ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian))

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ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian))

Identity

Other names	CD340
	HER2
	HER-2
	HER-2/neu
	MLN 19
	NEU
	NGL
	TKR1
HGNC (Hugo)
LocusID (NCBI)	2064
Location	17q12
Location_base_pair	Starts at 37844393 and ends at 37884915 bp from pter ( according to hg19-Feb_2009) [Mapping]


	Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

Note	Tyrosine-kinase receptor (RTK). The HER family of RTKs consists of four receptors: epidermal growth factor receptor (EGFR, also called HER-1 or erbB-1), HER-2 (also called erbB-2 or Neu), HER-3 and HER-4 (also called erbB-3 and erbB-4, respectively).

DNA/RNA

Description

Sequence length: 40522; CDS: 3678. 30 exons, 26 coding exons; total exon length: 4816, max exon length: 969, min exon length: 48. Number of SNPs: 17.
Polymorphisms: 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 B1 (Ile-654/Ile-655); allele B2 (Ile-654/Val-655); allele B3 (Val-654/Val-655). This nucleotide polymorphism could be associated with development of gastric carcinoma and with breast cancer risk, particularly among younger women.

Transcription

Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized.
- mRNA transcript variant: this variant (1) represents the shorter transcript but encodes the longer isoform (a) (protein: erbB-2 isoform (a)).
- mRNA transcript variant: this variant (2) (protein: erbB-2 isoform (b)) contains additional exons at its 5' end and lacks an alternate 5' noncoding exon, compared to variant (1). These differences result in translation initiation at an in-frame, downstream AUG and an isoform (b) with a shorter N-terminus compared to isoform (a).
- mRNA transcript variant: herstatin HER2-ECD 1300 bp alternative erbB-2 transcript that retains intron 8. This alternative transcript specifies 340 residues identical to subdomains I and II from the extracellular domain of p185erbB-2 followed by a unique C-terminal sequence of 79 aa encoded by intron 8. The herstatin mRNA is expressed in normal human fetal kidney and liver, but is at reduced levels relative to p185erbB-2 mRNA in carcinoma cells that contain an amplified erbB-2 gene.
- mRNA transcript variant: an alternative transcript form of the human homologous gene erbB-2, containing an in-frame deletion encompassing exon 19, has been detected in human breast carcinomas.
- mRNA transcript variant: an alternative transcript form of the human homologous gene erbB-2, called HER2Δ16, has been detected in human breast carcinomas. This splicing variant, contains an in-frame deletion and encodes a receptor lacking exon 16, which immediately precedes the transmembrane domain containing two cysteines. The loss of these cysteine residues might induce a change in the conformation of HER2 receptor extracellular domain that promotes intermolecular disulfide bonding and, in turn, homodimers capable of transforming cells. Ectopic expression of HER2Δ16 promotes receptor dimerization, cell invasion, and trastuzumab resistant tumor cell lines. The potential metastatic and oncogenic properties of HER2Δ16 were mediated through direct coupling of HER2Δ16 to Src kinase.

Protein



	HER2 protein: schematic representation. Receptor tyrosin-kinases (RTKs) are cell surface allosteric enzymes consisting of: an extracellular ligand-binding domain (blue); a single transmembrane (TM) domain has an extensive homology to the epidermal grow factor receptor (brown); a cytoplasmic domain with catalityc activity (green).

Description	erbB2 encodes a 185-kDa, 1255 amino acids, orphan receptor tyrosine kinase, and displays potent oncogenic activity when overexpressed. The proto-oncogene consists of three domains: a single transmembrane domain that separates an intracellular kinase domain from an extracellular ligand-binding domain. An aberrant form of HER2, missing the extracellular domain, so-called HER2p95, has been found in some breast cancers. HER2p95 is constitutively active because the external domain of these receptors acts as an inhibitor until they are bound by ligand. This isoform can cause resistance to trastuzumab, an antibody that works by binding to a domain in the external domain of HER2. HER2p95 fragments arise through at least 2 different mechanisms: proteolytic shedding of the extracellular domain of the full-length receptor and translation of the mRNA encoding HER2 from internal initiation codons. Shedding of the ectodomain of HER2 generates a 95- to 100-kDa HER2 p95 membrane-anchored fragment. Translation of the mRNA encoding HER2 can be initiated from the AUG codon that gives rise to the full-length protein of 1255 amino acids or, alternatively, from 2 internal initiation codons at positions 611 and 678, located upstream and downstream of the transmembrane domain, respectively.
Expression	HER2 protein is expressed in several human organs and tissues: normal epithelium, endometrium and ovarian epithelium and at neuromuscular level; prostate, pancreas, lung, kidney, liver, heart, hematopoietic cells. HER2 expression is low in mononuclear cells from bone marrow, peripheral blood (PB) and mobilized PB. The higher expression has been found in cord blood-derived cells. Quiescent CD34+ progenitor cells from all blood sources and resting lymphocytes are HER2 negative, but the expression of this receptor is up-regulated during cell-cycle recruitment of progenitor cells. Similarly, it increases in mature, hematopoietic proliferating cells, underlying the correlation between HER2 and the proliferating status of hematopoietic cells.
Localisation	Plasma membrane.
Function	Activation and interactions For the other member of the HER family, ligand binding induces receptor homo- or heterodimerization, which is essential for TKs activation and subsequent recruitment of target proteins, in turn initiating a complex signaling cascade that leads into distinct transcriptional programs. There are several HER-specific ligands. HER2, which apparently has no direct or specific ligand, plays a major coordinating role in the HER network because of its ability to enhance and stabilize the dimerization: each receptor with a specific ligand appears in fact to prefer HER-2 as its heterodimeric partner. HER-2-containing heterodimers are characterized by extremely high signaling potency because HER-2 dramatically reduces the rate of ligand dissociation, allowing strong and prolonged activation of downstream signaling pathways. Signaling and cellular The most important intracellular pathways activated by HER2 are those involving mitogen activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K). HER2 expression in cancer, besides its role in proliferation, enhances and prolongs survivals signals, associating up-regulation of this receptor to the malignant phenotype. At the same time, and depending on cellular status, the role of this receptor in controlling cell fate can also lead to differentiation and apoptosis. Physiological Role in development and differentiation: - HER2 has several non-oncogenic roles in regulating growth, differentiation, apoptosis and/or remodeling in normal mammary glands. Dominant-negative forms of HER2 have significant defects in mammary development and lactation. - HER2 has an important role in development and function of heart. Cre-Lox technology to mutate erbB-2 specifically in ventricular cardiomyocytes leads to a severe cardiomyopathy. This is inferred also by the adverse cardiac side effects observed in breast cancer patients treated with the monoclonal anti-HER2 Ab Trastuzumab. - HER2 has a role in control of Schwann cell myelination and it has been demonstrated that HER2 signaling is also critical for oligodendrocyte differentiation in vivo. - HER2 has a dual role in both muscle spindle maintenance and survival of myoblasts. Muscle-specific HER2 KO results in fact in viable mice with a progressive defect in proprioception due to loss of muscles spindles.
Homology	Homolog to avian erythroblastic leukemia viral (v-erb-b) oncogen 2.

Mutations

Somatic

The Cancer Genome Project and Collaborative Group sequenced the erbB-2 gene from 120 primary lung tumors and identified 4% that had mutations within the kinase domain; in the adenocarcinoma subtype of lung cancer, 10% of cases had mutations.
In non small cell lung cancer (adenocarcinoma) the following erbB-2 mutations were found: insertion/duplication of GCATACGTGATG at nucleotide 2322 of the erbB-2 gene, resulting in a 4-amino acid insertion (AYVM) at codon 774. Insertion of CTGTGGGCT at nucleotide 2335 of the erbB-2 gene, resulting in a 3-amino acid insertion (VGS) starting at codon 779; a 2-bp substitution in the erbB-2 gene, TT-CC at nucleotides 2263 and 2264, resulting in a leu755-to-pro (L755P) substitution.
In lung cancer a C44645G transition in the erbB-2 gene that caused a pro1170-to-ala substitution (P1170A).
In a glioblastoma a 2740G-A transition in the erbB-2 gene that caused a glu914-to-lys substitution (E914K).
In a gastric tumor a 2326G-A transition in the erbB-2 gene that caused a gly776-to-ser (G776S) substitution.
In an ovarian tumor, a 2570A-G transition in the erbB-2 gene that caused an asn857-to-ser (N857S) substitution.

Implicated in

Entity	Hematological malignancies
Disease	HER2 expression can be detected in blast cells from patients with hematological malignancies including acute lymphoblastic leukemia (ALL). It could be used as a potential target for the application of HER2-directed treatment strategies in ALL including vaccination approaches.

Entity	Bladder cancer
Prognosis	HER2 is overexpressed in 25% to 40% of several human tumors and associated with the malignancy of the disease, high mitotic index and a shorter survival time for the patient. Overexpression of ErbB-2 is also associated with transitional cell carcinoma of the bladder. HER2 overexpression occurs in muscle-invasive urothelial carcinomas of the bladder and is associated with worse survival; amplifications of erbB-2 gene are also frequently linked to alterations of the TOP2A gene in bladder cancer. Furthermore, HER2 overexpression and amplification in urothelial carcinoma of the bladder is found associated with MYC co-amplification.

Entity	Breast carcinoma
Prognosis	Normal tissues have a low content of HER2 membrane protein. Overexpression of HER2 is seen in 20% of breast and it confers worse biological behavior and clinical aggressiveness in breast cancer. Breast cancers can have up to 25 to 50 copies of the HER2 gene and up to a 40- to 100-fold increase in HER2 protein resulting in 2 million receptors expressed at the tumor cell surface. The differential HER2 expression between normal tissues and tumors helps to define HER2 as an ideal treatment target. Trastuzumab, the first treatment targeting HER2, is well tolerated in patients and has little toxicity because its effects are relatively specific for cancer cells overexpressing HER2. HER2 amplification is a relatively early event in human breast tumorigenesis, occurring in almost 50% of in situ carcinomas. HER2 status is maintained during progression to invasive disease and to nodal and distant metastasis. The fact that only 20% of invasive breast cancers are HER2 amplified suggests that many HER2-amplified in situ cancers never progress to the invasive stage. HER2 amplification defines a subtype of breast cancer with a unique signature of genes and this is maintained during progression. Some tumors lose HER2 expression following treatment with trastuzumab, presumably by selection of a HER2-negative clone not killed by treatment. Conversely, HER2 may become positive in some initially negative tumors over time, especially after endocrine therapy targeting ER. Indeed, estrogen receptor has been shown to downregulate HER2 and, conversely, HER2 is able to downregulate ER expression. Therefore, it is not surprising that blocking ER might upregulate HER2 and that blocking HER2 might upregulate ER. HER2-amplified breast cancers have unique biological and clinical characteristics. They have increased sensitivity to certain cytotoxic agents such as doxorubicin, relative resistance to hormonal agents, and propensity to metastasize to the brain and viscera. HER2-amplified tumors have an increased sensitivity to doxorubicin possibly due to coamplification of the topoisomerase-2 gene, which is near the HER2 locus on chromosome 17 and is the target of the drug. Half of HER2-positive breast cancers are ER positive but they generally have lower ER levels, and many have p53 alterations. These tumors have higher proliferation rates and more aneuploidy and are associated with poorer patient prognosis. The poor outcome is dramatically improved with appropriate chemotherapy combined with the HER2-targeting drug trastuzumab. Overexpression of the erbB-2 gene is associated with tumor aggressiveness, and with patient responsiveness to doxorubicin, cyclophosphamide, methotrexate, fluorouracil (CMF), and to paclitaxel, whereas tamoxifen was found to be ineffective and even detrimental in patients with HER2-positive tumors. In Paget's disease of breast, HER2 protein overexpression is caused by amplification of the erbB-2 gene. HER2 has a role in this disease of the breast, where the epidermis of the nipple is infiltrated by large neoplastic cells of glandular origin. It seems that binding of heregulin-alpha to the receptor complex on Paget cells results in chemotaxis of these breast cancer cells. The isoforms HER2p95 and HER2Δ16 are found in some breast cancers and the expression of these hyperactive forms of HER2 may contribute to the malignant progression.

Entity	Cervical cancer
Prognosis	HER2 may be activated in the early stage of pathogenesis of cervical carcinoma in geriatric patients and is frequently amplified in squamous cell carcinoma of the uterine cervix.

Entity	Childhood medulloblastoma
Prognosis	Overexpression of HER2 in medulloblastoma is associated with poor prognosis and metastasis and HER2-HER4 receptor heterodimerization is of particular biological significance in this disease.

Entity	Colorectal cancer
Prognosis	Overexpression of HER2 occurs in a significant number of colorectal cancers. It was significantly associated with poor survival and related to tumor progression in colorectal cancer.

Entity	Oral squamous cell carcinoma
Prognosis	E6/E7 proteins of HPV type 16 and HER2 cooperate to induce neoplastic transformation of primary normal oral epithelial cells. Overexpression of HER2 receptor is a frequent event in oral squamous cell carcinoma and is correlated with poor survival.

Entity	Gastric cancer
Prognosis	HER2 amplification/overexpression does not seem to play a role in the molecular pathogenesis of most gastrinomas. However, mild gene amplification occurs in a subset of them, and overexpression of this receptor is associated with aggressiveness of the disease. HER2 overexpression in patients with gastric cancer, and it has been solidly correlated to poor outcomes and a more aggressive disease. The overall HER2 positive rate is about 22%. HER2 overexpression rate in gastric cancer varies according to the site of the tumor. A higher overexpression rate (36%) was shown in gastroesophageal junction (GEJ) tumors in comparison to 21% in gastric tumors.

Entity	Germ-cell testicular tumor
Prognosis	A significant correlation was observed between HER2 overexpression and clinical outcome in germ-cell testicular tumors.

Entity	Cholangiocarcinoma
Prognosis	Data are still controversial about HER2 role in this carcinoma. Increased HER2 expression contributes to the development of cholangiocarcinogenesis into an advanced stage associated with tumor metastasis. In addition, overexpression of HER2 and COX-2 correlated directly with tumor differentiation. However, other studies report that HER2 expression is associated with more favorable clinical features, such as a polypoid macroscopic type and absence of other organ involvement, and has been reported that the proportion of HER2-positive cases in papillary adenocarcinoma is higher than in other histological types and is associated with an early disease stage. HER2 is preferentially expressed in well differentiated component, and it is also expressed in dedifferentiated components in progressive cases.

Entity	Lung cancer
Prognosis	HER2 is overexpressed in less than 20% of patients with non-small cell lung cancer (NSCLC) and studies have shown that overexpression of this receptor is correlated with a poor prognosis in both resected and advanced NSCLC. HER2 overexpression has an important function in the biology of NSCLC and may have a prognostic value for patients with metastatic NSCLC.

Entity	Osteosarcoma
Prognosis	Higher frequency of HER2 expression has been observed in samples from patients with metastatic disease at presentation and at the time of relapse, and it correlates with worse histologic response and decreased event-free survival. HER2 could be an effective target for the immunotherapy of osteosarcoma, especially the type with high metastatic potential.

Entity	Ovarian cancer
Prognosis	HER2 overexpression varies from 9% to 32% of all cases of ovarian cancer and its overexpression is more frequent in advanced stage of ovarian cancer. Overexpression of HER2 in ovarian cancer cells leads to faster cell growth, higher abilities in DNA repair and colony formation. A cross-talk between HER2 and estrogen receptor (ER) was identified in ovarian cancer cells. Estrogen has been proven to induce the phosphorylation of HER2, and initiate the HER2's signaling pathway.

Entity	Pancreatic adenocarcinoma
Prognosis	Overexpression of HER-2 in pancreatic adenocarcinoma seems to be a result of increased transcription rather than gene amplification. The coexpression of HER2 oncogene protein, epidermal growth factor receptor, and TGF-beta1 in pancreatic ductal adenocarcinoma is related to the histopathological grades and clinical stages of tumors. The blockade of HER2 inhibits the growth of pancreatic cancer cells in vitro. HER2 overexpression was reported to accumulate in well differentiated pancreas adenocarcinomas whereas it is only infrequently found in poorly differentiated or undifferentiated tumors, in vivo and in vitro analyses have suggested that targeting HER2 might increase treatment effects of conventional chemotherapies of pancreas adenocarcinoma. However, unlike in breast cancer, the application of antibodies directed against HER2 has not yet become an established therapy for pancreas adenocarcinoma.

Entity	Prostate cancer
Prognosis	HER2 plays pivotal roles in prostate cancer. Studies have shown that 25% of untreated primary tumors, 59% of localized tumors after neoadjuvant hormone therapy, and 78% of metastatic tumors overexpressed HER2. Several lines of evidence have implicated HER2 as a key mediator in the recurrence of prostate cancer to a hormone-refractory, androgen-independent tumor, which is the hallmark of prostate cancer progress. The driving force for prostate cancer recurrence is the reactivation of androgen receptor (AR), which is a type of nuclear receptors, activated by steroid hormone but ablated in hormonal therapy. Phosphorylation and reactivation of AR stimulate cancer cell growth and trigger tumor progression. It has been observed that overexpression of HER2 kinase enhanced AR function and hormone-independent growth in prostate tumor cells. HER2 activated AR through the MAPK pathway. Additionally, the HER2/HER3 dimmer increases AR protein stability and promotes the binding of AR to the promoter region of its target genes, resulting in AR activation in an androgen-depleted environment.

Entity	Salivary gland tumor
Prognosis	Several results demonstrated significant positive staining of HER2 in the salivary tumorigenic tissue but not in the surrounding non-tumorigenic tissue, pointing to a biological role in the tumorigenic process. HER2 amplification is present predominantly in tumors with high HER2 expression and seems to be the dominant mechanism for HER2 overexpression in this tumor type.

To be noted

Possible therapeutic strategies: 1) growth inhibitory antibodies (like Trastuzumab), used alone or in combination with standard chemotherapeutics; 2) tyrosin kinase inhibitors (TKI); 3) active immunotherapy, because HER2 oncoprotein is immunogenic in some breast carcinoma patients; 4) dimerization inhibitor antibodies, like Pertuzumab: its binding to HER2 inhibits the dimerization of HER2 with other HER receptors.

External links

	Nomenclature
HGNC (Hugo)	ERBB2 3430
Entrez_Gene (NCBI)	ERBB2 2064 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)
	Cards
Atlas	ERBB2ID162ch17q11
GeneCards (Weizmann)	ERBB2
Ensembl (Hinxton)	ENSG00000141736 [Gene_View] chr17:37844393-37884915 [Contig_View] ERBB2 [Vega]
AceView (NCBI)	ERBB2
Genatlas (Paris)	ERBB2
euGene (Indiana)	2064
SOURCE (Stanford)	NM_001005862 NM_004448
	Genomic and cartography
GoldenPath (UCSC)	ERBB2 - 17q12 chr17:37844393-37884915 + 17q11.2-q12\|17q21.1 [Description] (hg19-Feb_2009)
Ensembl	ERBB2 - 17q11.2-q12\|17q21.1 [CytoView]
Mapping of homologs : NCBI	ERBB2 [Mapview]
OMIM	137215 137800 164870 211980
	Gene and transcription
Genbank (Entrez)	AB025286 AF177761 AK131568 AK295195 AK296908
RefSeq transcript (SRS)	NM_001005862 NM_004448
RefSeq transcript (Entrez)	NM_001005862 NM_004448
RefSeq genomic (SRS)	AC_000149 NC_000017 NG_007503 NT_010783 NW_001838435
RefSeq genomic (Entrez)	AC_000149 NC_000017 NG_007503 NT_010783 NW_001838435
Consensus coding sequences : CCDS (NCBI)	ERBB2
Cluster EST : Unigene	Hs.446352 [ SRS ] Hs.446352 [ NCBI ]
Alternative Splicing : Fast-db (Paris)	9595
Alternative Splicing Gallery	ENSG00000141736
Gene Expression	ERBB2 [ NCBI-GEO ] ERBB2 [ EBI - ARRAY_EXPRESS ]
	Protein : pattern, domain, 3D structure
UniProt/SwissProt	P04626 (SRS) P04626 (Uniprot)
With graphics : InterPro	P04626
Splice isoforms : SwissVar	P04626(Swissvar)
Domaine pattern : Prosite (SRS)	PROTEIN_KINASE_ATP (PS00107) PROTEIN_KINASE_DOM (PS50011) PROTEIN_KINASE_TYR (PS00109)
Domaine pattern : Prosite (Expaxy)	PROTEIN_KINASE_ATP (PS00107) PROTEIN_KINASE_DOM (PS50011) PROTEIN_KINASE_TYR (PS00109)
Domains : Interpro (SRS)	Cyt_c1_TM_anchor_C EGF_rcpt_L Furin-like_Cys-rich_dom Furin_repeat Growth_fac_rcpt Kinase-like_dom Prot_kinase_cat_dom Protein_kinase_ATP_BS Ser-Thr/Tyr_kinase_cat_dom Tyr_kinase_AS Tyr_kinase_cat_dom Tyr_kinase_EGF/ERB/XmrK_rcpt
Domains : Interpro (EBI)	Cyt_c1_TM_anchor_C EGF_rcpt_L Furin-like_Cys-rich_dom Furin_repeat Growth_fac_rcpt Kinase-like_dom Prot_kinase_cat_dom Protein_kinase_ATP_BS Ser-Thr/Tyr_kinase_cat_dom Tyr_kinase_AS Tyr_kinase_cat_dom Tyr_kinase_EGF/ERB/XmrK_rcpt
Related proteins : CluSTr	P04626
Domain families : Pfam (SRS)	Furin-like (PF00757) Pkinase_Tyr (PF07714) Recep_L_domain (PF01030)
Domain families : Pfam (Sanger)	Furin-like (PF00757) Pkinase_Tyr (PF07714) Recep_L_domain (PF01030)
Domain families : Pfam (NCBI)	pfam00757 pfam07714 pfam01030
Domain families : Smart (EMBL)	FU (SM00261) TyrKc (SM00219)
Blocks (Seattle)	P04626
PDB (SRS)	1MFG 1MFL 1MW4 1N8Z 1OVC 1QR1 1S78 2A91 2JWA 2KS1 2L4K 3BE1 3H3B 3MZW 3N85 3PP0 3RCD
PDB (PDBSum)	1MFG 1MFL 1MW4 1N8Z 1OVC 1QR1 1S78 2A91 2JWA 2KS1 2L4K 3BE1 3H3B 3MZW 3N85 3PP0 3RCD
PDB (IMB)	1MFG 1MFL 1MW4 1N8Z 1OVC 1QR1 1S78 2A91 2JWA 2KS1 2L4K 3BE1 3H3B 3MZW 3N85 3PP0 3RCD
PDB (RSDB)	1MFG 1MFL 1MW4 1N8Z 1OVC 1QR1 1S78 2A91 2JWA 2KS1 2L4K 3BE1 3H3B 3MZW 3N85 3PP0 3RCD
Human Protein Atlas	ENSG00000141736
HPRD	01281
IPI	IPI00300384 IPI00845478 IPI00941360 IPI01009701 IPI00384288 IPI00964086
	Protein Interaction databases
DIP (DOE-UCLA)	P04626
IntAct (EBI)	P04626
FunCoup	ENSG00000141736
REACTOME	ERBB2
BioGRID	ERBB2
InParanoid	P04626
Interologous Interaction database	P04626
	Polymorphism : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)	ERBB2
SNP (GeneSNP Utah)	ERBB2
SNP : HGBase	ERBB2
Genetic variants : HAPMAP	ERBB2
Cancer Gene: Census	ERBB2
Somatic Mutations in Cancer : COSMIC	ERBB2
CONAN: Copy Number Analysis	ERBB2
Mutations and Diseases : HGMD	ERBB2
OMIM	137215 137800 164870 211980
GENETests	137215 137800 164870 211980
Disease Genetic Association	ERBB2
Huge Navigator	ERBB2 [HugePedia] ERBB2 [HugeCancerGEM]
Genomic Variants	ERBB2
snp3D : Map Gene to Disease	2064
	General knowledge
Homologs : HomoloGene	ERBB2
Homology/Alignments : Family Browser (UCSC)	ERBB2
Phylogenetic Trees/Animal Genes : TreeFam	ERBB2
Catalytic activity : Enzyme	2.7.10.1 [ Enzyme-Expasy ] 2.7.10.1 [ Enzyme-SRS ] 2.7.10.1 [ IntEnz-EBI ] 2.7.10.1 [ BRENDA ] 2.7.10.1 [ KEGG ]
Chemical/Protein Interactions : CTD	2064
Chemical/Pharm GKB Gene	PA27844
Drug Sensitivity	ERBB2
Clinical trial	ERBB2
Cancer Resource (Charite)	ENSG00000141736
Ontology : AmiGO	nucleotide binding RNA polymerase I core binding liver development positive regulation of protein phosphorylation glycoprotein binding protein tyrosine kinase activity protein tyrosine kinase activity protein tyrosine kinase activity transmembrane receptor protein tyrosine kinase activity receptor signaling protein tyrosine kinase activity receptor activity transmembrane signaling receptor activity epidermal growth factor-activated receptor activity protein binding ATP binding nucleus cytoplasm plasma membrane plasma membrane microvillus regulation of transcription, DNA-dependent protein phosphorylation signal transduction cell surface receptor signaling pathway enzyme linked receptor protein signaling pathway transmembrane receptor protein tyrosine kinase signaling pathway transmembrane receptor protein tyrosine kinase signaling pathway epidermal growth factor receptor signaling pathway nervous system development axon guidance peripheral nervous system development heart development skeletal muscle tissue development neuromuscular junction development protein C-terminus binding motor axon guidance cell proliferation basal plasma membrane glial cell differentiation endosome membrane phosphatidylinositol 3-kinase cascade positive regulation of phosphatidylinositol 3-kinase cascade integral to membrane basolateral plasma membrane apical plasma membrane growth factor binding protein phosphatase binding signal transduction by phosphorylation positive regulation of cell growth mammary gland development ubiquitin protein ligase binding positive regulation of Rho GTPase activity response to progesterone stimulus regulation of microtubule-based process negative regulation of immature T cell proliferation in thymus wound healing response to drug myelination identical protein binding negative regulation of apoptotic process ErbB-3 class receptor binding lateral loop receptor complex receptor complex positive regulation of MAP kinase activity positive regulation of MAPK cascade tongue development membrane raft postsynaptic membrane positive regulation of translation regulation of angiogenesis positive regulation of cell adhesion positive regulation of transcription from RNA polymerase I promoter positive regulation of transcription from RNA polymerase III promoter positive regulation of Ras protein signal transduction protein autophosphorylation protein heterodimerization activity protein heterodimerization activity protein heterodimerization activity protein dimerization activity phosphatidylinositol-mediated signaling perinuclear region of cytoplasm sympathetic nervous system development response to axon injury positive regulation of epithelial cell proliferation Hsp90 protein binding mammary gland involution estrus regulation of ERK1 and ERK2 cascade
Ontology : EGO-EBI	nucleotide binding RNA polymerase I core binding liver development positive regulation of protein phosphorylation glycoprotein binding protein tyrosine kinase activity protein tyrosine kinase activity protein tyrosine kinase activity transmembrane receptor protein tyrosine kinase activity receptor signaling protein tyrosine kinase activity receptor activity transmembrane signaling receptor activity epidermal growth factor-activated receptor activity protein binding ATP binding nucleus cytoplasm plasma membrane plasma membrane microvillus regulation of transcription, DNA-dependent protein phosphorylation signal transduction cell surface receptor signaling pathway enzyme linked receptor protein signaling pathway transmembrane receptor protein tyrosine kinase signaling pathway transmembrane receptor protein tyrosine kinase signaling pathway epidermal growth factor receptor signaling pathway nervous system development axon guidance peripheral nervous system development heart development skeletal muscle tissue development neuromuscular junction development protein C-terminus binding motor axon guidance cell proliferation basal plasma membrane glial cell differentiation endosome membrane phosphatidylinositol 3-kinase cascade positive regulation of phosphatidylinositol 3-kinase cascade integral to membrane basolateral plasma membrane apical plasma membrane growth factor binding protein phosphatase binding signal transduction by phosphorylation positive regulation of cell growth mammary gland development ubiquitin protein ligase binding positive regulation of Rho GTPase activity response to progesterone stimulus regulation of microtubule-based process negative regulation of immature T cell proliferation in thymus wound healing response to drug myelination identical protein binding negative regulation of apoptotic process ErbB-3 class receptor binding lateral loop receptor complex receptor complex positive regulation of MAP kinase activity positive regulation of MAPK cascade tongue development membrane raft postsynaptic membrane positive regulation of translation regulation of angiogenesis positive regulation of cell adhesion positive regulation of transcription from RNA polymerase I promoter positive regulation of transcription from RNA polymerase III promoter positive regulation of Ras protein signal transduction protein autophosphorylation protein heterodimerization activity protein heterodimerization activity protein heterodimerization activity protein dimerization activity phosphatidylinositol-mediated signaling perinuclear region of cytoplasm sympathetic nervous system development response to axon injury positive regulation of epithelial cell proliferation Hsp90 protein binding mammary gland involution estrus regulation of ERK1 and ERK2 cascade
Pathways : BIOCARTA	Role of ERBB2 in Signal Transduction and Oncology [Genes] Trefoil Factors Initiate Mucosal Healing [Genes]
Pathways : KEGG	Adherens junction Focal adhesion Dorso-ventral axis formation Calcium signaling pathway
	Other databases
	Probes
	Litterature
PubMed	499 Pubmed reference(s) in Entrez
PubGene	ERBB2
iHOP	ERBB2

Bibliography

Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.

Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL.

Science. 1987 Jan 9;235(4785):177-82.

PMID 3798106

EGF receptor and erbB-2 tyrosine kinase domains confer cell specificity for mitogenic signaling.

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Science. 1990 Apr 6;248(4951):79-83.

PMID 2181668

G to A polymorphism at amino acid codon 655 of the human erbB-2/HER2 gene.

Papewalis J, Nikitin AYu, Rajewsky MF.

Nucleic Acids Res. 1991 Oct 11;19(19):5452.

PMID 1681519

Clinicopathological significance of c-erbB-2 protein expression in human gastric carcinoma.

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PMID 1348293

Long-term follow-up study of patients with gastric adenomas with malignant transformation. An immunohistochemical and histochemical analysis.

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Cancer. 1994 Dec 1;74(11):2896-907.

PMID 7954254

ERBB2 (HER2/neu) oncogene is frequently amplified in squamous cell carcinoma of the uterine cervix.

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Cancer Res. 1994 Feb 1;54(3):637-9.

PMID 7905784

erbB-2 expression in well-differentiated adenocarcinoma of the stomach predicts shorter survival after curative resection.

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Surgery. 1994 Mar;115(3):349-54.

PMID 7907434

Neu differentiation factor activation of ErbB-3 and ErbB-4 is cell specific and displays a differential requirement for ErbB-2.

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Mol Cell Biol. 1995 Dec;15(12):6496-505.

PMID 8524214

The receptor tyrosine kinase p185HER2 is expressed on a subset of B-lymphoid blasts from patients with acute lymphoblastic leukemia and chronic myelogenous leukemia.

Buhring HJ, Sures I, Jallal B, Weiss FU, Busch FW, Ludwig WD, Handgretinger R, Waller HD, Ullrich A.

Blood. 1995 Sep 1;86(5):1916-23.

PMID 7544646

Prognostic significance of the c-erbB-2 oncogene product in childhood medulloblastoma.

Gilbertson RJ, Pearson AD, Perry RH, Jaros E, Kelly PJ.

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Clin Cancer Res. 2004 Jan 1;10(1 Pt 1):136-43.

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Contributor(s)

Written	12-2004	Patrizia Casalini, Marilena V Iorio
		Molecular Targeting Unit, Experimental Oncology Dept., Istituto Nazionale Tumori, Via Venezian, 1, 20133 Milano, Italy
Updated	05-2011	Luca Braccioli, Marilena V Iorio, Patrizia Casalini
		Molecular Targeting Unit, Experimenatal Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo, 42, 20133 Milano, Italy

Citation
This paper should be referenced as such :
Casalini P, Iorio MV . ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)). Atlas Genet Cytogenet Oncol Haematol. December 2004 .
URL : http://AtlasGeneticsOncology.org/Genes/ERBB2ID162ch17q11.html

Braccioli L, Iorio MV, Casalini P . ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)). Atlas Genet Cytogenet Oncol Haematol. May 2011 .
URL : http://AtlasGeneticsOncology.org/Genes/ERBB2ID162ch17q11.html

This paper is referenced by INIST as such :
   [ Bibliographic record ]

http://documents.irevues.inist.fr/bitstream/handle/2042/46053/05-2011-ERBB2ID162ch17q11.pdf   [ Bibliographic record ]

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