P04626 B2RZG3 B4DHN3 Q14256 Q6LDV1 Q9UMK4 ERBB2_HUMAN Receptor tyrosine-protein kinase erbB-2 2.7.10.1 Metastatic lymph node gene 19 protein MLN 19 Proto-oncogene Neu Proto-oncogene c-ErbB-2 Tyrosine kinase-type cell surface receptor HER2 p185erbB2 CD340 ERBB2 HER2 MLN19 NEU NGL Homo sapiens Human Eukaryota Metazoa Chordata Craniata Vertebrata Euteleostomi Mammalia Eutheria Euarchontoglires Primates Haplorrhini Catarrhini Hominidae Homo Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor. NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1) Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1) VARIANT ALA-1170 NUCLEOTIDE SEQUENCE [GENOMIC DNA] VARIANTS CYS-452; VAL-655 AND ALA-1170 NEDO human cDNA sequencing project focused on splicing variants. NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4) Brain NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1) Human HER2 (neu) promoter: evidence for multiple mechanisms for transcriptional initiation. NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-191 (ISOFORM 1) A v-erbB-related protooncogene, c-erbB-2, is distinct from the c-erbB-1/epidermal growth factor-receptor gene and is amplified in a human salivary gland adenocarcinoma. NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 737-1031 Amplification of a novel v-erbB-related gene in a human mammary carcinoma. NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 832-909 Mammary carcinoma Molecular cloning and sequencing of an intron of Her-2/neu (ERBB2) gene. NUCLEOTIDE SEQUENCE OF 1081-1245 VARIANT ALA-1170 ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases. INTERACTION WITH ERBB4 FUNCTION IN ACTIVATION OF STAT5A Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors. IDENTIFICATION IN A COMPLEX WITH PIK3C2A AND EGFR IDENTIFICATION IN A COMPLEX WITH PIK3C2B AND EGFR INTERACTION WITH PIK3C2B Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein. INTERACTION WITH MUC1 Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2. FUNCTION SUBCELLULAR LOCATION TISSUE SPECIFICITY Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2. INTERACTION WITH PLXNB1 Memo mediates ErbB2-driven cell motility. INTERACTION WITH MEMO1 Endosomal transport of ErbB-2: mechanism for nuclear entry of the cell surface receptor. SUBCELLULAR LOCATION NUCLEAR LOCALIZATION SIGNAL INTERACTION WITH KPNB1; RANBP2; CRM1; EEA1 AND CLTC Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-1248 MASS SPECTROMETRY Cervix carcinoma Biosynthesis of tumorigenic HER2 C-terminal fragments by alternative initiation of translation. FUNCTION ALTERNATIVE INITIATION (ISOFORMS 2 AND 3) SUBCELLULAR LOCATION MUTAGENESIS OF MET-611; MET-687; MET-706 AND MET-712 Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-735 MASS SPECTROMETRY Lung carcinoma Neuregulin-1 only induces trans-phosphorylation between ErbB receptor heterodimer partners. INTERACTION WITH ERBB4 AUTOPHOSPHORYLATION IN TRANS Plexin-B2, but not Plexin-B1, critically modulates neuronal migration and patterning of the developing nervous system in vivo. PHOSPHORYLATION AT TYR-1248 Multiple reaction monitoring for robust quantitative proteomic analysis of cellular signaling networks. PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-1248 MASS SPECTROMETRY Mammary epithelium Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1054 MASS SPECTROMETRY Cervix carcinoma A quantitative atlas of mitotic phosphorylation. PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1054 MASS SPECTROMETRY Cervix carcinoma Brk is coamplified with ErbB2 to promote proliferation in breast cancer. INTERACTION WITH PTK6 ENZYME REGULATION ErbB2-mediated Src and signal transducer and activator of transcription 3 activation leads to transcriptional up-regulation of p21Cip1 and chemoresistance in breast cancer cells. FUNCTION IN NUCLEUS ErbB2 receptor controls microtubule capture by recruiting ACF7 to the plasma membrane of migrating cells. FUNCTION Genetic and structural variation in the gastric cancer kinome revealed through targeted deep sequencing. CHROMOSOMAL REARRANGEMENT WITH CDK12 Nuclear ErbB2 enhances translation and cell growth by activating transcription of ribosomal RNA genes. FUNCTION IN NUCLEUS INTERACTION WITH ACTB AND RPA194 SUBCELLULAR LOCATION Dissociation of epidermal growth factor receptor and ErbB2 heterodimers in the presence of somatostatin receptor 5 modulate signaling pathways. INTERACTION WITH EGFR Poor binding of a HER-2/neu epitope (GP2) to HLA-A2.1 is due to a lack of interactions with the center of the peptide. X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 654-662 IN COMPLEX WITH HLA AND BETA-2 MICROGLOBULIN Novel mode of ligand recognition by the Erbin PDZ domain. X-RAY CRYSTALLOGRAPHY (1.25 ANGSTROMS) OF 1247-1255 IN COMPLEX WITH ERBB2IP INTERACTION WITH ERBB2IP Solution structure of the human Grb7-SH2 domain/erbB2 peptide complex and structural basis for Grb7 binding to ErbB2. STRUCTURE BY NMR OF 1135-1144 IN COMPLEX WITH GRB7 INTERACTION WITH GRB7 Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. X-RAY CRYSTALLOGRAPHY (2.52 ANGSTROMS) OF 23-629 IN COMPLEX WITH THE ANTIBODY HERCEPTIN Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. X-RAY CRYSTALLOGRAPHY (3.25 ANGSTROMS) OF 23-646 IN COMPLEX WITH THE ANTIBODY PERTUZUMAB INTERACTION WITH ERBB3 MUTAGENESIS OF 317-LEU-HIS-318 DISULFIDE BONDS GLYCOSYLATION AT ASN-187; ASN-259 AND ASN-530 Variants of the antibody herceptin that interact with HER2 and VEGF at the antigen binding site. X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 23-646 IN COMPLEX WITH THE ANTIBODY HERCEPTIN DISULFIDE BONDS GLYCOSYLATION AT ASN-259 AND ASN-530 Structural basis for high-affinity HER2 receptor binding by an engineered protein. X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 23-646 IN COMPLEX WITH ENGINEERED ANTIBODY ZHER2 DISULFIDE BONDS GLYCOSYLATION AT ASN-68; ASN-259 AND ASN-571 Structural analysis of the mechanism of inhibition and allosteric activation of the kinase domain of HER2 protein. X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 703-1029 IN COMPLEX WITH INHIBITOR SYR127063 CATALYTIC ACTIVITY SUBUNIT ENYZME REGULATION Characterization of a new allele of the human ERBB2 gene by allele-specific competition hybridization. VARIANTS VAL-654 AND VAL-655 Lung cancer: intragenic ERBB2 kinase mutations in tumours. VARIANTS PRO-755; SER-776; ALA-TYR-VAL-MET-774 INS AND VAL-GLY-SER-779 INS; SER-857 AND LYS-914 INVOLVEMENT IN CANCER Patterns of somatic mutation in human cancer genomes. VARIANTS [LARGE SCALE ANALYSIS] VAL-654; VAL-655; SER-768; SER-776; SER-857; ALA-1170 AND ASP-1216 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. ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. Activated by dimerization. Not activated by EGF, TGF-alpha and amphiregulin. Interaction with PTK6 increases its intrinsic kinase activity. Homodimer. Heterodimer with EGFR, ERBB3 and ERBB4. 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 (By similarity). false 3 P60709 false 10 Q15075 false 5 P00533 false 9 P21860 false 15 Q15303 false 2 Q14974 false 14 Q02297-7 false 2 O00750 false 2 O95602 false 16 Q05209 false 4 P23467 false 2 P08575 false 2 Q12913 false 2 Q15262 false 2 Q16827 false 2 P49792 false 3 P12931 false 10 O14980 false 2 Isoform 1 Cell membrane Single-pass type I membrane protein Cytoplasm Perinuclear region Nucleus Translocation to the nucleus requires endocytosis, probably endosomal sorting and is mediated by importin beta-1/KPNB1. Isoform 2 Cytoplasm Nucleus Isoform 3 Cytoplasm Nucleus P04626-1 1 ERBB2 HER2 P04626-2 2 CTF-611 Produced by alternative initiation at Met-611 of isoform 1. P04626-3 3 CTF-687 Produced by alternative initiation at Met-687 of isoform 1. P04626-4 4 Produced by alternative splicing of isoform 1. Expressed in a variety of tumor tissues including primary breast tumors and tumors from small bowel, esophagus, kidney and mouth. Autophosphorylated. Ligand-binding increases phosphorylation on tyrosine residues. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Signaling via SEMA4C promotes phosphorylation at Tyr-1248. There are fours alleles due to the variations in positions 654 and 655. Allele B1 (Ile-654/Ile-655) has a frequency of 0.782; allele B2 (Ile-654/Val-655) has a frequency of 0.206; allele B3 (Val-654/Val-655) has a frequency of 0.012. 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]. LNCR is 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. 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. Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily. Contains 1 protein kinase domain. ERBB2 entry 3D-structure ATP-binding Activator Alternative initiation Alternative splicing Cell membrane Chromosomal rearrangement Complete proteome Cytoplasm Disulfide bond Glycoprotein Kinase Membrane Nucleotide-binding Nucleus Phosphoprotein Polymorphism Receptor Reference proteome Signal Transcription Transcription regulation Transferase Transmembrane Transmembrane helix Tyrosine-protein kinase MELAALCRWGLLLALLPPGAAST MPRGSWKP W C I V I V L P L S M MAYVM G S S SVGS N S E K P A A D LH AA M A M A M A M A MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPASPETHLDMLRHLYQGCQVVQGNL ELTYLPTNASLSFLQDIQEVQGYVLIAHNQVRQVPLQRLRIVRGTQLFEDNYALAVLDNG DPLNNTTPVTGASPGGLRELQLRSLTEILKGGVLIQRNPQLCYQDTILWKDIFHKNNQLA LTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGCARCKGPLPTDCCHEQC AAGCTGPKHSDCLACLHFNHSGICELHCPALVTYNTDTFESMPNPEGRYTFGASCVTACP YNYLSTDVGSCTLVCPLHNQEVTAEDGTQRCEKCSKPCARVCYGLGMEHLREVRAVTSAN IQEFAGCKKIFGSLAFLPESFDGDPASNTAPLQPEQLQVFETLEEITGYLYISAWPDSLP DLSVFQNLQVIRGRILHNGAYSLTLQGLGISWLGLRSLRELGSGLALIHHNTHLCFVHTV PWDQLFRNPHQALLHTANRPEDECVGEGLACHQLCARGHCWGPGPTQCVNCSQFLRGQEC VEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCVARC PSGVKPDLSYMPIWKFPDEEGACQPCPINCTHSCVDLDDKGCPAEQRASPLTSIISAVVG ILLVVVLGVVFGILIKRRQQKIRKYTMRRLLQETELVEPLTPSGAMPNQAQMRILKETEL RKVKVLGSGAFGTVYKGIWIPDGENVKIPVAIKVLRENTSPKANKEILDEAYVMAGVGSP YVSRLLGICLTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLNWCMQIAKGMSYLEDVR LVHRDLAARNVLVKSPNHVKITDFGLARLLDIDETEYHADGGKVPIKWMALESILRRRFT HQSDVWSYGVTVWELMTFGAKPYDGIPAREIPDLLEKGERLPQPPICTIDVYMIMVKCWM IDSECRPRFRELVSEFSRMARDPQRFVVIQNEDLGPASPLDSTFYRSLLEDDDMGDLVDA EEYLVPQQGFFCPDPAPGAGGMVHHRHRSSSTRSGGGDLTLGLEPSEEEAPRSPLAPSEG AGSDVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTVPLPSETDGYVAPLTCSPQPEYV NQPDVRPQPPSPREGPLPAARPAGATLERPKTLSPGKNGVVKDVFAFGGAVENPEYLTPQ GGAAPQPHPPPAFSPAFDNLYYWDQDPPERGAPPSTFKGTPTAENPEYLGLDVPV Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms Distributed under the Creative Commons Attribution-NoDerivs License