Receptor epidermnog faktora rasta

Receptor epidermnog faktora rasta (EGFR, ErbB-1, HER1 kod ljudi je transmembranski protein, receptor za članove epidermnog faktora rasta porodice EGF vanćelijskog proteinskog liganda.[5]

EGFR
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1IVO, 1M14, 1M17, 1MOX, 1NQL, 1XKK, 1YY9, 1Z9I, 2EB2, 2EB3, 2GS2, 2GS6, 2GS7, 2ITN, 2ITO, 2ITP, 2ITQ, 2ITT, 2ITU, 2ITV, 2ITW, 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, 4R3P, 4R3R, 4R5S, 4RIW, 4RIX, 4RIY, 4RJ4, 4RJ5, 4RJ6, 4RJ7, 4RJ8, 4TKS, 4WKQ, 4WRG, 4ZJV, 5CNN, 5CNO, 5CAN, 2N5S, 5CAL, 5C8M, 4UV7, 5CAV, 5CZI, 5EDQ, 5CAS, 5CAO, 5CAP, 5EM5, 5HG5, 5EDR, 5EM8, 5EDP, 5HG7, 5CAU, 5C8K, 5C8N, 5CZH, 5CAQ, 5EM6, 4UIP, 5HG9, 5EM7, 5HG8, 4ZSE, 5HIB, 5HIC, 5D41, 4WD5

Identifikatori
AliasiEGFR
Vanjski ID-jeviOMIM: 131550 MGI: 95294 HomoloGene: 74545 GeneCards: EGFR
Lokacija gena (čovjek)
Hromosom 7 (čovjek)
Hrom.Hromosom 7 (čovjek)[1]
Hromosom 7 (čovjek)
Genomska lokacija za EGFR
Genomska lokacija za EGFR
Bend7p11.2Početak55,019,017 bp[1]
Kraj55,211,628 bp[1]
Lokacija gena (miš)
Hromosom 11 (miš)
Hrom.Hromosom 11 (miš)[2]
Hromosom 11 (miš)
Genomska lokacija za EGFR
Genomska lokacija za EGFR
Bend11 A2|11 9.41 cMPočetak16,702,203 bp[2]
Kraj16,868,158 bp[2]
Obrazac RNK ekspresije
https://ncbi.nlm.nih.gov/gene?cmd=retrieve&dopt=default&rn=1&list_uids=1956/ Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija kinase activity
nitric-oxide synthase regulator activity
transmembrane receptor protein tyrosine kinase activity
protein phosphatase binding
ATP binding
protein kinase activity
vezivanje enzima
MAP kinase kinase kinase activity
aktivnost sa transferazom
chromatin binding
actin filament binding
double-stranded DNA binding
transmembrane signaling receptor activity
nucleotide binding
signal transducer activity
vezivanje identičnih proteina
signaling receptor binding
protein tyrosine kinase activity
calmodulin binding
protein kinase binding
phosphatidylinositol-4,5-bisphosphate 3-kinase activity
protein heterodimerization activity
integrin binding
epidermal growth factor binding
GO:0008313 epidermal growth factor-activated receptor activity
ubiquitin protein ligase binding
cadherin binding
virus receptor activity
GO:0001948, GO:0016582 vezivanje za proteine
Ćelijska komponenta citoplazma
endozom
multivesicular body, internal vesicle lumen
Jedarna membrana
membrana
focal adhesion
extracellular region
perinuklearno područje citoplazme
jedro
cell surface
Endoplazmatski retikulum
integral component of membrane
Golđijev aparat
early endosome membrane
receptor complex
ćelijska membrana
endocytic vesicle
intracellular anatomical structure
AP-2 adaptor complex
endosome membrane
endoplasmic reticulum membrane
Golđijeva membrana
basolateral plasma membrane
Shc-EGFR complex
Lipidni splav
apical plasma membrane
sinapsa
Vanćelijsko
clathrin-coated vesicle membrane
integral component of plasma membrane
basal plasma membrane
GO:0009327 makromolekulani kompleks
Biološki proces positive regulation of protein phosphorylation
negative regulation of epidermal growth factor receptor signaling pathway
positive regulation of MAP kinase activity
protein phosphorylation
cell surface receptor signaling pathway
protein insertion into membrane
Ćelijska proliferacija
morphogenesis of an epithelial fold
ossification
GO:1903363 negative regulation of protein catabolic process
transmembrane receptor protein tyrosine kinase signaling pathway
positive regulation of fibroblast proliferation
activation of phospholipase C activity
epidermis development
learning or memory
protein autophosphorylation
positive regulation of phosphorylation
cerebral cortex cell migration
digestive tract morphogenesis
hair follicle development
Fosforilacija
positive regulation of epithelial cell proliferation
embryonic placenta development
eyelid development in camera-type eye
GO:0043006 activation of phospholipase A2 activity
positive regulation of DNA replication
response to UV-A
regulation of peptidyl-tyrosine phosphorylation
positive regulation of cell migration
positive regulation of nitric oxide biosynthetic process
cellular response to estradiol stimulus
GO:1900404 positive regulation of DNA repair
response to stress
regulation of nitric-oxide synthase activity
salivary gland morphogenesis
MAPK cascade
cellular response to epidermal growth factor stimulus
multicellular organism development
regulation of cell population proliferation
GO:0000767 cell morphogenesis
cellular response to amino acid stimulus
GO:0072468 Transdukcija signala
GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II
lung development
positive regulation of synaptic transmission, glutamatergic
positive regulation of ERK1 and ERK2 cascade
phosphatidylinositol phosphate biosynthetic process
Jednodnevni biološki ritam
positive regulation of superoxide anion generation
positive regulation of cell population proliferation
positive regulation of vasoconstriction
response to osmotic stress
tongue development
negative regulation of apoptotic process
response to cobalamin
liver regeneration
response to calcium ion
Zarastanje rana
cellular response to dexamethasone stimulus
negative regulation of mitotic cell cycle
cellular response to growth factor stimulus
hydrogen peroxide metabolic process
GO:0001306 response to oxidative stress
response to lipid
regulation of cell motility
GO:0007243 intracellular signal transduction
GO:1904578 response to organic cyclic compound
magnesium ion homeostasis
Biosinteza bjelančevina
positive regulation of production of miRNAs involved in gene silencing by miRNA
positive regulation of smooth muscle cell proliferation
positive regulation of bone resorption
midgut development
positive regulation of inflammatory response
liver development
diterpenoid metabolic process
ERBB2 signaling pathway
response to estradiol
positive regulation of cell growth
positive regulation of prolactin secretion
astrocyte activation
cellular response to mechanical stimulus
response to hydroxyisoflavone
neuron projection morphogenesis
ovulation cycle
GO:0044324, GO:0003256, GO:1901213, GO:0046019, GO:0046020, GO:1900094, GO:0061216, GO:0060994, GO:1902064, GO:0003258, GO:0072212 regulation of transcription by RNA polymerase II
peptidyl-tyrosine phosphorylation
membrane organization
positive regulation of protein kinase C activity
negative regulation of ERBB signaling pathway
positive regulation of protein localization to plasma membrane
negative regulation of cardiocyte differentiation
GO:0072353 cellular response to reactive oxygen species
GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated
regulation of JNK cascade
regulation of ERK1 and ERK2 cascade
cellular response to cadmium ion
positive regulation of NIK/NF-kappaB signaling
viral entry into host cell
epidermal growth factor receptor signaling pathway
positive regulation of peptidyl-serine phosphorylation
peptidyl-tyrosine autophosphorylation
cell-cell adhesion
regulation of phosphatidylinositol 3-kinase signaling
positive regulation of protein kinase B signaling
positive regulation of nitric oxide mediated signal transduction
Ćelijska diferencijacija
positive regulation of cyclin-dependent protein serine/threonine kinase activity
negative regulation of Notch signaling pathway
positive regulation of canonical Wnt signaling pathway
positive regulation of G1/S transition of mitotic cell cycle
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)
NM_001346897
NM_001346898
NM_001346899
NM_001346900
NM_001346941

NM_005228
NM_201282
NM_201283
NM_201284

NM_007912
NM_207655

RefSeq (bjelančevina)
NP_001333826
NP_001333827
NP_001333828
NP_001333829
NP_001333870

NP_005219
NP_958439
NP_958440
NP_958441

NP_031938
NP_997538

Lokacija (UCSC)Chr 7: 55.02 – 55.21 MbChr 11: 16.7 – 16.87 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Receptor epidermnog faktora rasta je član receptora porodice ErbB, potporodice od četiri blisko povezane receptorske tirozin-kinaze: EGFR (ErbB-1), HER2/neu (ErbB-2), 3 HER (ErbB-3) i HER-4 (ErbB-4). Kod mnogih tipova raka, mutacije koje utiču na ekspresiju ili aktivnost EGFR-a mogu dovesti do raka.[6]

Epidermni faktor rasta i njegov receptor otkrio je Stanley Cohen sa Vanderbilt University. Cohen je 1986. godine podijelio Nobelovu nagradu za fiziologiju ili medicinu sa Ritom Levi-Montalcini za njihovo otkriće faktora rasta.

Nedostatak signalizacije EGFR-a i drugih receptorska tirozin-kinaza kod ljudi povezan je s bolestima kao što je Alzheimerova bolest, dok je prekomjerna ekspresija povezana s razvojem širokog spektra tumora. Prekid EGFR signalizacije, bilo blokiranjem EGFR mjesta vezanja na vanćelijskom domenu receptora ili inhibicijom aktivnosti unutarćelijskih tirozin-kinaza, može spriječiti rast tumora koji eksprimiraju EGFR i poboljšati stanje pacijenta.

Aminokiselinska sekvenca

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Dužina polipeptidnog lanca je 1.210 aminokiselina, a molekulska težina 134.277 Da.[6]

1020304050
MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLS
LQRMFNNCEVVLGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIP
LENLQIIRGNMYYENSYALAVLSNYDANKTGLKELPMRNLQEILHGAVRF
SNNPALCNVESIQWRDIVSSDFLSNMSMDFQNHLGSCQKCDPSCPNGSCW
GAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGCTGPRESDCLV
CRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYV
VTDHGSCVRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLS
INATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKE
ITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGL
RSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCK
ATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFV
ENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVM
GENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGM
VGALLLLLVVALGIGLFMRRRHIVRKRTLRRLLQERELVEPLTPSGEAPN
QALLRILKETEFKKIKVLGSGAFGTVYKGLWIPEGEKVKIPVAIKELREA
TSPKANKEILDEAYVMASVDNPHVCRLLGICLTSTVQLITQLMPFGCLLD
YVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAARNVLVKTPQH
VKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSY
GVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKC
WMIDADSRPKFRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNFYRA
LMDEEDMDDVVDADEYLIPQQGFFSSPSTSRTPLLSSLSATSNNSTVACI
DRNGLQSCPIKEDSFLQRYSSDPTGALTEDSIDDTFLPVPEYINQSVPKR
PAGSVQNPVYHNQPLNPAPSRDPHYQDPHSTAVGNPEYLNTVQPTCVNST
FDSPAHWAQKGSHQISLDNPDYQQDFFPKEAKPNGIFKGSTAENAEYLRV
APQSSEFIGA

Funkcija

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Signalna kaskada EGFR
 
Dijagram EGF receptora sa važnim domenima

Receptor epidermalnog faktora rasta (EGFR) je transmembranski protein koji se aktivira vezivanjem njegovih specifičnih liganda, uključujući epidermni faktor rasta i transformirajući faktor rasta α (TGFα). ErbB2 nema poznatu direktnu aktivaciju liganda i može biti u konstitutivnom aktiviranom stanju ili postati aktivan nakon heterodimerizacije sa drugim članovima porodice kao što je EGFR. Nakon aktivacije svojim ligandima faktora rasta, EGFR prolazi kroz tranziciju iz neaktivnog monomernog oblika u aktivni homodimer.[7] – although there is some evidence that preformed inactive dimers may also exist before ligand binding.[8] Pored formiranja homodimera nakon vezivanja liganda, EGFR se može upariti sa drugim članom porodice ErbB receptora, kao što je ErbB2/Her2/neu, kako bi se stvorio aktivirani heterodimer. Postoje i dokazi koji ukazuju na to da se formiraju klasteri aktiviranih EGFR-ova, iako ostaje nejasno da li je ovo grupiranje važno za samu aktivaciju ili se javlja nakon aktivacije pojedinačnih dimera.

Dimerizacija EGFR-a stimuliše njegovu unutarćelijsku aktivnost protein-tirozin kinaze. Kao rezultat, dolazi do autofosforilacije nekoliko tirozinskih (Y) ostataka na C-terminalnom domenu EGFR. To uključuje Y992, Y1045, Y1068, Y1148 i Y1173, kao što je prikazano na susjednom dijagramu.[9] Ova autofosforilacija izaziva nizvodnu aktivaciju i signalizaciju nekoliko drugih proteina koji se povezuju sa fosforiliranim tirozinima preko vlastitih fosfotirozin-vezujućih SH2-domena. Ovi nizvodni signalni proteini pokreću nekoliko kaskada transdukcija signala, uglavnom MAPK, Akt i JNK puteve, što dovodi do DNK sinteze i proliferacija ćelija.[10] Takvi proteini moduliraju fenotipove kao što su ćelijska migracija, adhezija i proliferacija. Aktivacija receptora je važna za urođeni imunski odgovor u ljudskoj koži. Domen kinaze EGFR-a također može unakrsno fosforilirati tirozinske ostatke drugih receptora s kojima je agregiran i može se sam aktivirati na taj način.

Biološke uloge

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EGFR je neophodan za razvoj cjevastih mliječnih žlijezda,[11][12][13] i agonisti EGFR-a kao što su amfiregulin, TGF-α i heregulin induciraju i duktusni i lobuloalveolski razvoj, čak i u odsustvu estrogena i progesterona.[14][15]

Klinički značaj

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Kancer

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Mutacije koje dovode do prekomjerne ekspresije EGFR-a (poznate kao nadregulacija ili pojačanje) povezane su s brojnim karcinomima, uključujući adenokarcinom pluća (40% slučajeva), anusni rak,[16] glioblastom (50%) i epitelni tumori glave i vrata (80–100%).[17] Ove somatske mutacije koje uključuju EGFR dovode do njegove stalne aktivacije, što uzrokuje nekontrolirane diobe ćelija.[18] Kod glioblastoma se često opaža specifična mutacija EGFR, zvana EGFRvIII.[19] Mutacije, pojačanja ili pogrešna regulacija EGFR-a ili članova porodice su uključeni u oko 30% svih epitelnih karcinoma.[20]

Upalna bolest

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Aberantna EGFR signalizacija je implicirana kod psorijaze, ekcema i ateroskleroze.[21][22] Međutim, njegove tačne uloge u ovim uslovima su loše definisane.

Monogenska bolest

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Utvrđeno je da jedno dijete koje pokazuje upalu epitela više organa ima homozigotnu mutaciju gubitka funkcije u "EGFR" genu. Patogenost EGFR mutacije je potvrđena in vitro eksperimentima i funkcionalnom analizom biopsije kože. Njegov teški fenotip odražava mnoga ranija istraživanja funkcije EGFR. Njegove kliničke karakteristike su uključivale papulopustulni osip, suhu kožu, hroničnu dijareju, abnormalnosti rasta dlake, poteškoće s disanjem i neravnotežu elektrolita.[23]

Zacjeljivanje rana i fibroza

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Pokazalo se da EGFR ima ključnu ulogu u diferencijaciji TGF beta 1, zavisnoj od fibroblasta do miofibroblasta.[24][25] Aberantna perzistencija miofibroblasta unutar tkiva može dovesti do progresivnog tkiva fibroze, oštećenja funkcije tkiva ili organa (npr. kože hipertrofični ili keloidni ožiljci, ciroza jetre, fibroza miokarda, hronična bolest bubrega).

Medicinska primjena

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Meta lijekova

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Identifikacija EGFR-a kao onkogena dovela je do razvoja antikancerogenih lijekova usmjerenih protiv EGFR-a (koji se nazivaju "EGFR inhibitori", EGFRi), uključujući gefitinib,[26] erlotinib, afatinib, brigatinib i ikotinib[27] za rak pluća i cetuksimab za rak debelog crijeva. Nedavno je AstraZeneca razvila Osimertinib, treću generaciju inhibitora tirozin-kinaze.[28]

Mnogi terapijski pristupi usmjereni su na EGFR. Cetuksimab i panitumumab su primjeri inhibitorskih monoklonska antitijela. Međutim, prvi je tipa IgG1, a drugi tipa IgG2; posljedice na ćelijsku citotoksičnost zavisnu od antitijela mogu biti sasvim različite.[29] Ostali monoklonski agensi u kliničkom razvoju su zalutumumab, nimotuzumab i matuzumab. Monoklonska antitijela blokiraju domen za vezivanje vanćelijskog liganda. Sa blokiranim mjestom vezivanja, signalne molekule se više ne mogu vezati tamo i aktivirati tirozin-kinazu.

Drugi metod je korištenje malih molekula za inhibiciju EGFR tirozin-kinaze, koja se nalazi na citoplazmatskoj strani receptora. Bez aktivnosti kinaze, EGFR nije u stanju da se aktivira, što je preduslov za vezivanje nizvodnih adapterskih proteina. Navodno zaustavljanjem signalne kaskade u ćelijama koje se oslanjaju na ovaj put za ćelijski rast, proliferacija i migracija tumora je smanjena. Gefitinib, erlotinib, brigatinib i lapatinib (mješoviti EGFR i ERBB2 inhibitor) su primjeri inhibitora malih molekula kinaze.

CimaVax-EGF, aktivna vakcina koja cilja EGF kao glavni ligand EGF-a, koristi drugačiji pristup, podižući antitijela protiv samog EGF-a, čime se poriču EGFR zavisni karcinomi proliferativni stimulus;[30] koristi se kao terapija raka protiv karcinoma nemalih ćelija pluća (najčešći oblik raka pluća) na Kubi, a prolazi dalje ispitivanje za moguće licenciranje u Japanu, Evropi i Sjedinjenim Državama.[31]

Postoji nekoliko dostupnih kvantitativnih metoda koje koriste detekciju fosforilacije proteina za identifikaciju inhibitora porodice EGFR.[32]

Novi lijekovi kao što su osimertinib, gefitinib, erlotinib i brigatinib direktno ciljaju EGFR. Pacijenti su podijeljeni na EGFR-pozitivne i EGFR-negativne, na osnovu toga da li test tkiva pokazuje mutaciju. EGFR-pozitivni pacijenti pokazali su stopu odgovora od 60%, što premašuje stopu odgovora za konvencionalnu hemoterapiju.[33]

Međutim, mnogi pacijenti razvijaju otpornost. Dva primarna izvora rezistencije su mutacija T790M i MET onkogen.[33] Međutim, od 2010. nije postojao konsenzus o prihvaćenom pristupu borbi protiv otpora niti odobrenje FDA za određenu kombinaciju. Rezultati kliničkog ispitivanja faze II prijavljeni za brigatinib koji cilja na mutaciju T790M, a brigatinib je dobio status probojne terapije kod FDA u februaru 2015. godine.

Najčešći štetni efekat EGFR inhibitora, koji se nalazi kod više od 90% pacijenata, je papulopustulni osip koji se širi preko lica i trupa; prisustvo osipa je u korelaciji sa antitumorskim dejstvom lijeka.[34] Kod 10% do 15% pacijenata efekti mogu biti ozbiljni i zahtijevaju liječenje.[35][36]

Neki testovi imaju za cilj predviđanje koristi od EGFR tretmana, kao što je Veristrat.[37]

Laboratorijsko istraživanje koje koristi genetički modifikovane matične ćelije za ciljanje EGFR kod miševa objavljeno je 2014. da obećava.[38] EGFR is a well-established _target for monoclonal antibodies and specific tyrosine kinase inhibitors.[39]

Meta agenasa za snimanje

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Razvijeni su agensi za snimanje koji identifikuju karcinome zavisne od EGFR, koristeći označeni EGF.[40] Izvodljivost snimanja ekspresije in vivo EGFR pokazano je u nekoliko studija.[41][42]

Predloženo je da određeni nalazi kompjuterizirane tomografije kao što su opaciteti brušenog stakla, zračni bronhogram, spikulirane ivice, vaskularna konvergencija i pleuralna retrakcija mogu predvidjeti prisustvo EGFR mutacije kod pacijenata s karcinomom pluća nemalih ćelija.[43]

Interakcije

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Pokazalo se da receptor epidermalnog faktora rasta reaguje sa:

Kod voćnih mušica, receptor epidermnog faktora rasta stupa u interakciju sa Spic.[101]

Reference

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000146648 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020122 - Ensembl, maj 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Herbst RS (2004). "Review of epidermal growth factor receptor biology". International Journal of Radiation Oncology, Biology, Physics. 59 (2 Suppl): 21–6. doi:10.1016/j.ijrobp.2003.11.041. PMID 15142631.
  6. ^ a b Zhang H, Berezov A, Wang Q, Zhang G, Drebin J, Murali R, Greene MI (august 2007). "ErbB receptors: from oncogenes to _targeted cancer treatment". The Journal of Clinical Investigation. 117 (8): 2051–8. doi:10.1172/JCI32278. PMC 1934579. PMID 17671639.
  7. ^ Yarden Y, Schlessinger J (mart 1987). "Epidermal growth factor induces rapid, reversible aggregation of the purified epidermal growth factor receptor". Biochemistry. 26 (5): 1443–51. doi:10.1021/bi00379a035. PMID 3494473.
  8. ^ Maruyama IN (april 2014). "Mechanisms of activation of receptor tyrosine kinases: monomers or dimers". Cells. 3 (2): 304–30. doi:10.3390/cells3020304. PMC 4092861. PMID 24758840.
  9. ^ Downward J, Parker P, Waterfield MD (1984). "Autophosphorylation sites on the epidermal growth factor receptor". Nature. 311 (5985): 483–5. Bibcode:1984Natur.311..483D. doi:10.1038/311483a0. PMID 6090945. S2CID 4332354.
  10. ^ Oda K, Matsuoka Y, Funahashi A, Kitano H (2005). "A comprehensive pathway map of epidermal growth factor receptor signaling". Molecular Systems Biology. 1 (1): E1–E17. doi:10.1038/msb4100014. PMC 1681468. PMID 16729045.
  11. ^ Sebastian J, Richards RG, Walker MP, Wiesen JF, Werb Z, Derynck R, Hom YK, Cunha GR, DiAugustine RP (septembar 1998). "Activation and function of the epidermal growth factor receptor and erbB-2 during mammary gland morphogenesis". Cell Growth & Differentiation. 9 (9): 777–85. PMID 9751121.
  12. ^ McBryan J, Howlin J, Napoletano S, Martin F (juni 2008). "Amphiregulin: role in mammary gland development and breast cancer". Journal of Mammary Gland Biology and Neoplasia. 13 (2): 159–69. doi:10.1007/s10911-008-9075-7. PMID 18398673. S2CID 13229645.
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