ERBB2

Official Full Name

erb-b2 receptor tyrosine kinase 2

Organism

Homo sapiens

GeneID

2064

Background

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]

Synonyms

NEU; NGL; HER2; TKR1; CD340; HER-2; VSCN2; MLN 19; MLN-19; c-ERB2; c-ERB-2; HER-2/neu; p185(erbB2);

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Detailed Information

ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) is a member of the epidermal growth factor receptor (EGFR) family. The ErbB2 protein belongs to the tyrosine kinase ErbB family. Unlike other members of this family (EGFR), the ErbB2 protein has no ligands that can only be activated by forming dimers with other members of the family. More than 20 years ago, the researchers determined that the ErbB2 gene is a pro-cancer factor, and about 30% of breast cancer patients have ErbB2 gene amplification. The study found that ErbB2 gene amplification accounted for about 4% of patients with SCC.

ErbB2 is the most preferential or optimal dimerization partner. Its heterodimers formed with other members of the family have relatively strong signal transduction ability, so it can be said that ErbB-2 is at the center of the entire ErbB family signal network. The heterodimers containing ErbB-2 have strong signal transduction ability and may be related to the following mechanisms: ErbB2 can block the dissociation of ligands and heterodimers and increase the affinity of ligands; ErbB2 can reduce ErbB1 Endocytosis and degradation rate make the heterodimer more stable; in addition, ErbB2 can also promote ErbB-1 recycling.

ErbB2 Figure 1. Effect of bivalent NRG-1β (ΝΝ) in ErbB2-overexpressing breast cancer cells and cardiomyocytes. (Vermeulen, et al. 2016)

ErbB2 and Tumor

Amplification of the ErbB2 gene results in significant overexpression of the ErbB2 protein, causing the spontaneous formation of the ErbB2 homodimer, which is coupled to the RAS pathway. Furthermore, overexpression of ErbB2 can undergo spontaneous dimerization with ErbB3 and activation of the PI3K pathway. Thus, overexpressed ErbB2 is coupled to two major oncogenic pathways, RAS-ERK and PI3K-AKT to promote cell survival, proliferation and migration/invasion. A large amount of ErbB2 overexpression in breast cancer cells may be associated with the production of p95ErbB2. In ErbB2-overexpressing breast cancer, the ErbB2- ErbB3 dimer, rather than the EGFR-ErbB2 dimer, plays a major role in promoting tumorigenesis. Therefore, the formation of the ErbB2 /ErbB3 dimer is a new idea compared to the treatment scheme targeting only ErbB2.

The region in which ErbB2 forms a dimer with other ErbBs family receptor members is located in region II of its ECD. The new humanized monoclonal antibody, Pertuzumab, is designed for this region and can compete with the ErbBs family of receptor members to bind this region. Trastuzumab, which has been used clinically for many years in ErbB2 overexpressing breast cancer, binds to the IV region of ECD. Thus, pertuzumab prevented ErbB2 from binding to other ErbBs family receptors, including ErbB3, which did not inhibit the formation of dimers between ErbB2 and ErbB3. This property of pertuzumab inhibits the activation and amplification of cascaded signals that regulate cell proliferation and survival in the cell. Similar to trastuzumab, the ADCC effect may also be involved in the antitumor activity of pertuzumab. It is worth noting that in the tumors that do not necessarily overexpress ErbB2, such as ovarian cancer, prostate cancer, lung cancer and colorectal cancer. Pertuzumab also showed some effects in in vitro and in vivo studies.

The researchers found that the EGFR irreversible inhibitors afatinib, neratinib, and dacomitinib have a high inhibition rate for NSCLC cells with multiple expression of ERBB2. In Phase I clinical studies of neratinib, two of the six NSCLC patients with ERBB2 mutations responded partially to neratinib. The same situation occurred in the phase II clinical study of afatinib. Wichmann et al. showed that the Mrna and protein content of ErbB2 is inversely proportional to the prognosis of patients with soft tissue sarcoma.

Neuregulin 1-ErbB Signaling Pathway

NRG1 is a member of the neuregulin family, which contains an epidermal growth factor (EGF)-like domain. It is a transmembrane protein that, like EGF, activates or processes on the cell surface to become a soluble fragment. Studies have shown that embryonic striatum pluripotent neural progenitor cells (NPs) express a variety of NRG1 transcripts, as well as NRG1 specific receptors ErbB2 and ErbB4, but do not express ErbB3. ErbB4 and ErbB2 are expressed in mature cardiomyocytes, and NRG1 binds with ErbB4 with high affinity.

Matsukawa et al. found that NRG-1/ErbB signaling in the rostral ventral medulla (RVLM), a major vasomotor reflex center, has inhibitory and sympathetic inhibition. ErbB2 receptors are involved in the neurological mechanisms of hypertension, and NO can also induce sympathetic inhibition and depression in the ventrolateral medulla of the rostral medulla. In some tissues, NRG-1 increases the expression of NO synthase. Therefore, in RVLM, ErbB2 antagonists can increase blood pressure, increase heart rate, and increase norepinephrine secretion by reducing the expression of NO synthase in neurons and endothelium.

References:

Vermeulen, Z., Segers, V. F. M., & Keulenaer, G. W. D. (2016). ErbB2 signaling at the crossing between heart failure and cancer. Basic Research in Cardiology, 111(6), 60.
Fabi, A., Mottolese, M., & Segatto, O. (2014). Therapeutic targeting of ErbB2 in breast cancer: understanding resistance in the laboratory and combating it in the clinic. Journal of Molecular Medicine, 92(7), 681-695.
Wichmann, H., Güttler, A., Bache, M., Taubert, H., Vetter, M., & Würl, P., et al. (2014). Inverse prognostic impact of ErbB2 mrna and protein expression level in tumors of soft tissue sarcoma patients. , 190(10), 912-918.
Matsukawa, R., Hirooka, Y., Ito, K., & Sunagawa, K. (2013). Inhibition of neuregulin-1/ErbB signaling in the rostral ventrolateral medulla leads to hypertension through reduced nitric oxide synthesis. American Journal of Hypertension, 26(1), 51-57.
Brix, D. M., Clemmensen, K. K., & Kallunki, T. (2014). When good turns bad: regulation of invasion and metastasis by ErbB2 receptor tyrosine kinase. Cells, 3(1), 53-78.

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