ERBB2
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]
Full Name
Erb-B2 Receptor Tyrosine Kinase 2
Research Area
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.
Biological Process
Cell surface receptor signaling pathway Source: MGI
Cellular response to epidermal growth factor stimulus Source: UniProtKB
Cellular response to growth factor stimulus Source: UniProtKB
Enzyme linked receptor protein signaling pathway Source: ProtInc
Heart development Source: Ensembl
Intracellular signal transduction Source: UniProtKB
Motor neuron axon guidance Source: Ensembl
Myelination Source: Ensembl
Negative regulation of immature T cell proliferation in thymus Source: Ensembl
Neuromuscular junction development Source: Ensembl
Neuron differentiation Source: GO_Central
Oligodendrocyte differentiation Source: Ensembl
Peptidyl-tyrosine phosphorylation Source: UniProtKB
Peripheral nervous system development Source: Ensembl
Phosphatidylinositol 3-kinase signaling Source: BHF-UCL
Positive regulation of cell adhesion Source: BHF-UCL
Positive regulation of cell growth Source: UniProtKB
Positive regulation of cell population proliferation Source: GO_Central
Positive regulation of epithelial cell proliferation Source: UniProtKB
Positive regulation of GTPase activity Source: BHF-UCL
Positive regulation of kinase activity Source: GO_Central
Positive regulation of MAPK cascade Source: GO_Central
Positive regulation of MAP kinase activity Source: UniProtKB
Positive regulation of protein phosphorylation Source: BHF-UCL
Positive regulation of protein targeting to membrane Source: UniProtKB
Positive regulation of transcription by RNA polymerase I Source: UniProtKB
Positive regulation of translation Source: UniProtKB
Protein autophosphorylation Source: BHF-UCL
Protein phosphorylation Source: ProtInc
Regulation of angiogenesis Source: UniProtKB
Regulation of ERK1 and ERK2 cascade Source: UniProtKB
Regulation of microtubule-based process Source: UniProtKB
Signal transduction Source: UniProtKB
Transmembrane receptor protein tyrosine kinase signaling pathway Source: BHF-UCL
Wound healing Source: BHF-UCL
Cellular Location
Isoform 1: Early endosome; Nucleus; Cell membrane; Perinuclear region. Translocation to the nucleus requires endocytosis, probably endosomal sorting and is mediated by importin beta-1/KPNB1. Also detected in VPS35-positive endosome-to-TGN retrograde vesicles (PubMed:31138794).
Isoform 2&3: Nucleus; Cytoplasm
Involvement in disease
Glioma (GLM):
Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes.
Ovarian cancer (OC):
The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease.
Lung cancer (LNCR):
A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis.
Gastric cancer (GASC):
A malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions, resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease.
Chromosomal aberrations involving ERBB2 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with CDK12, leading to CDK12-ERBB2 fusion leading to truncated CDK12 protein not in-frame with ERBB2.
Topology
Extracellular: 23-652
Helical: 653-675
Cytoplasmic: 676-1255
PTM
Autophosphorylated. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit (Probable). Ligand-binding increases phosphorylation on tyrosine residues (PubMed:27134172). Signaling via SEMA4C promotes phosphorylation at Tyr-1248 (PubMed:17554007). Dephosphorylated by PTPN12 (PubMed:27134172).
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Datasheet