Signal transduction by epidermal growth factor occurs through the subclass of high affinity receptors.

Defize, L. H. K.; Boonstra, Johannes; Meisenhelder, Jill; Kruijer, W.; Tertoolen, Leon G.J.; Tilly, Ben C.; Hunter, Tony; Henegouwen, Paul M.P. van Bergen en; Moolenaar, Wouter H.; Laat, Siegfried W. de

doi:10.1083/jcb.109.5.2495

Cited by 184 publications

(138 citation statements)

References 61 publications

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“…No significant difference was observed in the incidence of EGFRpositivity among the histological subtypes of adenocarcinomas (Table II), as was also suggested before by Witmaack et al (1988). In general, the staining was cytoplasmic for both MoAbs, as has also been reported by others (Damjanov et al, 1986;Defize et al, 1986;Rodriquez et al, 1991;Berchuck et al, 1991 (Defize et al, 1989).…”

Section: Gene Amplificationsupporting

confidence: 83%

“…In many cell types the external domain displays high affinity (minor class) and low affinity (major class) EGF binding sites. The high-affinity binding sites prove to be most important for the activation of the signal transducing cascade (Defize et al, 1989). Both EGF and EGFR play an essential role in the development of mammary tissue (Tailor-Papadimitriou et al, 1977).…”

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confidence: 99%

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Epidermal growth factor receptor in ovarian tumours: correlation of immunohistochemistry with ligand binding assay

Henzen‐Logmans

Berns²,

Klijn³

et al. 1992

Br J Cancer

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Summary Epidermal growth factor receptor (EGFR) was studied in ovarian tumours with immunohistochemical (IH) and ligand-binding assay (LBA). Two different monoclonal antibodies (MoAbs: 2E9, EGFR1) with respect to detecting EGFR with different ligand-binding affinities (low, high and low) were used. When comparing the IH data of MoAbs 2E9 and EGFR1 a significant correlation was found (2P<0.0001). Both antibodies stained 77% of the adenocarcinoma samples. Evidence is increasing that growth factors and their receptors are involved not only in control of normal cell growth, but also in diseases, including cancer. The epidermal growth factor (EGF) and its receptor (EGFR) in particular have been investigated extensively in several tumour types. The EGFR molecule comprises a 170 kDa membrane protein, exhibiting an extracellular ligand (EGF or TGF-a) binding domain, a trans-membrane region and an intracellular domain facing the cytoplasm and exhibiting tyrosine kinase function. In many cell types the external domain displays high affinity (minor class) and low affinity (major class) EGF binding sites. The high-affinity binding sites prove to be most important for the activation of the signal transducing cascade (Defize et al., 1989). Both EGF and EGFR play an essential role in the development of mammary tissue (Tailor-Papadimitriou et al., 1977). Overexpression of EGFR in human primary breast cancer has been shown to be an indicator of a bad prognosis with respect to both relapse-free and overall survival (Sainsbury et al., 1987) and response to hormonal therapy of advanced disease (Nicholson et al., 1989). However, no consensus exists regarding the prognostic significance of EGFR . With respect to the ovary, changes in the level of EGF and EGFR in normal and neoplastic (benign/malignant) ovarian tissue specimens and its relation to clinical outcome have been studied less extensively (Bauknecht et al., , 1989(Bauknecht et al., , 1990Berchuck et al., 1991; Owens et al., 1991). In the present study we have investigated EGFR status in ovarian tissues with immunohistochemical (IH) and biochemical techniques (LBA: ligand binding assay). The IH technique was chosen for comparison with LBA because of its ability to identify tumour positivity at the cellular level, even in small tumour samples, excluding the influence of variance of tumour cellularity and the presence of EGFR in non-tumour tissue. Moreover, two different monoclonal antibodies (MoAbs: 2E9, EGFR1) were used to study possible differences in staining pattern between monoclonal antibodies reactive to different subtypes of receptor with respect to its ligand binding affinity. Materials and methods PatientsOne-hundred and twenty-eight tumours (121 epithelial and 7 non-epithelial), and 21 non-tumorous ovaries were analysed.Tumours were classifed in accordance with WHO classification (Serov et al., 1973). Forty-six patients (mean age 58 years) had a serous adenocarcinoma (37 primary, 9 metastatic), 20 patients (mean age 59 years) had a mucinous adenocarcinoma (20 prima...

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Section: Gene Amplificationsupporting

confidence: 83%

mentioning

confidence: 99%

Epidermal growth factor receptor in ovarian tumours: correlation of immunohistochemistry with ligand binding assay

Henzen‐Logmans

Berns²,

Klijn³

et al. 1992

Br J Cancer

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“…glycosylation patterns are cell type-specific, whereas 2E9 inhibits low-affinity EGFRs in various cell types (29,31,32), as well as the recombinant insect SF+ cell protein product in our experiments. Overall, our data support the view that DIII is the primary ligandbinding site, and the 2E9 antibody inhibits low-affinity EGF binding through preferential interactions with DI.…”

Section: Resultsmentioning

confidence: 66%

N -Glycosylation as determinant of epidermal growth factor receptor conformation in membranes

Kaszuba

Grzybek

Orłowski

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

146

156

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The epidermal growth factor receptor (EGFR) regulates several critical cellular processes and is an important target for cancer therapy. In lieu of a crystallographic structure of the complete receptor, atomistic molecular dynamics (MD) simulations have recently shown that they can excel in studies of the full-length receptor. Here we present atomistic MD simulations of the monomeric N-glycosylated human EGFR in biomimetic lipid bilayers that are, in parallel, also used for the reconstitution of full-length receptors. This combination enabled us to experimentally validate our simulations, using ligand binding assays and antibodies to monitor the conformational properties of the receptor reconstituted into membranes. We find that N-glycosylation is a critical determinant of EGFR conformation, and specifically the orientation of the EGFR ectodomain relative to the membrane. In the absence of a structure for full-length, posttranslationally modified membrane receptors, our approach offers new means to structurally define and experimentally validate functional properties of cell surface receptors in biomimetic membrane environments.R eceptor tyrosine kinases (RTKs) are cell surface receptors that receive and transduce signals mediating a variety of critical cellular processes, including cell growth, migration, proliferation, differentiation, and apoptosis. Among the many RTKs, the most studied is the epidermal growth factor receptor (EGFR), not least because of its involvement in the development and progression of epidermoid cancers and its resulting importance as a target for antineoplastic therapies.Structurally, the EGFR consists of the ectodomain (ECD) (further subdivided into four subdomains, DI-IV), the transmembrane domain (TMD), and the intracellular tyrosine kinase domain (TKD). Ligand binding induces conformational transitions of the ECD that stabilize receptor dimerization, culminating in the activation of the intracellular TKD and subsequent propagation of the activation signal (1). To prevent receptor activation and signaling in the absence of ligand, the structurally tethered ECD of monomeric EGFR blocks the intrinsic capacity of the TMD and the intracellular TKD to dimerize (2). Ligand binding is believed to release the self-inhibitory tether and facilitate receptor oligomerization and activation (3-6). A detailed understanding of the structural regulation of the intact full-length receptors in their native membranes promises to reveal the molecular basis for receptor regulation (7); however, the methodological limitations associated with crystallizing transmembrane proteins, together with the high flexibility of the full-length receptor, have prevented high-resolution crystallographic analysis.To fill this gap, extensive atom-scale molecular dynamics (MD) simulations were recently performed to elucidate the structural dynamics of the EGFR in a two-component lipid bilayer (8). These studies suggest a large interfacial contact area between the membrane and the ecto-and intracellular domains of the unli...

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“…This apparent difference between EGFR-positive and EGFR-negative tumor responses in colon cancer for cetuximab and ovarian cancers for gefitinib may be explained by a differential distribution of two distinct EGFR populations. The majority of EGFR are of low affinity (f95%) and do not contribute significantly to signal transduction (40). A small number of high-affinity EGFR are responsible for the biological activity.…”

Section: Discussionmentioning

confidence: 99%

Phase II Study of Gefitinib in Patients with Relapsed or Persistent Ovarian or Primary Peritoneal Carcinoma and Evaluation of Epidermal Growth Factor Receptor Mutations and Immunohistochemical Expression: A Gynecologic Oncology Group Study

Schilder¹,

Sill

Chen³

et al. 2005

Clinical Cancer Research

240

130

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Purpose: This phase II trial assessed the activity and tolerability of a daily oral dose of 500 mg gefitinib (ZD1839, Iressa) in patients with recurrent or persistent epithelial ovarian or primary peritoneal carcinoma, and explored the clinical value of determining the status of the epidermal growth factor receptor (EGFR). Experimental Design: Primary measure of efficacy was progression-free survival at 6 months. Mutations in exons 18 to 21 of EGFR and/or immunohistochemical expression of EGFR were evaluated in tumor specimens from patients enrolled in this trial as well as from patients not treated with gefitinib. Results: Twenty-seven of 30 (90%) patients were eligible and evaluable for analysis of gefitinib efficacy and toxicity. Of these, four survived progression-free >6 months with one objective response (4%). The most commonly observed grade 3 toxicities were dermatologic (15%, 4 of 27) and diarrhea (30%, 8 of 27). Specimens from 26 of 26 or 25 of 26 patients were evaluable for immunohistochemical or mutation analysis, respectively. The response rate for patients with EGFR-positive tumors was 9% (1 of 11). EGFR expression was associated with longer progression-free survival (P = 0.008) and possibly longer survival (P = 0.082). The patient with the only objective response had a mutation in the catalytic domain of the tumor's EGFR (P = 0.04). Among 32 invasive tumors from patients not treated with gefitinib, one exhibited a catalytic domain mutation. Conclusions: Gefitinib was well tolerated but had minimal activity in unscreened patients with recurrent ovarian or primary peritoneal carcinoma. Prescreening patients for activating mutations in EGFR may improve response rate to gefitinib. This report is the first to document activating mutations in catalytic domain of EGFR in 3.5% (2 of 57) of ovarian cancers.

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Signal transduction by epidermal growth factor occurs through the subclass of high affinity receptors.

Cited by 184 publications

References 61 publications

Epidermal growth factor receptor in ovarian tumours: correlation of immunohistochemistry with ligand binding assay

Epidermal growth factor receptor in ovarian tumours: correlation of immunohistochemistry with ligand binding assay

N -Glycosylation as determinant of epidermal growth factor receptor conformation in membranes

Phase II Study of Gefitinib in Patients with Relapsed or Persistent Ovarian or Primary Peritoneal Carcinoma and Evaluation of Epidermal Growth Factor Receptor Mutations and Immunohistochemical Expression: A Gynecologic Oncology Group Study

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