Epidermal growth factor receptor

Epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian)
Cartoon diagram of the epidermal growth factor receptor (EGFR) (rainbow colored, N-terminus = blue, C-terminus = red) complexed with its ligand epidermal growth factor (magenta) based on the PDB 1NQL crystallographic coordinates.
Available structures: 1ivo, 1m14, 1m17, 1mox, 1nql, 1xkk, 1yy9, 1z9i, 2gs2, 2gs6, 2gs7, 2itn, 2ito, 2itp, 2itq, 2itt, 2itu, 2itv, 2itw, 2itx, 2ity, 2itz, 2j5e, 2j5f, 2j6m
Identifiers
Symbols	EGFR; ERBB; ERBB1; mENA
External IDs	OMIM: 131550 MGI: 95294 HomoloGene: 74545
EC number	2.7.10.1
Gene ontology Molecular function: • nucleotide binding • double-stranded DNA binding • MAP/ERK kinase kinase activity • transmembrane receptor activity • epidermal growth factor receptor activity • ATP binding • transferase activity • nitric-oxide synthase regulator activity • identical protein binding • protein heterodimerization activity • actin filament binding Cellular component: • extracellular space • intracellular • nucleus • cytoplasm • endosome • plasma membrane • integral to membrane • basolateral plasma membrane • AP-2 adaptor complex • endocytic vesicle Biological process: • ossification • response to stress • cell cycle • cell surface receptor linked signal transduction • epidermal growth factor receptor signaling pathway • phospholipase C activation • cell proliferation • cell-cell adhesion • positive regulation of cell migration • positive regulation of phosphorylation • calcium-dependent phospholipase A2 activation • positive regulation of MAPK activity • positive regulation of nitric oxide biosynthetic process • negative regulation of progression through cell cycle • protein amino acid autophosphorylation • positive regulation of epithelial cell proliferation • regulation of peptidyl-tyrosine phosphorylation • regulation of nitric-oxide synthase activity • protein insertion into membrane
RNA expression pattern
More reference expression data
Orthologs
	Human	Mouse
Entrez	1956	13649
Ensembl	ENSG00000146648	ENSMUSG00000020122
Uniprot	P00533	Q3TQS6
Refseq	NM_005228 (mRNA) NP_005219 (protein)	NM_007912 (mRNA) NP_031938 (protein)
Location	Chr 7: 55.05 - 55.24 Mb	Chr 11: 16.65 - 16.81 Mb
Pubmed search	[1]	[2]

The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is the cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands.^[1] The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). Mutations affecting EGFR expression or activity could result in cancer.^[2]

Function

EGFR (epidermal growth factor receptor) exists on the cell surface and is activated by binding of its specific ligands, including epidermal growth factor and transforming growth factor α (TGFα) (note, a full list of the ligands able to activate EGFR and other members of the ErbB family is given in the ErbB article). ErbB2 has no known direct activating ligand, and may be in an activated state constitutively or become active upon heterodimerization with other family members such as EGFR.

Upon activation by its growth factor ligands, EGFR undergoes a transition from an inactive monomeric form to an active homodimer - although there is some evidence that preformed inactive dimers may also exist before ligand binding. In addition to forming homodimers after ligand binding, EGFR may pair with another member of the ErbB receptor family, such as ErbB2/Her2/neu, to create an activated heterodimer. There is also evidence to suggest that clusters of activated EGFRs form, although it remains unclear whether this clustering is important for activation itself or occurs subsequent to activation of individual dimers.

Diagram of the EGF receptor highlighting important domains

EGFR dimerization stimulates its intrinsic intracellular protein-tyrosine kinase activity. As a result, autophosphorylation of several tyrosine (Y) residues in the C-terminal domain of EGFR occurs. These include Y992, Y1045, Y1068, Y1148 and Y1173 as shown in the diagram to the left.^[3] This autophosphorylation elicits downstream activation and signaling by several other proteins that associate with the phosphorylated tyrosines through their own phosphotyrosine-binding SH2 domains. These downstream signaling proteins initiate several signal transduction cascades, principally the MAPK, Akt and JNK pathways, leading to DNA synthesis and cell proliferation.^[4] Such proteins modulate phenotypes such as cell migration, adhesion, and proliferation. Activation of the receptor is important for the innate immune response in human skin ^[5]. The kinase domain of EGFR can also cross-phosphorylate tyrosine residues of other receptors it is aggregated with, and can itself be activated in that manner.

Clinical applications

Mutations that lead to EGFR overexpression (known as upregulation) or overactivity have been associated with a number of cancers, including lung cancer and glioblastoma multiforme. In this latter case a more or less specific mutation of EGFR, called EGFRvIII is often observed.^[6]

Mutations involving EGFR could lead to its constant activation which could result in uncontrolled cell division – a predisposition for cancer.^[7] Consequently, mutations of EGFR have been identified in several types of cancer, and it is the target of an expanding class of anticancer therapies.^[2]

The identification of EGFR as an oncogene has led to the development of anticancer therapeutics directed against EGFR, including gefitinib^[8] and erlotinib for lung cancer, and cetuximab for colon cancer.

Many therapeutic approaches are aimed at the EGFR. Cetuximab and panitumumab are examples of monoclonal antibody inhibitors. However the former is of the IgG1 type, the latter of the IgG2 type; consequences on antibody dependent cellular cytotoxicity can be quite different.^[9] Other monoclonals in clinical development are zalutumumab, nimotuzumab, and matuzumab. Gefitinib, erlotinib, and lapatinib (the latter still in clinical trials) are examples of small molecule kinase inhibitors. The monoclonal antibodies block the extracellular ligand binding domain. With the binding site blocked, signal molecules can no longer attach there and activate the tyrosine kinase. Another method is using small molecules to inhibit the EGFR tyrosine kinase, which is on the cytoplasmic side of the receptor. Without kinase activity, EGFR is unable to activate itself, which is a prerequisite for binding of downstream adaptor proteins. Ostensibly by halting the signaling cascade in cells that rely on this pathway for growth, tumor proliferation and migration is diminished.

Efficient conversion of strongly absorbed light by plasmonic gold nanoparticles to heat energy and their easy bioconjugation suggest their use as selective photothermal agents in molecular cancer cell targeting. Two oral squamous carcinoma cell lines (HSC 313 and HOC 3 Clone 8) and one benign epithelial cell line (HaCaT) were incubated with anti-epithelial growth factor receptor (EGFR) antibody conjugated gold nanoparticles and then exposed to continuous visible argon ion laser at 514 nm. It is found that the malignant cells require less than half the laser energy to be killed than the benign cells after incubation with anti-EGFR antibody conjugated Au nanoparticles. No photothermal destruction is observed for all types of cells in the absence of nanoparticles at four times energy required to kill the malignant cells with anti-EGFR/Au conjugates bonded. Au nanoparticles thus offer a novel class of selective photothermal agents using a CW laser at low powers.^[10]

In July 2007 it was discovered that the blood clotting protein Fibrinogen activates EGFR, thereby blocking regrowth of injured neuronal cells in the spine.^[11] Other natural inhibitors include potato carboxypeptidase inhibitor (PCI), which contains a small cysteine-rich module, called a T-knot scaffold, that is shared by several different protein families, including the EGF family. Structural similarities with these factors can explain the antagonistic effect of PCI.^[12]

EGFR and Lung Cancer

New drugs such as Tarceva directly target the EGFR. Patients have been divided into EGFR positive and negative, based upon whether a tissue test shows a mutation. EGFR positive patients have shown an impressive 60% response rate which exceeds the response rate for conventional chemotherapy.

References

External links

• MeSH Epidermal Growth Factor Receptor

Further reading