ERBB2

Receptor tirozin-protein kinaze erbB-2, znan i kao CD340 (klaster diferencijacije 340), proto-onkogene Neu, Erbb2 (glodarski) ili ERBB2 (ljudski), je protein koji je kod ljudi kodiran genom ERBB2. ERBB je skraćeno od eritroblastičnog onkogena B, gena izoliranog iz ptičjeg genoma. Često se naziva i HER2 (od receptor ljudskog epidermnog faktora rasta 2) ili HER2/neu.^[5][6][7]

ERBB2
Dostupne strukture PDB Pretraga 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
Aliasi	ERBB2
Vanjski ID-jevi	OMIM: 164870 MGI: 95410 HomoloGene: 3273 GeneCards: ERBB2
EC broj	2.7.10.1
Lokacija gena (čovjek) Hrom. Hromosom 17 (čovjek)[1] Bend 17q12 Početak 39,687,914 bp[1] Kraj 39,730,426 bp[1]
Lokacija gena (miš) Hrom. Hromosom 11 (miš)[2] Bend 11 61.75 cM|11 D Početak 98,303,296 bp[2] Kraj 98,328,542 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 • heart development • 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
Vrste	Čovjek	Miš
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 Mb	Chr 11: 98.3 – 98.33 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

HER2 je član ljudske porodice receptora za epidermni faktor rasta (HER / EGFR / ERBB). Pokazalo se da pojačavanje ili pretjerano eksprimiranje ovog onkogena ima važnu ulogu u razvoju i napredovanju određenih agresivnih vrsta karcinoma dojke. Posljednjih godina protein je postao važan biomarker i cilj terapije za približno 30% pacijenata sa karcinomom dojke.^[8]

Gen

ERBB2, poznati proto-onkogen, nalazi se na dugom kraku ljudskog hromosoma 17 (17q12).

Ime

HER2 je tako nazvan jer ima sličnu strukturu kao receptor za ljudski epidermni faktor rasta ili HER1. Neu je nazvan zato što je izveden iz ćelijske linije glodarskog glioblastoma, tipa neuronskog tumora. ErbB-2 imenovan je zbog sličnosti sa ErbB (ptičji eritroblastozni onkogen B), za onkogen koji je kasnije utvrđeno da kodira EGFR. Molekulsko kloniranje gena pokazalo je da su svi HER2, Neu i ErbB-2 kodirani istim ortholozima.^[9]

Dužina polipeptidnog lanca je 1.255 aminokiselina, a molekulska težina 137.910 Da.^[10]

Aminokiselinska sekvenca

10		20		30		40		50
MELAALCRWG		LLLALLPPGA		ASTQVCTGTD		MKLRLPASPE		THLDMLRHLY
QGCQVVQGNL		ELTYLPTNAS		LSFLQDIQEV		QGYVLIAHNQ		VRQVPLQRLR
IVRGTQLFED		NYALAVLDNG		DPLNNTTPVT		GASPGGLREL		QLRSLTEILK
GGVLIQRNPQ		LCYQDTILWK		DIFHKNNQLA		LTLIDTNRSR		ACHPCSPMCK
GSRCWGESSE		DCQSLTRTVC		AGGCARCKGP		LPTDCCHEQC		AAGCTGPKHS
DCLACLHFNH		SGICELHCPA		LVTYNTDTFE		SMPNPEGRYT		FGASCVTACP
YNYLSTDVGS		CTLVCPLHNQ		EVTAEDGTQR		CEKCSKPCAR		VCYGLGMEHL
REVRAVTSAN		IQEFAGCKKI		FGSLAFLPES		FDGDPASNTA		PLQPEQLQVF
ETLEEITGYL		YISAWPDSLP		DLSVFQNLQV		IRGRILHNGA		YSLTLQGLGI
SWLGLRSLRE		LGSGLALIHH		NTHLCFVHTV		PWDQLFRNPH		QALLHTANRP
EDECVGEGLA		CHQLCARGHC		WGPGPTQCVN		CSQFLRGQEC		VEECRVLQGL
PREYVNARHC		LPCHPECQPQ		NGSVTCFGPE		ADQCVACAHY		KDPPFCVARC
PSGVKPDLSY		MPIWKFPDEE		GACQPCPINC		THSCVDLDDK		GCPAEQRASP
LTSIISAVVG		ILLVVVLGVV		FGILIKRRQQ		KIRKYTMRRL		LQETELVEPL
TPSGAMPNQA		QMRILKETEL		RKVKVLGSGA		FGTVYKGIWI		PDGENVKIPV
AIKVLRENTS		PKANKEILDE		AYVMAGVGSP		YVSRLLGICL		TSTVQLVTQL
MPYGCLLDHV		RENRGRLGSQ		DLLNWCMQIA		KGMSYLEDVR		LVHRDLAARN
VLVKSPNHVK		ITDFGLARLL		DIDETEYHAD		GGKVPIKWMA		LESILRRRFT
HQSDVWSYGV		TVWELMTFGA		KPYDGIPARE		IPDLLEKGER		LPQPPICTID
VYMIMVKCWM		IDSECRPRFR		ELVSEFSRMA		RDPQRFVVIQ		NEDLGPASPL
DSTFYRSLLE		DDDMGDLVDA		EEYLVPQQGF		FCPDPAPGAG		GMVHHRHRSS
STRSGGGDLT		LGLEPSEEEA		PRSPLAPSEG		AGSDVFDGDL		GMGAAKGLQS
LPTHDPSPLQ		RYSEDPTVPL		PSETDGYVAP		LTCSPQPEYV		NQPDVRPQPP
SPREGPLPAA		RPAGATLERP		KTLSPGKNGV		VKDVFAFGGA		VENPEYLTPQ
GGAAPQPHPP		PAFSPAFDNL		YYWDQDPPER		GAPPSTFKGT		PTAENPEYLG
LDVPV

Simboli

C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin

Funkcija

Porodica ErbB sastoji se od četiri plazmamembranske vezana receptora tirozin-kinaza. Jedan od njih je erbB-2, a drugi članovi su receptori za epidermni faktor rasta, erbB-3 (vezanje neuregulina; nedostaje kinazni domen) i erbB-4. Sva četiri sadrže po domen koji važi kao vanćelijski ligand, transmembranski i unutarćelijski domen, koji mogu komunicirati s mnoštvom signalnih molekula i ispoljavati aktivnost koja ovisi o ligandu i neovisno o ligandu. Značajno je da još nisu identificirani ligandi za HER2.^[11][12] HER2 može heterodimerizovati sa bilo kojim od preostala tri receptora i smatra se preferiranim partnerom za dimerizaciju ostalih ErbB receptora.^[13]

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

Transdukcija signala

Signalni putevi koje aktivira HER2 uključuju:^[14]

• mitogen-aktivirana protein kinaza (MAPK)
• fosfoinozitid 3-kinaza (PI3K / Akt)
• fosfolipaza C γ
• protein-kinaza C (PKC)
• Pretvarač signala i aktivator transkripcije (STAT).

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

Klinički značaj

Rak

Amplifikacija, poznata i kao pretjerana ekspresija gena ERBB2, javlja se u približno 15-30% karcinoma dojke.^[8][15] Snažno je povezana sa povećanim ponavljanjem bolesti i lošom prognozom; međutim, agensi s lijekovima koji ciljaju HER2 u raku dojke značajno su pozitivno promijenili inače lošu prognozu prirodne historije HER2 pozitivnog karcinoma dojke.^[16] Također je poznato da se prekomjerna ekspresija javlja i jajnicima,^[17] stomaku, adenokarcinomu pluća^[18] i agresivnim oblicima karcinoma maternice, kao što je maternični serozni karcinom endometrija,^[19][20] npr. HER2 je prekomjerno eksprimiran kod približno 7-34% pacijenata sa karcinomom želuca ^[21][22] i kod 30% karcinoma pljuvačnih kanala.^[23]

HER2 je kolokaliziran i većinu vremena se pojačava s genom GRB7, koji je proto-onkogen povezan s tumorima dojke, zametnih ćelija testisa, želuca i jednjaka.

Pokazalo se da proteini HER2 formiraju nakupine u ćelijskim membranama koje mogu imati ulogu u tumorigenezi.^[24][25]

Dokazi su takođe implicirali signalizaciju HER2 u otpornosti na EGFR-ciljani lijek protiv raka, cetuksimab.^[26]

Mutacije

Identificirane su različite strukturne promjene koje uzrokuju mutiranje ovog receptora neovisno o ligandu, i to u odsustvu pretjerane ekspresije receptora. HER2 se nalazi u raznim tumorima, a neki od tih tumora nose točkaste mutacije u nizu koji određuje transmembranski domen HER2. Zamjena valina glutaminskom kiselinom u transmembranskom domenu može rezultirati konstitutivnom dimerizacijom ovog proteina u odsustvu liganda.^[27]

Mutacije HER2 pronađene su u raku pluća ne-malih ćelija (NSCLC) i mogu usmjeriti liječenje.^[28]

Kao meta lijekova

HER2 je meta monoklonskih antitijela trastuzumab (u prodaji kao Herceptin). Trastuzumab je efikasan samo kod karcinoma kod kojih je HER2 prekomjerno eksprimiran. Jednogodišnja terapija trastuzumabom preporučuje se svim pacijentima sa HER2 pozitivnim karcinomom dojke koji također primaju hemoterapiju.^[29] Dvanaest mjeseci terapije trastuzumabom je optimalno. Randomizirana ispitivanja nisu pokazala dodatnu korist nakon 12 mjeseci, dok se pokazalo da je šest mjeseci inferiorno u odnosu na 12. Trastuzumab se daje intravenozno sedmično ili svake tri sedmice.^[30]

Važan nizvodni učinak vezanja trastuzumaba za HER2 je povećanjep27, proteina koji zaustavlja proliferaciju ćelija.^[31] FDA je odobrila za upotrebu u kombinaciji sa trastuzumabom u junu 2012. godine još jedno monoklonsko antitelo, Pertuzumab, koje inhibira dimerizaciju HER2 i HER3 receptora.

Od novembra 2015. postoji niz tekućih i nedavno završenih kliničkih ispitivanja novih ciljanih sredstava za HER2 + metastatski rak dojke, npr. margetuximab.^[32]

Pored toga, NeuVax (marka Galena Biopharma) je imunoterapija zasnovana na peptidu, koja usmjerava T-ćelije "ubice" na ciljanje i uništavanje ćelija karcinoma koje eksprimiraju HER2. Ušao je u fazu 3 kliničkih ispitivanja.

Utvrđeno je da pacijenti sa ER + (estrogenski receptor pozitivan) / HER2 + u poređenju sa ER-/ HER2 + karcinomom dojke zapravo mogu imati veću korist od lijekova koji inhibirajuPI3K / AKT molekulski put.^[33]

Prekomjerna ekspresija HER2 također se može suzbiti pojačavanjem drugih gena. Sada se provodi istraživanje kako bi se otkrilo koji geni mogu imati ovaj željeni efekat.

Ekspresija HER2 regulira se signaliziranjem putem estrogenskih receptora. Uobičajeno, estradiol i tamoksifen, koji deluju preko estrogenskog receptora reguliraju ekspresiju HER2. Međutim, kada odnoskoaktivator< AIB-3 premaši odnos korepresor PAX2, ekspresija HER2 povećana je u prisustvu tamoksifena, što dovodi do rezistencije raka dojke na tamoksifen.^[34][35]

Distribucija Her2 i Her3 na ćelijama dojke (3D dvojna mikroskopska superrezolucija u boji SPDMphymod/LIMON, označeno programom Alexa 488 i 568)

Dijagnostika

Biopsija raka

Ispitivanje HER2 vrši se kod pacijenata sa rakom dojke radi procjene prognoze i utvrđivanja pogodnosti za terapiju trastuzumabom. Važno je da je trastuzumab ograničen na HER2 pozitivne osobe jer je skup i povezan je sa toksičnošću za srce.^[36] Za HER2 pozitivne tumore, rizici trastuzumaba očito premašuju koristi.

Bojenje Her 2 u tkivu karcinoma dojke identificirano kao stadij 3

Bojenjem se vidi ćelijska membrana kontinuirane smeđe boje.

Testovi se obično izvode na uzorcima biopsija dojke, dobijenih bilo putem aspiracija tanke igle, biopsijom jezgrene igle, biopsijom dojke uz pomoć vakuuma ili hirurškim izrezivanjem. Imunohistohemijski metodi koriste se za mjerenje količine HER2 proteina prisutnog u uzorku. Primjeri ovog ispitivanja uključuju HercepTest, Dako, Glostrup i Danmark. Uzorak se ocjenjuje na osnovu uzorka bojenja ćelijske membrane.

Imunohistohemija

Rezultat[37][38]	Status[37][38]	Svojstvo
0	Negativni HER2 (Nema)	Negativna ekspresija proteina HER2 [39]
1+		Slabo ili nepotpuno bojenje membrane u bilo kojim ćelijama tumora.[39]
2+	Granično/nedvosmisleno	Potpuno bojenje membrane koje je ili neujednačenog ili slabog intenziteta, ali ima obodnu distribuciju u najmanje 10% ćelija.[38][39] ili ujednačeno intenzivno bojenje membrane na 30% ili manje tumorskih ćelija.[39]
3+	Pozitivan HER2	Ujednačeno intenzivno bojenje membrane na 30% ili manje tumorskih ćelija.[38][39]

Uzorci s dvosmislenim IHC rezultatima bi potom trebali biti potvrđeni upotrebom fluorescentnom in situ hibridizacijom (FISH). FISH se može koristiti za mjerenje broja prisutnih kopija gena i smatra se pouzdanijim od IHC.^[40]

Serum

Vanćelijski domen HER2 može se izbaciti s površine tumorskih ćelija i ući u cirkulaciju. Mjerenje serumskog HER2 enzimski povezanim imunosorbentskim testom (ELISA) nudi daleko manje invazivnu metodu određivanja HER2 statusa od biopsije i stoga je opsežno istraženo. Dosadašnji rezultati sugeriraju da bi promjene u koncentraciji HER2 u serumu mogle biti korisne u predviđanju odgovora na terapiju trastuzumabom.^[41] However, its ability to determine eligibility for trastuzumab therapy is less clear.^[42]

Interakcije

Dokazano je da HER2 / neu ima interakcije sa:

• CTNNB1,^[43][44][45]
• DLG4,^[46]
• Erbinom,^[47][48][49]
• GRB2,^[50][51][52]
• HSP90AA1,^[53][54]
• IL6ST,^[55]
• MUC1,^[56][57]
• PICK1^[47] and
• PIK3R2,^[58]
• PLCG1,^[59][60] i
• SHC1.^[50][52][61]

See also

• Ann Marie Rogers, campaigned for UK NHS to provide Herceptin
• SkBr3 Cell Line, over-expresses HER2

Reference

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Vanjski linkovi

• ERBB2 expression across human cancerous and healthy tissues^{[trajno mrtav link]}
• AACR Cancer Concepts Factsheet on HER2
• Breast Friends for Life Network - A South African Breast Cancer Support Forum for HER2 Positive Women
• HerceptinR : Herceptin Resistance Database for Understanding Mechanism of Resistance in Breast Cancer Patients. Sci. Rep. 4:4483
• Receptor, erbB-2 na US National Library of Medicine Medical Subject Headings (MeSH)
• PDBe-KB provides an overview of all the structure information available in the PDB for Human Receptor tyrosine-protein kinase erbB-2

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