EGFR ЭФР

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Рецептор эпидермального фактора роста

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Рецептор эпидермального фактора роста
Обозначения
СимволыEGFR; ERBB1
Entrez Gene1956
HGNC3236
OMIM131550
RefSeqNM_005228
UniProtQ9GZX1
Другие данные
Локус

7-я хр.7p12

Рецептор эпидермального фактора роста (epidermal growth factor receptor, EGFR, ErbB-1) — трансмембранный рецептор, связывающий экстраклеточные лиганды из группы эпидермальных факторов роста. Относится к семейству рецепторов ErbB, в частности к подсемейству тирозинкиназных рецепторов (обладающих внутренней тирозинкиназной активностью): EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) и Her 4 (ErbB-4). Мутации рецептора, приводящие к гиперэкспрессии или повышению активности, могут приводить к раковым заболеваниям.

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http://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor

Epidermal growth factor receptor

From Wikipedia, the free encyclopedia

This article is about a cell surface receptor. For estimated measure of kidney function (eGFR), see Glomerular filtration rate.
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Epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian)
Cartoon diagram of the epidermal growth factor receptor (EGFR) (rainbow colored, N-terminus = blue, C-terminus = red) complexed with its ligand epidermal growth factor (magenta) based on the PDB 1NQL crystallographic coordinates.
Available structures: 1ivo1m141m171mox1nql,1xkk1yy91z9i2gs22gs62gs72itn2ito2itp2itq,2itt2itu2itv2itw2itx2ity2itz2j5e2j5f2j6m
Identifiers
SymbolsEGFR; ERBB; ERBB1; mENA
External IDsOMIM131550 MGI95294HomoloGene74545
EC number2.7.10.1
[show]Gene ontology
RNA expression pattern

More reference expression data

Orthologs
HumanMouse
Entrez195613649
EnsemblENSG00000146648ENSMUSG00000020122
UniprotP00533Q3TQS6
RefseqNM_005228(mRNA)
NP_005219(protein)
NM_007912(mRNA)
NP_031938(protein)
LocationChr 7: 55.05 - 55.24 MbChr 11: 16.65 - 16.81 Mb
Pubmedsearch[1][2]

The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is thecell-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 relatedreceptor 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]

Contents

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[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 andtransforming 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. 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.

Diagram of the EGF receptor highlighting important domains

EGFR dimerization stimulates its intrinsic intracellular protein-tyrosine kinase activity. As a result, autophosphorylation of severaltyrosine (Y) residues in the C-terminal domainof 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 MAPKAkt and JNKpathways, leading to DNA synthesis and cell proliferation.[4] Such proteins modulate phenotypes such as cell migrationadhesion, 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.

[edit]Clinical applications

Mutations that lead to EGFR overexpression (known as upregulation) or overactivity have been associated with a number of cancers, including lung cancerand glioblastoma multiforme. In this latter case a more or less specific mutation of EGFR, called EGFRvIII is often observed.[6] 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 forcancer.[7] 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, includinggefitinib[8] 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 antibodyinhibitors. However the former is of the IgG1 type, the latter of the IgG2 type; consequences on antibody dependent cellular cytotoxicity can be quite different.[9] Other monoclonals in clinical development are zalutumumabnimotuzumab, and matuzumab.Gefitiniberlotinib, and lapatinib (the latter still in clinical trials) are examples of small molecule kinase inhibitors. 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. There are several quantitative methods available that use protein phosphorylation detection to identify EGFR family inhibitors.[10]

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.[11]

In July 2007 it was discovered that the blood clotting protein Fibrinogen activates EGFR, thereby blocking regrowth of injured neuronal cells in the spine.[12] Other natural inhibitors include potato carboxypeptidase inhibitor (PCI), which contains a smallcysteine-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.[13]

[edit]EGFR and Lung Cancer

New drugs such as Tarceva directly target the EGFR. Patients have been divided into EGFR positive and 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.

[edit]Interactions

Epidermal growth factor receptor has been shown to interact with PLCG1,[14][15] NCK1,[16][17][18] Janus kinase 2,[19] CDC25A,[20]MUC1,[21][22] Caveolin 1,[23] STAT5A,[24][19] PTPN1,[25][26] CRK,[24][27] SHC1,[24][28] Beta-catenin,[29][30][31] PTPN11,[24][32]PTPN6,[32][33] STAT1,[19][34] CBLC,[35][36] Src,[19][37][38] Androgen receptor,[39][40] STAT3,[41][19] GRB14,[42]Grb2,[24][43][44][45][46][47][42][48][49][18] PLSCR1,[50] Wiskott-Aldrich syndrome protein,[51] SH2D3A,[52] Epidermal growth factor,[53][45]CBLB,[24][54] Cbl gene,[54][14][55][56][57] ARF4,[58] PKC alpha,[59] SOS1,[60][61][48] SH3KBP1,[62][63] Caveolin 3,[23] Decorin,[64][65]NCK2[66][18][67] and Ubiquitin C.[68][55][56]

[edit]References

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[edit]External links

[edit]Further reading

  • Carpenter G (1987). "Receptors for epidermal growth factor and other polypeptide mitogens". Annu. Rev. Biochem. 56: 881–914.doi:10.1146/annurev.bi.56.070187.004313PMID 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;2-1PMID 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-XPMID 11897506.
  • Tiganis T (2002). "Protein tyrosine phosphatases: dephosphorylating the epidermal growth factor receptor". IUBMB Life 53 (1): 3–14.doi:10.1080/15216540210811PMID 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-XPMID 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.xPMID 12153558.
  • Leu TH, Maa MC (2004). "Functional implication of the interaction between EGF receptor and c-Src". Front. Biosci. 8: s28–38.doi:10.2741/980PMID 12456372.
  • Anderson NL, Anderson NG (2003). "The human plasma proteome: history, character, and diagnostic prospects". Mol. Cell Proteomics 1(11): 845–67. 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.xPMID 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: 39–47. 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. 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/BST0320742PMID 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:10.1080/08977190412331286900PMID 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-zPMID 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.2006.06.011PMID 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.xPMID 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.2006.046102PMID 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-06-1992PMID 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:10.1517/14728222.11.4.463PMID 17373877.
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