Epidermal growth factor receptor
From Wikipedia, the free encyclopedia
| Image:EGFR structure.png | |
| The extracellular domain of EGFR in a complex with EGF PDB 1NQL | |
| Epidermal growth factor receptor
| |
| Identifiers | |
| Symbol(s) | EGFR ERBB1 |
| Entrez | 1956 |
| OMIM | 131550 |
| RefSeq | NM_005228 |
| UniProt | P00533 |
| Other data | |
| EC number | 2.7.1.112 |
| Locus | Chr. 7 p12 |
Epidermal growth factor receptor (EGFR) is the receptor for epidermal growth factor (EGF). It is a member of the ErbB family 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.
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[edit] Structure
[edit] Function
EGFR exist on the cell surface as inactive monomers and is activated by binding of its specific ligands, including epidermal growth factor, transformation growth factor α (TGFα), neuregulin (neu)or others. On activation, EGFR can pair with another EGFR to form an active homodimer or an EGF receptor may pair with another member of the ErbB receptor family, such as Her 2/neu, to create a heterodimer. Evidence also suggests that a cluster of active EGFR can form.
The binding of the ligand stimulates the intrinsic protein-tyrosine kinase activity of EGFR which initiates a signal transduction cascade, principally involving the MAPK, Akt and JNK pathways, leading to DNA synthesis and cell proliferation[1]. The kinase activity can also result in autophosphorylation of five tyrosine residues in the C-terminal domain of EGFR. Autophosphorylation elicits downstream activation and signaling events of other proteins that are often distinct from those activated by the kinase domain of EGFR. 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.
[edit] Clinical applications
Mutations that lead to EGFR overexpression (known as upregulation) or overactivity have been associated with a number of cancers, including glioblastoma multiforme and lung cancer.
Mutations involving EGFR could lead to its constant activation which could result in uncontrolled cell division - a predisposition for cancer[2] . 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 gefitinib[3] and erlotinib for lung cancer, cetuximab for colon cancer, and trastuzumab for breast cancer.
These therapies are based in the use of monoclonal antibodies against EGFR or in protein kinase inhibitors. The monoclonal antibodies block the extracellular ligand binding domain with the use of anti-EGFR antibodies. 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. This molecule travels down the EGFR polypedptide and blocks the relay proteins from binding to the tyrosine kinase. Both methods result in inhibition of downstream components of the EGFR pathway. By halting the signaling cascade, tumor growth is stopped.
[edit] Links
[edit] References
- a A comprehensive pathway map of epidermal growth factor receptor signaling. Molecular Systems Biology doi:10.1038/msb4100014, 2005 May [1]
- a Image:Free text.png 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
- a EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004 Jun 4; 304(5676): 1497-500. PMID 15118125de:EGF-Rezeptor
