Epidermal growth factor receptor

This article is about a cell surface receptor. For estimated measure of kidney function (eGFR), see Glomerular filtration rate.

Epidermal growth factor receptor
Available structures PDB 1DNQ, 1DNR, 1IVO, 1M14, 1M17, 1MOX, 1NQL, 1XKK, 1YY9, 1Z9I, 2EB2, 2EB3, 2EXP, 2EXQ, 2GS2, 2GS6, 2GS7, 2ITN, 2ITO, 2ITP, 2ITQ, 2ITT, 2ITU, 2ITV, 2ITW, 2ITX, 2ITY, 2ITZ, 2J5E, 2J5F, 2J6M, 2JIT, 2JIU, 2JIV, 2KS1, 2RF9, 2RFD, 2RFE, 2RGP, 3B2U, 3B2V, 3BEL, 3BUO, 3C09, 3G5V, 3G5Y, 3GT8, 3IKA, 3NJP, 3OB2, 3OP0
Identifiers
Symbols	EGFR; ERBB; ERBB1; HER1; PIG61; mENA
External IDs	OMIM: 131550 MGI: 95294 HomoloGene: 74545 GeneCards: EGFR Gene
EC number	2.7.10.1
Gene Ontology Molecular function • nucleotide binding • double-stranded DNA binding • MAP/ERK kinase kinase activity • protein tyrosine kinase activity • protein tyrosine kinase activity • protein tyrosine kinase activity • transmembrane receptor protein tyrosine kinase activity • receptor signaling protein tyrosine kinase activity • transmembrane receptor activity • epidermal growth factor receptor activity • epidermal growth factor receptor activity • protein binding • ATP binding • protein phosphatase binding • nitric-oxide synthase regulator activity • identical protein binding • protein heterodimerization activity • actin filament binding Cellular component • Golgi membrane • extracellular region • extracellular space • intracellular • nucleus • cytoplasm • endosome • endoplasmic reticulum • endoplasmic reticulum membrane • Golgi apparatus • plasma membrane • plasma membrane • plasma membrane • membrane • integral to membrane • basolateral plasma membrane • AP-2 adaptor complex • endocytic vesicle • nuclear membrane • Shc-EGFR complex Biological process • cell morphogenesis • ossification • embryonic placenta development • hair follicle development • response to stress • signal transduction • signal transduction • cell surface receptor linked signaling pathway • epidermal growth factor receptor signaling pathway • epidermal growth factor receptor signaling pathway • epidermal growth factor receptor signaling pathway • activation of phospholipase C activity • axon guidance • salivary gland morphogenesis • cell proliferation • positive regulation of cell proliferation • cell-cell adhesion • cerebral cortex cell migration • positive regulation of cell migration • positive regulation of cyclin-dependent protein kinase activity involved in G1/S • positive regulation of catenin import into nucleus • negative regulation of epidermal growth factor receptor signaling pathway • positive regulation of phosphorylation • activation of phospholipase A2 activity by calcium-mediated signaling • negative regulation of apoptosis • positive regulation of MAP kinase activity • positive regulation of nitric oxide biosynthetic process • protein autophosphorylation • digestive tract morphogenesis • positive regulation of epithelial cell proliferation • regulation of peptidyl-tyrosine phosphorylation • regulation of nitric-oxide synthase activity • protein insertion into membrane • positive regulation of protein kinase B signaling cascade • morphogenesis of an epithelial fold • response to UV-A Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1956	13649
Ensembl	ENSG00000146648	ENSMUSG00000020122
UniProt	P00533	Q3TQS6
RefSeq (mRNA)	NM_005228.3	NM_007912
RefSeq (protein)	NP_005219.2	NP_031938
Location (UCSC)	Chr 7: 55.09 – 55.32 Mb	Chr 11: 16.65 – 16.82 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] Epidermal Growth Factor was discovered by Stanley Cohen of Vanderbilt University along with Rita Levi-Montalcini for which both received the Nobel prize in Physiology or Medicine in 1986.

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^{[citation needed]}. 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^{[citation needed]}.

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, anal cancers^[6] and glioblastoma multiforme. In this latter case a more or less specific mutation of EGFR, called EGFRvIII is often observed.^[7] Mutations, amplifications or misregulations of EGFR or family members are implicated in about 30% of all epithelial cancers.

Mutations involving EGFR could lead to its constant activation, which could result in uncontrolled cell division – a predisposition for cancer.^[8] 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^[9] 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.^[10] Other monoclonals in clinical development are zalutumumab, nimotuzumab, and matuzumab. 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. Gefitinib, erlotinib, and lapatinib (mixed EGFR and ERBB2 inhibitor) are examples of small molecule kinase inhibitors.

There are several quantitative methods available that use protein phosphorylation detection to identify EGFR family inhibitors.^[11]

EGFR and Lung Cancer

New drugs such as IRESSA and Tarceva directly target the EGFR. Patients have been divided into EGFR-positive and EGFR-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.^[12]

However, many patients develop resistance. Two primary sources of resistance are the T790M Mutation and MET oncogene.^[12] However, as of 2010 there was no consensus of an accepted approach to combat resistance nor FDA approval of a specific combination. Preclinical results have been reported for AP26113 which targets the T790M mutation.

Preclinical

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.^[13]

Possible involvement in axonal regeneration

In 2005 it was shown that inhibitors of EGFR could enhance axonal regeneration on non-conducive substrates such as CNS myelin.^[14] In July 2007 it was discovered that the blood clotting protein fibrinogen also activates EGFR, thereby inhibiting regeneration of axons.^[15]

Natural EGFR inhibitors

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.^[16]

Interactions

Epidermal growth factor receptor has been shown to interact with:

• Androgen receptor,^[17][18]
• ARF4,^[19]
• Beta-catenin,^[20][21][22]
• Caveolin 1,^[23]
• Caveolin 3,^[23]
• Cbl gene,^{[24][25][26][27][28]}
• CBLB,^[29][25]
• CBLC,^[30][31]
• CDC25A,^[32]
• CRK,^[29][33]
• Decorin,^[34][35]
• Epidermal growth factor,^[36][37]
• GRB14,^[38]
• Grb2,^{[39][29][38][40][41][36][42][43][44][45]}
• Janus kinase 2,^[46]
• MUC1,^[47][48]
• NCK1,^[49][50][39]
• NCK2^[39][51][52]
• PKC alpha,^[53]
• PLCG1,^[24][54]
• PLSCR1,^[55]
• PTPN1,^[56][57]
• PTPN11,^[29][58]
• PTPN6,^[58][59]
• SH2D3A,^[60]
• SH3KBP1,^[61][62]
• SHC1,^[29][63]
• SOS1,^[44][64][65]
• Src,^[46][66][67]
• STAT1,^[46][68]
• STAT3,^[46][69]
• STAT5A,^[46][29]
• Ubiquitin C,^[26][27][70] and
• Wiskott-Aldrich syndrome protein.^[71]

References

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Further reading

• Carpenter G (1987). "Receptors for epidermal growth factor and other polypeptide mitogens". Annu. Rev. Biochem. 56 (1): 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. doi:10.1006/cbir.1995.1086. PMID 7640657. 
• 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. doi:10.1016/S0960-0760(01)00190-X. PMID 11897506. 
• Tiganis T (2002). "Protein tyrosine phosphatases: dephosphorylating the epidermal growth factor receptor". IUBMB Life 53 (1): 3–14. doi:10.1080/15216540210811. PMID 12018405. 
• Di Fiore PP, Scita G (2002). "Eps8 in the midst of GTPases". Int. J. Biochem. Cell Biol. 34 (10): 1178–83. doi:10.1016/S1357-2725(02)00064-X. PMID 12127568. 
• Benaim G, Villalobo A (2002). "Phosphorylation of calmodulin. Functional implications". Eur. J. Biochem. 269 (15): 3619–31. doi:10.1046/j.1432-1033.2002.03038.x. PMID 12153558. 
• Leu TH, Maa MC (2004). "Functional implication of the interaction between EGF receptor and c-Src". Front. Biosci. 8 (1-3): s28–38. doi:10.2741/980. PMID 12456372. 
• Anderson NL, Anderson NG (2003). "The human plasma proteome: history, character, and diagnostic prospects". Mol. Cell Proteomics 1 (11): 845–67. doi:10.1074/mcp.R200007-MCP200. 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. 
• Bonaccorsi L, Muratori M, Carloni V, et al. (2003). "Androgen receptor and prostate cancer invasion". Int. J. Androl. 26 (1): 21–5. doi:10.1046/j.1365-2605.2003.00375.x. PMID 12534934. 
• 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 (1): 39–47. doi:10.1111/j.1749-6632.2003.tb03208.x. 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. doi:10.1080/08977190410001700998. PMID 15253384. 
• 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. 
• 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. 
• 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. PMC 2598028. PMID 17158592. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2598028. 
• 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. 
• 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. 

External links

• MeSH Epidermal Growth Factor Receptor