The HER2/neu gene encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases.
The HER2/neu gene is 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 directly. Instead, it binds tightly to other ligand-bound members of the EGF receptor family to form heterodimers. These heterodimers stabilise ligand binding and enhance the 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 found in numerous cancers, including breast and ovarian tumours. Alternative splicing also occurs, resulting in several additional transcript variants. Some of these variants encode different isoforms, while others have not yet been fully characterised.
Source: https://www.ncbi.nlm.nih.gov/gene/2064
The tyrosine kinase is an important component of several cell surface receptor complexes but apparently requires a co-receptor for ligand binding. It is particularly important in a neuregulin receptor complex, although neuregulins do not interact with it exclusively. GP30 is considered a possible ligand for this receptor. The tyrosine kinase regulates the growth and stabilisation of peripheral microtubules (MTs).
Activation of ERBB2 triggers the MEMO1–RHOA–DIAPH1 signalling pathway, resulting in phosphorylation and thus inhibition of GSK3B at the cell membrane. This in turn prevents the phosphorylation of APC and CLASP2 and allows their association with the cell membrane. Anchoring of membrane-bound APC at the cell membrane allows the localisation of MACF1, which is crucial for capturing and stabilising microtubules.
The tyrosine kinase also plays a role in transcriptional regulation. It binds to the 5′-TCAAATTC-3′ sequence in the PTGS2/COX-2 promoter and thereby activates its transcription. It is also involved in the transcriptional activation of CDKN1A, a function involving STAT3 and SRC. Furthermore, it is involved in the transcription of rRNA genes by RNA Pol I, thereby promoting protein synthesis and cell growth.
Source: https://www.uniprot.org/uniprot/P04626
Cytogenetic location:
17q12, the long (q) arm of chromosome 17 at position 12
Molecular location:
Base pairs 39,688,084 to 39,728,662 on chromosome 17 (Homo sapiens Updated Annotation Release 109.20200228, GRCh38.p13) (NCBI)
Diseases associated with the ERBB2/HER2/neu gene
Breast cancer: if very high levels of HER2 are detected in breast cancer tissue (IHC 3+ or IHC 2+ ISH+ or ISH+), these patients are described as HER2-positive. HER2/neu-positive patients are known to suffer from a comparatively more aggressive form of breast cancer and therefore to have a less favourable prognosis. According to the literature, about 20% of patients with breast cancer are HER2-positive. HER2-positive, however, also means that these patients can benefit from targeted and effective therapy against these cells.
Ovarian cancer (OC): the term ovarian cancer refers to malignancies arising from ovarian tissue. Although many histological types of ovarian tumour have been described, epithelial ovarian cancer is the most common form. Ovarian cancer is often asymptomatic, and the signs and symptoms identified, even in late-stage disease, are vague. As a result, most patients are diagnosed with advanced disease.
Gastric cancer (GASC): a malignant disease that begins in the stomach, can spread to the oesophagus or small intestine and can extend through the stomach wall to nearby lymph nodes and organs. It can also metastasise to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach, which accounts for most malignant gastric tumours. Two main histological types are recognised: diffuse-type and intestinal-type carcinomas. Diffuse tumours are poorly differentiated infiltrating lesions that lead to thickening of the stomach. In contrast, intestinal-type tumours are usually exophytic, often ulcerating and associated with intestinal metaplasia of the stomach, most frequently observed in sporadic disease.
Glioma (GLM): gliomas are benign or malignant neoplasms of the central nervous system that arise from glial cells. They include astrocytomas and glioblastoma multiforme, which arise from astrocytes, oligodendrogliomas, which arise from oligodendrocytes, and ependymomas, which arise from ependymal cells.
Lung cancer (LNCR): a common malignancy affecting the tissue of the lungs. The most common form of lung cancer is non-small cell lung cancer (NSCLC), which can be divided into three important histological subtypes: squamous cell carcinoma, adenocarcinoma and large cell lung cancer. NSCLC is frequently diagnosed at an advanced stage and has a poor prognosis.
Synonyms for ERBB2
- CD340
- HER-2
- HER-2/neu
- HER2
- MLN 19
- NEU
- NGL
- TKR1
