Epidermal growth factor receptor 1902394 226115588 2008-07-16T21:54:58Z 128.36.121.125 /* Function */ corrected typo {{PBB|geneid=1956}} {{otheruses4|a cell surface receptor|estimated measure of kidney function (eGFR)|Glomerular filtration rate}} The '''epidermal growth factor receptor''' (EGFR; ErbB-1; HER1 in humans) is the [[Cell membrane|cell-surface]] [[receptor (biochemistry)|receptor]] for members of the [[epidermal growth factor]] family (EGF-family) of [[extracellular]] protein [[ligand (biochemistry)|ligands]]. The epidermal growth factor receptor is a member of the [[ErbB]] family of receptors, a subfamily of four closely related [[receptor tyrosine kinase]]s: EGFR (ErbB-1), [[HER2/neu|HER2/c-neu]] (ErbB-2), [[ERBB3|Her 3]] (ErbB-3) and [[Her 4]] (ErbB-4). Mutations affecting EGFR expression or activity could result in [[cancer]]. ==Function== EGFR (epidermal growth factor receptor) exists on the cell surface and is activated by binding of its specific [[ligand]]s, including [[epidermal growth factor]] and [[TGF alpha|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#Kinase activation|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. [[Image:EGF Receptor.jpg|left|thumb|Diagram of the EGF receptor highlighting important domains]] EGFR dimerization stimulates its intrinsic intracellular protein-tyrosine kinase activity. As a result, [[protein kinase#regulation|autophosphorylation]] of several [[tyrosine]] (Y) residues in the C-terminal [[Protein domains|domain]] of EGFR occurs. These are Y845, Y992, Y1045, Y1068, Y1148 and Y1173 as shown in the diagram to the left. This autophosphorylation elicits downstream activation and signaling by several other proteins that associate with the phosphorylated tyrosines through their own phosphotyrosine-binding [[SH2 domain]]s. These downstream signaling proteins initiate several [[signal transduction]] cascades, principally the [[MAPK/ERK pathway|MAPK]], [[AKT|Akt]] and [[JNK]] pathways, leading to [[DNA replication|DNA synthesis]] and cell proliferation{{ref_N|1|a}}. Such proteins modulate phenotypes such as [[cell migration]], [[adhesion]], and [[Cell growth|proliferation]]. 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== [[Mutation]]s that lead to EGFR overexpression (known as upregulation) or overactivity have been associated with a number of [[cancer]]s, including [[lung cancer]] and [[glioblastoma multiforme]]. In this latter case a more or less specific mutation of EGFR, called EGFRvIII is often met with [http://www.healthvalue.net/egfreceptor.html]. Mutations involving EGFR could lead to its constant activation which could result in uncontrolled cell division &ndash; a predisposition for [[cancer]]{{ref_N|2|a}} . Consequently, mutations of EGFR have been identified in several types of cancer, and it is the target of an expanding class of anticancer therapies. The identification of EGFR as an [[oncogene]] has led to the development of anticancer therapeutics directed against EGFR, including [[gefitinib]]{{ref_N|3|a}} and [[erlotinib]] for lung cancer, and [[cetuximab]] for [[colon cancer]]. Many therapeutic approaches are aimed at the EGFR [http://www.healthvalue.net/EGFR-engl.html]. [[Cetuximab]] and [[panitumumab]] are examples of [[monoclonal antibodies|monoclonal antibody]] [[Enzyme inhibitor|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 [http://www.healthvalue.net/IgG1_IgG2.html]. Other monoclonals in clinical development are [[zalutumumab]], [[nimotuzumab]], and [[matuzumab]]. [[Gefitinib]], [[erlotinib]], 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. In July 2007 it was discovered that the blood clotting protein Fibrinogen activates EGFR, thereby blocking regrowth of injured neuronal cells in the spine.<ref>{{cite journal |author=Schachtrup C, Lu P, Jones LL, ''et al'' |title=Fibrinogen inhibits neurite outgrowth via beta 3 integrin-mediated phosphorylation of the EGF receptor |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=104 |issue=28 |pages=11814–9 |year=2007 |pmid=17606926 |doi=10.1073/pnas.0704045104|laysummary=http://www.eurekalert.org/pub_releases/2007-07/uoc--bcp070307.php}}</ref> Other 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.{{ref_N|4|a}} <!-- Image with unknown copyright status removed: [[Image:Egfr inhibitor diagram.jpg]] --> ==References== #{{note_N|1|a}} A comprehensive pathway map of epidermal growth factor receptor signaling. ''[[Molecular Systems Biology]] doi:10.1038/msb4100014, 2005 May'' [http://www.nature.com/msb/journal/v1/n1/full/msb4100014.html] #{{note_N|2|a}} [[Image:Free text.png]] Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. ''[[N Engl J Med]] 2004 May 20; 350(21): 2129-39. PMID 15118073'' [http://content.nejm.org/cgi/content/full/350/21/2129 Free text] #{{note_N|3|a}} EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. ''[[Science (journal)|Science]] 2004 Jun 4; 304(5676): 1497-500. PMID 15118125'' #{{note_N|4|a}} Potato Carboxypeptidase Inhibitor, a T-knot Protein, Is an Epidermal Growth Factor Antagonist That Inhibits Tumor Cell Growth. ''J Biol Chem, Vol. 273, Issue 20, 12370-12377, May 15, 1998. PMID 9575190'' [http://www.jbc.org/cgi/content/full/273/20/12370 Free text] ==External links== * {{cite journal |author=Herbst R |title=Review of epidermal growth factor receptor biology |journal=Int J Radiat Oncol Biol Phys |volume=59 |issue=2 Suppl |pages=21–6 |year=2004 |pmid=15142631}} * {{MeshName|Epidermal+Growth+Factor+Receptor|3=Epidermal Growth Factor Receptor}} * [http://www.eurekalert.org/pub_releases/2007-07/uoc--bcp070307.php Fibrinogen, a blood-clotting protein, found to inhibit EGFR] Explains lack of healing in spinal injuries. ==Further reading== {{refbegin | 2}} {{PBB_Further_reading | citations = *{{cite journal | author=Carpenter G |title=Receptors for epidermal growth factor and other polypeptide mitogens. |journal=Annu. Rev. Biochem. |volume=56 |issue= |pages= 881–914 |year= 1987 |pmid= 3039909 |doi= 10.1146/annurev.bi.56.070187.004313 }} *{{cite journal | author=Boonstra J, Rijken P, Humbel B, ''et al.'' |title=The epidermal growth factor. |journal=Cell Biol. Int. |volume=19 |issue= 5 |pages= 413–30 |year= 1995 |pmid= 7640657 |doi=10.1006/cbir.1995.1086 }} *{{cite journal | author=Carpenter G |title=The EGF receptor: a nexus for trafficking and signaling. |journal=Bioessays |volume=22 |issue= 8 |pages= 697–707 |year= 2000 |pmid= 10918300 |doi= 10.1002/1521-1878(200008)22:8<697::AID-BIES3>3.0.CO;2-1 }} *{{cite journal | author=Filardo EJ |title=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. |journal=J. Steroid Biochem. Mol. Biol. |volume=80 |issue= 2 |pages= 231–8 |year= 2002 |pmid= 11897506 |doi=10.1016/S0960-0760(01)00190-X }} *{{cite journal | author=Tiganis T |title=Protein tyrosine phosphatases: dephosphorylating the epidermal growth factor receptor. |journal=IUBMB Life |volume=53 |issue= 1 |pages= 3–14 |year= 2002 |pmid= 12018405 |doi=10.1080/15216540210811 }} *{{cite journal | author=Di Fiore PP, Scita G |title=Eps8 in the midst of GTPases. |journal=Int. J. Biochem. Cell Biol. |volume=34 |issue= 10 |pages= 1178–83 |year= 2002 |pmid= 12127568 |doi=10.1016/S1357-2725(02)00064-X }} *{{cite journal | author=Benaim G, Villalobo A |title=Phosphorylation of calmodulin. Functional implications. |journal=Eur. J. Biochem. |volume=269 |issue= 15 |pages= 3619–31 |year= 2002 |pmid= 12153558 |doi=10.1046/j.1432-1033.2002.03038.x }} *{{cite journal | author=Leu TH, Maa MC |title=Functional implication of the interaction between EGF receptor and c-Src. |journal=Front. Biosci. |volume=8 |issue= |pages= s28–38 |year= 2004 |pmid= 12456372 |doi=10.2741/980 }} *{{cite journal | author=Anderson NL, Anderson NG |title=The human plasma proteome: history, character, and diagnostic prospects. |journal=Mol. Cell Proteomics |volume=1 |issue= 11 |pages= 845–67 |year= 2003 |pmid= 12488461 |doi= }} *{{cite journal | author=Kari C, Chan TO, Rocha de Quadros M, Rodeck U |title=Targeting the epidermal growth factor receptor in cancer: apoptosis takes center stage. |journal=Cancer Res. |volume=63 |issue= 1 |pages= 1–5 |year= 2003 |pmid= 12517767 |doi= }} *{{cite journal | author=Bonaccorsi L, Muratori M, Carloni V, ''et al.'' |title=Androgen receptor and prostate cancer invasion. |journal=Int. J. Androl. |volume=26 |issue= 1 |pages= 21–5 |year= 2003 |pmid= 12534934 |doi=10.1046/j.1365-2605.2003.00375.x }} *{{cite journal | author=Reiter JL, Maihle NJ |title=Characterization and expression of novel 60-kDa and 110-kDa EGFR isoforms in human placenta. |journal=Ann. N. Y. Acad. Sci. |volume=995 |issue= |pages= 39–47 |year= 2003 |pmid= 12814937 |doi= }} *{{cite journal | author=Adams TE, McKern NM, Ward CW |title=Signalling by the type 1 insulin-like growth factor receptor: interplay with the epidermal growth factor receptor. |journal=Growth Factors |volume=22 |issue= 2 |pages= 89–95 |year= 2005 |pmid= 15253384 |doi= }} *{{cite journal | author=Ferguson KM |title=Active and inactive conformations of the epidermal growth factor receptor. |journal=Biochem. Soc. Trans. |volume=32 |issue= Pt 5 |pages= 742–5 |year= 2005 |pmid= 15494003 |doi= 10.1042/BST0320742 }} *{{cite journal | author=Chao C, Hellmich MR |title=Bi-directional signaling between gastrointestinal peptide hormone receptors and epidermal growth factor receptor. |journal=Growth Factors |volume=22 |issue= 4 |pages= 261–8 |year= 2005 |pmid= 15621729 |doi= 10.1080/08977190412331286900 }} *{{cite journal | author=Carlsson J, Ren ZP, Wester K, ''et al.'' |title=Planning for intracavitary anti-EGFR radionuclide therapy of gliomas. Literature review and data on EGFR expression. |journal=J. Neurooncol. |volume=77 |issue= 1 |pages= 33–45 |year= 2006 |pmid= 16200342 |doi= 10.1007/s11060-005-7410-z }} *{{cite journal | author=Scartozzi M, Pierantoni C, Berardi R, ''et al.'' |title=Epidermal growth factor receptor: a promising therapeutic target for colorectal cancer. |journal=Anal. Quant. Cytol. Histol. |volume=28 |issue= 2 |pages= 61–8 |year= 2006 |pmid= 16637508 |doi= }} *{{cite journal | author=Prudkin L, Wistuba II |title=Epidermal growth factor receptor abnormalities in lung cancer. Pathogenetic and clinical implications. |journal=Annals of diagnostic pathology |volume=10 |issue= 5 |pages= 306–15 |year= 2006 |pmid= 16979526 |doi= 10.1016/j.anndiagpath.2006.06.011 }} *{{cite journal | author=Ahmed SM, Salgia R |title=Epidermal growth factor receptor mutations and susceptibility to targeted therapy in lung cancer. |journal=Respirology |volume=11 |issue= 6 |pages= 687–92 |year= 2007 |pmid= 17052295 |doi= 10.1111/j.1440-1843.2006.00887.x }} *{{cite journal | author=Zhang X, Chang A |title=Somatic mutations of the epidermal growth factor receptor and non-small-cell lung cancer. |journal=J. Med. Genet. |volume=44 |issue= 3 |pages= 166–72 |year= 2007 |pmid= 17158592 |doi= 10.1136/jmg.2006.046102 }} *{{cite journal | author=Cohenuram M, Saif MW |title=Epidermal growth factor receptor inhibition strategies in pancreatic cancer: past, present and the future. |journal=JOP |volume=8 |issue= 1 |pages= 4–15 |year= 2007 |pmid= 17228128 |doi= }} *{{cite journal | author=Mellinghoff IK, Cloughesy TF, Mischel PS |title=PTEN-mediated resistance to epidermal growth factor receptor kinase inhibitors. |journal=Clin. Cancer Res. |volume=13 |issue= 2 Pt 1 |pages= 378–81 |year= 2007 |pmid= 17255257 |doi= 10.1158/1078-0432.CCR-06-1992 }} *{{cite journal | author=Nakamura JL |title=The epidermal growth factor receptor in malignant gliomas: pathogenesis and therapeutic implications. |journal=Expert Opin. Ther. Targets |volume=11 |issue= 4 |pages= 463–72 |year= 2007 |pmid= 17373877 |doi= 10.1517/14728222.11.4.463 }} }} {{refend}} {{Receptor tyrosine kinases}} {{Oncogenes}} {{Growth factor receptors}} [[Category:Tyrosine kinase receptors]] [[Category:Oncogenes]] [[de:EGF-Rezeptor]] [[fr:Récepteur à l'EGF]] [[it:Recettore del fattore di crescita dell'epidermide]] [[ja:上皮成長因子受容体]] [[fi:Epidermaalisen kasvutekijän reseptori]] <!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. --> {{PBB_Controls | update_page = yes | require_manual_inspection = no | update_protein_box = yes | update_summary = no | update_citations = yes }}