Extracellular region of epidermal growth factor receptor: a potential target for anti-EGFR drug discovery

Oncogene ◽  
2016 ◽  
Vol 36 (17) ◽  
pp. 2337-2344 ◽  
Author(s):  
A Dokala ◽  
S S Thakur
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Drug Discovery ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Potential Target ◽  
Extracellular Region ◽  
Epidermal Growth

scholarly journals A Premature Termination of Human Epidermal Growth Factor Receptor Transcription inEscherichia coli

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Jihene Elloumi-Mseddi ◽  
Karim Jellali ◽  
Antonio Villalobo ◽  
Sami Aifa
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Western Blot ◽  
Blot Analysis ◽  
Growth Factor Receptor ◽  
Full Length ◽  
Glutathione S Transferase ◽  
Extracellular Region ◽  
Epidermal Growth

Our success in producing an active epidermal growth factor receptor (EGFR) tyrosine kinase inEscherichia coliencouraged us to express the full-length receptor in the same host. Despite its large size, we were successful at producing the full-length EGFR protein fused to glutathione S-transferase (GST) that was detected by Western blot analysis. Moreover, we obtained a majoritarian truncated GST-EGFR form detectable by gel electrophoresis and Western blot. This truncated protein was purified and confirmed by MALDI-TOF/TOF analysis to belong to the N-terminal extracellular region of the EGFR fused to GST. Northern blot analysis showed two transcripts suggesting the occurrence of a transcriptional arrest.

Active and inactive conformations of the epidermal growth factor receptor

2004 ◽  
Vol 32 (5) ◽  
pp. 742-745 ◽  
Author(s):  
K.M. Ferguson
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Structural Studies ◽  
Her Family ◽  
Extracellular Region ◽  
Epidermal Growth

The members of the EGFR (epidermal growth factor receptor) family of RTKs (receptor tyrosine kinases), also known as the ErbB or HER family, have been implicated in many human cancers. Structural studies of the EGFR extracellular region (sEGFR) have led to the proposal of a novel mechanism for ligand-induced receptor dimerization. In this model EGF binding induces a dramatic conformational change in EGFR, exposing a dimerization site that is normally occluded in the inactivated conformation, and thus promoting the formation of an entirely receptor-mediated dimer. It is well established that antibodies against the extracellular region of EGFR that prevent ligand binding and/or receptor signalling can inhibit tumour growth in vivo. At least five such anti-EGFR antibodies are currently in clinical trials and one, C225/cetuximab (Erbitux™), was recently approved in the U.S. and Europe for use in advanced colorectal cancers. Recent structural studies of ErbB2 in complex with anti-ErbB2 antibodies (trastuzumab/Herceptin™ and pertuzumab/Omnitarg™) have provided significant insights into how these drugs function. There have been no such studies for similar EGFR-targeted drugs to date. The implications of this model for the possible mechanisms of antibody-mediated inhibition of EGFR are discussed.

scholarly journals Epidermal Growth Factor Receptor Dimerization and Activation Require Ligand-Induced Conformational Changes in the Dimer Interface

2005 ◽  
Vol 25 (17) ◽  
pp. 7734-7742 ◽  
Author(s):  
Jessica P. Dawson ◽  
Mitchell B. Berger ◽  
Chun-Chi Lin ◽  
Joseph Schlessinger ◽  
Mark A. Lemmon ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Conformational Changes ◽  
Growth Factor Receptor ◽  
Intramolecular Interactions ◽  
Receptor Dimerization ◽  
Dimer Interface ◽  
Extracellular Region ◽  
Epidermal Growth

ABSTRACT Structural studies have shown that ligand-induced epidermal growth factor receptor (EGFR) dimerization involves major domain rearrangements that expose a critical dimerization arm. However, simply exposing this arm is not sufficient for receptor dimerization, suggesting that additional ligand-induced dimer contacts are required. To map these contributions to the dimer interface, we individually mutated each contact suggested by crystallographic studies and analyzed the effects on receptor dimerization, activation, and ligand binding. We find that domain II contributes >90% of the driving energy for dimerization of the extracellular region, with domain IV adding little. Within domain II, the dimerization arm forms much of the dimer interface, as expected. However, a loop from the sixth disulfide-bonded module (immediately C-terminal to the dimerization arm) also makes a critical contribution. Specific ligand-induced conformational changes in domain II are required for this loop to contribute to receptor dimerization, and we identify a set of ligand-induced intramolecular interactions that appear to be important in driving these changes, effectively “buttressing” the dimer interface. Our data also suggest that similar conformational changes may determine the specificity of ErbB receptor homo- versus heterodimerization.

Human epidermal growth factor receptor (HER1) aligned on the plasma membrane adopts key features of Drosophila EGFR asymmetry

2012 ◽  
Vol 40 (1) ◽  
pp. 184-188 ◽  
Author(s):  
Marisa L. Martin-Fernandez
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Plasma Membrane ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Ligand Binding ◽  
Growth Factor Receptor ◽  
Structural Basis ◽  
Extracellular Region ◽  
Epidermal Growth ◽  
Key Features

Current models suggest that ligand-binding heterogeneity in HER1 [human EGFR (epidermal growth factor receptor] arises from negative co-operativity in signalling HER1 dimers, for which the asymmetry of the extracellular region of the Drosophila EGFR has recently provided a structural basis. However, no asymmetry is apparent in the current crystal structure of the isolated extracellular region of HER1. This receptor also differs from the Drosophila EGFR in that negative co-operativity is found only in full-length receptors in cells. Structural insights into HER1 in epithelial cells, derived from FLIM (fluorescence lifetime imaging microscopy) and two-dimensional FRET (Förster resonance energy transfer) combined with Monte Carlo and molecular dynamics simulations, have demonstrated a high-affinity ligand-binding HER1 conformation consistent with the extracellular region aligned flat on the plasma membrane. This conformation shares key features with that of the Drosophila EGFR, suggesting that the structural basis for negative co-operativity is conserved from invertebrates to humans, but that, in HER1, the extracellular region asymmetry requires interactions with the plasma membrane.

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