Epidermal growth factor receptor

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EGFR
1NQL.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases EGFR, ERBB, ERBB1, HER1, NISBD2, PIG61, mENA, epidermal growth factor receptor
External IDs MGI: 95294 HomoloGene: 74545 GeneCards: EGFR
Genetically Related Diseases
glioma[1]
Targeted by Drug
afatinib, 5-chloro-N2-(4-(4-(dimethylamino)-1-piperidinyl)-2-methoxyphenyl)-N4-(2-(dimethylphosphinyl)phenyl)-2,4-pyrimidinediamine, canertinib, dacomitinib anhydrous, erlotinib, gefitinib, icotinib, lapatinib, neratinib, vandetanib, osimertinib[2]
RNA expression pattern
PBB GE EGFR 201983 s at.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_201284
NM_005228
NM_201282
NM_201283

NM_007912
NM_207655

RefSeq (protein)

NP_005219.2
NP_958439.1
NP_958440.1
NP_958441.1

NP_997538.1

Location (UCSC) Chr 7: 55.02 – 55.26 Mb Chr 11: 16.75 – 16.92 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.[5]

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.[6]

Epidermal growth factor and its receptor was discovered by Stanley Cohen of Vanderbilt University. Cohen shared the 1986 Nobel Prize in Medicine with Rita Levi-Montalcini for their discovery of growth factors.

Function[edit]

EGFR signaling cascades
Diagram of the EGF receptor highlighting important domains

Epidermal growth factor receptor (EGFR) 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[7] – 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]

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 adjacent diagram.[8] 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.[9] 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. 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.

Biological roles[edit]

The EGFR is essential for ductal development of the mammary glands,[10][11][12] and agonists of the EGFR such as amphiregulin, TGF-α, and heregulin induce both ductal and lobuloalveolar development even in the absence of estrogen and progesterone.[13][14]

Role in human disease[edit]

Cancer[edit]

Mutations that lead to EGFR overexpression (known as upregulation) or overactivity have been associated with a number of cancers, including squamous-cell carcinoma of the lung (80% of cases), anal cancers,[15] glioblastoma (50%) and epithelian tumors of the head and neck (80-100%).[16] These somatic mutations involving EGFR lead to its constant activation, which produces uncontrolled cell division.[17] In glioblastoma a more or less specific mutation of EGFR, called EGFRvIII is often observed.[18] Mutations, amplifications or misregulations of EGFR or family members are implicated in about 30% of all epithelial cancers.[citation needed]

Inflammatory disease[edit]

Aberrant EGFR signaling has been implicated in psoriasis, eczema and atherosclerosis.[19][20] However, its exact roles in these conditions are ill-defined.

Monogenic disease[edit]

A single child displaying multi-organ epithelial inflammation was found to have a homozygous loss of function mutation in the EGFR gene. The pathogenicity of the EGFR mutation was supported by in vitro experiments and functional analysis of a skin biopsy. His severe phenotype reflects many previous research findings into EGFR function. His clinical features included a papulopustular rash, dry skin, chronic diarrhea, abnormalities of hair growth, breathing difficulties and electrolyte imbalances.[21]

Medical applications[edit]

Drug target[edit]

The identification of EGFR as an oncogene has led to the development of anticancer therapeutics directed against EGFR (called "EGFR inhibitors"), including gefitinib,[22] erlotinib, afatinib, brigatinib and icotinib[23] 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.[24] 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, brigatinib and lapatinib (mixed EGFR and ERBB2 inhibitor) are examples of small molecule kinase inhibitors.

CimaVax-EGF, an active vaccine targeting EGF as the major ligand of EGF, uses a different approach, raising antibodies against EGF itself, thereby denying EGFR-dependent cancers of a proliferative stimulus;[25] it is in use as a cancer therapy against non-small-cell lung carcinoma (the most common form of lung cancer) in Cuba, and is undergoing further trials for possible licensing in Japan, Europe, and the United States.[26]

There are several quantitative methods available that use protein phosphorylation detection to identify EGFR family inhibitors.[27]

New drugs such as gefitinib, erlotinib and brigatinib 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 a 60% response rate, which exceeds the response rate for conventional chemotherapy.[28]

However, many patients develop resistance. Two primary sources of resistance are the T790M Mutation and MET oncogene.[28] However, as of 2010 there was no consensus of an accepted approach to combat resistance nor FDA approval of a specific combination. Clinical trial phase II results reported for brigatinib targeting the T790M mutation, and brigatinib received Breakthrough Therapy designation status by FDA in Feb. 2015.

The most common adverse effect of EGFR inhibitors, found in more than 90% of patients, is a papulopustular rash that spreads across the face and torso; the rash's presence is correlated with the drug's antitumor effect.[29] In 10% to 15% of patients the effects can be serious and require treatment.[30][31]

Some tests are aiming at predicting benefit from EGFR treatment, as Veristrat.[32]

Laboratory research using genetically engineered stem cells to target EGFR in mice was reported in 2014 to show promise.[33]

Target for imaging agents[edit]

Imaging agents have been developed which identify EGFR-dependent cancers using labeled EGF[34] or anti-EGFR.[35]

Interactions[edit]

Epidermal growth factor receptor has been shown to interact with:

References[edit]

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  2. ^ "Drugs that physically interact with Epidermal growth factor receptor view/edit references on wikidata". 
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Further reading[edit]

  • Carpenter G (1987). "Receptors for epidermal growth factor and other polypeptide mitogens". Annual Review of Biochemistry. 56 (1): 881–914. doi:10.1146/annurev.bi.56.070187.004313. PMID 3039909. 
  • Boonstra J, Rijken P, Humbel B, Cremers F, Verkleij A, van Bergen en Henegouwen P (May 1995). "The epidermal growth factor". Cell Biology International. 19 (5): 413–30. doi:10.1006/cbir.1995.1086. PMID 7640657. 
  • Carpenter G (August 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 (February 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". The Journal of Steroid Biochemistry and Molecular Biology. 80 (2): 231–8. doi:10.1016/S0960-0760(01)00190-X. PMID 11897506. 
  • Tiganis T (January 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 (October 2002). "Eps8 in the midst of GTPases". The International Journal of Biochemistry & Cell Biology. 34 (10): 1178–83. doi:10.1016/S1357-2725(02)00064-X. PMID 12127568. 
  • Benaim G, Villalobo A (August 2002). "Phosphorylation of calmodulin. Functional implications". European Journal of Biochemistry / FEBS. 269 (15): 3619–31. doi:10.1046/j.1432-1033.2002.03038.x. PMID 12153558. 
  • Leu TH, Maa MC (January 2003). "Functional implication of the interaction between EGF receptor and c-Src". Frontiers in Bioscience. 8 (1-3): s28–38. doi:10.2741/980. PMID 12456372. 
  • Anderson NL, Anderson NG (November 2002). "The human plasma proteome: history, character, and diagnostic prospects". Molecular & Cellular Proteomics. 1 (11): 845–67. doi:10.1074/mcp.R200007-MCP200. PMID 12488461. 
  • Kari C, Chan TO, Rocha de Quadros M, Rodeck U (January 2003). "Targeting the epidermal growth factor receptor in cancer: apoptosis takes center stage". Cancer Research. 63 (1): 1–5. PMID 12517767. 
  • Bonaccorsi L, Muratori M, Carloni V, Zecchi S, Formigli L, Forti G, Baldi E (February 2003). "Androgen receptor and prostate cancer invasion". International Journal of Andrology. 26 (1): 21–5. doi:10.1046/j.1365-2605.2003.00375.x. PMID 12534934. 
  • Reiter J, Maihle NJ (May 2003). "Characterization and expression of novel 60-kDa and 110-kDa EGFR isoforms in human placenta". Annals of the New York Academy of Sciences. 995 (1): 39–47. doi:10.1111/j.1749-6632.2003.tb03208.x. PMID 12814937. 
  • Adams TE, McKern NM, Ward CW (June 2004). "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 (November 2004). "Active and inactive conformations of the epidermal growth factor receptor". Biochemical Society Transactions. 32 (Pt 5): 742–5. doi:10.1042/BST0320742. PMID 15494003. 
  • Chao C, Hellmich MR (December 2004). "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, Sundberg AL, Heldin NE, Hesselager G, Persson M, Gedda L, Tolmachev V, Lundqvist H, Blomquist E, Nistér M (March 2006). "Planning for intracavitary anti-EGFR radionuclide therapy of gliomas. Literature review and data on EGFR expression". Journal of Neuro-Oncology. 77 (1): 33–45. doi:10.1007/s11060-005-7410-z. PMID 16200342. 
  • Scartozzi M, Pierantoni C, Berardi R, Antognoli S, Bearzi I, Cascinu S (April 2006). "Epidermal growth factor receptor: a promising therapeutic target for colorectal cancer". Analytical and Quantitative Cytology and Histology / the International Academy of Cytology [And] American Society of Cytology. 28 (2): 61–8. PMID 16637508. 
  • Prudkin L, Wistuba II (October 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 (November 2006). "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 (March 2007). "Somatic mutations of the epidermal growth factor receptor and non-small-cell lung cancer". Journal of Medical Genetics. 44 (3): 166–72. doi:10.1136/jmg.2006.046102. PMC 2598028Freely accessible. 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 (January 2007). "PTEN-mediated resistance to epidermal growth factor receptor kinase inhibitors". Clinical Cancer Research. 13 (2 Pt 1): 378–81. doi:10.1158/1078-0432.CCR-06-1992. PMID 17255257. 
  • Nakamura JL (April 2007). "The epidermal growth factor receptor in malignant gliomas: pathogenesis and therapeutic implications". Expert Opinion on Therapeutic Targets. 11 (4): 463–72. doi:10.1517/14728222.11.4.463. PMID 17373877. 

External links[edit]