上皮成長因子レセプター遺伝子

関: epidermal growth factor receptor gene

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(genetics) a segment of DNA that is involved in producing a polypeptide chain; it can include regions preceding and following the coding DNA as well as introns between the exons; it is considered a unit of heredity; "genes were formerly called factors" (同)cistron, factor
informal term for information; "give me the gen on your new line of computers"

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/11/12 21:01:53」(JST)

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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

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^[4] – 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 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.

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^[7] and glioblastoma multiforme. These somatic mutations involving EGFR lead to its constant activation, which produces uncontrolled cell division.^[8] In glioblastoma a more or less specific mutation of EGFR, called EGFRvIII is often observed.^[9] 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.^[10]^[11] 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.^[12]

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,^[13]erlotinib, afatinib, and icotinib^[14] 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.^[15] 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.^[16]

New drugs such as gefitinib and erlotinib 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.^[17]

However, many patients develop resistance. Two primary sources of resistance are the T790M Mutation and MET oncogene.^[17] 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.

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.^[18] In 10% to 15% of patients the effects can be serious and require treatment.^[19]^[20]

Some tests are aiming at predicting benefit from EGFR treatment, as Veristrat.^[21]

Laboratory research using genetically engineered stem cells to target EGFR in mice was reported in 2014 to show promise.^[22]

Interactions

Epidermal growth factor receptor has been shown to interact with:

AR,^[23]^[24]
ARF4,^[25]
CAV1,^[26]
CAV3,^[26]
CBL,^[27]^[28]^[29]^[30]^[31]
CBLB,^[28]^[32]
CBLC,^[33]^[34]
CDC25A,^[35]
CRK,^[32]^[36]
CTNNB1,^[37]^[38]^[39]
DCN,^[40]^[41]
EGF,^[42]^[43]
GRB14,^[44]
Grb2,^[32]^[42]^[44]^[45]^[46]^[47]^[48]^[49]^[50]^[51]
JAK2,^[52]
MUC1,^[53]^[54]
NCK1,^[45]^[55]^[56]
NCK2^[45]^[57]^[58]
PKC alpha,^[59]
PLCG1,^[27]^[60]
PLSCR1,^[61]
PTPN1,^[62]^[63]
PTPN11,^[32]^[64]
PTPN6,^[64]^[65]
PTPRK,^[66]
SH2D3A,^[67]
SH3KBP1,^[68]^[69]
SHC1,^[32]^[70]
SOS1,^[50]^[71]^[72]
Src,^[52]^[73]^[74]
STAT1,^[52]^[75]
STAT3,^[52]^[76]
STAT5A,^[32]^[52]
UBC,^[29]^[30]^[77] and
WAS.^[78]

References

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External links

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

UpToDate Contents

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1. 進行非小細胞肺癌に対する遺伝子型による個別治療 personalized genotype directed therapy for advanced non small cell lung cancer
2. 肺癌の初期評価、治療、および予後の概要 overview of the initial evaluation treatment and prognosis of lung cancer
3. 成人における抗癌剤の投与 dosing of anticancer agents in adults
4. 大腸癌の分子遺伝学 molecular genetics of colorectal cancer
5. 前立腺癌の分子生物学 molecular biology of prostate cancer

English Journal

Circulating tumor DNA identified by targeted sequencing in advanced-stage non-small cell lung cancer patients.

Xu S1, Lou F2, Wu Y1, Sun DQ3, Zhang JB2, Chen W2, Ye H2, Liu JH1, Wei S1, Zhao MY2, Wu WJ2, Su XX2, Shi R2, Jones L4, Huang XF4, Chen SY5, Chen J6.
Cancer letters.Cancer Lett.2016 Jan 28;370(2):324-31. doi: 10.1016/j.canlet.2015.11.005. Epub 2015 Nov 12.
Non-small cell lung cancers (NSCLC) have unique mutation patterns, and some of these mutations may be used to predict prognosis or guide patient treatment. Mutation profiling before and during treatment often requires repeated tumor biopsies, which is not always possible. Recently, cell-free, circul
PMID 26582655

CT Radiogenomic Characterization of EGFR, K-RAS, and ALK Mutations in Non-Small Cell Lung Cancer.

Rizzo S1, Petrella F2, Buscarino V3, De Maria F3, Raimondi S4, Barberis M5, Fumagalli C5, Spitaleri G6, Rampinelli C7, De Marinis F6, Spaggiari L2, Bellomi M7,3.
European radiology.Eur Radiol.2016 Jan;26(1):32-42. doi: 10.1007/s00330-015-3814-0. Epub 2015 May 9.
OBJECTIVES: To assess the association between CT features and EGFR, ALK, KRAS mutations in non-small cell lung cancer.METHODS: Patients undergoing chest CT and testing for the above gene mutations were included. Qualitative evaluation of CTs included: lobe; lesion diameter; shape; margins; ground-gl
PMID 25956936

Phylogenetic analysis of multiple FISH markers in oral tongue squamous cell carcinoma suggests that a diverse distribution of copy number changes is associated with poor prognosis.

Wangsa D1,2, Chowdhury SA3,4, Ryott M5, Gertz EM6, Elmberger G7, Auer G2, Åvall Lundqvist E2,8, Küffer S9, Ströbel P9, Schäffer AA6, Schwartz R4,10, Munck-Wikland E11, Ried T1, Heselmeyer-Haddad K1.
International journal of cancer. Journal international du cancer.Int J Cancer.2016 Jan 1;138(1):98-109. doi: 10.1002/ijc.29691. Epub 2015 Aug 28.
Oral tongue squamous cell carcinoma (OTSCC) is associated with poor prognosis. To improve prognostication, we analyzed four gene probes (TERC, CCND1, EGFR and TP53) and the centromere probe CEP4 as a marker of chromosomal instability, using fluorescence in situ hybridization (FISH) in single cells f
PMID 26175310

Japanese Journal

分子異常診断法新時代 (特集変化する肺癌治療)

萩原弘一
日本呼吸器学会誌 = Annals of the Japanese Respiratory Society 3(1), 9-15, 2014-01-10
NAID 40019962001

Epidermal growth factor receptor abnormalities in atypical teratoid/rhabdoid tumors and an unusual case with gene amplification

Satomi Kaishi,Morishita Yukio,Murata Yoshihiko,Shiba-Ishii Aya,Sugano Masato,Noguchi Masayuki,里見介史,柴綾,菅野雅人,野口雅之
Pathology, research and practice 209(8), 521-526, 2013-08
… Atypical teratoid/rhabdoid tumor (AT/RT) is a rhabdoid tumor of the central nervous system comprising a mixture of small round cells and mesenchymal and/or epithelial elements, showing mutation of the SMARCB1 gene or SMARCA4 gene. … The epidermal growth factor receptor (EGFR) is one of the tyrosine kinase receptors whose overexpressed protein plays important roles in the malignant characteristics of various tumors. …
NAID 120005373267

〈Review〉Driver oncogene mutations and personalized treatment of lung cancer

Mitsudomi Tetsuya
Acta Medica Kinki University 38(1), 7-24, 2013-06
… [Abstract]　Discovery of activating mutation of the EGFR gene in 2004 opened the era of personalized therapy in thoracic oncology. … These tumors are highly dependent on the EGFR pathway and inhibition of this pathway results in dramatic induction of apoptosis in vitro, even though cancer cells may have various genetic alterations (oncogene addiction). …
NAID 120005324275

Related Pictures

★リンクテーブル★

リンク元	「epidermal growth factor receptor gene」「EGFR遺伝子」「上皮成長因子レセプター遺伝子」
関連記事	「eGFR」「EGFR」「EGF」「EG」

「epidermal growth factor receptor gene」

Epidermal growth factor receptor
	; Extracellular domain of Epidermal growth factor receptor in complex with EGF. PDB 1nql
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
Identifiers
Symbols	EGFR ; ERBB; ERBB1; HER1; 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	• glycoprotein binding; • 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; • integrin binding; • protein binding; • ATP binding; • enzyme binding; • protein kinase binding; • protein phosphatase binding; • nitric-oxide synthase regulator activity; • identical protein binding; • protein heterodimerization activity; • epidermal growth factor binding; • actin filament binding;
Cellular component	• Golgi membrane; • extracellular space; • nucleus; • cytoplasm; • endosome; • endoplasmic reticulum membrane; • plasma membrane; • cell surface; • endosome membrane; • membrane; • integral component of membrane; • basolateral plasma membrane; • apical plasma membrane; • AP-2 adaptor complex; • nuclear membrane; • receptor complex; • membrane raft; • perinuclear region of cytoplasm; • Shc-EGFR complex;
Biological process	• MAPK cascade; • activation of MAPKK activity; • ossification; • liver development; • embryonic placenta development; • positive regulation of protein phosphorylation; • hair follicle development; • polysaccharide metabolic process; • translation; • response to stress; • response to osmotic stress; • response to oxidative 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; • circadian rhythm; • cell proliferation; • positive regulation of cell proliferation; • fibroblast growth factor receptor signaling pathway; • magnesium ion homeostasis; • diterpenoid metabolic process; • single organismal cell-cell adhesion; • peptidyl-tyrosine phosphorylation; • alkanesulfonate metabolic process; • cerebral cortex cell migration; • lung development; • 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 superoxide anion generation; • response to cobalamin; • response to hydroxyisoflavone; • positive regulation of catenin import into nucleus; • cellular response to drug; • Fc-epsilon receptor signaling pathway; • negative regulation of epidermal growth factor receptor signaling pathway; • negative regulation of protein catabolic process; • positive regulation of phosphorylation; • ovulation cycle; • hydrogen peroxide metabolic process; • activation of phospholipase A2 activity by calcium-mediated signaling; • negative regulation of apoptotic process; • positive regulation of MAP kinase activity; • tongue development; • innate immune response; • positive regulation of nitric oxide biosynthetic process; • positive regulation of DNA repair; • positive regulation of DNA replication; • positive regulation of vasoconstriction; • positive regulation of vasodilation; • negative regulation of mitotic cell cycle; • positive regulation of transcription from RNA polymerase II promoter; • protein autophosphorylation; • neurotrophin TRK receptor signaling pathway; • phosphatidylinositol-mediated signaling; • astrocyte activation; • positive regulation of fibroblast proliferation; • digestive tract morphogenesis; • positive regulation of smooth muscle cell proliferation; • positive regulation of epithelial cell proliferation; • positive regulation of inflammatory response; • regulation of peptidyl-tyrosine phosphorylation; • regulation of nitric-oxide synthase activity; • protein insertion into membrane; • response to calcium ion; • positive regulation of protein kinase B signaling; • positive regulation of synaptic transmission, glutamatergic; • morphogenesis of an epithelial fold; • response to UV-A; • positive regulation of ERK1 and ERK2 cascade; • cellular response to mechanical stimulus; • cellular response to epidermal growth factor stimulus; • cellular response to estradiol stimulus; • cellular response to dexamethasone stimulus;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	This box: view; talk; edit;

　　[★]

上皮増殖因子受容体遺伝子、上皮成長因子受容体遺伝子、上皮細胞成長因子受容体遺伝子

関: EGFR gene

「EGFR遺伝子」

　　[★]

英: EGFR gene
同: epidermal growth factor receptor遺伝子
関: 神経腫瘍学

「上皮成長因子レセプター遺伝子」

　　[★]

英: EGFR gene
関: 上皮細胞成長因子受容体遺伝子

「eGFR」

　　[★]

同: estimated glomerular filtration rate, 推算糸球体濾過量
関: 腎不全,糸球体濾過量

非日本人の推定式

推算糸球体濾過率 = 175 x Cr ^ -1.154 x age ^ -0.203 (ml/min/1.73m2)

女性は0.742をかける

アフリカ系アメリカ人の場合は1.212をかける

日本人の推定式

推算糸球体濾過率 = 194 x Cr ^ -1.094 x age ^ -0.287 (ml/min/1.73m2)

女性は0.739をかける

計算

数字を入力

「EGFR」

　　[★]

「EGF」

　　[★] 上皮細胞増殖因子 epidermal growth factor

「EG」

　　[★] 好酸球性肉芽腫症 eosinophilic granuloma

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EGFR gene