Entry - *131550 - EPIDERMAL GROWTH FACTOR RECEPTOR; EGFR

Location	Phenotype View Clinical Synopses	Phenotype MIM number	Inheritance	Phenotype mapping key
7p11.2	?Inflammatory skin and bowel disease, neonatal, 2	616069	AR	3
	{Nonsmall cell lung cancer, susceptibility to}	211980	AD, SMu	3
	Adenocarcinoma of lung, response to tyrosine kinase inhibitor in	211980	AD, SMu	3
	Nonsmall cell lung cancer, response to tyrosine kinase inhibitor in	211980	AD, SMu	3

TEXT

▼ Description

EGFR and its ligands are cell signaling molecules involved in diverse cellular functions, including cell proliferation, differentiation, motility, and survival, and in tissue development (Wang et al., 2004).

▼ Cloning and Expression

Using as one parental cell the mouse A9 line, which is incapable of binding labeled epidermal growth factor (EGF; 131530), Shimizu et al. (1980) studied human-mouse cell hybrids and concluded that a receptor for EGF is located on human chromosome 7 in the p22-qter region. Since the EGF receptor is a glycoprotein, Shimizu et al. (1980) hypothesized that EGF may be either a structural gene for receptor protein or a gene for glycosylation of the receptor protein. EGF enhances phosphorylation of several endogenous membrane proteins, including EGF receptor. The EGF receptor is a tyrosine protein kinase. It has 2 components of different molecular weight; both contain phosphotyrosine and phosphothreonine but only the higher molecular weight form contains phosphoserine (Carlin and Knowles, 1982).

Carlin et al. (1982) showed that the specific cell surface antigen previously called SA7 (Aden and Knowles, 1976) is identical to the receptor for epidermal growth factor. Western blot analysis revealed a doublet 145 and 165 kD in detergent extracts of A431 cells. Both proteins were phosphorylated. Reiter et al. (2001) stated that A431 cells exhibit an approximately 30-fold amplification of the EGFR gene and express an aberrant transcript that arises from a genomic rearrangement involving some of the amplified alleles.

Kondo and Shimizu (1983) stated that the EGFR molecule has 3 regions: one projects outside the cell and contains the site for binding EGF; the second is embedded in the membrane; the third projects into the cytoplasm of the cell's interior. EGFR is a kinase that attaches phosphate groups to tyrosine residues in proteins.

By RT-PCR of a human placenta cDNA library, Reiter and Maihle (1996) cloned a splice variant of EGF, which they called ERBB1-S, that arises by the read-through of a splice donor site at the end of exon 10 and the use of an alternative polyadenylation signal in intron 10. The deduced 381-amino acid protein has a calculated molecular mass of 44.7 kD. It has an N-terminal signal sequence followed by a portion of the extracellular ligand-binding domain, including subdomains 1 and 2, and part of subdomain 3. The last 2 amino acids are unique. ERBB1-S lacks the transmembrane domain and the intracellular tyrosine kinase catalytic domain of full-length EGFR, and it is predicted to be a soluble secreted protein. Northern blot analysis detected a 1.8-kb ERBB1-S transcript in placenta. Transfected quail fibroblasts secreted ERBB1-S into the culture medium. ERBB1-S had an apparent molecular mass of 60 kD by SDS-PAGE.

Using computational and experimental methods, Reiter et al. (2001) identified 2 EGFR splice variants derived from novel exons 15A and 15B located in intron 15. By screening a placenta cDNA library, they cloned a 3.0-kb transcript, which contains exon 15B. The deduced 705-amino acid protein has an N-terminal signal peptide, all 4 subdomains of the extracellular ligand-binding domain, and 78 unique C-terminal residues. It has no transmembrane domain and no intracellular domains. Northern blot analysis detected the full-length EGFR transcript in all tissues examined, but the 3.0-kb EGFR transcript was detected only in placenta and in carcinoma cell lines that contain amplification of the EGFR gene. The 3.0-kb EGFR transcript expressed in quail fibroblasts migrated at 110 kD on SDS-PAGE; inhibition of N-glycosylation reduced the apparent molecular mass to 77 kD.

▼ Gene Structure

Reiter et al. (2001) determined that the EGFR gene contains 28 exons and spans nearly 200 kb. Intron 1 spans 123 kb. The gene contains several repeat elements, including SINEs and LINEs, as well as a trinucleotide (TGG/A) repeat-rich region in intron 15, and 2 long CA repeats in intron 27.

Haley et al. (1987) determined that exon 1 of the EGFR gene is highly GC-rich. Functional analysis revealed positive transcription elements both within exon 1 and 5-prime to the transcription start site. A negative regulatory region was found between -140 and +80. SP1 (189906) was required for maximal activity.

▼ Mapping

Carlin et al. (1982) indicated 7p22-p12 as the localization of the EGFR gene. Kondo and Shimizu (1983) concluded that EGFR is in the 7p13-q22 region.

▼ Biochemical Features

Zhang et al. (2006) found that the human EGFR kinase domain could be activated by increasing its local concentration or by mutating leu834 in the activation loop to arg, suggesting that the kinase domain is intrinsically autoinhibited. Using mutation analysis and crystallography, they showed that the autoinhibited conformation of the EGFR kinase domain resembled that of SRC (190090) and cyclin-dependent kinases (see CDK1; 116940). EGFR activation resulted from the formation of an asymmetric EGFR dimer in which the C-terminal lobe of 1 kinase domain played a role analogous to that of cyclin (see 604036) in activated cyclin/CDK complexes.

Zhang et al. (2007) determined the crystal structure of a complex between the EGFR kinase domain and a fragment of MIG6 (ERRFI1; 608089) at 2.9-angstrom resolution, which showed that an approximately 25-residue epitope from MIG6 binds to the distal surface of the C lobe of the kinase domain. Biochemical and cell-based analyses confirmed that this interaction contributes to EGFR inhibition by blocking the formation of the activating dimer interface. A longer MIG6 peptide that is extended C terminal to segment 1 has increased potency as an inhibitor of the activated EGFR kinase domain, while retaining a critical dependence on segment 1. Zhang et al. (2007) showed that signaling by EGFR molecules that contain constitutively active kinase domains still requires formation of the asymmetric dimer, underscoring the importance of dimer interface blockage in MIG6-mediated inhibition.

Dimerization Dynamics

Chung et al. (2010) used quantum dot-based optical tracking of single molecules combined with a novel time-dependent diffusivity analysis to study the dimerization dynamics of individual EGFRs on living cells. Before ligand addition, EGFRs spontaneously formed finite-lifetime dimers kinetically stabilized by their dimerization arms. The dimers were primed both for ligand binding and for signaling, such that after EGF addition they rapidly showed a very slow diffusivity state that correlated with activation. Although the kinetic stability of unliganded dimers was in principle sufficient for EGF-independent activation, ligand binding was still required for signaling. Interestingly, dimers were enriched in the cell periphery in an actin- and receptor expression-dependent fashion, resulting in a peripheral enhancement of EGF-induced signaling that may enable polarized responses to growth factors.

▼ Gene Function

Carlin et al. (1982) showed that both the 145- and 165-kD EGFR proteins from A431 cells bound radiolabeled EGF, and both were phosphorylated upon EGF stimulation. Haley et al. (1987) showed that the activity of the EGFR promoter was modulated by adenovirus protein E1A. Stimulation with phorbol ester or fetal calf serum increased EGFR mRNA levels.

EGFR signaling involves small GTPases of the Rho family, and EGFR trafficking involves small GTPases of the Rab family. Lanzetti et al. (2000) reported that the EPS8 (600206) protein connects these signaling pathways. EPS8 is a substrate of EGFR that is held in a complex with SOS1 (182530) by the adaptor protein E3B1 (603050), thereby mediating activation of RAC (602048). Through its SH3 domain, EPS8 interacts with RNTRE (605405). Lanzetti et al. (2000) showed that RNTRE is a RAB5 (179512) GTPase-activating protein whose activity is regulated by EGFR. By entering in a complex with EPS8, RNTRE acts on RAB5 and inhibits internalization of the EGFR. Furthermore, RNTRE diverts EPS8 from its RAC-activating function, resulting in the attenuation of RAC signaling. Thus, depending on its state of association with E3B1 or RNTRE, EPS8 participates in both EGFR signaling through RAC and EGFR trafficking through RAB5.

Yang et al. (1996) demonstrated that treatment with genistein, an inhibitor of tyrosine kinase activity, inhibited EGF-induced tyrosine phosphorylation and degradation of EGFR in HepG2 cells, suggesting to the authors that tyrosine kinase activity is required for either the internalization or the degradation of EGF-EGFR receptor complexes.

Downward et al. (1984) presented evidence that oncogene ERBB may be derived from the gene coding for EGFR. Spurr et al. (1984) assigned the oncogene ERBB to chromosome 7 by study of mouse-human somatic cell hybrids. The amino acid sequence of the protein encoded by v-erb B (deduced from the nucleotide sequence of the gene) displays strong homologies to tyrosine-specific protein kinases (Privalsky et al., 1984). Both ERBA and ERBB are on mouse chromosome 11, which carries alpha-globin genes and genes for colony-stimulating factor and interleukin-3 (Silver et al., 1985). Neither of the oncogenes is on chromosome 16, which carries alpha-globin genes in man. The most striking and consistent chromosomal finding in a series of human glioblastoma (137800) cell lines was an increase in copy number of chromosome 7. Henn et al. (1986) found that in all of the cell lines ERBB-specific mRNA was increased to levels even higher than expected from the number of chromosomes 7 present. These changes were not found in benign astrocytomas.

Using Southern blot analysis, Yamazaki et al. (1988) found in 2 cases of human glioblastoma multiforme that cells carried amplified ERBB genes which bore short deletion mutations within the ligand-binding domain of the EGF receptor. The products of these mutated ERBB genes were about 30 kD smaller than the normal 170-kD EGF receptor, and the tumor cell membrane fractions containing the 140-kD abnormal EGF receptor showed a significant elevation of tyrosine kinase activity without its ligand. In these 2 tumors, only the rearranged ERBB genes were amplified. This suggested that DNA rearrangement had occurred before gene amplification. Yamazaki et al. (1988) could not detect any abnormal bands of ERBB in other brain tumors tested.

Maternal uniparental disomy (UPD) of chromosome 7 has been reported in approximately 10% of cases of Silver-Russell syndrome (SRS2; 618905). This suggests that at least 1 gene on chromosome 7 is imprinted and involved in the pathogenesis of SRS. Wakeling et al. (1998) investigated the EGFR gene as a candidate for imprinting because the gene maps to 7p12, a region homologous to an imprinted region on mouse chromosome 11. Using a restriction fragment length polymorphism, they found, however, biallelic expression of EGFR in a range of normal human fetal tissues. Expression was also demonstrated in fibroblasts and lymphoblasts from SRS patients with maternal UPD7. Thus, no evidence that EGFR is imprinted was found, making its involvement in SRS unlikely. However, EGFR was shown to be widely expressed in the human fetus, providing evidence that it plays an important role in early development. The only gene known to be imprinted on chromosome 7 at that time was MEST, also called paternally expressed gene-1 (601029), which maps to 7q32.

Verveer et al. (2000) presented evidence for a novel signaling mechanism consisting of ligand-independent lateral propagation of receptor activation in the plasma membrane. They visualized the phosphorylation of green fluorescent protein-tagged ERBB1 receptors in cells focally stimulated with EGF covalently attached to beads. This was achieved by quantitative imaging of protein reaction states in cells by fluorescence resonance energy transfer (FRET) with global analysis of fluorescence lifetime imaging microscopy data. The rapid and extensive propagation of receptor phosphorylation over the entire cell after focal stimulation demonstrated a signaling wave at the plasma membrane resulting in full activation of all receptors.

Activation of epidermal growth factor receptor triggers mitogenic signaling in gastrointestinal mucosa, and its expression is also upregulated in colon cancers and most neoplasms. Pai et al. (2002) investigated whether prostaglandins transactivate EGFR. Pai et al. (2002) demonstrated that prostaglandin E2 (PGE2; see 176804) rapidly phosphorylates EGFR and triggers the extracellular signal-regulated kinase 2 (ERK2; 176948)-mitogenic signaling pathway in normal gastric epithelial and colon cancer cell lines. Inactivation of EGFR kinase with selective inhibitors significantly reduced PGE2-induced ERK2 activation, c-fos mRNA expression, and cell proliferation. Inhibition of matrix metalloproteinases, TGFA, or c-Src (190090) blocked PGE2-mediated EGFR transactivation and downstream signaling, indicating that PGE2-induced EGFR transactivation involves signaling transduced via TGF-alpha, an EGFR ligand, likely released by c-Src-activated MMPs.

Using transgenic mice and inhibitor studies, Mak and Chan (2003) showed that EGFR signaling was indispensable for the initiation of hair growth in the anagen phase of the hair cycle, but continuous expression arrested follicular development at later stages.

Schlessinger (2004) reviewed the signaling pathways that are activated by EGF and fibroblast growth factor (FGF) receptors (e.g., 136350). Both receptors stimulate a similar complement of intracellular signaling pathways. However, whereas activated EGF receptors function as the main platform for recruitment of signaling proteins, signaling through the FGF receptors is mediated primarily by assembly of a multidocking protein complex. Furthermore, FGF receptor signaling is subject to additional intracellular and extracellular control mechanisms that do not affect EGF receptor signaling.

Tran et al. (2003) found that Caml (CAMLG; 601118)-deficient mouse epithelial cells expressed a functional EGFR. However, EGF (131530) stimulation resulted in impaired Egfr recycling and cytoplasmic accumulation of Egfr. Immunoprecipitation analysis indicated a direct interaction between wildtype Caml and Egfr that was dependent on ligand binding. Mutation analysis indicated that Caml bound the kinase domain of Egfr, and the proteins colocalized in the ER. Tran et al. (2003) concluded that CAML may play a role in EGFR recycling during long-term proliferative responses.

Wang et al. (2003) demonstrated that human cytomegalovirus (CMV) infects cells by interacting with EGFR and inducing signaling. Transfecting EGFR-negative cells with an EGFR cDNA renders nonsusceptible cells susceptible to human CMV. Ligand displacement and crosslinking analyses showed that human CMV interacts with EGFR through gB, its principal envelope glycoprotein. gB preferentially binds EGFR and EGFR-ERBB3 (190151) with oligomeric molecules in CHO cells transfected with ERBB family cDNAs. Wang et al. (2003) concluded that, taken together, their data indicate that EGFR is a necessary component for human CMV-triggered signaling and viral entry.

Koprivica et al. (2005) demonstrated that suppressing the kinase function of EGFR blocks the activities of both myelin inhibitors and chondroitin sulfate proteoglycans in inhibiting neurite outgrowth. In addition, regeneration inhibitors trigger the phosphorylation of EGFR in a calcium-dependent manner. Local administration of EGFR inhibitors promoted significant regeneration of injured mouse optic nerve fibers, pointing to a promising therapeutic avenue for enhancing axon regeneration after central nervous system (CNS) injury.

Jamnongjit et al. (2005) found that EGFR signaling promoted steroidogenesis in mouse oocyte-granulosa cell complexes and luteinizing hormone (LH; see 152780)-induced steroidogenesis in a mouse Leydig cell line. Inhibition of metalloproteinase-mediated cleavage of membrane-bound Egf abrogated LH-induced steroidogenesis in ovarian follicles, but not in the Leydig cell line, suggesting that LH receptor (LHCGR; 152790) signaling activates EGFR by different mechanisms in these 2 systems.

Using microarray analysis and quantitative real-time PCR, Kario et al. (2005) observed upregulated expression of SOCS4 (616337) and SOCS5 (607094) in HeLa cells following treatment with EGF. Overexpression of SOCS4 or SOCS5 in CHO cells downregulated EGFR expression, irrespective of EGF treatment. SOCS5 and other SOCS proteins, but not SOCS4, were phosphorylated following EGF stimulation. Coimmunoprecipitation analysis showed that SOCS5 interacted directly with EGFR. SOCS5 also reduced expression of the EGFR-related receptors ERBB2 (164870) and ERBB4 (600543), but not other cell surface receptors. SOCS5 recruited EGFR to an elongin B (600787)- and elongin C (600788)-containing E3 ubiquitin ligase complex. SOCS5 also caused relocalization of EGFR from the cell surface to intracellular vesicles and reduced EGFR-mediated cell signaling. Proteasome inhibition curtailed SOCS5-dependent EGFR downregulation. Enhanced degradation of EGFR in the presence of SOCS5 was accompanied by enhanced degradation of SOCS5 itself. Kario et al. (2005) concluded that SOCS4 and SOCS5 negatively regulate EGFR signaling, most likely via distinct mechanisms.

Using immunohistochemistry with a tissue microarray containing 406 NSCLC samples, Tai et al. (2006) documented overexpression of EGFR and FGF3 (164950) in 69% and 61% of samples, respectively. They found a significant correlation (p less than 0.001) between overexpression of EGFR and of FGF3. Tai et al. (2006) suggested that co-overexpression of EGFR and FGF3 may play an important role in the pathogenesis of lung carcinoma.

Jones et al. (2006) used microarrays comprising virtually every Src homology 2 (SH2) and phosphotyrosine-binding (PTB) domain encoded in the human genome to measure the equilibrium dissociation constant of each domain for 61 peptides representing physiologic sites of tyrosine phosphorylation on the 4 ErbB receptors. By slicing through the network at different affinity thresholds, Jones et al. (2006) found surprising differences between the receptors. Most notably, EGFR and ErbB2 became markedly more promiscuous as the threshold was lowered, whereas ErbB3 (190151) did not. Because EGFR and ErbB2 are overexpressed in many human cancers, Jones et al. (2006) concluded that the extent to which promiscuity changes with protein concentration may contribute to the oncogenic potential of receptor tyrosine kinases.

Using healthy human skin fragments obtained as surgical residua, Sorensen et al. (2006) demonstrated that sterile wounding of human skin induces epidermal expression of the antimicrobial polypeptides beta-defensin-103 (DEFB103; 606611), lipocalin-2 (LCN2; 600181), and secretory leukocyte protease inhibitor (SLPI; 107285) through activation of EGFR by heparin-binding EGF (HBEGF; 126150). Studies in epidermal cultures showed that activation of EGFR generated antimicrobial concentrations of DEFB103 and increased activity of the cultures against Staphylococcus aureus. Sorensen et al. (2006) concluded that sterile wounding initiates an innate immune response that increases resistance to overt infection and microbial colonization.

Using comparative gene analysis, Weller et al. (2010) identified a positive correlation between transduction of the gene therapy vector adeno-associated virus serotype-6 (AAV6) and EGFR expression. AAV1 was able to transduce into cells expressing EGFR, but less efficiently than AAV6, and AAV2 and AAV5 showed no transduction. Inhibitors of EGFR blocked AAV6 entry into cells. Weller et al. (2010) concluded that EGFR is a coreceptor for AAV6.

Aguirre et al. (2010) demonstrated that functional cell-cell interaction between neural progenitor cells (NPCs) and neural stem cells (NSCs) through EGFR and Notch (190198) signaling has a crucial role in maintaining the balance between these cell populations in the subventricular zone of the lateral ventricle and dentate gyrus of the hippocampus. Enhanced EGFR signaling in vivo results in expansion of the NPC pool and reduces NSC number and self-renewal. This occurs through a non-cell-autonomous mechanism involving EGFR-mediated regulation of Notch signaling. Aguirre et al. (2010) concluded that their findings defined a novel interaction between EGFR and Notch pathways in the adult subventricular zone, and thus provided a mechanism for NSC and NPC pool maintenance.

Knox et al. (2010) hypothesized that parasympathetic innervation is required for epithelial progenitor cell function during organogenesis. Removal of the parasympathetic ganglion in mouse explant organ culture decreased the number and morphogenesis of keratin-5 (148040)-positive epithelial progenitor cells. These effects were rescued with an acetylcholine analog. Knox et al. (2010) demonstrated that acetylcholine signaling, via the muscarinic M1 receptor (118510) and EGFR, increased epithelial morphogenesis and proliferation of the keratin-5-positive progenitor cells. Parasympathetic innervation maintained the epithelial progenitor cell population in an undifferentiated state, which was required for organogenesis.

Ryan et al. (2010) found that there are at least 2 constitutive pathways for targeting Egfr to basolateral membranes in mouse renal epithelia cells. One pathway involved direct interaction between a highly conserved Egfr dileucine motif and adaptor protein-1B (AP1B, or AP1B1; 600157). The other constitutive pathway was independent of AP1B. Ryan et al. (2010) also identified a latent basolateral pathway that traverses Rab11 (see 605570)-positive subapical compartments independent of AP1B. They found that the bpk mouse model of autosomal recessive polycystic kidney disease (see 263200), which is caused by a mutation in the Bicc1 gene (614295), resulted in missorting of Egfr to apical membranes in addition to its normal basolateral localization. The bpk mutation specifically interfered with constitutive Ap1b-dependent Egfr trafficking. The resultant lack of polarity in Egfr localization in turn permitted Egf-dependent signaling from both apical and basolateral membranes and was associated with prolonged Erk1 (MAPK3; 601795)/Erk2 activation.

Berlin et al. (2010) found that depletion of USP8 (603158) in HeLa cells accelerated EGFR degradation and that USP8 mitigated EGFR degradation via an HRS (HGS; 604375)-dependent pathway. Mutation analysis using mouse proteins showed that regulation of EGFR ubiquitination required a central region of Usp8 containing 3 RxxK motifs that had low-affinity interactions with the SH3 domains of the ESCRT-0 proteins Stam1 (601899) and Stam2 (606244). Usp8-mediated deubiquitination slowed progression of EGFR past the early-to-recycling endosome circuit in an RxxK motif-dependent manner. Berlin et al. (2010) concluded that the USP8-STAM complex is a protective mechanism that regulates early endosomal sorting of EGFR between pathways destined for lysosomal degradation and recycling.

Feng et al. (2011) found that mouse Shkbp1 (617322) negatively regulated endocytosis and lysosomal degradation of EGF-activated EGFR. Yeast 2-hybrid and coimmunoprecipitation assays revealed that Shkbp1 interacted with CIN85 (SH3KBP1; 300374). Interaction of Shkbp1 with CIN85 abrogated interaction of CIN85 with CBL (165360) on endocytic vesicles and interfered with endocytosis and degradation of EGF-activated EGFR. Mutation analysis revealed that at least 1 of the 2 PxxxPR motifs of Shkbp1 was required for interaction of Shkbp1 with the SH3 domains of CIN85 and for inhibition of EGFR degradation. Wildtype Shkbp1 or mutant Shkbp1 with 1 functional PxxxPR motif elevated expression of an EGFR-dependent reporter.

Shen et al. (2013) demonstrated that EGFR, the product of a well-characterized oncogene in human cancers, suppresses the maturation of specific tumor suppressor-like microRNAs in response to hypoxic stress through phosphorylation of argonaute-2 (AGO2; 606229) at tyr393 (Y393). The association between EGFR and AGO2 is enhanced by hypoxia, leading to elevated AGO2-Y393 phosphorylation, which in turn reduces the binding of Dicer (606241) to Ago2 and inhibits miRNA processing from precursor to mature miRNA. Shen et al. (2013) also identified a long-loop structure in precursor miRNAs as a critical regulatory element in phospho-Y393-AGO2-mediated miRNA maturation. Furthermore, AGO2-Y393 phosphorylation mediates EGFR-enhanced cell survival and invasiveness under hypoxia, and correlates with poorer overall survival in breast cancer (114480) patients. Shen et al. (2013) concluded that their study revealed a function of EGFR in microRNA maturation and demonstrated how EGFR is likely to function as a regulator of AGO2 through novel posttranslational modification.

Wei et al. (2013) showed that EGFR bound the autophagy protein BECN1 (604378), leading to its multisite tyrosine phosphorylation, enhanced binding to inhibitors, and decreased BECN1-associated VPS34 (602609) kinase activity. Inhibition of EGFR disrupted BECN1 tyrosine phosphorylation and restored autophagy in human nonsmall-cell lung carcinoma cells. Wei et al. (2013) proposed that oncogenic receptor tyrosine kinases directly regulate the core autophagy machinery.

Scafidi et al. (2014) examined whether enhanced EGFR signaling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioral recovery in the developing brain. Using an established mouse model of very preterm brain injury, Scafidi et al. (2014) demonstrated that selective overexpression of human EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin-binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells, and promotes functional recovery. Furthermore, these interventions diminished ultrastructural abnormalities and alleviated behavioral deficits on white matter-specific paradigms. Inhibition of EGFR signaling with a molecularly targeted agent used for cancer therapy demonstrated that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after diffuse white matter injury. Scafidi et al. (2014) concluded that their study provided direct evidence that targeting EGFR in oligodendrocyte progenitor cells at a specific time after injury is clinically feasible and potentially applicable to the treatment of premature children with white matter injury.

Wang et al. (2013) found that human SGEF (ARHGEF26; 617552) had an RHOG (179505)- and guanine nucleotide exchange factor activity-independent role in regulating trafficking of EGFR from early to late endosomes. SGEF overexpression in prostate cancer cell lines stabilized EGFR and inhibited its degradation by slowing exit of EGFR from early endosomes and its transport to late endosomes. In contrast, depletion of SGEF increased EGFR degradation and attenuated EGF-induced AKT (see 164730) signaling and cell migration. SGEF had little effect on EGFR cell surface expression.

Using a yeast 2-hybrid screen of a human brain cDNA library with the ESCRT-0 component HRS as bait, followed by biochemical analyses, Sirisaengtaksin et al. (2014) found that HRS interacted with UBE4B (613565). Further analysis using human neuroblastoma and HeLa cells showed binding of UBE4B to endosomes via its interaction with HRS and ubiquitination and degradation of EGFR that had bound to HRS. Binding of the ESCRT-0 component STAM to HRS did not affect interaction of HRS with UBE4B. The deubiquitinating enzyme USP8 was also required for EGFR sorting and degradation. Sirisaengtaksin et al. (2014) proposed that UBE4B, the ESCRT-0 complex, and USP8 couple the ubiquitination and sorting machineries to promote endosomal sorting and lysosomal degradation of EGFR.

Fillmore et al. (2015) demonstrated that EZH2 (601573) inhibition has differential effects on the TopoII inhibitor response of nonsmall-cell lung cancers in vitro and in vivo. EGFR and BRG1 (603254) mutations are genetic biomarkers that predict enhanced sensitivity to TopoII inhibitor in response to EZH2 inhibition. BRG1 loss-of-function mutant tumors respond to EZH2 inhibition with increased S phase, anaphase bridging, apoptosis, and TopoII inhibitor sensitivity. Conversely, EGFR and BRG1 wildtype tumors upregulate BRG1 in response to EZH2 inhibition and ultimately become more resistant to TopoII inhibitor. EGFR gain-of-function mutant tumors are also sensitive to dual EZH2 inhibition and TopoII inhibitor, because of genetic antagonism between EGFR and BRG1.

Glioblastomas arise from astrocytes and their precursors, neural stem cells, and are frequently associated with activating mutations of EGFR. The most common activating mutation of EGFR in glioblastoma is deletion of exons 2 through 7, which generates a constitutively active EGFR, termed EGFRvIII, that induces phosphorylation of STAT3 to drive tumorigenesis. Using RNA sequencing analysis, Western blot analysis, and deletion and knockdown experiments, Jahani-Asl et al. (2016) found that OSMR (601743) was highly expressed in a STAT3-dependent manner in EGFRvIII-expressing human brain tumor stem cells (BTSCs) and mouse astrocytes compared with controls. Chromatin immunoprecipitation and sequencing showed that STAT3 occupied the promoter of the OSMR gene. There was significant overlap among OSMR-, STAT3-, and EGFRvIII-dependent target genes. Immunohistochemical analysis demonstrated that OSMR and EGFRvIII formed a coreceptor complex at the cell membrane, and gp130 (IL6ST; 600694) and wildtype EGFR were not required for the interaction. OSM (165095) signaling induced phosphorylation and activation of EGFR, leading to EGFR-OSMR interaction. Knockdown of OSMR inhibited proliferation of BTSCs and astrocytes. Furthermore, knockdown of Osmr suppressed tumor growth in SCID mice injected with EgfrvIII-expressing astrocytes or BTSCs. Jahani-Asl et al. (2016) concluded that OSMR is a cell surface receptor that defines a feed-forward mechanism with EGFRvIII and STAT3 in glioblastoma pathogenesis.

Runkle et al. (2016) found that silencing ZDHHC20 (617972) in human breast cancer cells increased EGF-induced sustained activation and signaling of EFGR and caused endosomal accumulation of active EGFR. Further analysis revealed that ZDHHC20 palmitoylated cysteine residues within the C-terminal tail of EGFR, and such palmitoylation of EGFR promoted association of its C-terminal tail with the plasma membrane, impeded EGFR activation, and induced turnover of activated EGFR.

The integration of endocytic routes is critical to regulate receptor signaling. A nonclathrin endocytic (NCE) pathway of EGFR is activated at high ligand concentrations and targets receptors to degradation, attenuating signaling. Caldieri et al. (2017) performed an unbiased molecular characterization of EGFR-NCE and identified NCE-specific regulators, including the endoplasmic reticulum (ER)-resident protein reticulon-3 (RTN3; 604249) and a specific cargo, CD147 (109480). RTN3 was critical for EGFR/CD147-NCE, promoting the creation of plasma membrane (PM)-ER contact sites that were required for the formation and/or maturation of NCE invaginations. Ca(2+) release at these sites, triggered by inositol 1,4,5-trisphosphate (IP3)-dependent activation of ER Ca(2+) channels, was needed for the completion of EGFR internalization. The authors concluded that they identified a mechanism of EGFR endocytosis that relies on ER-PM contact sites and local Ca(2+) signaling.

Using immunofluorescence analysis in U2OS cells, Ho and Lin (2018) showed that EGF stimulation induced dynamic interaction between the E3 ubiquitin ligase RNF144A (619454) and EGFR, resulting in colocalization of RNF144A and EGFR in the plasma membrane and intracellular vesicles. Inhibitor analysis revealed that RNF144A interacted with endocytosed EGFR in early endosomes upon EGF stimulation, and both EGFR and RNF144A were transported together to late endosomes and lysosomes. By interacting with EGFR, RNF144A promoted ubiquitination of EGFR and regulated EGFR protein levels and localization through its E3 ligase activity. A positive correlation between expression of EGFR and RNF144A was found in several types of cultured cancer cells. Knockout analysis in human cells and mouse embryonic fibroblasts revealed a role for RNF144A in EGF-dependent gene activation and cell proliferation.

▼ Cytogenetics

To investigate the global landscape of in-frame gene fusions in glioblastoma (see 137800), Frattini et al. (2013) analyzed a large RNA-sequencing data set of primary glioblastomas and glioma sphere cultures. The authors identified recurrent translocations that fuse the coding sequence of EGFR to several partners, with EGFR/SEPT14 being the most frequent functional gene fusion in human glioblastoma. EGFR/SEPT14 fusions activate STAT3 (102582) signaling and confer mitogen independence and sensitivity to EGFR inhibition.

▼ Molecular Genetics

Bivona et al. (2011) used a pooled RNA interference (RNAi) screen to show that knockdown of FAS (134637) and several components of the NF-kappa-B pathway (see 164011) specifically enhanced cell death induced by the EGFR tyrosine kinase inhibitor (TKI) erlotinib in EGFR-mutant lung cancer cells. Activation of NF-kappa-B through overexpression of c-FLIP (603599) or IKK (603258), or silencing of I-kappa-B (see 164008), rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic or pharmacologic inhibition of NF-kappa-B enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF-kappa-B inhibitor I-kappa-B predicted improved response and survival in EGFR-mutant lung cancer patients treated with EGFR TKI. Bivona et al. (2011) concluded that their data identified NF-kappa-B as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers and provided insight into the mechanisms by which tumor cells escape from oncogene dependence.

Using a functional RNAi kinase screen, Lupberger et al. (2011) identified EGFR and EPHA2 (176946) as host cofactors for hepatitis C virus (HCV; see 609532) entry into cells. Clinically approved receptor tyrosine kinase (RTK) inhibitors (erlotinib and dasatinib) or RTK-specific antibodies impaired infection by all major HCV genotypes and viral escape variants in cell culture and in a human liver chimeric mouse model. EGFR and EPHA2 mediated HCV entry by regulating CD81 (186845)-claudin-1 (CLDN1; 603718) coreceptor associations and viral glycoprotein-dependent membrane fusion. Lupberger et al. (2011) concluded that RTKs are HCV entry cofactors and that RTK inhibitors have substantial antiviral activity that may be useful for prevention and treatment of HCV infection.

Using immunohistochemical analysis, Bollee et al. (2011) found that expression of HBEGF was induced in human crescentic rapidly progressive glomerulonephritis (RPGN) and in a mouse model of RPGN. Upregulation of Hbegf in RPGN mice increased Egfr phosphorylation and induced a migratory phenotype in podocytes in vitro. Deficiency for Hbegf in mice or conditional deletion of Egfr from podocytes significantly improved the course of RPGN and survival. Pharmacologic blockade of Egfr likewise alleviated the severity of experimental RPGN. Bollee et al. (2011) concluded that activation of the HBEGF-EGFR pathway in podocytes results in RPGN.

Yang et al. (2011) demonstrated in human cancer cells that EGFR activation induces translocation of PKM2, but not PKM1 (see 179050), into the nucleus, where K433 of PKM2 binds to c-Src-phosphorylated Y333 of beta-catenin (116806). This interaction is required for both proteins to be recruited to the CCND1 (168461) promoter, leading to HDAC3 (605166) removal from the promoter, histone H3 acetylation, and cyclin D1 expression. PKM2-dependent beta-catenin transactivation is instrumental in EGFR-promoted tumor cell proliferation and brain tumor development. In addition, positive correlations were identified between c-Src activity, beta-catenin Y333 phosphorylation, and PKM2 nuclear accumulation in human glioblastoma specimens. Furthermore, levels of beta-catenin phosphorylation and nuclear PKM2 were correlated with grades of glioma malignancy and prognosis. Yang et al. (2011) concluded that their findings revealed that EGF induces beta-catenin transactivation via a mechanism distinct from that induced by Wnt/Wingless (see 164820) and highlighted the essential nonmetabolic functions of PKM2 in EGFR-promoted beta-catenin transactivation, cell proliferation, and tumorigenesis.

Response to Tyrosine Kinase Inhibitors

Most patients with nonsmall cell lung cancer (NSCLC; 211980) have no response to gefitinib, which targets the epidermal growth factor receptor. However, approximately 10% of patients have a rapid and often dramatic clinical response. Lynch et al. (2004) identified activating somatic mutations in the tyrosine kinase domain of the EGFR gene in 8 of 9 patients with gefitinib-responsive lung cancer (see 131550.0001-131550.0004) as compared with none of the 7 patients with no response (P less than 0.001). Mutations were either small in-frame deletions or amino acid substitutions that were clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients (8%) with primary NSCLC who had not been exposed to gefitinib. All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutations demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. See comments by Sorscher (2004).

Paez et al. (2004) observed a correlation between mutation in the EGFR gene in lung cancer and therapeutic response to gefitinib. They found EGFR mutations in lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinib-insensitive tumors or cell lines. Paez et al. (2004) found somatic mutations in EGFR in 15 of 58 unselected NSCLC tumors from Japan and 1 of 61 from the United States. EGFR mutations showed a striking correlation with patient characteristics. Mutations were more frequent in adenocarcinomas than in other NSCLCs, being present in 15 of 70 (21%) and 1 of 49 (2%), respectively; more frequent in women than in men, being present in 9 of 45 (20%) and 7 of 74 (9%), respectively; and more frequent in patients from Japan than in those from the United States, being present in 15 of 58 (26%) and 14 of 41 adenocarcinomas (32%) versus 1 of 61 (2%) and 1 of 29 adenocarcinomas (3%), respectively. The patient characteristics that correlated with the presence of EGFR mutations were those that correlated with clinical response to gefitinib treatment. Paez et al. (2004) suggested that identification of EGFR mutations in other malignancies, perhaps including glioblastomas in which EGFR alterations had previously been identified (Yamazaki et al., 1988), may identify other patients who would similarly benefit from treatment with EGFR inhibitors. The striking difference in the frequency of EGFR mutation and response to gefitinib between Japanese and U.S. patients raised general questions regarding variation in the molecular pathogenesis of cancer in different ethnic, cultural, and geographic groups and argued for the benefit of population diversity in cancer clinical trials.

Pao et al. (2004) found that in-frame deletions in exon 19 and somatic point mutations in codon 858 in exon 21 (see 131550.0002) of the EGFR gene were particularly common in lung cancers from 'never smokers' and were associated with sensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib. Because most of the mutation-positive tumors were adenocarcinomas from 'never smokers' (defined as patients who smoked less than 100 cigarettes in a lifetime), Pao et al. (2004) screened EGFR exons 2-28 for mutations in 15 adenocarcinomas resected from untreated 'never smokers.' Seven tumors had tyrosine kinase domain mutations, in contrast to 4 of 81 nonsmall cell lung cancers (NSCLC; 211980) resected from untreated former or current smokers (p = 0.0001). Pao et al. (2004) suggested that these findings, together with those of Paez et al. (2004) and Lynch et al. (2004), showed that adenocarcinomas from 'never smokers' comprise a distinct subset of lung cancers, frequently containing mutations within the tyrosine kinase domain of EGFR that are associated with kinase inhibitor sensitivity.

Sordella et al. (2004) reported that mutant EGFRs selectively activate AKT (164730) and STAT (see 600555) signaling pathways, which promote cell survival, but have no effect on extracellular signal-regulated kinase signaling, which induces proliferation. Non-small cell lung cancer cells expressing mutant EGFRs underwent extensive apoptosis after siRNA-mediated knockdown of the mutant EGFR or treatment with pharmacologic inhibitors of AKT and STAT signaling and were relatively resistant to apoptosis induced by conventional chemotherapeutic drugs. Thus, Sordella et al. (2004) concluded that mutant EGFR selectively transduced survival signals on which nonsmall cell lung cancers become dependent; inhibition of those signals by gefitinib may contribute to the drug's efficacy.

Despite the dramatic responses to EGFR inhibitors in patients with nonsmall cell lung cancer, most patients ultimately have a relapse. Kobayashi et al. (2005) reported a patient with EGFR-mutant, gefitinib-responsive, advanced nonsmall cell lung cancer who had a relapse after 2 years of complete remission during treatment with gefitinib. The DNA sequence of the EGFR gene in his tumor biopsy specimen at relapse revealed the presence of a second mutation (131550.0006). Structural modeling and biochemical studies showed that this second mutation led to the gefitinib resistance.

In a study of EGFR expression and mutations in 325 patients with NSCLC treated with erlotinib, Tsao et al. (2005) found that expression of EGFR and an increased number of copies of EGFR, but not mutations in EGFR, were associated with responsiveness to erlotinib but not with increased survival. Tsao et al. (2005) suggested that mutation analysis is not necessary to identify patients in whom treatment with EGFR inhibitors is appropriate.

Marie et al. (2005) found no EGFR mutations in 95 gliomas, including glioblastomas, anaplastic oligodendrogliomas, and low-grade gliomas, which suggested that EGFR inhibitors would not be effective treatment for these tumors.

Gu et al. (2007) reported the creation of an EGFR mutation database that curates somatic EGFR mutations in nonsmall cell lung cancer. The authors analyzed 809 mutations collected from 26 publications. Four super hotspots accounted for 70% of the mutations, while two-thirds of 131 unique mutations were reported only once and counted for 11% of reported mutations. Microdeletions (1 to 50 nt) and microindels (loss or gain of 1 to 50 nt) were common in a region of exon 19. Microdeletions and microindels were significantly more frequent in responders to the tyrosine kinase inhibitors gefitinib or erlotinib. EGFR mutations in smokers did not carry signatures of mutagens in cigarette smoke.

The EGFR kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Engelman et al. (2007) described a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET (164860) protooncogene. Inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. Engelman et al. (2007) found that amplification of MET caused gefitinib resistance by driving ERBB3-dependent activation of phosphoinositide 3-kinase, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, Engelman et al. (2007) proposed that MET amplification may promote drug resistance in other ERBB-driven cancers as well.

Bean et al. (2007) found that MET was amplified in lung tumors from 9 (21%) of 43 patients with acquired resistance to EGFR kinase inhibitors, but in only 2 (3%) tumors from 62 untreated patients. Among 10 resistant tumors from the 9 patients with MET amplification, 4 tumors also had the T790M mutation (131550.0006), which confers resistance. In addition, a cell line with a drug-sensitive EGFR mutation, MET amplification, and the T790M mutation was found to be resistant to EGFR inhibitors but sensitive to a multikinase inhibitor with potent activity against MET. The data suggested that MET amplification occurs independent of the T790M mutation and that MET may be a therapeutic target in appropriate patients.

Gao et al. (2007) identified activated STAT3 (102582) and increased levels of IL6 (147620) in lung adenocarcinomas harboring somatic activating mutations in the EGFR gene. Treatment of cell lines with an EGFR inhibitor had no effect on STAT3 levels, but a pan-JAK (see 147795) inhibitor or an IL6 inhibitor blocked activation of STAT3 and inhibited tumorigenesis. Inhibition of EGFR partially blocked IL6. Gao et al. (2007) concluded that mutant EGFR can activate the JAK/STAT3 pathway by upregulation of IL6 in primary human lung adenocarcinomas.

Maheswaran et al. (2008) identified the T790M mutation in pretreatment tumor samples from 10 (38%) of 26 patients with nonsmall cell lung cancer. Although low levels of the drug-resistant mutation did not preclude response to treatment, it was highly correlated with reduced progression-free survival. Use of a microfluidic-based isolation device and sequence amplification technology allowed for detection of EGFR mutations in circulating tumor cells from 11 (92%) of 12 patients. Serial analysis of circulating tumor cells showed that a reduction in the number of captured cells was associated with a radiographic tumor response; an increase in the number of cells was associated with tumor progression, with the emergence of additional EGFR mutations in some cases. Maheswaran et al. (2008) concluded that molecular analysis of circulating tumor cells from the blood of patients with nonsmall cell lung cancer offers the possibility of monitoring changes in tumor genotype.

Liu et al. (2008) explored a wide-range genetic basis for the involvement of genetic alterations in receptor tyrosine kinases (RTKs) and phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK pathways in anaplastic thyroid cancer (ATC) and follicular thyroid cancer (FTC; see 188470). They found frequent copy gains of RTK genes including EGFR and VEGFR1 (165070), and PIK3CA (171834) and PIK3CB (602925) in the P13K/Akt pathway. Copy number gain of EGFR was found in 19 of 41 ATCs (46%) and 19 of 59 FTCs (32%). RTK gene copy gains were preferentially associated with phosphorylation of Akt, suggesting their dominant role in activating the P13K/Akt pathway. Liu et al. (2008) concluded that genetic alterations in the RTKs and P13K/Akt and MAPK pathways are extremely prevalent in ATC and FTC, providing a strong genetic basis for an extensive role of these signaling pathways and the development of therapies targeting these pathways for ATC and FTC, particularly the former.

In a randomized control trial of 1,217 East Asian patients with nonsmall cell lung cancer, Mok et al. (2009) found that the 12-month rate of progression-free survival was 24.9% in patients treated with gefitinib and 6.7% in those treated with carboplatin-paclitaxel. In the subgroup of 261 patients who were positive for an EGFR mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel, whereas in the subgroup of 176 patients who were negative for a mutation, progression-free survival was significantly longer among those who received carboplatin-paclitaxel. The findings indicated that gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia, and showed that the presence in the tumor of an EGFR mutation is a strong predictor of a better outcome with gefitinib.

Rosell et al. (2009) concluded that large-scale screening of patients with lung cancer for EGFR mutations is feasible and can have a role in treatment decisions. EGFR mutations were identified in tumor tissue of 350 (16.6%) of 2,105 Spanish patients with nonsmall cell lung cancer. Mutations were more frequent in women (69.7%), in patients who had never smoked (66.6%), and in those with adenocarcinomas (80.9%). The mutations were deletions in exon 19 (62.2%) and L858R (131550.0002) (37.8%). Median progression-free survival and overall survival for 217 patients who received erlotinib were 14 months and 27 months, respectively. Multivariate analysis showed an association between poor progression-free survival and male sex (hazard ratio of 2.94), and the presence of the L858R mutation (hazard ratio of 1.92) as compared with a deletion in exon 19. The most common adverse events were mild rashes and diarrhea. The results suggested that EGFR-mutant lung cancer is a distinct class of nonsmall cell lung cancer.

Seike et al. (2009) stated that mutations of EGFR are more frequent in lung cancers from never smokers than smokers. They had previously shown that upregulation of several microRNAs, including MIR21 (611020), correlates with poor survival in smokers with lung cancer. Using RT-PCR, Seike et al. (2009) found that MIR21 expression was significantly higher in cancer tissue than in noncancer tissue from 28 never smokers, 6 of whom had activating mutations in the EGFR tyrosine kinase domain. Expression of MIR21 and phosphorylated EGFR protein correlated in lung carcinoma cell lines, and activation of EGFR signaling enhanced MIR21 expression. Conversely, inhibition of EGFR tyrosine kinase activity repressed MIR21 expression. Repression of MIR21 by antisense RNA enhanced the apoptotic response of cells to inhibition of EGFR tyrosine kinase activity.

Somatic Mutations Conferring Antibody Resistance in Colorectal Cancer

Montagut et al. (2012) described an acquired EGFR ectodomain mutation (S492R) that prevents cetuximab binding and confers resistance to cetuximab. Cells with this mutation, however, retain binding to and are growth inhibited by panitumumab. Two of 10 subjects studied with metastatic colon cancer progression after cetuximab treatment acquired this mutation. One subject with cetuximab resistance harboring the S492R mutation responded to treatment with panitumumab.

Neonatal Inflammatory Skin and Bowel Disease 2

By whole-exome sequencing of DNA from a Polish Roma boy who died from neonatal inflammatory skin and bowel disease (NISBD2; 616069), Campbell et al. (2014) identified homozygosity for a missense mutation in the EGFR gene (G428D; 131550.0007). Functional analysis demonstrated loss of membrane localization with the G428D mutant as well as loss of function compared to wildtype.

▼ Animal Model

Atrioventricular and semilunar valve abnormalities are common birth defects. During studies of genetic interaction between Egr2 and Ptpn11, encoding the protein-tyrosine phosphatase Shp2 (176876), Chen et al. (2000) found that Egfr is required for semilunar, but not atrioventricular, valve development. Although unnoticed in earlier studies, mice homozygous for the hypomorphic Egfr allele 'waved-2' (wa2) exhibited semilunar valve enlargement resulting from overabundant mesenchymal cells. Egfr -/- mice (on CD1 background) had similar defects. The penetrance and severity of the defects in the homozygous wa2 mice were enhanced by heterozygosity for a targeted mutation of exon 2 of Ptpn11. Compound mutant mice also showed premature lethality. Electrocardiography, echocardiography, and hemodynamic analyses showed that affected mice developed aortic stenosis and regurgitation. The results identified Egfr and Shp2 as components of a growth-factor signaling pathway required specifically for semilunar valvulogenesis, supported the hypothesis that Shp2 is required for Egfr signaling in vivo, and provided an animal model for aortic valve disease.

EGFR is required for skin development and is implicated in epithelial tumor formation. Sibilia et al. (2000) found that transgenic mice expressing SOS-F (a dominant form of 'son of sevenless' (SOS1) lacking the C-terminal region containing the GRB2 (108355)-binding site and instead carrying the c-Ha-ras farnesylation site, which provides constitutive activity) driven by the keratin-5 (K5, or KRT5; 148040) promoter in basal keratinocytes developed skin papillomas with 100% penetrance. Tumor formation was inhibited, however, in mice with a hypomorphic (wa2) and null Egfr background. Similarly, Egfr-deficient fibroblasts were resistant to transformation by SOS-F and rasV12, although tumorigenicity could be restored by expression of the antiapoptotic Bcl2 gene (151430). The K5-SOS-F papillomas and primary keratinocytes from wa2 mice displayed increased apoptosis and reduced Akt (164730) phosphorylation, and grafting experiments implied a cell-autonomous requirement for Egfr in keratinocytes. Therefore, the authors concluded that EGFR functions as a survival factor in oncogenic transformation and provides a valuable target for therapeutic intervention.

The circadian clock in the suprachiasmatic nucleus is thought to drive daily rhythms of behavior by secreting factors that act locally within the hypothalamus. In a systematic screen, Kramer et al. (2001) identified transforming growth factor-alpha (TGFA; 190170) as a likely suprachiasmatic nucleus inhibitor of locomotion. TGFA is expressed rhythmically in the suprachiasmatic nucleus, and when infused into the third ventricle it reversibly inhibited locomotor activity and disrupted circadian sleep-wake cycles. These actions were mediated by epidermal growth factor receptors on neurons in the hypothalamic subparaventricular zone. Mice with a hypomorphic EGF receptor mutation exhibited excessive daytime locomotor activity and failed to suppress activity when exposed to light. Kramer et al. (2001) concluded that their results implicate EGF receptor signaling in the daily control of locomotor activity. They identified a neural circuit in the hypothalamus that likely mediates the regulation of behavior both by the suprachiasmatic nucleus and the retina using TGFA and EGF receptors in the retinohypothalamic tract.

Thaung et al. (2002) carried out a genomewide screen for novel N-ethyl-N-nitrosourea-induced mutations that give rise to eye and vision abnormalities in the mouse, and identified 25 inherited phenotypes that affect all parts of the eye. A combination of genetic mapping, complementation, and molecular analysis revealed that 14 of these were mutations in genes previously identified to play a role in eye pathophysiology, namely Pax6 (607108), Mitf (156845), Egfr, and Pde6b (180072). Many of the others were located in genomic regions lacking candidate genes.

Lautrette et al. (2005) found that angiotensin II (see 106150) infusion in mice over 2 months produced severe renal lesions, mainly glomerulosclerosis, tubular atrophy and/or dilation with little microcyst formation, mild interstitial fibrosis, and multifocal mononuclear cell infiltration. In contrast, mice overexpressing a dominant-negative isoform of EGFR were protected from renal lesions during chronic angiotensin II infusion. Tgfa and its sheddase, Tace (ADAM17; 603639), were induced by angiotensin II treatment, Tace was redistributed to apical membranes, and Egfr was phosphorylated. Angiotensin II-induced lesions were reduced in mice lacking Tgfa or in mice given a Tace inhibitor. Inhibition of angiotensin II prevented Tgfa and Tace accumulation and renal lesions after nephron reduction. Lautrette et al. (2005) concluded that EGFR transactivation is crucial for angiotensin II-associated renal deterioration.

Wang et al. (2004) analyzed long bone development in Egfr-deficient mouse embryos and found that Egfr deficiency delayed primary ossification of the cartilage anlage and delayed osteoclast and osteoblast recruitment. Ossification of the growth plates was also abnormal, resulting in an expanded area of growth plate hypertrophic cartilage and few bony trabeculae. Inhibition of Egfr tyrosine kinase activity decreased the generation of osteoclasts from cultured mouse bone marrow cells.

Natarajan et al. (2007) deleted Egfr in livers of adult and fetal mice. Perinatal deletion of Egfr in hepatocytes resulted in decreased body weight, whereas deletion in adult liver did not affect body mass. Following partial hepatectomy, adult mutant mice showed impaired liver regeneration, and the regenerating livers displayed an impaired stress response.

▼ ALLELIC VARIANTS ( 7 Selected Examples):

Table View ClinVar

.0001 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

EGFR, 18-BP DEL, NT2240

RCV000018082...

In tumors from 2 patients with nonsmall cell lung cancer (211980), Lynch et al. (2004) identified an 18-bp deletion (2240del18) in the EGFR gene, resulting in an in-frame deletion of amino acids 747-753 and insertion of a serine residue. The tumors in these 2 patients were responsive to gefitinib. In another patient with nonsmall cell lung cancer, the same mutation was identified; the patient had had no exposure to gefitinib.

In a tumor with the 2240del18 mutation from a patient with nonsmall cell lung cancer who showed responsiveness to gefitinib with complete remission over a 2-year period, Kobayashi et al. (2005) identified the development of a second mutation in EGFR, thr790 to met (T790M; 131550.0006), responsible for secondary resistance to gefitinib.

.0002 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

ADENOCARCINOMA OF LUNG, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC, INCLUDED

EGFR, LEU858ARG

RCV000018083...

In tumors from 2 patients with nonsmall cell lung cancer (211980), Lynch et al. (2004) identified a 2573T-G transversion in the EGFR gene, resulting in a leu858-to-arg (L858R) substitution.

In 3 lung adenocarcinomas and 3 NSCLC tumors, Paez et al. (2004) identified the L858R mutation in heterozygous state.

Pao et al. (2004) identified the L858R mutation in lung cancers from 'never smokers,' which were associated with sensitivity to 2 tyrosine kinase inhibitors. The tumors were most often adenocarcinomas. They identified this mutation as being adjacent to the highly conserved DGF motif in the activation loop of the kinase.

Toyooka et al. (2005) identified 2 EGFR mutations, T790M (131550.0006) and L858R, in resected tumor specimens taken from 2 women with nonsmall cell lung cancer before treatment with chemotherapy or radiation. Both patients later had recurrent disease and eventually died, suggesting that tumors with both these mutations are very aggressive. One patient was treated with gefitinib and had progression.

.0003 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

EGFR, 12-BP DEL, NT2240

RCV000018085...

In a tumor from a patient with nonsmall cell lung cancer (211980) responsive to gefitinib, Lynch et al. (2004) identified a 12-bp deletion (2240del12) in the EGFR gene, resulting in an in-frame deletion of amino acids 747-751 and insertion of a serine residue.

.0004 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

EGFR, GLY719CYS (rs28929495)

RCV000018086...

In a tumor from a patient with nonsmall cell lung cancer (211980) responsive to gefitinib, Lynch et al. (2004) identified a somatic 2155G-T transversion in the EGFR gene, resulting in a gly719-to-cys (G719C) mutation.

.0005 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

EGFR, GLY719SER

RCV000018087...

In 2 nonsmall cell lung cancer (211980) tumors, Paez et al. (2004) identified a somatic gly719-to-ser (G719S) mutation in the EGFR gene in heterozygous state.

.0006 NONSMALL CELL LUNG CANCER, RESISTANCE TO TYROSINE KINASE INHIBITOR IN

EGFR, THR790MET

RCV000018088...

In a tumor with the 2240del18 mutation in the EGFR gene (131550.0001) from a patient with nonsmall cell lung cancer (211980) who showed responsiveness to gefitinib with complete remission over a 2-year period, Kobayashi et al. (2005) identified the development of a second mutation in EGFR, thr790 to met (T790M), responsible for secondary resistance to gefitinib. Kobayashi et al. (2005) noted that one of the most common imatinib resistance mutations in ABL1/BCR in leukemia replaces threonine at position 315 (the amino acid structurally corresponding to T790 of EGFR) with isoleucine in the ABL tyrosine kinase domain (thr315 to ile; 189980.0001). The T315I substitution leads to a structural change very similar to that observed with T790M (Gorre et al., 2001).

In 2 women with nonsmall cell lung cancer, Toyooka et al. (2005) identified 2 EGFR mutations, T790M and L858R (131550.0002), in resected tumor specimens taken before treatment with chemotherapy or radiation. Both patients later had recurrent disease and eventually died, suggesting that tumors with both these mutations are very aggressive. One patient was treated with gefitinib and had progression.

Approximately 10% on of nonsmall cell lung cancers respond markedly to treatment with tyrosine kinase inhibitors that target EGFR. Responsive tumors are characteristically adenocarcinomas, often with bronchoalveolar (BAC) differentiation, and they are most common in nonsmokers, women, and Asians. Molecular analyses identified specific mutations in the kinase domain of EGFR in approximately 80% of responsive cases, e.g., an 18-bp deletion (131550.0001) and a missense mutation, L858R (131550.0002). These characteristic missense mutations and in-frame deletions affect residues of the ATP binding pocket, selectively enhancing ligand-dependent activation of the AKT/STAT survival pathways by the receptor. The T790M mutation was reported in cases of nonsmall cell lung cancers that recurred after initial response to tyrosine kinase inhibitors. Bell et al. (2005) studied a family of European descent in which multiple members developed the BAC subtype of nonsmall cell lung cancer. Six persons in 3 generations were affected. The cancer was found to be associated with germline transmission of the T790M mutation, suggesting that this mutation confers a growth advantage even in the absence of selective pressure of a tyrosine kinase inhibitor. Four of 6 tumors analyzed showed a secondary somatic activating EGFR mutation, arising in cis with the germline EGFR mutation T790M. These observations implicated altered EGFR signaling in genetic susceptibility to lung cancer.

Yun et al. (2008) noted that thr790 is located at the entrance to a hydrophobic pocket in the back of the ATP binding cleft of EGFR. Substitution of thr790 with a bulky methionine has been postulated to cause resistance to reversible tyrosine kinase inhibitors through steric interference. However, Yun et al. (2008) used crystal structure analysis to show that certain irreversible inhibitors could still bind to the T790M-mutant EGFR, which is inconsistent with steric interference as a mechanism of drug resistance. Kinetic studies indicated that the L858R/T790M mutant receptor had increased ATP affinity compared to the L858R mutant alone, restoring ATP affinity close to that of wildtype. The T790M mutant alone and with L858R significantly increased kinase activity compared to wildtype. Yun et al. (2008) concluded that the T790M mutation will reduce the potency of any ATP-competitive kinase inhibitor, and that the primary mechanism of drug resistance conferred by T790M is increased ATP affinity.

Zhou et al. (2009) identified a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wildtype EGFR, than quinazoline-based EGFR inhibitors in vitro. They were also affected in murine models of lung cancer driven by EGFR T790M.

.0007 INFLAMMATORY SKIN AND BOWEL DISEASE, NEONATAL, 2 (1 family)

EGFR, GLY428ASP

RCV000144851...

By whole-exome sequencing of DNA from a Polish Roma boy who died from neonatal inflammatory skin and bowel disease-2 (NISBD2; 616069), Campbell et al. (2014) identified homozygosity for a c.1283G-A transition in exon 1 of the EGFR gene, resulting in a gly428-to-asp (G428D) substitution at a highly conserved residue. His unaffected mother was heterozygous for the mutation, which was not present in an unaffected sib; no DNA from the father was available. The mutation was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 900 unrelated European in-house control exomes. Functional analysis in MCF-7 cells demonstrated that mutant EGFR was distributed throughout the cytoplasm in contrast to wildtype, which was present primarily on the cell membrane; EGF stimulation resulted in robust translocation of wildtype EGFR to the plasma membrane, whereas mutant EGFR remained in the cytoplasm. In addition, mutant EGFR was able to undergo recycling to the plasma membrane but could only be retained there by blockade of endocytic signaling, suggesting that G428D-mutant EGFR at the plasma membrane is highly unstable and thus more susceptible to constitutive endocytosis. EGF-stimulated phosphorylation of EGFR, AKT (164730), and ERK (see 601795) was undetectable following ligand binding to mutant EGFR-expressing cells, in contrast to that seen with wildtype EGFR; this suggested that G428D results in loss of function as well as loss of membrane localization.

▼ See Also:

Carpenter (1984); Davies et al. (1980); Maciag (1982); Reynolds et al. (1981); Spurr et al. (1984); Ullrich et al. (1984)

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Zhou, W., Ercan, D., Chen, L., Yun, C.-H., Li, D., Capelletti, M., Cortot, A. B., Chirieac, L., Iacob, R. E., Padera, R., Engen, J. R., Wong, K.-K., Eck, M. J., Gray, N. S., Janne, P. A. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 462: 1070-1074, 2009. [PubMed: 20033049, images, related citations] [Full Text]

Contributors:

Bao Lige - updated : 07/22/2021

Bao Lige - updated : 05/10/2018
Paul J. Converse - updated : 01/05/2018
Paul J. Converse - updated : 10/04/2017
Ada Hamosh - updated : 08/14/2017
Patricia A. Hartz - updated : 06/23/2017
Paul J. Converse - updated : 03/07/2017
Patricia A. Hartz - updated : 01/30/2017
Ada Hamosh - updated : 07/06/2015
Patricia A. Hartz - updated : 4/30/2015
Ada Hamosh - updated : 11/19/2014
Marla J. F. O'Neill - updated : 10/28/2014
Ada Hamosh - updated : 3/13/2014
Ada Hamosh - updated : 8/27/2013
Patricia A. Hartz - updated : 7/23/2012
Ada Hamosh - updated : 3/13/2012
Ada Hamosh - updated : 1/4/2012
Patricia A. Hartz - updated : 10/26/2011
Paul J. Converse - updated : 5/12/2011
Ada Hamosh - updated : 5/12/2011
Patricia A. Hartz - updated : 2/15/2011
Ada Hamosh - updated : 11/10/2010
Ada Hamosh - updated : 9/29/2010
Paul J. Converse - updated : 7/6/2010
Matthew B. Gross - updated : 5/5/2010
Ada Hamosh - updated : 4/28/2010
Ada Hamosh - updated : 4/13/2010
Cassandra L. Kniffin - updated : 9/3/2009
John A. Phillips, III - updated : 5/7/2009
Cassandra L. Kniffin - updated : 8/20/2008
Cassandra L. Kniffin - updated : 8/13/2008
Patricia A. Hartz - updated : 7/8/2008
Patricia A. Hartz - updated : 6/25/2008
Cassandra L. Kniffin - updated : 3/13/2008
Cassandra L. Kniffin - updated : 2/5/2008
Ada Hamosh - updated : 1/22/2008
Cassandra L. Kniffin - updated : 10/10/2007
Ada Hamosh - updated : 6/27/2007
Ada Hamosh - updated : 6/14/2007
Marla J. F. O'Neill - updated : 11/16/2006
Ada Hamosh - updated : 5/1/2006
Marla J. F. O'Neill - updated : 4/6/2006
Patricia A. Hartz - updated : 3/24/2006
Victor A. McKusick - updated : 12/16/2005
Ada Hamosh - updated : 11/21/2005
Patricia A. Hartz - updated : 9/16/2005
Patricia A. Hartz - updated : 9/12/2005
Cassandra L. Kniffin - updated : 8/19/2005
Marla J. F. O'Neill - updated : 7/28/2005
Cassandra L. Kniffin - updated : 6/16/2005
Victor A. McKusick - updated : 3/7/2005
Victor A. McKusick - updated : 2/2/2005
Ada Hamosh - updated : 12/10/2004
Victor A. McKusick - updated : 10/6/2004
Victor A. McKusick - updated : 5/28/2004
Ada Hamosh - updated : 8/5/2003
George E. Tiller - updated : 10/25/2002
Ada Hamosh - updated : 4/2/2002
Ada Hamosh - updated : 1/3/2002
Ada Hamosh - updated : 11/29/2000
Ada Hamosh - updated : 11/15/2000
Stylianos E. Antonarakis - updated : 8/8/2000
Victor A. McKusick - updated : 3/1/2000
Victor A. McKusick - updated : 10/1/1998
Jennifer P. Macke - updated : 11/5/1996

Creation Date:

Victor A. McKusick : 6/4/1986

Edit History:

alopez : 04/18/2024

alopez : 04/17/2024
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carol : 05/08/2019
alopez : 03/28/2019
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carol : 01/23/2018
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carol : 11/06/2017
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mgross : 10/05/2017
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carol : 08/15/2017
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mgross : 06/23/2017
mgross : 03/07/2017
mgross : 03/07/2017
mgross : 01/30/2017
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mgross : 4/30/2015
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carol : 11/3/2014
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carol : 10/1/2013
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tpirozzi : 10/1/2013
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terry : 4/4/2013
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alopez : 3/14/2012
terry : 3/13/2012
alopez : 1/12/2012
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terry : 1/4/2012
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mgross : 10/31/2011
terry : 10/26/2011
alopez : 5/20/2011
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terry : 5/12/2011
alopez : 5/12/2011
mgross : 2/15/2011
alopez : 11/15/2010
terry : 11/10/2010
alopez : 10/4/2010
terry : 9/29/2010
terry : 9/29/2010
mgross : 7/8/2010
terry : 7/6/2010
wwang : 5/5/2010
alopez : 4/29/2010
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terry : 4/13/2010
wwang : 9/22/2009
ckniffin : 9/3/2009
alopez : 5/7/2009
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wwang : 10/14/2008
wwang : 8/26/2008
ckniffin : 8/20/2008
wwang : 8/19/2008
ckniffin : 8/13/2008
mgross : 7/8/2008
mgross : 7/8/2008
alopez : 7/3/2008
terry : 6/25/2008
wwang : 5/16/2008
ckniffin : 3/13/2008
ckniffin : 3/13/2008
wwang : 2/25/2008
ckniffin : 2/5/2008
alopez : 1/24/2008
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wwang : 10/12/2007
joanna : 10/12/2007
ckniffin : 10/10/2007
alopez : 7/24/2007
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terry : 6/27/2007
terry : 6/14/2007
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terry : 11/16/2006
alopez : 5/3/2006
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terry : 5/1/2006
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carol : 4/14/2006
wwang : 4/7/2006
terry : 4/6/2006
mgross : 3/28/2006
terry : 3/24/2006
alopez : 12/29/2005
alopez : 12/28/2005
terry : 12/16/2005
alopez : 11/22/2005
terry : 11/21/2005
mgross : 9/16/2005
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wwang : 8/19/2005
ckniffin : 8/19/2005
wwang : 8/3/2005
terry : 7/28/2005
wwang : 7/1/2005
wwang : 6/29/2005
ckniffin : 6/16/2005
tkritzer : 3/16/2005
terry : 3/7/2005
carol : 2/23/2005
wwang : 2/7/2005
terry : 2/2/2005
alopez : 12/14/2004
alopez : 12/14/2004
terry : 12/10/2004
terry : 11/3/2004
alopez : 10/8/2004
terry : 10/6/2004
tkritzer : 7/15/2004
tkritzer : 6/22/2004
terry : 5/28/2004
alopez : 8/6/2003
terry : 8/5/2003
cwells : 10/25/2002
alopez : 4/4/2002
terry : 4/2/2002
alopez : 1/9/2002
terry : 1/3/2002
mgross : 12/1/2000
terry : 11/29/2000
mgross : 11/15/2000
mgross : 8/8/2000
mgross : 8/8/2000
alopez : 3/1/2000
terry : 3/1/2000
carol : 10/5/1998
terry : 10/2/1998
terry : 10/2/1998
terry : 10/1/1998
carol : 9/14/1998
mark : 11/9/1996
carol : 11/5/1996
carol : 10/26/1993
supermim : 3/16/1992
supermim : 3/20/1990
supermim : 2/27/1990
supermim : 1/12/1990
ddp : 10/26/1989

* 131550

EPIDERMAL GROWTH FACTOR RECEPTOR; EGFR

Alternative titles; symbols

V-ERB-B AVIAN ERYTHROBLASTIC LEUKEMIA VIRAL ONCOGENE HOMOLOG
ONCOGENE ERBB
ERBB1
HER1
SPECIES ANTIGEN 7; SA7

Other entities represented in this entry:

EGFR/SEPT14 FUSION GENE, INCLUDED

HGNC Approved Gene Symbol: EGFR

Cytogenetic location: 7p11.2 Genomic coordinates (GRCh38): 7:55,019,017-55,211,628 (from NCBI)

Gene-Phenotype Relationships

Location	Phenotype	Phenotype MIM number	Inheritance	Phenotype mapping key
7p11.2	?Inflammatory skin and bowel disease, neonatal, 2	616069	Autosomal recessive	3
	{Nonsmall cell lung cancer, susceptibility to}	211980	Autosomal dominant; Somatic mutation	3
	Adenocarcinoma of lung, response to tyrosine kinase inhibitor in	211980	Autosomal dominant; Somatic mutation	3
	Nonsmall cell lung cancer, response to tyrosine kinase inhibitor in	211980	Autosomal dominant; Somatic mutation	3

TEXT

Description

Cloning and Expression

Gene Structure

Mapping

Carlin et al. (1982) indicated 7p22-p12 as the localization of the EGFR gene. Kondo and Shimizu (1983) concluded that EGFR is in the 7p13-q22 region.

Biochemical Features

Dimerization Dynamics

Gene Function

Cytogenetics

Molecular Genetics

Response to Tyrosine Kinase Inhibitors

Somatic Mutations Conferring Antibody Resistance in Colorectal Cancer

Neonatal Inflammatory Skin and Bowel Disease 2

Animal Model

ALLELIC VARIANTS 7 Selected Examples):

.0001 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

EGFR, 18-BP DEL, NT2240
SNP: rs121913438, ClinVar: RCV000018082, RCV000154194, RCV003996103

.0002 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

ADENOCARCINOMA OF LUNG, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC, INCLUDED

EGFR, LEU858ARG
SNP: rs121434568, ClinVar: RCV000018083, RCV000018084, RCV000150629, RCV000211323, RCV000418019, RCV000435684, RCV000987885

In tumors from 2 patients with nonsmall cell lung cancer (211980), Lynch et al. (2004) identified a 2573T-G transversion in the EGFR gene, resulting in a leu858-to-arg (L858R) substitution.

In 3 lung adenocarcinomas and 3 NSCLC tumors, Paez et al. (2004) identified the L858R mutation in heterozygous state.

.0003 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

EGFR, 12-BP DEL, NT2240
SNP: rs397509368, ClinVar: RCV000018085, RCV000154240

.0004 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

EGFR, GLY719CYS ({dbSNP rs28929495})
SNP: rs28929495, ClinVar: RCV000018086, RCV000038380, RCV000426731, RCV000433465

.0005 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

EGFR, GLY719SER
SNP: rs28929495, ClinVar: RCV000018087, RCV000154198, RCV000423860, RCV000434135, RCV001851901, RCV003996104

In 2 nonsmall cell lung cancer (211980) tumors, Paez et al. (2004) identified a somatic gly719-to-ser (G719S) mutation in the EGFR gene in heterozygous state.

.0006 NONSMALL CELL LUNG CANCER, RESISTANCE TO TYROSINE KINASE INHIBITOR IN

EGFR, THR790MET
SNP: rs121434569, gnomAD: rs121434569, ClinVar: RCV000018088, RCV000154232, RCV000154233, RCV000211319, RCV000425417, RCV000557450, RCV001015308, RCV001588815, RCV001787805, RCV001823098, RCV003466864, RCV003996105

.0007 INFLAMMATORY SKIN AND BOWEL DISEASE, NEONATAL, 2 (1 family)

EGFR, GLY428ASP
SNP: rs606231253, gnomAD: rs606231253, ClinVar: RCV000144851, RCV001849972

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Contributors:

Bao Lige - updated : 07/22/2021
Bao Lige - updated : 05/10/2018
Paul J. Converse - updated : 01/05/2018
Paul J. Converse - updated : 10/04/2017
Ada Hamosh - updated : 08/14/2017
Patricia A. Hartz - updated : 06/23/2017
Paul J. Converse - updated : 03/07/2017
Patricia A. Hartz - updated : 01/30/2017
Ada Hamosh - updated : 07/06/2015
Patricia A. Hartz - updated : 4/30/2015
Ada Hamosh - updated : 11/19/2014
Marla J. F. O'Neill - updated : 10/28/2014
Ada Hamosh - updated : 3/13/2014
Ada Hamosh - updated : 8/27/2013
Patricia A. Hartz - updated : 7/23/2012
Ada Hamosh - updated : 3/13/2012
Ada Hamosh - updated : 1/4/2012
Patricia A. Hartz - updated : 10/26/2011
Paul J. Converse - updated : 5/12/2011
Ada Hamosh - updated : 5/12/2011
Patricia A. Hartz - updated : 2/15/2011
Ada Hamosh - updated : 11/10/2010
Ada Hamosh - updated : 9/29/2010
Paul J. Converse - updated : 7/6/2010
Matthew B. Gross - updated : 5/5/2010
Ada Hamosh - updated : 4/28/2010
Ada Hamosh - updated : 4/13/2010
Cassandra L. Kniffin - updated : 9/3/2009
John A. Phillips, III - updated : 5/7/2009
Cassandra L. Kniffin - updated : 8/20/2008
Cassandra L. Kniffin - updated : 8/13/2008
Patricia A. Hartz - updated : 7/8/2008
Patricia A. Hartz - updated : 6/25/2008
Cassandra L. Kniffin - updated : 3/13/2008
Cassandra L. Kniffin - updated : 2/5/2008
Ada Hamosh - updated : 1/22/2008
Cassandra L. Kniffin - updated : 10/10/2007
Ada Hamosh - updated : 6/27/2007
Ada Hamosh - updated : 6/14/2007
Marla J. F. O'Neill - updated : 11/16/2006
Ada Hamosh - updated : 5/1/2006
Marla J. F. O'Neill - updated : 4/6/2006
Patricia A. Hartz - updated : 3/24/2006
Victor A. McKusick - updated : 12/16/2005
Ada Hamosh - updated : 11/21/2005
Patricia A. Hartz - updated : 9/16/2005
Patricia A. Hartz - updated : 9/12/2005
Cassandra L. Kniffin - updated : 8/19/2005
Marla J. F. O'Neill - updated : 7/28/2005
Cassandra L. Kniffin - updated : 6/16/2005
Victor A. McKusick - updated : 3/7/2005
Victor A. McKusick - updated : 2/2/2005
Ada Hamosh - updated : 12/10/2004
Victor A. McKusick - updated : 10/6/2004
Victor A. McKusick - updated : 5/28/2004
Ada Hamosh - updated : 8/5/2003
George E. Tiller - updated : 10/25/2002
Ada Hamosh - updated : 4/2/2002
Ada Hamosh - updated : 1/3/2002
Ada Hamosh - updated : 11/29/2000
Ada Hamosh - updated : 11/15/2000
Stylianos E. Antonarakis - updated : 8/8/2000
Victor A. McKusick - updated : 3/1/2000
Victor A. McKusick - updated : 10/1/1998
Jennifer P. Macke - updated : 11/5/1996

Creation Date:

Victor A. McKusick : 6/4/1986

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terry : 7/6/2010
wwang : 5/5/2010
alopez : 4/29/2010
terry : 4/28/2010
alopez : 4/15/2010
terry : 4/13/2010
wwang : 9/22/2009
ckniffin : 9/3/2009
alopez : 5/7/2009
alopez : 5/7/2009
alopez : 5/7/2009
wwang : 10/14/2008
wwang : 8/26/2008
ckniffin : 8/20/2008
wwang : 8/19/2008
ckniffin : 8/13/2008
mgross : 7/8/2008
mgross : 7/8/2008
alopez : 7/3/2008
terry : 6/25/2008
wwang : 5/16/2008
ckniffin : 3/13/2008
ckniffin : 3/13/2008
wwang : 2/25/2008
ckniffin : 2/5/2008
alopez : 1/24/2008
terry : 1/22/2008
wwang : 10/12/2007
joanna : 10/12/2007
ckniffin : 10/10/2007
alopez : 7/24/2007
alopez : 6/28/2007
terry : 6/27/2007
terry : 6/14/2007
wwang : 11/17/2006
terry : 11/16/2006
alopez : 5/3/2006
alopez : 5/3/2006
terry : 5/1/2006
carol : 4/14/2006
carol : 4/14/2006
wwang : 4/7/2006
terry : 4/6/2006
mgross : 3/28/2006
terry : 3/24/2006
alopez : 12/29/2005
alopez : 12/28/2005
terry : 12/16/2005
alopez : 11/22/2005
terry : 11/21/2005
mgross : 9/16/2005
mgross : 9/12/2005
wwang : 8/19/2005
ckniffin : 8/19/2005
wwang : 8/3/2005
terry : 7/28/2005
wwang : 7/1/2005
wwang : 6/29/2005
ckniffin : 6/16/2005
tkritzer : 3/16/2005
terry : 3/7/2005
carol : 2/23/2005
wwang : 2/7/2005
terry : 2/2/2005
alopez : 12/14/2004
alopez : 12/14/2004
terry : 12/10/2004
terry : 11/3/2004
alopez : 10/8/2004
terry : 10/6/2004
tkritzer : 7/15/2004
tkritzer : 6/22/2004
terry : 5/28/2004
alopez : 8/6/2003
terry : 8/5/2003
cwells : 10/25/2002
alopez : 4/4/2002
terry : 4/2/2002
alopez : 1/9/2002
terry : 1/3/2002
mgross : 12/1/2000
terry : 11/29/2000
mgross : 11/15/2000
mgross : 8/8/2000
mgross : 8/8/2000
alopez : 3/1/2000
terry : 3/1/2000
carol : 10/5/1998
terry : 10/2/1998
terry : 10/2/1998
terry : 10/1/1998
carol : 9/14/1998
mark : 11/9/1996
carol : 11/5/1996
carol : 10/26/1993
supermim : 3/16/1992
supermim : 3/20/1990
supermim : 2/27/1990
supermim : 1/12/1990
ddp : 10/26/1989

NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM^® and Online Mendelian Inheritance in Man^® are registered trademarks of the Johns Hopkins University.
Copyright^® 1966-2024 Johns Hopkins University.
Printed: June 1, 2024

▼ External Links

EPIDERMAL GROWTH FACTOR RECEPTOR; EGFR

V-ERB-B AVIAN ERYTHROBLASTIC LEUKEMIA VIRAL ONCOGENE HOMOLOG ONCOGENE ERBB ERBB1 HER1 SPECIES ANTIGEN 7; SA7

TEXT

▼ Description

▼ Cloning and Expression

▼ Gene Structure

▼ Mapping

▼ Biochemical Features

▼ Gene Function

▼ Cytogenetics

▼ Molecular Genetics

▼ Animal Model

▼ ALLELIC VARIANTS ( 7 Selected Examples):

.0001 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

.0002 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

.0003 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

.0004 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

.0005 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

.0006 NONSMALL CELL LUNG CANCER, RESISTANCE TO TYROSINE KINASE INHIBITOR IN

.0007 INFLAMMATORY SKIN AND BOWEL DISEASE, NEONATAL, 2 (1 family)

▼ See Also:

▼ REFERENCES

* 131550

EPIDERMAL GROWTH FACTOR RECEPTOR; EGFR

V-ERB-B AVIAN ERYTHROBLASTIC LEUKEMIA VIRAL ONCOGENE HOMOLOG ONCOGENE ERBB ERBB1 HER1 SPECIES ANTIGEN 7; SA7

Gene-Phenotype Relationships

TEXT

Description

Cloning and Expression

Gene Structure

Mapping

Biochemical Features

Gene Function

Cytogenetics

Molecular Genetics

Animal Model

ALLELIC VARIANTS 7 Selected Examples):

.0001 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

.0002 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

.0003 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

.0004 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

.0005 NONSMALL CELL LUNG CANCER, RESPONSE TO TYROSINE KINASE INHIBITOR IN, SOMATIC

.0006 NONSMALL CELL LUNG CANCER, RESISTANCE TO TYROSINE KINASE INHIBITOR IN

.0007 INFLAMMATORY SKIN AND BOWEL DISEASE, NEONATAL, 2 (1 family)

See Also:

REFERENCES

▼

External Links

V-ERB-B AVIAN ERYTHROBLASTIC LEUKEMIA VIRAL ONCOGENE HOMOLOG
ONCOGENE ERBB
ERBB1
HER1
SPECIES ANTIGEN 7; SA7

V-ERB-B AVIAN ERYTHROBLASTIC LEUKEMIA VIRAL ONCOGENE HOMOLOG
ONCOGENE ERBB
ERBB1
HER1
SPECIES ANTIGEN 7; SA7