Mol Cell. 2003 Feb;11(2):507-17.

EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization.

Ferguson KM, Berger MB, Mendrola JM, Cho HS, Leahy DJ, Lemmon MA.

Source

Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. fertuso2@mail.med.upenn.edu

Abstract

Epidermal growth factor (EGF) receptor is the prototype of the ErbB (HER) family receptor tyrosine kinases (RTKs), which regulate cell growth and differentiation and are implicated in many human cancers. EGF activates its receptor by inducing dimerization of the 621 amino acid EGF receptor extracellular region. We describe the 2.8 A resolution crystal structure of this entire extracellular region (sEGFR) in an unactivated state. The structure reveals an autoinhibited configuration, where the dimerization interface recently identified in activated sEGFR structures is completely occluded by intramolecular interactions. To activate the receptor, EGF binding must promote a large domain rearrangement that exposes this dimerization interface. This contrasts starkly with other RTK activation mechanisms and suggests new approaches for designing ErbB receptor antagonists.

PMID:: 12620237; [PubMed - indexed for MEDLINE]

Publication Types, MeSH Terms, Substances, Secondary Source ID, Grant Support

Publication Types

MeSH Terms

Substances

Secondary Source ID

PDB/1NQL

Grant Support

LinkOut - more resources

Full Text Sources

Other Literature Sources

Supplemental Content

Save items

Related citations in PubMed

Ligand-binding enhances the affinity of dimerization of the extracellular domain of the epidermal growth factor receptor. [J Biochem. 1997]
Ligand-binding enhances the affinity of dimerization of the extracellular domain of the epidermal growth factor receptor.
Odaka M, Kohda D, Lax I, Schlessinger J, Inagaki F. J Biochem. 1997 Jul; 122(1):116-21.
Two EGF molecules contribute additively to stabilization of the EGFR dimer. [EMBO J. 1997]
Two EGF molecules contribute additively to stabilization of the EGFR dimer.
Lemmon MA, Bu Z, Ladbury JE, Zhou M, Pinchasi D, Lax I, Engelman DM, Schlessinger J. EMBO J. 1997 Jan 15; 16(2):281-94.
Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. [Cell. 2002]
Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains.
Ogiso H, Ishitani R, Nureki O, Fukai S, Yamanaka M, Kim JH, Saito K, Sakamoto A, Inoue M, Shirouzu M, et al. Cell. 2002 Sep 20; 110(6):775-87.
Review Epidermal growth factor receptor (EGFR) signaling in cancer. [Gene. 2006]
Review Epidermal growth factor receptor (EGFR) signaling in cancer.
Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, Carotenuto A, De Feo G, Caponigro F, Salomon DS. Gene. 2006 Jan 17; 366(1):2-16. Epub 2005 Dec 27.
Review The ErbB/HER receptor protein-tyrosine kinases and cancer. [Biochem Biophys Res Commun. 2004]
Review The ErbB/HER receptor protein-tyrosine kinases and cancer.
Roskoski R Jr. Biochem Biophys Res Commun. 2004 Jun 18; 319(1):1-11.

See reviews... See all...

Cited by 75 PubMed Central articles

Rational identification of an optimal antibody mixture for targeting the epidermal growth factor receptor. [MAbs. 2011]
Rational identification of an optimal antibody mixture for targeting the epidermal growth factor receptor.
Koefoed K, Steinaa L, Søderberg JN, Kjær I, Jacobsen HJ, Meijer PJ, Haurum JS, Jensen A, Kragh M, Andersen PS, et al. MAbs. 2011 Nov-Dec; 3(6):584-95. Epub 2011 Nov 1.
ErbB1 dimerization is promoted by domain co-confinement and stabilized by ligand binding. [Nat Struct Mol Biol. 2011]
ErbB1 dimerization is promoted by domain co-confinement and stabilized by ligand binding.
Low-Nam ST, Lidke KA, Cutler PJ, Roovers RC, van Bergen en Henegouwen PM, Wilson BS, Lidke DS. Nat Struct Mol Biol. 2011 Oct 23; 18(11):1244-9. Epub 2011 Oct 23.
Molecular Mechanisms that Regulate Epidermal Growth Factor Receptor Inactivation. [Clin Med Oncol. 2008]
Molecular Mechanisms that Regulate Epidermal Growth Factor Receptor Inactivation.
Ceresa BP, Vanlandingham PA. Clin Med Oncol. 2008; 2:47-61. Epub 2008 Feb 9.

See all...

Structures reported by this article

Structure Of The Extracellular Domain Of Human Epidermal Growth Factor (Egf) Receptor In An Inactive (Low Ph) Complex With Egfÿ

PDB: 1NQL

Source: Homo sapiens

Method: X-Ray Diffraction

Resolution: 2.8 Å

Related information

Related Citations
Calculated set of PubMed citations closely related to the selected article(s) retrieved using a word weight algorithm. Related articles are displayed in ranked order from most to least relevant, with the “linked from” citation displayed first.
BioSystems
Pathways and biological systems (BioSystems) that cite the current articles. Citations are from the BioSystems source databases (KEGG and BioCyc).
Compound (MeSH Keyword)
PubChem chemical compound records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.
Gene
Gene records that cite the current articles. Citations in Gene are added manually by NCBI or imported from outside public resources.
Gene (GeneRIF)
Gene records that have the current articles as Reference into Function citations (GeneRIFs). NLM staff reviewing the literature while indexing MEDLINE add GeneRIFs manually.
HomoloGene
HomoloGene clusters of homologous genes and sequences that cite the current articles. These are references on the Gene and sequence records in the HomoloGene entry.
Nucleotide (RefSeq)
NCBI nucleotide Reference Sequences (RefSeqs) that are cited in the current articles, included in the corresponding Gene Reference into Function, or that include the PubMed articles as references.
Nucleotide (Weighted)
Nucleotide records associated with the current articles through the Gene database. These are the related sequences on the Gene record that are added manually by NCBI.
Protein (RefSeq)
NCBI protein Reference Sequences (RefSeqs) that are cited in the current articles, included in the corresponding Gene Reference into Function, or that include the PubMed articles as references.
Protein (Weighted)
Protein records associated with the current articles through related Gene database records. These are the related sequences on the Gene record that are added manually by NCBI.
Substance (MeSH Keyword)
PubChem chemical substance (submitted) records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.
Taxonomy via GenBank
Taxonomy records associated with the current articles through taxonomic information on related molecular database records (Nucleotide, Protein, Gene, SNP, Structure).
UniGene
UniGene clusters of expressed sequences that are associated with the current articles through references on the clustered sequence records and related Gene records.
Protein
Protein translation features of primary database (GenBank) nucleotide records reported in the current articles as well as Reference Sequences (RefSeqs) that include the articles as references.
Structure
Three-dimensional structure records in the NCBI Structure database for data reported in the current articles.
GEO Profiles
Gene Expression Omnibus (GEO) Profiles of molecular abundance data. The current articles are references on the Gene record associated with the GEO profile.
Cited in PMC
Full-text articles in the PubMed Central Database that cite the current articles.

Recent activity

Clear Turn Off Turn On

EGF activates its receptor by removing interactions that autoinhibit ectodomain ...
EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization.
Mol Cell. 2003 Feb ;11(2):507-17.

PubMed
The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase.
The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase.
Mol Cell. 2003 Feb ;11(2):437-44.

PubMed
Transcriptional activation: getting a grip on condensed chromatin.
Transcriptional activation: getting a grip on condensed chromatin.
Curr Biol. 2003 Mar 4 ;13(5):R195-7.

PubMed
Gastroesophageal reflux disease.
Gastroesophageal reflux disease.
J Fam Pract. 2003 Mar ;52(3):240-7.

PubMed
Fusions of breast cancer and dendritic cells as a novel cancer vaccine.
Fusions of breast cancer and dendritic cells as a novel cancer vaccine.
Clin Breast Cancer. 2003 Feb ;3 Suppl 4:S158-63.

PubMed

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

PubMed

Result Filters

Display Settings:

Send to: