Epidermal growth factor receptor

Epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian)
File:EGFR structure.png PDB rendering based on 1nql.
Identifiers
Symbols	EGFR ; ERBB; ERBB1; mENA
External IDs	Template:OMIM5 Template:MGI HomoloGene: 74545
Gene ontology Molecular function Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Cellular component Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Biological process Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO
RNA expression pattern
File:PBB GE EGFR 201984 s at.png
File:PBB GE EGFR 210984 x at.png
More reference expression data
Orthologs
Template:GNF Ortholog box
Species	Human	Mouse
Entrez	n/a	n/a
Ensembl	n/a	n/a
UniProt	n/a	n/a
RefSeq (mRNA)	n/a	n/a
RefSeq (protein)	n/a	n/a
Location (UCSC)	n/a	n/a
PubMed search	n/a	n/a

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Overview

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. 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.

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 are Y845, Y992, Y1045, Y1068, Y1148 and Y1173 as shown in the diagram to the left. 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 proliferationTemplate:Ref N. Such proteins modulate phenotypes such as cell migration, adhesion, and proliferation. 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 met with [1].

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

The identification of EGFR as an oncogene has led to the development of anticancer therapeutics directed against EGFR, including gefitinibTemplate:Ref N and erlotinib for lung cancer, and cetuximab for colon cancer.

Many therapeutic approaches are aimed at the EGFR [2]. 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 [3]. Other monoclonals in clinical development are zalutumumab, nimotuzumab, 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.

In July 2007 it was discovered that the blood clotting protein Fibrinogen inhibits EGFR, thereby blocking regrowth of injured neuronal cells in the spine. [4]

References

1. Template:Note N A comprehensive pathway map of epidermal growth factor receptor signaling. Molecular Systems Biology doi:10.1038/msb4100014, 2005 May [5]
2. Template:Note N Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004 May 20; 350(21): 2129-39. PMID 15118073 Free text
3. Template:Note N EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004 Jun 4; 304(5676): 1497-500. PMID 15118125

External links

• Herbst R (2004). "Review of epidermal growth factor receptor biology". Int J Radiat Oncol Biol Phys. 59 (2 Suppl): 21–6. PMID 15142631.
• Epidermal Growth Factor Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)
• Fibrinogen, a blood-clotting protein, found to inhibit EGFR Explains lack of healing in spinal injuries.

Further reading

• Carpenter G (1987). "Receptors for epidermal growth factor and other polypeptide mitogens". Annu. Rev. Biochem. 56: 881–914. doi:10.1146/annurev.bi.56.070187.004313. PMID 3039909.
• Boonstra J, Rijken P, Humbel B; et al. (1995). "The epidermal growth factor". Cell Biol. Int. 19 (5): 413–30. PMID 7640657.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Carpenter G (2000). "The EGF receptor: a nexus for trafficking and signaling". Bioessays. 22 (8): 697–707. doi:10.1002/1521-1878(200008)22:8<697::AID-BIES3>3.0.CO;2-1. PMID 10918300.
• Filardo EJ (2002). "Epidermal growth factor receptor (EGFR) transactivation by estrogen via the G-protein-coupled receptor, GPR30: a novel signaling pathway with potential significance for breast cancer". J. Steroid Biochem. Mol. Biol. 80 (2): 231–8. PMID 11897506.
• Tiganis T (2002). "Protein tyrosine phosphatases: dephosphorylating the epidermal growth factor receptor". IUBMB Life. 53 (1): 3–14. PMID 12018405.
• Di Fiore PP, Scita G (2002). "Eps8 in the midst of GTPases". Int. J. Biochem. Cell Biol. 34 (10): 1178–83. PMID 12127568.
• Benaim G, Villalobo A (2002). "Phosphorylation of calmodulin. Functional implications". Eur. J. Biochem. 269 (15): 3619–31. PMID 12153558.
• Leu TH, Maa MC (2004). "Functional implication of the interaction between EGF receptor and c-Src". Front. Biosci. 8: s28–38. PMID 12456372.
• Anderson NL, Anderson NG (2003). "The human plasma proteome: history, character, and diagnostic prospects". Mol. Cell Proteomics. 1 (11): 845–67. PMID 12488461.
• Kari C, Chan TO, Rocha de Quadros M, Rodeck U (2003). "Targeting the epidermal growth factor receptor in cancer: apoptosis takes center stage". Cancer Res. 63 (1): 1–5. PMID 12517767.CS1 maint: Multiple names: authors list (link)
• Bonaccorsi L, Muratori M, Carloni V; et al. (2003). "Androgen receptor and prostate cancer invasion". Int. J. Androl. 26 (1): 21–5. PMID 12534934.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Reiter JL, Maihle NJ (2003). "Characterization and expression of novel 60-kDa and 110-kDa EGFR isoforms in human placenta". Ann. N. Y. Acad. Sci. 995: 39–47. PMID 12814937.
• Adams TE, McKern NM, Ward CW (2005). "Signalling by the type 1 insulin-like growth factor receptor: interplay with the epidermal growth factor receptor". Growth Factors. 22 (2): 89–95. PMID 15253384.CS1 maint: Multiple names: authors list (link)
• Ferguson KM (2005). "Active and inactive conformations of the epidermal growth factor receptor". Biochem. Soc. Trans. 32 (Pt 5): 742–5. doi:10.1042/BST0320742. PMID 15494003.
• Chao C, Hellmich MR (2005). "Bi-directional signaling between gastrointestinal peptide hormone receptors and epidermal growth factor receptor". Growth Factors. 22 (4): 261–8. doi:10.1080/08977190412331286900. PMID 15621729.
• Carlsson J, Ren ZP, Wester K; et al. (2006). "Planning for intracavitary anti-EGFR radionuclide therapy of gliomas. Literature review and data on EGFR expression". J. Neurooncol. 77 (1): 33–45. doi:10.1007/s11060-005-7410-z. PMID 16200342.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Scartozzi M, Pierantoni C, Berardi R; et al. (2006). "Epidermal growth factor receptor: a promising therapeutic target for colorectal cancer". Anal. Quant. Cytol. Histol. 28 (2): 61–8. PMID 16637508.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Prudkin L, Wistuba II (2006). "Epidermal growth factor receptor abnormalities in lung cancer. Pathogenetic and clinical implications". Annals of diagnostic pathology. 10 (5): 306–15. doi:10.1016/j.anndiagpath.2006.06.011. PMID 16979526.
• Ahmed SM, Salgia R (2007). "Epidermal growth factor receptor mutations and susceptibility to targeted therapy in lung cancer". Respirology. 11 (6): 687–92. doi:10.1111/j.1440-1843.2006.00887.x. PMID 17052295.
• Zhang X, Chang A (2007). "Somatic mutations of the epidermal growth factor receptor and non-small-cell lung cancer". J. Med. Genet. 44 (3): 166–72. doi:10.1136/jmg.2006.046102. PMID 17158592.
• Cohenuram M, Saif MW (2007). "Epidermal growth factor receptor inhibition strategies in pancreatic cancer: past, present and the future". JOP. 8 (1): 4–15. PMID 17228128.
• Mellinghoff IK, Cloughesy TF, Mischel PS (2007). "PTEN-mediated resistance to epidermal growth factor receptor kinase inhibitors". Clin. Cancer Res. 13 (2 Pt 1): 378–81. doi:10.1158/1078-0432.CCR-06-1992. PMID 17255257.CS1 maint: Multiple names: authors list (link)
• Nakamura JL (2007). "The epidermal growth factor receptor in malignant gliomas: pathogenesis and therapeutic implications". Expert Opin. Ther. Targets. 11 (4): 463–72. doi:10.1517/14728222.11.4.463. PMID 17373877.