Disease relevance of Egfr

• Newborn Egfr-/- mice have facial mediolateral defects including narrow, elongated snouts, underdeveloped lower jaw and a high incidence of cleft palate [1].
• Treatment with EKI-785 produced a dose-dependent reduction in tumor growth, suggesting that Egfr inhibitors may be useful for advanced colorectal cancer treatment [2].
• Surprisingly, the size, expansion, and pathological progression of the polyps appear Egfr-independent [2].
• Transfer of the Apc(Min) allele onto a homozygous Egfr(wa2) background results in a 90% reduction in intestinal polyp number relative to Apc(Min) mice carrying a wild-type Egfr allele [2].
• Genetic ablation of Egfr similarly delayed epidermal hyperplasia in response to UV exposure [3].

Psychiatry related information on Egfr

• To study the role of EGF, TGF-alpha and EGFR in early human development, two methods applicable for analysis of expression at the single embryo level have been employed [4].
• Although the female transgenic mice possessing mutant EGFR developed mammary tumors, the tumors occurred only after a delayed latency period, and were fewer in number [5].
• Our results also suggest that other uncontrolled genetic or environmental parameters confounded previous experiments linking EGFR activity to daily locomotor activity and provide a cautionary tale for genetically uncontrolled studies [6].

High impact information on Egfr

• We find that the EGFR kinase domain can be activated by increasing its local concentration or by mutating a leucine (L834R) in the activation loop, the phosphorylation of which is not required for activation [7].
• The mechanism by which the epidermal growth factor receptor (EGFR) is activated upon dimerization has eluded definition [7].
• (2006) in this issue of Cell provides compelling evidence that the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) is activated by the formation of an asymmetric dimer, with one kinase domain in the EGF-mediated dimer activating the other through an allosteric mechanism [8].
• Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha [9].
• The penetrance and severity of the defects in Egfrwa2/wa2 mice are enhanced by heterozygosity for a targeted mutation of exon 2 of Ptpn11 (ref. 3). Compound (Egfrwa2/wa2:Ptpn11+/-) mutant mice also show premature lethality [10].

Chemical compound and disease context of Egfr

• Squamous papillomas produced by grafting Egfr -/- v-ras(Ha) keratinocytes onto nude mice were only 21% of the size of wild-type v-ras(Ha) tumors, and a striking redistribution of S-phase cells was detected by immunostaining for bromodeoxyuridine [11].
• PTEN/Akt signaling through epidermal growth factor receptor is prerequisite for angiogenesis by hepatocellular carcinoma cells that is susceptible to inhibition by gefitinib [12].
• Abrogation of transforming growth factor-alpha/epidermal growth factor receptor autocrine signaling by an RXR-selective retinoid (LGD1069, Targretin) in head and neck cancer cell lines [13].
• Inhibition of EGF-R tyrosine kinase activity with either Tyrphostin B42 or genestein blocked TC formation and produced nodular blastemal hyperplasia and decreased distal nephron differentiation [14].
• Mice harboring a defective epidermal growth factor receptor (waved-2) have an increased susceptibility to acute dextran sulfate-induced colitis [15].

Biological context of Egfr

• In addition, morphogenesis of Meckel's cartilage was deficient in cultured mandibular processes from Egfr-/- embryos [1].
• The severity of the phenotypes correlates with the expression levels of the hEGFRKI allele, which is not efficiently expressed in epithelial and bone cells, but is expressed at similar and even higher levels as the endogenous Egfr in brain and heart [16].
• Ductal growth and development was normal in transplants of mammary epithelium from Egfr-/- mice into wild-type (WT) gland-free fat pads and in tissue recombinants prepared with WT stroma, irrespective of the source of epithelium (StromaWT/Epi-/-, StromaWT/EpiWT) [17].
• The Ikaros gene maps at a syntenic locus located on the short arm of human chromosome 7 and on mouse chromosome 11 next to the epidermal growth factor receptor (Egfr) [18].
• Egfr, localized on proximal chromosome 11, is amplified two to three times and leads to an easily identifiable, stable marker chromosome with a large amplification unit, which is present in each metaphase [19].

Anatomical context of Egfr

• The role of Egfr signaling during later stages of tumorigenesis was examined by using nude mice xenografts of two human colorectal cancer cell lines [2].
• Stimulation of lobulo-alveolar development in the mammary gland grafts by inclusion of a pituitary isograft under the renal capsule as a source of prolactin resulted in normal alveolar development in both Egfr-/- and wild-type transplants [17].
• Moreover, hEGFRKI/KI mice display accelerated chondrocyte and osteoblast differentiation, a phenotype that is also present in Egfr-/- mice and has not been previously described [16].
• Expression of ubiquitylated Egfr (Egfr-Ub) was increased in Min/+ enterocytes and tumors [20].
• Egf ligand increased MT1-MMP mRNA by tenfold in lung fibroblasts from wild type, but not from Egfr(-/-) mice [21].

Associations of Egfr with chemical compounds

• Inhibition of endogenous Egfr signaling with the Egfr inhibitor gefitinib (Iressa) or replacement of wild-type Egfr with the kinase-deficient protein encoded by the hypomorphic Egfr(wa2) allele completely rescued skin defects in Erffi1(-/-) mice [22].
• Pharmacological inhibition with EKI-785, an Egfr tyrosine kinase inhibitor, produced similar results in the Apc(Min) model [2].
• Evidence is provided that phosphorylation and activation of p70(S6K)/p90(RSK) induced by UVA were prevented in Egfr(-/-) cells and were also markedly inhibited by the EGFR-specific tyrosine kinase inhibitors AG1478 and PD153035 [23].
• PURPOSE: Therefore, we have studied the role of EGF-R expression on cisplatin-mediated cytotoxicity [24].
• Additionally, EGFR protein expression was down-regulated in response to estrogen and up-regulated in response to fulvestrant in vitro, suggesting that the EGFR pathway is activated when estrogen is depleted in NSCLC cells [25].

Physical interactions of Egfr

• Neuropeptide-induced transactivation of a neuronal epidermal growth factor receptor is mediated by metalloprotease-dependent formation of heparin-binding epidermal growth factor [26].
• The Grb2 SH2 domain binds to Tyr1068 of EGFR and Tyr317 of Shc while its SH3 domains bind to mSos1 [27].
• Phosphorylation of Y845 on the epidermal growth factor receptor mediates binding to the mitochondrial protein cytochrome c oxidase subunit II [28].
• Contribution of the transforming growth factor alpha B-loop beta-sheet to binding and activation of the epidermal growth factor receptor [29].
• Schwannoma-derived growth factor interacts with the epidermal growth factor receptor [30].

Enzymatic interactions of Egfr

• A 120 kDa nuclear phospholipase Cgamma1 protein fragment is stimulated in vivo by EGF signal phosphorylating nuclear membrane EGFR [31].
• We conclude that Stat3 isoforms can be directly phosphorylated and thereby activated in vitro by the epidermal growth factor receptor kinase [32].
• Shc proteins contain a carboxy terminal SH2 domain and a novel non-SH2 phosphotyrosine-binding (PTB) domain that specifically recognizes a phosphorylated NPXpY motif in target proteins such as the epidermal growth factor receptor [33].
• Furthermore, cleaved PLC-gamma1 could not be tyrosine-phosphorylated by EGFR in vitro [34].
• Eps15R protein(s) are tyrosine-phosphorylated following epidermal growth factor receptor activation in NIH-3T3 cells overexpressing the receptor, even at low levels of receptor occupancy, thus behaving as physiological substrates [35].

Regulatory relationships of Egfr

• Moreover, we observe a concordant loss of Pten and EGFR overexpression in nearly all high-grade gliomas induced by either EGFRvIII introduction or Pten inactivation [36].
• Several EGFR agonists also stimulated Adam17(-/-) mammary organoid growth in culture, but only AREG was expressed abundantly in the developing ductal system in vivo [37].
• We found that EGF continues to stimulate maximal tyrosine phosphorylation of EGFR following internalization, while, as expected, TGFalpha stimulates markedly less [38].
• Tumor necrosis factor-alpha converting enzyme (TACE) regulates epidermal growth factor receptor ligand availability [39].
• With differential ligand-induced internalization and trafficking-restricted receptor variants, we find that calpain activity is triggered only by plasma membrane-restricted activated EGFR, not by internalized (although still active) EGFR [40].

Other interactions of Egfr

• Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis [10].
• Transforming growth factor-alpha (TGF-alpha) and its sheddase, TACE (also known as ADAM17), were induced by AngII treatment, TACE was redistributed to apical membranes and EGFR was phosphorylated [41].
• Immunoprecipitation and immunoblot analyses with EGFR- and Neu-specific antisera, however, failed to detect physical complexes of these two receptors [42].
• In wild-type EGFR-expressing Ba/F3 cells, the major EGF-mediated signaling pathways were still intact [43].
• Epidermal growth factor receptor-mediated activation of Stat3 during multistage skin carcinogenesis [44].

Analytical, diagnostic and therapeutic context of Egfr

• Because Egfr-/- mice die perinatally, transplantation methods were used to study these processes [17].
• However, UV exposure increased cell proliferation, as measured by Ki67 immunohistochemistry and proliferating cell nuclear antigen immunoblotting, maximally at 48 h to a level more than three times higher in wild-type compared with Egfr-null skin [45].
• Apoptotic cell death, as measured by terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling (TUNEL) analysis, was also increased in UV-exposed Egfr-null skin when compared with wild-type 1-2 days post-UV [45].
• Expression profiling using microarrays, which was selectively validated and extended by immunophenotyping of Neu*-induced PIN and CAP, led to the identification of some novel biomarkers and also revealed increased expression of Egfr, Erbb3 and phosphorylated androgen receptor [46].
• RESULTS: Selected clones (MDA-468/AS-EGFR) exhibited more than 90% loss of both 125I-EGF binding and receptor content determined by western blot analysis, whereas clones transfected with the vector alone (MDA-468/p-CAT) had EGF-R levels similar to those of the parent cells [24].

References