Epidermal growth factor receptor

Epidermal growth factor receptor
Extracellular domain of Epidermal growth factor receptor in complex with EGF. PDB 1nql[1]
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 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​, 2M0B​, 2M20​, 2RF9​, 2RFD​, 2RFE​, 2RGP​, 3B2U​, 3B2V​, 3BEL​, 3BUO​, 3C09​, 3G5V​, 3G5Y​, 3GOP​, 3GT8​, 3IKA​, 3LZB​, 3NJP​, 3OB2​, 3OP0​, 3P0Y​, 3PFV​, 3POZ​, 3QWQ​, 3UG1​, 3UG2​, 3VJN​, 3VJO​, 3VRP​, 3VRR​, 3W2O​, 3W2P​, 3W2Q​, 3W2R​, 3W2S​, 3W32​, 3W33​, 4G5J​, 4G5P​, 4HJO​, 4I1Z​, 4I20​, 4I21​, 4I22​, 4I23​, 4I24​, 4JQ7​, 4JQ8​, 4JR3​, 4JRV​, 4KRL​, 4KRM​, 4KRO​, 4KRP​, 4LI5​, 4LL0​, 4LQM​, 4LRM​, 4R5S​, 4RIW​, 4RIX​, 4RIY​, 4RJ4​, 4RJ5​, 4RJ6​, 4RJ7​, 4RJ8​, 4TKS​, 4WKQ​, 4WRG​
Identifiers
Symbols	EGFR ; ERBB; ERBB1; HER1; NISBD2; PIG61; mENA
External IDs	OMIM: 131550 MGI: 95294 HomoloGene: 74545 ChEMBL: 203 GeneCards: EGFR Gene
EC number	2.7.10.1
Gene ontology Molecular function • chromatin binding • double-stranded DNA binding • MAP kinase kinase kinase activity • protein tyrosine kinase activity • transmembrane receptor protein tyrosine kinase activity • receptor signaling protein tyrosine kinase activity • transmembrane signaling receptor activity • epidermal growth factor-activated receptor activity • protein binding • ATP binding • enzyme binding • protein phosphatase binding • nitric-oxide synthase regulator activity • ubiquitin protein ligase binding • identical protein binding • protein heterodimerization activity • actin filament binding Cellular component • Golgi membrane • extracellular space • nucleus • cytoplasm • endosome • endoplasmic reticulum membrane • plasma membrane • focal adhesion • cell surface • endosome membrane • membrane • integral component of membrane • basolateral plasma membrane • AP-2 adaptor complex • early endosome membrane • nuclear membrane • receptor complex • membrane raft • perinuclear region of cytoplasm • Shc-EGFR complex • multivesicular body, internal vesicle lumen Biological process • MAPK cascade • activation of MAPKK activity • ossification • embryonic placenta development • positive regulation of protein phosphorylation • hair follicle development • response to stress • signal transduction • cell surface receptor signaling pathway • epidermal growth factor receptor signaling pathway • activation of phospholipase C activity • axon guidance • salivary gland morphogenesis • learning or memory • cell proliferation • positive regulation of cell proliferation • fibroblast growth factor receptor signaling pathway • single organismal cell-cell adhesion • peptidyl-tyrosine phosphorylation • cerebral cortex cell migration • positive regulation of cell migration • positive regulation of cyclin-dependent protein serine/threonine kinase activity involved in G1/S transition of mitotic cell cycle • positive regulation of catenin import into nucleus • Fc-epsilon receptor signaling pathway • negative regulation of epidermal growth factor receptor signaling pathway • negative regulation of protein catabolic process • positive regulation of phosphorylation • activation of phospholipase A2 activity by calcium-mediated signaling • negative regulation of apoptotic process • positive regulation of MAP kinase activity • innate immune response • positive regulation of nitric oxide biosynthetic process • positive regulation of DNA repair • positive regulation of DNA replication • positive regulation of transcription from RNA polymerase II promoter • protein autophosphorylation • neurotrophin TRK receptor signaling pathway • phosphatidylinositol-mediated signaling • positive regulation of fibroblast proliferation • 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 • morphogenesis of an epithelial fold • response to UV-A • positive regulation of ERK1 and ERK2 cascade • cellular response to amino acid stimulus • cellular response to epidermal growth factor stimulus • cellular response to estradiol stimulus Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1956	13649
Ensembl	ENSG00000146648	ENSMUSG00000020122
UniProt	P00533	Q01279
RefSeq (mRNA)	NM_005228	NM_007912
RefSeq (protein)	NP_005219	NP_031938
Location (UCSC)	Chr 7: 55.02 – 55.26 Mb	Chr 11: 16.75 – 16.92 Mb
PubMed search

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.^[2]

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.^[3]

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

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^[4] – 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 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.^[5] 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.^[6] 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

The EGFR is essential for ductal development of the mammary glands,^[7][8][9] 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.^[10][11]

Role in human disease

Cancer

Mutations that lead to EGFR overexpression (known as upregulation) or overactivity have been associated with a number of cancers, including lung cancer, anal cancers^[12] and glioblastoma multiforme. These somatic mutations involving EGFR lead to its constant activation, which produces uncontrolled cell division.^[13] In glioblastoma a more or less specific mutation of EGFR, called EGFRvIII is often observed.^[14] Mutations, amplifications or misregulations of EGFR or family members are implicated in about 30% of all epithelial cancers.

Inflammatory disease

Aberrant EGFR signaling has been implicated in psoriasis, eczema and atherosclerosis.^[15][16] However, its exact roles in these conditions are ill-defined.

Monogenic disease

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.^[17]

Medical applications

Cancer treatment

The identification of EGFR as an oncogene has led to the development of anticancer therapeutics directed against EGFR (called "EGFR inhibitors"), including gefitinib,^[18] erlotinib, afatinib, brigatinib and icotinib^[19] 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.^[20] 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;^[21] 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.^[22]

There are several quantitative methods available that use protein phosphorylation detection to identify EGFR family inhibitors.^[23]

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.^[24]

However, many patients develop resistance. Two primary sources of resistance are the T790M Mutation and MET oncogene.^[24] 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.^[25] In 10% to 15% of patients the effects can be serious and require treatment.^[26][27]

Some tests are aiming at predicting benefit from EGFR treatment, as Veristrat.^[28]

Laboratory research using genetically engineered stem cells to target EGFR in mice was reported in 2014 to show promise.^[29]

Interactions

Epidermal growth factor receptor has been shown to interact with:

• AR,^[30][31]
• ARF4,^[32]
• CAV1,^[33]
• CAV3,^[33]
• CBL,^{[34][35][36][37][38]}
• CBLB,^[35][39]
• CBLC,^[40][41]
• CD44,^[42]
• CDC25A,^[43]
• CRK,^[39][44]
• CTNNB1,^[45][46][47]
• DCN,^[48][49]
• EGF,^[50][51]
• GRB14,^[52]
• Grb2,^{[39][50][52][53][54][55][56][57][58][59]}
• JAK2,^[60]
• MUC1,^[61][62]
• NCK1,^[53][63][64]
• NCK2^[53][65][66]
• PKC alpha,^[67]
• PLCG1,^[34][68]
• PLSCR1,^[69]
• PTPN1,^[70][71]
• PTPN11,^[39][72]
• PTPN6,^[72][73]
• PTPRK,^[74]
• SH2D3A,^[75]
• SH3KBP1,^[76][77]
• SHC1,^[39][78]
• SOS1,^[58][79][80]
• Src,^[60][81][82]
• STAT1,^[60][83]
• STAT3,^[60][84]
• STAT5A,^[39][60]
• UBC,^[36][37][85] and
• WAS.^[86]

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". 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 (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.
• 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

• Epidermal Growth Factor Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)

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