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HER2

Nepregledano
S Wikipedije, slobodne enciklopedije
ERBB2
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1MFG, 1MFL, 1MW4, 1N8Z, 1QR1, 1S78, 2A91, 2JWA, 2KS1, 2L4K, 3BE1, 3H3B, 3N85, 3PP0, 3RCD, 3MZW, 3WLW, 3WSQ, 4GFU, 4HRL, 4HRM, 4HRN, 2N2A

Identifikatori
AliasiERBB2
Vanjski ID-jeviOMIM: 164870 MGI: 95410 HomoloGene: 3273 GeneCards: ERBB2
EC broj2.7.10.1
Lokacija gena (čovjek)
Hromosom 17 (čovjek)
Hrom.Hromosom 17 (čovjek)[1]
Hromosom 17 (čovjek)
Genomska lokacija za ERBB2
Genomska lokacija za ERBB2
Bend17q12Početak39,687,914 bp[1]
Kraj39,730,426 bp[1]
Lokacija gena (miš)
Hromosom 11 (miš)
Hrom.Hromosom 11 (miš)[2]
Hromosom 11 (miš)
Genomska lokacija za ERBB2
Genomska lokacija za ERBB2
Bend11 61.75 cM|11 DPočetak98,303,296 bp[2]
Kraj98,328,542 bp[2]
Obrazac RNK ekspresije


Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija• ErbB-3 class receptor binding
• aktivnost sa transferazom
• nucleotide binding
• protein kinase activity
• protein dimerization activity
• growth factor binding
• RNA polymerase I core binding
• kinase activity
• protein C-terminus binding
• GO:0001948, GO:0016582 vezivanje za proteine
• vezivanje identičnih proteina
• protein heterodimerization activity
• transmembrane receptor protein tyrosine kinase activity
• protein tyrosine kinase activity
• protein phosphatase binding
• ATP binding
• transmembrane signaling receptor activity
• phosphatidylinositol-4,5-bisphosphate 3-kinase activity
• Receptorska tirozin-kinaza
Ćelijska komponenta• integral component of membrane
• membrana
• myelin sheath
• receptor complex
• ćelijska membrana
• basolateral plasma membrane
• apical plasma membrane
• perinuklearno područje citoplazme
• endosome membrane
• GO:0016023 citoplazmatska vezikula
• jedro
• citoplazma
• citosol
• integral component of plasma membrane
• basal plasma membrane
Biološki proces• positive regulation of protein phosphorylation
• peripheral nervous system development
• GO:0009373 regulation of transcription, DNA-templated
• negative regulation of immature T cell proliferation in thymus
• positive regulation of MAP kinase activity
• Fosforilacija
• transmembrane receptor protein tyrosine kinase signaling pathway
• positive regulation of epithelial cell proliferation
• cellular response to growth factor stimulus
• Zarastanje rana
• oligodendrocyte differentiation
• regulation of angiogenesis
• positive regulation of translation
• transcription, DNA-templated
• nervous system development
• MAPK cascade
• protein phosphorylation
• development of the heart
• cell surface receptor signaling pathway
• GO:0032320, GO:0032321, GO:0032855, GO:0043089, GO:0032854 positive regulation of GTPase activity
• positive regulation of cell growth
• regulation of microtubule-based process
• neuromuscular junction development
• regulation of ERK1 and ERK2 cascade
• myelination
• protein autophosphorylation
• phosphatidylinositol 3-kinase signaling
• positive regulation of transcription by RNA polymerase I
• Ćelijska proliferacija
• positive regulation of transcription by RNA polymerase III
• motor neuron axon guidance
• enzyme linked receptor protein signaling pathway
• GO:0072468 Transdukcija signala
• positive regulation of cell adhesion
• positive regulation of protein targeting to membrane
• ERBB2 signaling pathway
• phosphatidylinositol phosphate biosynthetic process
• GO:1901313 positive regulation of gene expression
• peptidyl-tyrosine phosphorylation
• regulation of cell motility
• cellular response to epidermal growth factor stimulus
• 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
• negative regulation of ERBB signaling pathway
• positive regulation of protein kinase B signaling
• negative regulation of signal transduction
• Ćelijska diferencijacija
• negative regulation of apoptotic process
• positive regulation of ERK1 and ERK2 cascade
• GO:0007243 intracellular signal transduction
• positive regulation of cell population proliferation
• neuron differentiation
• positive regulation of MAPK cascade
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez

2064

13866

Ensembl

ENSG00000141736

ENSMUSG00000062312

UniProt

P04626

P70424

RefSeq (mRNK)

NM_001005862
NM_001289936
NM_001289937
NM_001289938
NM_004448

NM_001003817
NM_010152

RefSeq (bjelančevina)
NP_001005862
NP_001276865
NP_001276866
NP_001276867
NP_004439

NP_001369711
NP_001369712
NP_001369713
NP_001369714
NP_001369715
NP_001369716
NP_001369717
NP_001369718
NP_001369719
NP_001369720
NP_001369721
NP_001369722
NP_001369723
NP_001369724
NP_001369725
NP_001369726
NP_001369727
NP_001369728
NP_001369729
NP_001369730
NP_001369731
NP_001369732
NP_001369733
NP_001369734
NP_001369735

NP_001003817

Lokacija (UCSC)Chr 17: 39.69 – 39.73 MbChr 11: 98.3 – 98.33 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Receptor tirozin-protein kinaze erbB-2 je protein koji se normalno nalazi u ćelijskim membranama i kodiran je genom ERBB2. ERBB je skraćenica od eritroblastnog onkogena B, gena prvobitno izolovanog iz ptičjeg genoma. Ljudski protein se također često naziva HER2 (receptor 2 ljudskog epidermnog faktora rasta) ili CD340 (klaster diferencijacije 340)[5][6][7]

HER2 je član ljudske receptora epidermnog faktora rasta (HER/EGFR/ERBB). Ali za razliku od drugih članova porodice ERBB, HER2 se ne veže direktno za ligand. Aktivacija HER2 nastaje heterodimerizacijom s drugim članom ERBB ili homodimerizacijom kada je koncentracija HER2 visoka, naprimjer kod raka.[8] Amplifikacija ili prekomjerna ekspresija ovog onkogena pokazala se važnom ulogom u razvoju i progresiji određenih agresivnih tipova raka dojke. Posljednjih godina protein je postao važan biomarker i meta terapije za otprilike 30% pacijenata s [[rak dojke[rakom dojke]].[9]

Naziv

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HER2 je tako nazvan zbog strukturnih sličnosti s receptorom 1 ljudskog epidermalnog faktora rasta ili HER1.

Pseudonim Neu za HER2 izveden je iz matične ćelijske linije glioblastoma - vrste nervnog tumora koji se nalazi kod glodara.

ErbB-2 je dobio ime po sličnosti s onkogenom B ptičje eritroblastoze, ErbB; onkogen za koji se kasnije pokazalo da kodira receptor epidermalnog faktora rasta, EGFR.

Molekularno kloniranje EGFR-a otkrilo je da su HER2, Neu i ErbB-2 kodirani istim ortologom.[10]

Gen

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ERBB2, poznati proto-onkogen,[11] nalazi se na dugom kraku ljudskog hromosoma 17 (sekvenca 17q12).[12]

Funkcija

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Porodica ErbB se sastoji od četiri pojedinačna sa plazmamembrana-vezana receptor tirozin kinaze receptora. Jedan od njih je erbB-2, a ostali članovi su erbB-1, erbB-3 (vezuje se za neuregulin; nema kinaznu domenu) i erbB-4. Sva četiri sadrže ekstrai domen vezivanja liganda, transmembranski i unutarćelijski domen koji može inter-ragovati sa mnoštvom signalnih molekula i pokazivati i ligand-zavisnu i ligand-nezavisnu aktivnost. Važno je napomenuti da još nisu identifikovani ligandi za HER2.[13][14] HER2 se može heterodimerizirati s bilo kojim od ostala tri receptora i smatra se preferiranim partnerom za dimerizaciju ostalih ErbB receptora.[15]

Dimerizacija rezultira autofosforilacijom tirozinskih ostataka unutar citoplazmatskog domena receptora i pokreće različite signalne puteve.

Transdukcija signala

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Signalni putevi koje aktivira HER2 uključuju:[16]

Ukratko, signalizacija putem porodice ErbB receptora potiče proliferaciju ćelija i suprotstavlja se apoptozi, te stoga mora biti strogo regulirana kako bi se spriječio nekontrolirani rast ćelija.

Klinički značaj

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Kancer

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Amplifikacija, poznata i kao prekomjerna ekspresija gena ERBB2, javlja se kod približno 15-30% rakova dojke.[9][17] HER2-pozitivni karcinomi dojke su dobro poznati po povezanosti s povećanim recidivom bolesti i lošom prognozom u usporedbi s drugim genetički prepoznatljivim karcinomima dojke s drugim poznatim, ili nedostatkom istih, genetičkim markerima za koje se smatra da su povezani s drugim karcinomima dojke; međutim, lijekovi koji ciljaju HER2 kod raka dojke značajno su i pozitivno promijenili inače lošu prognozu historijski problematičnih poteškoća povezanih s HER2-pozitivnim karcinomom dojke.[18] Poznato je da se prekomjerna ekspresija javlja i u jajnicima,[19] želucu, adenokarcinomu pluća[20] i agresivnim oblicima raka maternice, kao što su serozni karcinom materničnog endometrija,[21][22] npr. HER2 je prekomjerno eksprimiran kod otprilike 7-34% pacijenata s rakom želuca.[23][24] i u 30% slučajeva karcinoma pljuvačnih kanala.[25]

HER2 je kolokaliziran i većinu vremena koamplificiran s genom GRB7, koji je protoonkogen povezan s tumorima dojke, testikularnih zametnih ćelija, želuca i jednjaka.

Pokazano je da HER2 proteini formiraju klastere u ćelijskim membranama koje mogu imati ulogu u tumorigenezi.[26][27]

Dokazi također ukazuju na HER2 signalizaciju u rezistenciji na lijek protiv raka cetuksimab usmjeren na receptor epidermnog faktora rasta.[28] Visoka ekspresija HER2 korelira s boljim preživljavanjem kod adenokarcinoma jednjaka.[29]

Visoka amplifikacija broja kopija HER2 pozitivno doprinosi vremenu preživljavanja pacijenata s adenokarcinomom kardialnog dijela želuca.[30]

Mutacije

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Nadalje, identificirane su različite strukturne promjene koje uzrokuju aktiviranje ovog receptora neovisno o ligandu, u odsustvu prekomjerne ekspresije receptora. HER2 se nalazi u raznim tumorima, a neki od ovih tumora nose tačkaste mutacije u sekvenci koja određuje transmembranski domen HER2. Zamjena valinom za glutaminsku kiselinu ili glutamin u transmembranskom domenu može rezultirati konstitutivnom dimerizacijom ovog proteina u odsustvu liganda.[31]

HER2 mutacije su pronađene kod nemikroćelijskog karcinoma pluća (NSCLC) i mogu usmjeriti liječenje.[32]

Kao meta lijeka

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HER2 je meta monoklonskog antitijela trastuzumaba (koji se prodaje kao Herceptin). Trastuzumab je efikasan samo kod karcinoma gdje je HER2 prekomjerno eksprimiran. |Preporučuje se jedna godina terapije trastuzumabom za sve pacijente sa HER2-pozitivnim rakom dojke koji također primaju hemoterapiju.[33] Randomizirana ispitivanja nisu pokazala dodatnu korist nakon 12 mjeseci, dok se pokazalo da je šest mjeseci inferiornije u odnosu na 12. Trastuzumab se primjenjuje intravenski jednom sedmično ili svake tri sedmice.[34]

Važan nizvodni efekat vezivanja trastuzumaba za HER2 je povećanje p27, proteina koji zaustavlja proliferaciju ćelija.[35] Još jedno monoklonsko antitijelo, Pertuzumab, koje inhibira dimerizaciju HER2 i HER3 receptora, odobreno je od strane FDA za upotrebu u kombinaciji s trastuzumabom u junu 2012.

Od novembra 2015. godine, postoji niz tekućih i nedavno završenih kliničkih ispitivanja novih ciljanih lijekova za HER2+ metastatski rak dojke, npr. margetuksimab.[36]

Osim toga, NeuVax (Galena Biopharma) je imunoterapija bazirana na peptidima koja usmjerava "ubice" T-ćelije da ciljaju i uništavaju ćelije raka koje eksprimiraju HER2. Ušla je u fazu 3 kliničkih ispitivanja.

Utvrđeno je da pacijenti sa ER+ (estrogenski receptor pozitivni)/HER2+ u poređenju sa ER-/HER2+ karcinomom dojke mogu zapravo imati više koristi od lijekova koji inhibiraju molekularni put PI3K/AKT.[37]

Prekomjerna ekspresija HER2 može se suzbiti i amplifikacijom drugih gena. Trenutno se provode istraživanja kako bi se otkrilo koji geni mogu imati ovaj željeni učinak.

Ekspresija HER2 regulirana je signalizacijom putem estrogenih receptora. Normalno, estradiol i tamoksifen koji djeluju putem estrogenog receptora smanjuju ekspresiju HER2. Međutim, kada omjer koaktivatora AIB-3 premaši omjer korepresora PAX2, ekspresija HER2 se povećava u prisustvu tamoksifena, što dovodi do raka dojke otpornog na tamoksifen.[38][39]

Među odobrenim anti-HER2 terapijama su i inhibitori tirozin-kinaza (kao što su lapatinib, neratinib i tucatinib) i konjugati antitijela i lijeka (ado-trastuzumab emtanzin i trastuzumab derukstekan).[40]

Distribucija Her2 i Her3 na ćeliji dojke, (3D dvobojna superrezoluciona mikroskopija SPDMphymod / LIMON, označeno sa Alexa 488 i 568)

Dijagnostika

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HER2 testiranje se provodi kod biopsija dojke pacijenata s rakom dojke kako bi se procijenila prognoza i utvrdila prikladnost za terapiju trastuzumabom. Važno je da se trastuzumab ograniči na HER2-pozitivne osobe jer je skup i povezan je sa srčanom toksičnošću.[41] Za HER2-pozitivne tumore, koristi trastuzumaba jasno nadmašuju rizike.

Testovi se obično izvode na uzorcima biopsije dojke dobijenim aspiracijom tankom iglom, biopsijom jezgre iglom, vakuumski potpomognutom biopsijom dojke ili hirurškom ekscizijom.

Imunohistohemija (IHC) se općenito koristi za mjerenje količine HER2 proteina prisutnog u uzorku, pri čemu se fluorescentna hibridizacija in situ (FISH) koristi na uzorcima koji su sumnjivi u IHC-u. Međutim, na nekoliko lokacija, FISH se koristi prvo, a zatim IHC u sumnjivim slučajevima.[42]

Imunohistohemija

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Imunohistohemijom se uzorku daje rezultat na osnovu obrasca bojenja ćelijske membrane.

Imunohistohemija
Rezultat [43][44]Obilježje[45]Status[43][44]
0 Ili:[45]
  • Nije uočeno bojenje.
  • Nepotpuno bojenje membrane koje je slabo ili jedva primjetno i unutar ≤10% invazivnih tumorskih ćelija
 HER2 negativno
(nije prisutno)
1+Nepotpuno bojenje membrane koje je slabo ili jedva primjetno i unutar >10% invazivnih tumorskih ćelija.[45]
2+Slabo do umjereno potpuno bojenje membrane uočeno je u >10% tumorskih ćelija.[45] Granično/Sumnjivo
3+Cirkumferencijalno bojenje membrane koje je potpuno, intenzivno i u >10% tumorskih ćelija.[45]HER2 pozitivno

Mikrografije koje prikazuju svaki rezultat:[46]

Fluorescentna hibridizacija in situ

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FISH se može koristiti za mjerenje broja kopija gena koje su prisutne i smatra se pouzdanijim od imunohistohemije.[47] I Obično se koristi „sonda za brojanje hromosoma 17“ (CEP17) za brojanje broja hromosoma. Stoga, odnos HER2/CEP17 odražava svaku amplifikaciju HER2 u poređenju s brojem hromosoma. Obično se broje signali 20 ćelija.

Klasifikacija HER2 pomoću fluorescentna in situ hibridizacija (FISH)[48]
Omjer HER2/CEP17
≥2.0 <2.0
Prosječan broj kopija HER2 po ćeliji ≥4.0 HER2 pozitivan Potrebna dodatna obrada
<4.0 Potrebna dodatna obrada HER2 negativan

Ako je početni rezultat HER2 biopsije iglom primarnog raka dojke negativan, novi HER2 test se može izvršiti prilikom sljedeće ekscizije dojke.[48]

Serum

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Eksćelijski domen HER2 može se odvojiti od površine tumorskih ćelija i ući u cirkulaciju. Mjerenje serumskog HER2 enzimsko-imunosorbentnog testa (ELISA) nudi daleko manje invazivnu metodu određivanja HER2 statusa od biopsije i stoga je opsežno istraženo. Dosadašnji rezultati sugeriraju da promjene u serumskim koncentracijama HER2 mogu biti korisne u predviđanju odgovora na terapiju trastuzumabom.[49] Međutim, njegova sposobnost da utvrdi podobnost za terapiju trastuzumabom je manje jasna.[50]

Interakcije

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Pokazano je da HER2/neu interraguje sa:

Također pogledajte

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Reference

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  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000141736 - Ensembl, maj 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000062312 - 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. ↑ "ERBB2 erb-b2 receptor tyrosine kinase 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Pristupljeno 14. 6. 2016.
  6. ↑ "ERBB2". Genetics Home Reference. Arhivirano s originala, 16. 12. 2012. Pristupljeno 19. 6. 2016.
  7. ↑ Barh D, Gunduz M (22. 1. 2015). Noninvasive Molecular Markers in Gynecologic Cancers. CRC Press. str. 427. ISBN 978-1-4665-6939-3.
  8. ↑ Hsu JL, Hung MC (2016). "The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer". Cancer and Metastasis Reviews. 35 (4): 575–588. doi:10.1007/s10555-016-9649-6. PMC 5215954. PMID 27913999.
  9. 1 2 Mitri Z, Constantine T, O'Regan R (2012). "The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy". Chemotherapy Research and Practice. 2012. doi:10.1155/2012/743193. PMC 3539433. PMID 23320171.
  10. ↑ Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U (decembar 1985). "Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene". Science. 230 (4730): 1132–1139. Bibcode:1985Sci...230.1132C. doi:10.1126/science.2999974. PMID 2999974.
  11. ↑ Bargmann CI, Hung MC, Weinberg RA (januar 1986). "The neu oncogene encodes an epidermal growth factor receptor-related protein". Nature. 319 (6050): 226–230. Bibcode:1986Natur.319..226B. doi:10.1038/319226a0. PMID 3945311.
  12. ↑ Fukushige S, Matsubara K, Yoshida M, Sasaki M, Suzuki T, Semba K, Toyoshima K, Yamamoto T (mart 1986). "Localization of a novel v-erbB-related gene, c-erbB-2, on human chromosome 17 and its amplification in a gastric cancer cell line". Molecular and Cellular Biology. 6 (3): 955–958. doi:10.1128/mcb.6.3.955-958.1986. PMC 367597. PMID 2430175.
  13. ↑ Keshamouni VG, Mattingly RR, Reddy KB (juni 2002). "Mechanism of 17-beta-estradiol-induced Erk1/2 activation in breast cancer cells. A role for HER2 AND PKC-delta". The Journal of Biological Chemistry. 277 (25): 22558–22565. doi:10.1074/jbc.M202351200. PMID 11960991.
  14. ↑ Rusnak DW, Affleck K, Cockerill SG, Stubberfield C, Harris R, Page M, Smith KJ, Guntrip SB, Carter MC, Shaw RJ, Jowett A, Stables J, Topley P, Wood ER, Brignola PS, Kadwell SH, Reep BR, Mullin RJ, Alligood KJ, Keith BR, Crosby RM, Murray DM, Knight WB, Gilmer TM, Lackey K (oktobar 2001). "The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer". Cancer Research. 61 (19): 7196–7203. PMID 11585755.
  15. ↑ Olayioye MA (2001). "Update on HER-2 as a target for cancer therapy: intracellular signaling pathways of ErbB2/HER-2 and family members". Breast Cancer Research. 3 (6): 385–389. doi:10.1186/bcr327. PMC 138705. PMID 11737890.
  16. ↑ Roy V, Perez EA (novembar 2009). "Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer". The Oncologist. 14 (11): 1061–1069. doi:10.1634/theoncologist.2009-0142. PMID 19887469. S2CID 207242039.
  17. ↑ Burstein HJ (oktobar 2005). "The distinctive nature of HER2-positive breast cancers". The New England Journal of Medicine. 353 (16): 1652–1654. doi:10.1056/NEJMp058197. PMID 16236735. S2CID 26675265.
  18. ↑ Tan M, Yu D (2007). "Molecular Mechanisms of ErbB2-Mediated Breast Cancer Chemoresistance". Breast Cancer Chemosensitivity. Advances in Experimental Medicine and Biology. 608. str. 119–29. doi:10.1007/978-0-387-74039-3_9. ISBN 978-0-387-74037-9. PMID 17993237.
  19. ↑ Kumar V, Abbas A, Aster J (2013). Robbins basic pathology. Philadelphia: Elsevier/Saunders. str. 697. ISBN 978-1-4377-1781-5.
  20. ↑ Kumar V, Abbas A, Aster J (2013). Robbins basic pathology. Philadelphia: Elsevier/Saunders. str. 179. ISBN 978-1-4377-1781-5.
  21. ↑ Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S (august 2008). "Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu". International Journal of Gynaecology and Obstetrics. 102 (2): 128–131. doi:10.1016/j.ijgo.2008.04.008. PMID 18555254. S2CID 25674060.
  22. ↑ Buza N, Roque DM, Santin AD (mart 2014). "HER2/neu in Endometrial Cancer: A Promising Therapeutic Target With Diagnostic Challenges". Archives of Pathology & Laboratory Medicine. 138 (3): 343–350. doi:10.5858/arpa.2012-0416-RA. PMID 24576030.
  23. ↑ Rüschoff J, Hanna W, Bilous M, Hofmann M, Osamura RY, Penault-Llorca F, van de Vijver M, Viale G (maj 2012). "HER2 testing in gastric cancer: a practical approach". Modern Pathology. 25 (5): 637–650. doi:10.1038/modpathol.2011.198. PMID 22222640.
  24. ↑ Meza-Junco J, Au HJ, Sawyer MB (mart 2011). "Critical appraisal of trastuzumab in treatment of advanced stomach cancer". Cancer Management and Research. 3 (3): 57–64. doi:10.2147/CMAR.S12698. PMC 3085240. PMID 21556317.
  25. ↑ Chiosea SI, Williams L, Griffith CC, Thompson LD, Weinreb I, Bauman JE, Luvison A, Roy S, Seethala RR, Nikiforova MN (juni 2015). "Molecular characterization of apocrine salivary duct carcinoma". The American Journal of Surgical Pathology. 39 (6): 744–752. doi:10.1097/PAS.0000000000000410. PMID 25723113. S2CID 34106002.
  26. ↑ Nagy P, Jenei A, Kirsch AK, Szöllosi J, Damjanovich S, Jovin TM (juni 1999). "Activation-dependent clustering of the erbB2 receptor tyrosine kinase detected by scanning near-field optical microscopy". Journal of Cell Science. 112 (11): 1733–1741. doi:10.1242/jcs.112.11.1733. hdl:2437/166028. PMID 10318765.
  27. ↑ Kaufmann R, Müller P, Hildenbrand G, Hausmann M, Cremer C (april 2011). "Analysis of Her2/neu membrane protein clusters in different types of breast cancer cells using localization microscopy". Journal of Microscopy. 242 (1): 46–54. doi:10.1111/j.1365-2818.2010.03436.x. PMID 21118230. S2CID 2119158.
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  69. ↑ Wong L, Deb TB, Thompson SA, Wells A, Johnson GR (mart 1999). "A differential requirement for the COOH-terminal region of the epidermal growth factor (EGF) receptor in amphiregulin and EGF mitogenic signaling". The Journal of Biological Chemistry. 274 (13): 8900–8909. doi:10.1074/jbc.274.13.8900. PMID 10085134.

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