ErbB2

Human epidermal growth factor receptor 2 (HER2), also known as ErbB2, NEU, and CD340, is a type I membrane glycoprotein, and belongs to the epidermal growth factor (EGF) receptor family. HER2 protein cannot bind growth factors due to the lacking of ligand binding domain of its own and autoinhibited constitutively. However, HER2 forms a heterodimer with other ligand-bound EGF receptor family members, therefore stabilizes ligand binding and enhances kinase-mediated activation of downstream molecules. HER2 plays a key role in development, cell proliferation and differentiation. HER2 gene has been reported to associate with malignancy and a poor prognosis in numerous carcinomas, including breast, prostate, ovarian, lung cancers and so on.

ErbB2 Related Areas

Enzyme>>Protein Kinase>>Receptor Tyrosine Kinase>>ErbB2/HER2

Signal Transduction>>Protein Kinase>>Receptor Tyrosine Kinase>>ErbB2/HER2

Cancer>>Cancer Biomarkers>>ErbB2/HER2

Cancer>>Growth Factor & Receptor>>EGF Family & Receptor>>ErbB2/HER2

Cancer>>Growth Factor & Receptor>>Receptor Tyrosine Kinase>>ErbB2/HER2

Immunology>>Cluster of Differentiation>>Other>>ErbB2/HER2/CD340

ErbB2 Related Pathways

• EGFR Signaling Pathway

ErbB2 Alternative Names

HER2, HER-2, ERBB2, CD340, NEU, NGL, TKR1, c-erbB-2, HER-2/neu [Homo sapiens]
HER2, HER-2, Erbb2, Erbb-2, RP23-355L10.8, Neu, c-erbB2, c-neu, mKIAA3023 [Mus musculus]

Summaries for ErbB2

Entrez Gene summary for 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.

OMIM - description for ErbB2:

aised antibodies against a synthetic peptide corresponding to 14 amino acid residues at the COOH terminus of a protein deduced from the ERBB2 nucleotide sequence. With these antibodies, they precipitated the ERBB2 gene product from adenocarcinoma cells and demonstrated it to be a 185-kD glycoprotein with tyrosine kinase activity.

Wikipedia summary for ErbB2:

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.

Human ErbB2 Protein General Information

 

• Protein names: Recommended name: Receptor tyrosine-protein kinase erbB-2
  Short name: ErbB2
• Sequence length: 1255 AA
• Domain: Signal Transmembrane Transmembrane helix
• Sequence similarities: Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily. Contains 1 protein kinase domain.
• Post-translational modification: Ligand-binding increases phosphorylation on tyrosine residues
• Subunit structure: Homodimer. Heterodimer with ERBB3. Heterodimer with each of the other ERBB receptors Potential. Part of a complex with EGFR and either PIK3C2A or PIK3C2B. May interact with PIK3C2B when phosphorylated on Tyr-1196. Interacts with PRKCABP and PLXNB1. Interacts (when phosphorylated on Tyr-1248) with MEMO1. Interacts with MUC1; the interaction is enhanced by heregulin (HRG). Interacts (when phosphorylated on Tyr-1139) with GRB7 (via SH2 domain). Interacts (when phosphorylated on Tyr-1248) with ERBB2IP. Interacts with KPNB1, RANBP2, EEA1, CRM1, CLTC, PTK6, RPA94 and ACTB. Interacts with SRC
• Subcellular location: Isoform 1: Cell membrane; Single-pass type I membrane protein. Cytoplasm › perinuclear region. Nucleus. Note: Translocation to the nucleus requires endocytosis, probably endosomal sorting and is mediated by importin beta-1/KPNB1.
• Tissue specificity: Expressed in a variety of tumor tissues including primary breast tumors and tumors from small bowel, esophagus, kidney and mouth.
• Involvement in disease: Defects in ERBB2 are a cause of hereditary diffuse gastric cancer (HDGC) [MIM:137215]. A cancer predisposition syndrome with increased susceptibility to diffuse gastric cancer. Diffuse gastric cancer is a malignant disease characterized by poorly differentiated infiltrating lesions resulting in thickening of the stomach. Malignant tumors start 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. Defects in ERBB2 are involved in the development of glioma (GLM) [MIM:137800]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Defects in ERBB2 are a cause of susceptibility to ovarian cancer (OC) [MIM:167000]. Ovarian cancer common malignancy originating from ovarian tissue. Although many histologic types of ovarian neoplasms 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. Defects in ERBB2 may be a cause of lung cancer (LNCR) [MIM:211980]. Defects in ERBB2 are a cause of gastric cancer (GASC) [MIM:613659]. 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. Note=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 trunctated CDK12 protein not in-frame with ERBB2.

General information above from UniProt

Function for ErbB2 Protein

UniProtKB:

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. Ref.11 Ref.14 Ref.19 Ref.27 Ref.28 Ref.30 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.

Genatlas:

• ERBB2 acting as a coreceptor for multiple stroma-derived growth factors i.e EGF-like ligands and neuregulins, and as a coreceptor for GPCR signaling in the heart
• ERBB2 is involved in androgen receptor transactivation of inducing prostate-specific antigen (PSA) through the MAP kinase pathway
• ERBB2 playing a critical role for normal cardiac function and prevention of dilated cardiomyopathy (together with ERBB4 and neuregulin)
• ERBB2 modulating epidemal growth factor signaling pathways resulting in growth arrest
• ERBB2 playing a pivotal role for integrating signaling networks involving multiple classes of extracellular signals
• ERBB2 requires ITGA5 for anoikis resistance via SRC regulation of receptor activity in human mammary epithelial cells (Pubmed 20332114)
• ERBB2 regulation having important implications in cancer, and for developing therapeutic approaches that target novel aspects of this orphan receptor (Pubmed 19718021)
• ERBB2 controls microtubule capture by recruiting MACF1 to the plasma membrane of migrating cells (Pubmed 20937854)
• ERBB2 may be dependent on ERBB3 to drive growth and survival of breast cancer cells (Pubmed 21385943)
• nuclear ERBB2 functions as a regulator of rRNA synthesis and cellular translation, which may contribute to tumor development and progression (Pubmed 21555369)

Homology for human ErbB2

• homolog to rattus Erbb2 (88.13 pc)
• homolog to murine Erbb2 (87.73 pc)
• homolog to zebrafish erbb2 (59.08 pc)

Phenotype Information for ErbB2

• Gene/Locus: ERBB2, NGL, NEU, HER2
• Phenotype: Adenocarcinoma of lung, somatic
  Gastric cancer, somatic
  Glioblastoma, somatic
  Ovarian cancer, somatic

Phenotype Information for ErbB2 from OMIM (Online Mendelian Inheritance in Man)

Drugs for ErbB2

Target	Drug Name	Disease	Drug Status
ErbB2	Trastuzumab	Breast cancer	Approved
ErbB2	Lapatinib	Breast cancer	Approved
ErbB2	Tyverb/Tykerb	Refractory breast cancer	Approved
ErbB2	Tyverb/Tykerb	Head & neck squamous cell carcinoma	Phase II
ErbB2	Tyverb/Tykerb	Gastric cancer	Phase III

Drugs for ErbB2 from TTD (Therapeutic Targets Database)