ERBB2 (erb-b2 receptor tyrosine kinase 2)

Gene

• Entrez ID: 2064
• Gene name: Erb-b2 receptor tyrosine kinase 2
• Gene symbol: ERBB2
• Synonyms: CD340, HER-2, HER-2/neu, HER2, MLN 19, NEU, NGL, TKR1, VSCN2
• Chromosome: 17
• Chromosome location: 17q12
• Summary: This gene encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. This protein has no ligand binding domain of its own and therefore cannot bind growth factors. However, it does bind tightly to other ligand-bound EGF receptor family members to form a heterodimer, stabilizing ligand binding and enhancing kinase-mediated activation of downstream signalling pathways, such as those involving mitogen-activated protein kinase and phosphatidylinositol-3 kinase. Allelic variations at amino acid positions 654 and 655 of isoform a (positions 624 and 625 of isoform b) have been reported, with the most common allele, Ile654/Ile655, shown here. Amplification and/or overexpression of this gene has been reported in numerous cancers, including breast and ovarian tumors. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized. [provided by RefSeq, Jul 2008]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs121913468	G>A,C,T	Likely-pathogenic, pathogenic	Coding sequence variant, missense variant, non coding transcript variant, genic downstream transcript variant
rs121913469	TT>CC	Pathogenic, likely-pathogenic	Coding sequence variant, missense variant, non coding transcript variant, genic downstream transcript variant
rs121913470	T>C,G	Likely-pathogenic	Coding sequence variant, missense variant, non coding transcript variant, genic downstream transcript variant
rs1057519787	G>A,C	Likely-pathogenic	Coding sequence variant, non coding transcript variant, missense variant
rs1057519816	C>A,T	Likely-pathogenic	Coding sequence variant, non coding transcript variant, missense variant
rs1057519862	G>A	Likely-pathogenic, not-provided	Coding sequence variant, genic downstream transcript variant, non coding transcript variant, missense variant
rs1057519890	T>A	Likely-pathogenic	Coding sequence variant, genic downstream transcript variant, non coding transcript variant, missense variant
rs1131692241	TGAGGGAAAACACAT>-	Pathogenic	Coding sequence variant, genic downstream transcript variant, non coding transcript variant, inframe deletion

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT000036	hsa-miR-559	Luciferase reporter assay, Reporter assay;Other	19486885
MIRT000037	hsa-miR-548d-3p	Luciferase reporter assay, Reporter assay;Other	19486885
MIRT002939	hsa-miR-125b-5p	Western blot	19825990
MIRT002939	hsa-miR-125b-5p	Luciferase reporter assay, Northern blot, qRT-PCR, Western blot	17110380
MIRT002939	hsa-miR-125b-5p	Luciferase reporter assay, Microarray, Western blot	20864407
MIRT002939	hsa-miR-125b-5p	Luciferase reporter assay, Western blot	22460089
MIRT002939	hsa-miR-125b-5p	qRT-PCR, Luciferase reporter assay, Immunoblot, Western blot	25388283
MIRT002939	hsa-miR-125b-5p	Luciferase reporter assay, Western blot	26966351
MIRT002939	hsa-miR-125b-5p	Luciferase reporter assay	26544868
MIRT002939	hsa-miR-125b-5p	Luciferase reporter assay, qRT-PCR, Western blot	25833836
MIRT004318	hsa-miR-21-5p	qRT-PCR, Western blot	19419954
MIRT005118	hsa-miR-125a-5p	Luciferase reporter assay, Northern blot, qRT-PCR, Western blot	17110380
MIRT005118	hsa-miR-125a-5p	Luciferase reporter assay	21220473
MIRT005118	hsa-miR-125a-5p	Western blot, qRT-PCR	23519125
MIRT005118	hsa-miR-125a-5p	Luciferase reporter assay, qRT-PCR, Western blot	25833836
MIRT005805	hsa-miR-331-3p	Luciferase reporter assay, Microarray, Western blot	20864407
MIRT005805	hsa-miR-331-3p	Flow, Immunohistochemistry, Luciferase reporter assay, qRT-PCR, Western blot	24775712
MIRT005805	hsa-miR-331-3p	Luciferase reporter assay	24148764
MIRT005805	hsa-miR-331-3p	Luciferase reporter assay, Western blot	26718987
MIRT006982	hsa-miR-205-5p	qRT-PCR, Western blot	21787752
MIRT006982	hsa-miR-205-5p	Luciferase reporter assay, qRT-PCR, Western blot	26181203
MIRT007152	hsa-miR-199b-5p	Luciferase reporter assay, qRT-PCR, Western blot	23296799
MIRT007265	hsa-miR-199a-5p	Western blot	23437196
MIRT007265	hsa-miR-199a-5p	Immunoblot, Immunohistochemistry, Luciferase reporter assay, qRT-PCR	23146892
MIRT023179	hsa-miR-124-3p	Microarray	18668037
MIRT043637	hsa-miR-326	CLASH	23622248
MIRT053780	hsa-miR-375	Luciferase reporter assay, qRT-PCR, Western blot	24926380
MIRT053780	hsa-miR-375	HITS-CLIP	24906430
MIRT053780	hsa-miR-375	Flow, qRT-PCR, Western blot	26893657
MIRT054130	hsa-miR-25-3p	Luciferase reporter assay, qRT-PCR, Western blot	25043310
MIRT076987	hsa-miR-670-3p	HITS-CLIP	24906430
MIRT076993	hsa-miR-4326	HITS-CLIP	24906430
MIRT438501	hsa-miR-552-3p	Luciferase reporter assay	24148764
MIRT438502	hsa-miR-541-3p	Luciferase reporter assay	24148764
MIRT438503	hsa-miR-498	Luciferase reporter assay	24148764
MIRT438504	hsa-miR-323b-5p	Luciferase reporter assay	24148764
MIRT438505	hsa-miR-193a-5p	Luciferase reporter assay	24148764
MIRT438505	hsa-miR-193a-5p	Luciferase reporter assay	27203740
MIRT438506	hsa-miR-193a-3p	Luciferase reporter assay	24148764
MIRT438507	hsa-miR-134-5p	Luciferase reporter assay	24148764
MIRT608163	hsa-miR-6739-3p	HITS-CLIP	24906430
MIRT608164	hsa-miR-4677-5p	HITS-CLIP	24906430
MIRT608165	hsa-miR-7156-5p	HITS-CLIP	24906430
MIRT608166	hsa-miR-4273	HITS-CLIP	24906430
MIRT608167	hsa-miR-7109-5p	HITS-CLIP	24906430
MIRT608168	hsa-miR-4790-5p	HITS-CLIP	24906430
MIRT608169	hsa-miR-6868-3p	HITS-CLIP	24906430
MIRT608170	hsa-miR-3127-5p	HITS-CLIP	24906430
MIRT608171	hsa-miR-22-5p	HITS-CLIP	24906430
MIRT608172	hsa-miR-2116-5p	HITS-CLIP	24906430
MIRT608173	hsa-miR-593-3p	HITS-CLIP	24906430
MIRT608174	hsa-miR-6885-5p	HITS-CLIP	24906430
MIRT608175	hsa-miR-328-5p	HITS-CLIP	24906430
MIRT608176	hsa-miR-6887-5p	HITS-CLIP	24906430
MIRT608177	hsa-miR-486-3p	HITS-CLIP	24906430
MIRT608178	hsa-miR-6795-5p	HITS-CLIP	24906430
MIRT608179	hsa-miR-3140-3p	HITS-CLIP	24906430
MIRT608180	hsa-miR-3116	HITS-CLIP	24906430
MIRT608181	hsa-miR-1254	HITS-CLIP	24906430
MIRT608182	hsa-miR-4790-3p	HITS-CLIP	24906430
MIRT608183	hsa-miR-6730-3p	HITS-CLIP	24906430
MIRT608184	hsa-miR-4680-3p	HITS-CLIP	24906430
MIRT608185	hsa-miR-5187-3p	HITS-CLIP	24906430
MIRT608186	hsa-miR-4427	HITS-CLIP	24906430
MIRT608187	hsa-miR-4653-5p	HITS-CLIP	24906430
MIRT608188	hsa-miR-3921	HITS-CLIP	24906430
MIRT608189	hsa-miR-301b-5p	HITS-CLIP	24906430
MIRT608190	hsa-miR-301a-5p	HITS-CLIP	24906430
MIRT608191	hsa-miR-4315	HITS-CLIP	24906430
MIRT608192	hsa-miR-146a-3p	HITS-CLIP	24906430
MIRT608193	hsa-miR-3667-3p	HITS-CLIP	24906430
MIRT608194	hsa-miR-6734-3p	HITS-CLIP	24906430
MIRT608195	hsa-miR-6891-3p	HITS-CLIP	24906430
MIRT608196	hsa-miR-6072	HITS-CLIP	24906430
MIRT608197	hsa-miR-6754-5p	HITS-CLIP	24906430
MIRT608198	hsa-miR-4441	HITS-CLIP	24906430
MIRT608199	hsa-miR-4270	HITS-CLIP	24906430
MIRT608200	hsa-miR-211-3p	HITS-CLIP	24906430
MIRT608201	hsa-miR-4748	HITS-CLIP	24906430
MIRT608202	hsa-miR-329-5p	HITS-CLIP	24906430
MIRT608203	hsa-miR-4464	HITS-CLIP	24906430
MIRT608204	hsa-miR-7845-5p	HITS-CLIP	24906430
MIRT608205	hsa-miR-888-3p	HITS-CLIP	24906430
MIRT608206	hsa-miR-4506	HITS-CLIP	24906430
MIRT732771	hsa-miR-34a-5p	Luciferase reporter assay, Western blot	27813227
MIRT733558	hsa-miR-155-3p	Luciferase reporter assay, qRT-PCR, Western blot	27065318
MIRT733635	hsa-miR-130b-3p	Luciferase reporter assay	26316103
MIRT733746	hsa-miR-1296-5p	Luciferase reporter assay, qRT-PCR, Western blot	28099468
MIRT733749	hsa-miR-133a-3p	Luciferase reporter assay, qRT-PCR, Western blot	28109082
MIRT734069	hsa-miR-3622b-5p	Luciferase reporter assay, qRT-PCR, Western blot	28160563
MIRT734579	hsa-miR-22-3p	Luciferase reporter assay	26544868

Transcription factors

Transcription factor	Regulation	Reference
AR	Activation	21613411
AR	Unknown	21741601
ATF1	Unknown	10698518
ATF7	Unknown	10698518
CREB1	Unknown	10698518
DENND4A	Repression	23421821
ELF1	Unknown	7914192
ELK1	Unknown	7914192
EP300	Unknown	9045619
ETV4	Repression	10655108;15235125;16632435;17168666
ETV4	Unknown	7914192
FOXP3	Unknown	17570480
GABPA	Unknown	7914192
GATA4	Repression	19276186
JUND	Unknown	10698518
MYB	Unknown	2577338
NCOA3	Unknown	10991938
PAX2	Unknown	10991938
PGR	Repression	18483177
PURA	Unknown	22899247
SP1	Activation	12802284;22553354
SP3	Activation	22553354
SP4	Activation	22553354
TFAP2A	Unknown	10698518;15870067;18218085;22577344
TFAP2B	Unknown	10645007
TFAP2C	Unknown	10645007
VDR	Unknown	10765127
XRCC5	Unknown	22899247
XRCC6	Unknown	22899247
YBX1	Activation	19648825
YBX1	Unknown	20838384
YY1	Activation	19435870
YY1	Unknown	15870067;18218085

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000165	Process	MAPK cascade	TAS
GO:0001042	Function	RNA polymerase I core binding	IDA	21555369
GO:0001934	Process	Positive regulation of protein phosphorylation	ISS
GO:0004713	Function	Protein tyrosine kinase activity	IDA	7556068, 12000754
GO:0004713	Function	Protein tyrosine kinase activity	IGI	7556068
GO:0004713	Function	Protein tyrosine kinase activity	TAS
GO:0004714	Function	Transmembrane receptor protein tyrosine kinase activity	IBA	21873635
GO:0004714	Function	Transmembrane receptor protein tyrosine kinase activity	IDA	7514177
GO:0004888	Function	Transmembrane signaling receptor activity	IDA	7514177
GO:0005515	Function	Protein binding	IPI	7592681, 9079677, 9705354, 10572067, 10805725, 11940572, 12061724, 12122014, 12975581, 15282549, 15345710, 15657067, 16273093, 16314522, 16516204, 16767099, 16843263, 17148612, 17426253, 18719096, 19167335, 19372587, 19411071, 19650109, 19933325, 20010870, 20227043, 20558745, 206500
GO:0005524	Function	ATP binding	IEA
GO:0005634	Component	Nucleus	IDA	16314522, 21555369
GO:0005769	Component	Early endosome	IEA
GO:0005829	Component	Cytosol	IDA
GO:0005886	Component	Plasma membrane	IDA	20010870
GO:0005886	Component	Plasma membrane	NAS	12000754
GO:0005886	Component	Plasma membrane	TAS
GO:0005887	Component	Integral component of plasma membrane	IBA	21873635
GO:0006357	Process	Regulation of transcription by RNA polymerase II	TAS
GO:0006468	Process	Protein phosphorylation	TAS	10851066
GO:0007165	Process	Signal transduction	IDA	10572067
GO:0007166	Process	Cell surface receptor signaling pathway	IDA	9685399
GO:0007167	Process	Enzyme linked receptor protein signaling pathway	TAS	9590694
GO:0007169	Process	Transmembrane receptor protein tyrosine kinase signaling pathway	IBA	21873635
GO:0007169	Process	Transmembrane receptor protein tyrosine kinase signaling pathway	IDA	7514177
GO:0007169	Process	Transmembrane receptor protein tyrosine kinase signaling pathway	TAS	7556068
GO:0007275	Process	Multicellular organism development	IBA	21873635
GO:0007422	Process	Peripheral nervous system development	IEA
GO:0007507	Process	Heart development	IEA
GO:0007528	Process	Neuromuscular junction development	IEA
GO:0008022	Function	Protein C-terminus binding	IPI	15520177
GO:0008045	Process	Motor neuron axon guidance	IEA
GO:0008284	Process	Positive regulation of cell population proliferation	IBA	21873635
GO:0009925	Component	Basal plasma membrane	IBA	21873635
GO:0010008	Component	Endosome membrane	IDA	16314522
GO:0014065	Process	Phosphatidylinositol 3-kinase signaling	IDA	7556068
GO:0016021	Component	Integral component of membrane	NAS	15609325
GO:0016323	Component	Basolateral plasma membrane	IDA	12646923
GO:0016324	Component	Apical plasma membrane	IEA
GO:0018108	Process	Peptidyl-tyrosine phosphorylation	IDA	12000754
GO:0019838	Function	Growth factor binding	IDA	7514177
GO:0019903	Function	Protein phosphatase binding	IPI	15899872
GO:0030182	Process	Neuron differentiation	IBA	21873635
GO:0030307	Process	Positive regulation of cell growth	IMP	21555369
GO:0032886	Process	Regulation of microtubule-based process	IDA	20937854
GO:0033088	Process	Negative regulation of immature T cell proliferation in thymus	IEA
GO:0033674	Process	Positive regulation of kinase activity	IBA	21873635
GO:0035556	Process	Intracellular signal transduction	IDA	19372587
GO:0038128	Process	ERBB2 signaling pathway	TAS
GO:0038143	Component	ERBB3:ERBB2 complex	IDA	12000754
GO:0042060	Process	Wound healing	IDA	12646923
GO:0042552	Process	Myelination	IEA
GO:0042802	Function	Identical protein binding	IPI	12000754, 16843263, 17148612, 19650109, 21203579, 21255571, 21480528, 22733765, 23436906
GO:0043125	Function	ErbB-3 class receptor binding	IPI	12000754
GO:0043209	Component	Myelin sheath	IEA
GO:0043235	Component	Receptor complex	IBA	21873635
GO:0043235	Component	Receptor complex	IDA	7514177, 23382219
GO:0043235	Component	Receptor complex	TAS	7556068
GO:0043406	Process	Positive regulation of MAP kinase activity	IDA	10572067
GO:0043410	Process	Positive regulation of MAPK cascade	IBA	21873635
GO:0043547	Process	Positive regulation of GTPase activity	ISS
GO:0045727	Process	Positive regulation of translation	IMP	21555369
GO:0045765	Process	Regulation of angiogenesis	NAS	15609325
GO:0045785	Process	Positive regulation of cell adhesion	IDA	7556068
GO:0045943	Process	Positive regulation of transcription by RNA polymerase I	IMP	21555369
GO:0046777	Process	Protein autophosphorylation	IDA	7556068
GO:0046982	Function	Protein heterodimerization activity	IPI	7556068
GO:0048471	Component	Perinuclear region of cytoplasm	IEA
GO:0048709	Process	Oligodendrocyte differentiation	IEA
GO:0050679	Process	Positive regulation of epithelial cell proliferation	IDA	10572067
GO:0051897	Process	Positive regulation of protein kinase B signaling	TAS
GO:0070372	Process	Regulation of ERK1 and ERK2 cascade	IMP	16314522
GO:0071363	Process	Cellular response to growth factor stimulus	IDA	20010870
GO:0071364	Process	Cellular response to epidermal growth factor stimulus	IMP	27134172
GO:0090314	Process	Positive regulation of protein targeting to membrane	IDA	20010870
GO:1901185	Process	Negative regulation of ERBB signaling pathway	TAS
GO:2000145	Process	Regulation of cell motility	TAS

Other IDs

• MIM: 164870
• HGNC: 3430
• e!Ensembl: ENSG00000141736

Protein

• UniProt ID: P04626
• Protein name: Receptor tyrosine-protein kinase erbB-2 (EC 2.7.10.1) (Metastatic lymph node gene 19 protein) (MLN 19) (Proto-oncogene Neu) (Proto-oncogene c-ErbB-2) (Tyrosine kinase-type cell surface receptor HER2) (p185erbB2) (CD antigen CD340)
• Protein function: Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1 signaling pathway elicits the phosphorylation and thus the inhibition of GSK3B at cell membrane. This prevents the phosphorylation of APC and CLASP2, allowing its association with the cell membrane. In turn, membrane-bound APC allows the localization of MACF1 to the cell membrane, which is required for microtubule capture and stabilization. ; In the nucleus is involved in transcriptional regulation. Associates with the 5'-TCAAATTC-3' sequence in the PTGS2/COX-2 promoter and activates its transcription. Implicated in transcriptional activation of CDKN1A; the function involves STAT3 and SRC. Involved in the transcription of rRNA genes by RNA Pol I and enhances protein synthesis and cell growth.
• PDB: 1MFG, 1MFL, 1MW4, 1N8Z, 1OVC, 1QR1, 1S78, 2A91, 2JWA, 2KS1, 2L4K, 2N2A, 3BE1, 3H3B, 3MZW, 3N85, 3PP0, 3RCD, 3WLW, 3WSQ, 4GFU, 4HRL, 4HRM, 4HRN, 5K33, 5KWG, 5MY6, 5O4G, 5OB4, 5TQS, 6ATT, 6BGT, 6J71, 6LBX, 6OGE
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF01030	Recep_L_domain	52 → 173	Receptor L domain	Repeat
  PF00757	Furin-like	183 → 343	Furin-like cysteine rich region	Domain
  PF01030	Recep_L_domain	366 → 486	Receptor L domain	Repeat
  PF14843	GF_recep_IV	510 → 643	Growth factor receptor domain IV	Domain
  PF07714	PK_Tyr_Ser-Thr	720 → 976	Protein tyrosine and serine/threonine kinase	Domain

• Sequence:

  MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPASPETHLDMLRHLYQGCQVVQGNL
  ELTYLPTNASLSFLQDIQEVQGYVLIAHNQVRQVPLQRLRIVRGTQLFEDNYALAVLDNG
  DPLNNTTPVTGASPGGLRELQLRSLTEILKGGVLIQRNPQLCYQDTILWKDIFHKNNQLA
  LTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGCARCKGPLPTDCCHEQC
  AAGCTGPKHSDCLACLHFNHSGICELHCPALVTYNTDTFESMPNPEGRYTFGASCVTACP
  YNYLSTDVGSCTLVCPLHNQEVTAEDGTQRCEKCSKPCARVCYGLGMEHLREVRAVTSAN
  IQEFAGCKKIFGSLAFLPESFDGDPASNTAPLQPEQLQVFETLEEITGYLYISAWPDSLP
  DLSVFQNLQVIRGRILHNGAYSLTLQGLGISWLGLRSLRELGSGLALIHHNTHLCFVHTV
  PWDQLFRNPHQALLHTANRPEDECVGEGLACHQLCARGHCWGPGPTQCVNCSQFLRGQEC
  VEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCVARC
  PSGVKPDLSYMPIWKFPDEEGACQPCPINCTHSCVDLDDKGCPAEQRASPLTSIISAVVG
  ILLVVVLGVVFGILIKRRQQKIRKYTMRRLLQETELVEPLTPSGAMPNQAQMRILKETEL
  RKVKVLGSGAFGTVYKGIWIPDGENVKIPVAIKVLRENTSPKANKEILDEAYVMAGVGSP
  YVSRLLGICLTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLNWCMQIAKGMSYLEDVR
  LVHRDLAARNVLVKSPNHVKITDFGLARLLDIDETEYHADGGKVPIKWMALESILRRRFT
  HQSDVWSYGVTVWELMTFGAKPYDGIPAREIPDLLEKGERLPQPPICTIDVYMIMVKCWM
  IDSECRPRFRELVSEFSRMARDPQRFVVIQNEDLGPASPLDSTFYRSLLEDDDMGDLVDA
  EEYLVPQQGFFCPDPAPGAGGMVHHRHRSSSTRSGGGDLTLGLEPSEEEAPRSPLAPSEG
  AGSDVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTVPLPSETDGYVAPLTCSPQPEYV
  NQPDVRPQPPSPREGPLPAARPAGATLERPKTLSPGKNGVVKDVFAFGGAVENPEYLTPQ
  GGAAPQPHPPPAFSPAFDNLYYWDQDPPERGAPPSTFKGTPTAENPEYLGLDVPV

• Sequence length: 1255