V-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)
PDB rendering based on 1n8z.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1MFG, 1MFL, 1N8Z, 1QR1, 1S78, 2A91, 2JWA, 2KS1, 2L4K, 3BE1, 3H3B, 3MZW, 3N85, 3PP0, 3RCD
Identifiers
Symbols	ERBB2; CD340; HER-2; HER-2/neu; HER2; MLN 19; NEU; NGL; TKR1
External IDs	OMIM: 164870 MGI: 95410 HomoloGene: 3273 ChEMBL: 1824 GeneCards: ERBB2 Gene
EC number	2.7.10.1
Gene Ontology Molecular function • nucleotide binding • RNA polymerase I core binding • 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 • protein C-terminus binding • growth factor binding • protein phosphatase binding • ubiquitin protein ligase binding • identical protein binding • ErbB-3 class receptor binding • protein heterodimerization activity • protein heterodimerization activity • protein heterodimerization activity • protein dimerization activity • Hsp90 protein binding Cellular component • nucleus • cytoplasm • plasma membrane • plasma membrane • microvillus • basal plasma membrane • endosome membrane • integral to membrane • basolateral plasma membrane • apical plasma membrane • lateral loop • receptor complex • receptor complex • membrane raft • postsynaptic membrane • perinuclear region of cytoplasm Biological process • liver development • positive regulation of protein phosphorylation • 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 • motor axon guidance • cell proliferation • glial cell differentiation • phosphatidylinositol 3-kinase cascade • positive regulation of phosphatidylinositol 3-kinase cascade • signal transduction by phosphorylation • positive regulation of cell growth • mammary gland development • 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 • negative regulation of apoptotic process • positive regulation of MAP kinase activity • positive regulation of MAPK cascade • tongue development • 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 • phosphatidylinositol-mediated signaling • sympathetic nervous system development • response to axon injury • positive regulation of epithelial cell proliferation • mammary gland involution • estrus • regulation of ERK1 and ERK2 cascade Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2064	13866
Ensembl	ENSG00000141736	ENSMUSG00000062312
UniProt	P04626	P70424
RefSeq (mRNA)	NM_001005862.1	NM_001003817.1
RefSeq (protein)	NP_001005862.1	NP_001003817.1
Location (UCSC)	Chr 17: 37.84 – 37.88 Mb	Chr 11: 98.27 – 98.3 Mb
PubMed search	[1]	[2]
This box: view talk edit

HER2 (Human Epidermal Growth Factor Receptor 2) also known as Neu, ErbB-2, CD340 (cluster of differentiation 340) or p185 is a protein that in humans is encoded by the ERBB2 gene. HER2 is a member of the epidermal growth factor receptor (EGFR/ErbB) family. Amplification or over-expression of this gene has been shown to play an important role in the pathogenesis and progression of certain aggressive types of breast cancer and in recent years it has evolved to become an important biomarker and target of therapy for the disease.

Function[link]

Gene[link]

HER2 is encoded by ERBB2, a known proto-oncogene located at the long arm of human chromosome 17(17q21-q22). HER2 is named because it has a similar structure to human epidermal growth factor receptor, or HER1. Neu is so named because it was derived from a rodent glioblastoma cell line, a type of neural tumor. ErbB-2 was named for its similarity to ERBB (avian erythroblastosis oncogene B), the oncogene later found to code for EGFR. Gene cloning showed that HER2, Neu, and ErbB-2 are all encoded by the same gene.^[1]

Protein[link]

The ErbB family is composed of four plasma membrane-bound receptor tyrosine kinases. All four contain an extracellular ligand binding domain, a transmembrane domain, and an intracellular domain that can interact with a multitude of signaling molecules. Unlike the other family members, HER2 is considered to be an orphan receptor as it has no known ligand. However, all of the other three ErbB receptors have known ligands and will form either homodimers or heterodimers upon ligand binding. HER2 can heterodimerise with any of the other three receptors and is considered to be the preferred dimerisation partner of the other ErbB receptors.^[2] Dimerisation results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways.

Signal transduction[link]

Signaling pathways activated by HER2 include:^[3]

• mitogen-activated protein kinase (MAPK)
• phosphoinositide 3-kinase (PI3K/Akt)
• phospholipase C γ
• protein kinase C (PKC)
• Signal transducer and activator of transcription (STAT)

In summary, signaling through the ErbB family of receptors promotes cell proliferation and opposes apoptosis, and therefore must be tightly regulated to prevent uncontrolled cell growth from occurring.

HER2 and cancer[link]

Amplification or over-expression of the ERBB2 gene occurs in approximately 30% of breast cancers. It is strongly associated with increased disease recurrence and a worse prognosis.^[4] Over-expression is also known to occur in ovarian, stomach, and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma.^[5]

HER2 is co-localized, and, most of the time, co-amplified with the gene GRB7, which is a proto-oncogene associated with breast, testicular germ cell, gastric, and esophageal tumours.

HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis.^[6][7]

Drugs targeting HER2[link]

HER2 is the target of the monoclonal antibody trastuzumab (marketed as Herceptin). Trastuzumab is effective only in cancers where HER2 is over-expressed. An important downstream effect of trastuzumab binding to HER2 is an increase in p27, a protein that halts cell proliferation.^[8] Another monoclonal antibody, Pertuzumab, which inhibits dimerization of HER2 and HER3 receptors, is in advanced clinical trials.

Additionally, NeuVax (Galena Biopharma) is a peptide-based immunotherapy that directs "killer" T cells to target and destroy cancer cells that express HER2. It has entered phase 3 clinical trials.

It is revealed that patients with ER+ (Estrogen receptor positive)/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the PI3K/AKT molecular pathway.^[9]

Over-expression of HER2 can also be suppressed by the amplification of other genes. Research is currently being conducted to discover which genes may have this desired effect.

The expression of HER2 is regulated by signaling through estrogen receptors. Normally, estradiol and tamoxifen acting through the estrogen receptor down-regulate the expression of HER2. However, when the ratio of the coactivator AIB-3 exceeds that of the corepressor PAX2, the expression of HER2 is upregulated in the presence of tamoxifen, leading to tamoxifen-resistant breast cancer.^[10][11]

Recent evidence has implicated HER2 signaling in resistance to the EGFR-targeted cancer drug cetuximab.^[12]

Furthermore, diverse structural alterations have been identified that cause ligand-independent firing of this receptor, doing so in the absence of receptor over-expression. As stated the HER2 is found in a variety of tumours and some of these tumours carry point mutations in the sequence specifying the transmembrane domain of HER2. The resulting substitution of a valine for a glutamic acid results in the constitutive dimerisation of this protien in the absence of a ligand.

Her2 and Her3 distribution on a breast cell, (3D Dual Colour Super Resolution Microscopy SPDMphymod / LIMON,marked with Alexa 488 and 568)

HER2 testing[link]

HER2 testing is performed in breast cancer patients to assess prognosis and to determine suitability for Herceptin therapy. It is important that Herceptin is restricted to HER2-positive individuals as it is expensive and has been associated with cardiac toxicity.^[13] For HER2-negative tumours, the risks of Herceptin clearly outweigh the benefits.

Tests are usually performed on biopsy samples obtained by either fine-needle aspiration, core needle biopsy, vacuum-assisted breast biopsy, or surgical excision. Immunohistochemistry is used to measure the amount of HER2 protein present in the sample. Alternatively, fluorescence in situ hybridisation (FISH) can be used to measure the number of copies of the gene which are present.

The extracellular domain of HER2 can be shed from the surface of tumour cells and enter the circulation. Measurement of serum HER2 by enzyme-linked immunosorbent assay (ELISA) offers a far less invasive method of determining HER2 status than a biopsy and consequently has been extensively investigated. Results so far have suggested that changes in serum HER2 concentrations may be useful in predicting response to Herceptin therapy.^[14] However, its ability to determine eligibility for Herceptin therapy is less clear.^[15]

HER2 interactions[link]

HER2 has been shown to interact with Beta-catenin,^[16][17][18] Glycoprotein 130,^[19] PLCG1,^[20][21] Erbin,^[22][23][24] MUC1,^[25][26] Grb2,^[27][28][29] Heat shock protein 90kDa alpha (cytosolic), member A1,^[30][31] DLG4,^[32] PIK3R2,^[33] PICK1^[22] and SHC1.^[27][29][34]

See also[link]

• SkBr3 Cell Line

References[link]

Further reading[link]

External links[link]

• ERBB2 expression across human cancerous and healthy tissues
• AACR Cancer Concepts Factsheet on HER2
• Her2/neu Vaccine Protects Against Tumor Growth
• Chimeric molecules and Methods of Use
• Breast Friends for Life Network - A South African Breast Cancer Support Forum for HER2 Positive Women
• Receptor,+erbB-2 at the US National Library of Medicine Medical Subject Headings (MeSH)

v t e PDB gallery 1n8z: Crystal structure of extracellular domain of human HER2 complexed with Herceptin Fab   1s78: Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex   2a91: Crystal structure of ErbB2 domains 1-3