytosolic tyrosine residues. The kinase domain of each receptor moiety will phosphorylate tyrosine residues on its adjacent dimer partner through a conformational change in the receptor that places the tyrosine substrate in access to the kinase domain. These phosphotyrosines then serve as docking sites for various cytoplasmic enzymes, known as effector molecules. By docking to the phosphotyrosines, these effectors become activated and modulate various cellular processes that contribute to the overall signaling and biology of the cell. Depending on the cell type, these EGFR-mediated responses include cell proliferation, migration, differentiation, regulation of cell viability, ion channel activity, and DNA and protein synthesis (Ceresa and Peterson 2014).

Activation of the EGFR stimulates a myriad of effector molecules and downstream signal transduction cascades. The challenge for those studying EGFR biology is to identify which receptor-effector communication occurs under physiological and pathophysiological conditions; not only are some pathways redundant, often multiple effectors converge on the same downstream molecules. Further, receptor-effector interactions are impacted by the relative concentration of each protein. In cell lines that overexpress EGFRs, either due to cell transformation or deliberate bioengineering, the increased receptor density might drive an interaction that does not typically occur.

Equally important to receptor activation is the appropriate attenuation of EGFR signaling. Ligand-mediated endocytic trafficking is one of the principal ways this occurs. Co-incident with ligand binding and receptor activation, the ligand-receptor complex is internalized into the cell in either a clathrin-mediated or clathrin-independent manner. Through immunoelectron microscopy, Sigismund et al. revealed that clathrin-mediated EGFR endocytosis is observed at low EGF concentrations (1–2 ng/mL), whereas with higher concentrations (10–100 ng/mL) the receptor enters the cytoplasm via caveolae. Once inside the cell, the EGFR enters the endocytic pathway and can be trafficked to a number of different subcellular locations. Lysosomal degradation and recycling back to the plasma membrane are the major fates of the receptor (Fig. 2), although receptors have also been reported to traffic to the nucleus and the endoplasmic reticulum. The endocytic pathway regulates the activity of the EGFR both spatially and temporally. Spatial regulation denotes that at different subcellular locations, the receptor will interact with different effector molecules, facilitating different signaling cascades. Temporal regulation is indicative of the time it takes for the receptor to traverse the entire endocytic pathway, dictating the duration of its intracellular signaling (Ceresa 2012). The route and rates of endocytic trafficking are dependent on the level of EGFR expression, whether the EGFR heterodimerizes with another ErbB family member (i.e., ErbB2, ErbB3, and ErbB4), cell type, and the stimulating ligand.
Epidermal Growth Factor Receptor, Fig. 2

Physiological concentrations of ligand promote clathrin-mediated endocytosis. Major routes of endocytosis of the EGFR and the effect of individual endogenous ligands that specifically and preferentially direct receptor trafficking.

Despite the common mode of receptor activation, the endogenous EGFR ligands provide an additional layer of signal regulation. Roepstorff et al. used an approach of prebinding various EGFR ligands on ice to later observe the synchronized wave of receptor internalization. After subsequent FACS analyses, TGFα and EREG were found to elicit complete receptor recycling, whereas BTC and HB-EGF selectively targeted the EGFR to the lysosome for degradation. EGF and AR were found to yield intermediary responses. EGF invoked recycling of approximately 50% of the receptors, with the remaining 50% being targeted for lysosomal degradation. AR did not target the EGFR for lysosomal degradation, but rather elicited both fast and slow receptor recycling. The fate of the EGFR, whether it is degradation or recycling, directly impacts the duration of receptor signaling. Not only are the natural ligands of the EGFR mediators of temporal and spatial regulation, but they also impact the initiation of different signaling cascades downstream of receptor activation (Ceresa 2012).



The EGFR is frequently overexpressed and/or hyperactivated in many types of epithelial cancers and is associated with poor patient prognosis. This association is consistent with the receptor’s ability to promote cell proliferation, migration, and viability. Much of the EGFR-specific research has been driven by scientists trying to understand the receptor’s role in cancer biology and identifying molecular targets to specifically inhibit cancer growth.

Glioblastoma multiforme (GBM) was the first cancer associated with perturbations in EGFR expression. Approximately 70% of GBMs express a constitutively active, truncated mutant (EGFRvIII) with deletions in exons 2–7 of the extracellular domain (Kuan et al. 2001). The loss of the extracellular domain allows spontaneous, ligand-independent receptor dimerization and activation. The EGFRvIII mutation is also overexpressed due to gene amplification. Conversely, activating mutations of the intracellular portion of the receptor are associated with non-small cell lung cancer (NSCLC), one of the most common and lethal forms of lung cancer with a 5-year survival rate of only 17%. Approximately 50% of NSCLC patients who identify as “never smokers” have EGFR exon 19 deletions, exon 20 insertions, and the amino acid point mutation L858R (Shigematsu et al. 2005). All three of these mutations change the kinase domain of the receptor to favor an active state to induce constitutive kinase activity and signaling of EGFR.

In contrast to activating mutations, other cancers are driven by EGFR overexpression (e.g., colorectal, breast, pancreatic, and head and neck). There are multiple mechanisms by which EGFR levels may be enhanced, including increased gene amplification, mRNA production, and protein translation. In breast carcinomas, EGFR gene amplification occurs in 6% of tumors, and 91% of these tumors also exhibit EGFR protein overexpression (Bhargava et al. 2005). In approximately 20% of high-grade cervical intraepithelial neoplasias (CIN) and invasive cervical carcinomas, EGFR gene amplification has also been linked to EGFR overexpression and poor prognosis (Li et al. 2014). However, approximately 65% of pancreatic ductal adenocarcinomas (PDAC) exhibit overexpression of EGFR, but without EGFR-specific gene amplification (Dancer et al. 2007). For PDAC, these changes in protein levels are likely due to overexpression of other ErbB family members such as ErbB2 (more commonly referred to as HER2) (Dancer et al. 2007). Elevated levels of receptor lead to a net increase in receptor signaling, enhanced sensitivity to ligand, and decreased rate of downregulation of the ligand-receptor complex.

Polycystic Kidney Disease

Dysregulated EGFR signaling is also associated with autosomal recessive and autosomal dominant polycystic kidney disease (PKD). PKD is the most common inheritable kidney disorder and is characterized by numerous fluid-filled sacs on the kidney that impair its function. In normal polarized renal tubule cells, EGFR expression is restricted to the basolateral surface. However, in both types of PKD, the receptor is distributed on both apical and basolateral surfaces (Fig. 3). This dysregulation of receptor localization increases its capacity for ligand binding via growth factors circulating in the kidney lumen, thus dramatically increasing its activation and signaling. This is considered to be one of the major driving forces of cyst formation in PKD (Du and Wilson 1995).
Epidermal Growth Factor Receptor, Fig. 3

EGFR antagonists

EGFR Therapies

Although EGFR is implicated in numerous types of cancer and PKD, there are only four FDA-approved drugs that target the receptor. All approved compounds antagonize receptor function and fall into two classes: humanized monoclonal antibodies (mAbs) and small molecule kinase inhibitors. In 2004, cetuximab (Bristol-Myers Squibb) was the first EGFR-targeted mAb to be FDA-approved (in combination with standard chemotherapeutics) for the treatment of metastatic colorectal cancer. In 2006, panitumumab (Amgen) was approved by the FDA and is currently used as part of a multidrug regimen for the treatment of metastatic colorectal cancer (Ciardiello and Tortora 2008). The mAbs target the extracellular ligand-binding domain of the receptor and prevent interaction with endogenous, extracellular activating ligands (Fig. 4a). The binding of mAbs to EGFR induces cell death via multiple mechanisms, including: blocking proliferative signaling, reducing the production and release of growth factors, internalizing and degrading EGFR via endocytosis, and inducing the host immune system via antibody-dependent cytotoxicity (Ciardiello and Tortora 2008). EGFR mAbs are generally approved for the treatment of cancers that express high levels of EGFR, such as colorectal and head and neck cancers.
Epidermal Growth Factor Receptor, Fig. 4

Aberrantly localized EGFRs in polarized kidney cells are associated with polycystic kidney disease (PKD). Green kinase domain indicates increased EGFR activity due to apical membrane localization of the receptor in PKD

Tyrosine kinase inhibitors (TKIs) are small, membrane-permeable molecules that bind (reversibly or irreversibly) to the kinase domain of the receptor, blocking effector activation and downstream signaling cascades (Fig. 4b). EGFR-specific TKIs induce cell death by hindering EGFR-mediated proliferation and growth factor production and inducing G0-G1 phase cell cycle arrest (Ciardiello and Tortora 2008). In 2003, gefitinib was the first EGFR-TKI to be FDA approved and erlotinib was approved shortly thereafter. Gefitinib originally received accelerated approval by the FDA based on preliminary trials showing its benefit over chemotherapy for NSCLC patients. Subsequent studies found no improvement in survival with gefitinib treatment, causing the FDA to limit the drug’s approval to patients with a demonstrated benefit to the drug. Interestingly, in 2015 the FDA reapproved gefitinib as a first-line therapy for patients with metastatic NSCLC based on more recent clinical trials (Bogdanowicz et al. 2016). In 2004 another TKI, erlotinib, was FDA approved for NSCLC and is still used in clinics today. Both erlotinib and gefitinib are approved for use in NSCLC patients with EGFR kinase activating mutations [exon 19 and exon 20 deletions/insertions and L858R substitution]. Erlotinib is also approved for the treatment of metastatic pancreatic cancer in combination with the chemotherapeutic gemcitabine.

Both classes of EGFR antagonists are initially effective for inhibiting cancers with EGFR overexpression or hyperactivation; however, virtually all patients develop resistance to the drugs. The exact mechanism by which resistance occurs is unclear. Some studies suggest that the inhibited receptors can continue signaling by forming heterodimers with other ErbB family members, or even with the insulin-like growth factor type-1 receptor (IGF-1R), another RTK with mitogenic effects. Many clinical trials are ongoing to test new drugs for cancers that develop resistance to EGFR antagonists. One such drug, rociletinib, specifically targets the T790M activating mutation commonly found in resistant cancers. Other drugs in development, including afatinib and lapatinib, irreversibly target multiple members of the ErbB family of receptors.

There are also EGFR antagonists, although not approved for clinical applications that are used frequently in laboratory research. Ab-1 is a commercially available mouse monoclonal antibody that targets the extracellular ligand-binding domain of the human EGFR and prevents occupancy of endogenous ligands, similar to the mechanism of action of cetuximab and panitumumab. Experimentally, Ab-1 is particularly useful in immunofluorescence studies to monitor the intracellular trafficking of the unliganded EGFR. Developed in the late 1980s by targeting EGFRs isolated from A431 cells, Ab-1 has been shown to block tumor growth in vivo, but never made it to the clinic. However, Ab-1 (originally called mAb 528) and other EGFR antibodies developed in the lab led to the clinical EGFR mAbs used today. Another EGFR antagonist commercially available for lab use is a small molecule kinase inhibitor, AG1478. AG1478 potently inhibits the kinase domain of EGFR and has been shown to suppress the proliferation and invasion of breast cancer cells.


EGFR has long been the prototypical RTK, and studying this receptor has had a tremendous impact on our comprehension of developmental biology, tissue homeostasis, and cancer biology. With decades of research, scientists have identified the receptor and its ligands, how signals are propagated and regulated, and identified new drugs to inhibit deregulated EGFR signaling in cancer. Despite all the advances, there is still much more that remains to be understood. For instance, from a clinical perspective, therapies need to be expanded to other tissue-specific cancers characterized by hyperactivated EGFR signaling. A balance needs to be found between inhibiting the EGFR in cancerous tissue and preserving the necessary receptor signaling in healthy tissues. This will help minimize the unpleasant side effects experienced by patients using EGFR antagonists for their cancer treatment regimens. Further, can findings from cancer biology be exploited and applied to other diseases with aberrant EGFR expression? For instance, will EGFR inhibitors eventually treat PKD? Antagonizing the EGFR is not the only strategy for pharmacological intervention; enhancing EGFR activity holds great promise for promoting tissue regeneration, particularly in the epithelial tissues of the cornea, colon, and skin.

The answers to many of these questions require a much greater understanding of the cell biology that regulates the EGFR. How does the spatial and temporal regulation of the EGFR impact its signaling? What dictates the formation of EGFR homodimers versus heterodimerization with another ErbB family member? How does receptor density impact EGFR signaling? Elucidating these underlying molecular mechanisms can be a slow and labor-intensive process due to functional redundancies of ligands and receptors, the interplay between regulatory mechanisms, and lack of synthetic agonists and antagonists. These basic science questions will advance our understanding of receptor biology and cancer and provide a foundation to developing new pharmacological therapies.


  1. Bhargava R, Gerald WL, Li AR, Pan Q, Lal P, Ladanyi M, et al. EGFR gene amplification in breast cancer: correlation with epidermal growth factor receptor mRNA and protein expression and HER-2 status and absence of EGFR-activating mutations. Mod Pathol. 2005;18:1027–33.  https://doi.org/10.1038/modpathol.3800438.CrossRefPubMedGoogle Scholar
  2. Bogdanowicz BS, Hoch MA, Hartranft ME. Flipped script for gefitinib: a reapproved tyrosine kinase inhibitor for first-line treatment of epidermal growth factor receptor mutation positive metastatic nonsmall cell lung cancer. J Oncol Pharm Pract. 2016;  https://doi.org/10.1177/1078155216634179.CrossRefPubMedGoogle Scholar
  3. Carpenter G, Cohen S. Epidermal growth factor. J Biol Chem. 1990;265:7709–12.PubMedGoogle Scholar
  4. Ceresa BP. Spatial regulation of epidermal growth factor receptor signaling by endocytosis. Int J Mol Sci. 2012;14:72–87.  https://doi.org/10.3390/ijms14010072.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Ceresa BP, Peterson JL. Cell and molecular biology of epidermal growth factor receptor. Int Rev Cell Mol Biol. 2014;313:145–78.  https://doi.org/10.1016/B978-0-12-800177-6.00005-0.CrossRefPubMedGoogle Scholar
  6. Chen JC, Zeng FH, Forrester SJ, Eguchi S, Zhang MZ, Harris RC. Expression and function of the epidermal growth factor receptor in physiology and disease. Physiol Rev. 2016;6:1025–69.CrossRefGoogle Scholar
  7. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358:1160–74.  https://doi.org/10.1056/NEJMra0707704.CrossRefPubMedGoogle Scholar
  8. Dancer J, Takei H, Ro JY, Lowery-Nordberg M. Coexpression of EGFR and HER-2 in pancreatic ductal adenocarcinoma: a comparative study using immunohistochemistry correlated with gene amplification by fluorescencent in situ hybridization. Oncol Rep. 2007;18:151–5.PubMedGoogle Scholar
  9. Du J, Wilson PD. Abnormal polarization of EGF receptors and autocrine stimulation of cyst epithelial growth in human ADPKD. Am J Phys. 1995;269:C487–95.CrossRefGoogle Scholar
  10. Estrada C, Villalobo A. Epidermal growth factor receptor in the adult brain. In: Janigro D, editor. Cell cycle in the central nervous system. Totowa: Humana Press Inc.; 2006. p. 265–77.CrossRefGoogle Scholar
  11. Fowler KJ, Walker F, Alexander W, Hibbs ML, Nice EC, Bohmer RM, et al. A mutation in the epidermal growth factor receptor in waved-2 mice has a profound effect on receptor biochemistry that results in impaired lactation. PNAS (USA). 1995;92:1465–9.CrossRefGoogle Scholar
  12. Kohler J, Schuler M. Afatinib, erlotinib and gefitinib in the first-line therapy of EGFR mutation-positive lung adenocarcinoma: a review. Onkologie. 2013;36:510–8.  https://doi.org/10.1159/000354627.CrossRefPubMedGoogle Scholar
  13. Kuan CT, Wikstrand CJ, Bigner DD. EGF mutant receptor vIII as a molecular target in cancer therapy. Endocr Relat Cancer. 2001;8:83–96.CrossRefPubMedGoogle Scholar
  14. Li Q, Tang Y, Cheng X, Ji J, Zhang J, Zhou X. EGFR protein expression and gene amplification in squamous intraepithelial lesions and squamous cell carcinomas of the cervix. Int J Clin Exp Pathol. 2014;7:733–41.PubMedPubMedCentralGoogle Scholar
  15. Luetteke NC, Qiu TH, Fenton SE, Troyer KL, Riedel RF, Chang A, et al. Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development. Development. 1999;126:2739–50.PubMedGoogle Scholar
  16. Roskoski Jr R. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res. 2014;79:34–74.  https://doi.org/10.1016/j.phrs.2013.11.002.CrossRefPubMedGoogle Scholar
  17. Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97:339–46.  https://doi.org/10.1093/jnci/dji055.CrossRefPubMedGoogle Scholar
  18. Taylor SR, Markesbery MG, Harding PA. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) and proteolytic processing by a disintegrin and metalloproteinases (ADAM): a regulator of several pathways. Semin Cell Dev Biol. 2014;28:22–30.  https://doi.org/10.1016/j.semcdb.2014.03.004.CrossRefPubMedGoogle Scholar
  19. Ullrich A, Coussens L, Hayflick JS, Dull TJ, Gray A, Tam AW, et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature. 1984;309:418–25.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Brian P. Ceresa
    • 1
    Email author
  • Julie A. Gosney
    • 1
  • Nicole M. Jackson
    • 1
  • Jamie S. Rush
    • 1
  1. 1.Department of Pharmacology and ToxicologyUniversity of LouisvilleLouisvilleUSA