Epidermal growth factor receptor

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The extracellular domain of EGFR in a complex with EGF PDB 1NQL
Epidermal growth factor receptor
Identifiers
Symbol	EGFR ERBB1
HUGO	3236
Entrez	1956
OMIM	131550
RefSeq	NM_005228
UniProt	P00533
Other data
EC number	2.7.1.112
Locus	Chr. 7 p12

In molecular biology, epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is the receptor for epidermal growth factor (EGF). It 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.

Contents 1 Function 2 Clinical applications 3 References 4 External links

[edit] 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). The related ErbB3 and ErbB4 receptors are activated by neuregulins (NRGs). ErbB2 has no known direct activating ligand, and may be in an activated state constitutively. 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.

EGFR dimerization stimulates its intrinsic intracellular protein-tyrosine kinase activity. As a result, autophosphorylation of five tyrosine residues in the C-terminal domain of EGFR occurs. 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^[1]. 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] References

1. ^a  A comprehensive pathway map of epidermal growth factor receptor signaling. Molecular Systems Biology doi:10.1038/msb4100014, 2005 May [1]
2. ^a  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. ^a  EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004 Jun 4; 304(5676): 1497-500. PMID 15118125

[edit] 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. 
• MeSH Epidermal+Growth+Factor+Receptor