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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ERBB2 (HER-2/neu) protooncogene encodes a transmembrane protein with an intracellular tyrosine kinase activity. It is principally activated by gene amplification and its product, the erbB2 protein, becomes oncogenic when overexpressed. Quantitative PCR is both a simple and reliable method for the evaluation of ERBB2 activation, whereas immunoenzymatic methods allow quantitative determination of erbB2 protein in tissue and sera. ERBB2 amplification and/or surexpression is actually recognized as a prognostic factor in breast cancer and would be predictive in the therapeutic response. It might lead also to new therapeutic modalities using specific targeted drugs.
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PMID:[Current aspects of the evaluation of ERBB2 activation in breast cancer. Therapeutic perspectives]. 949 14

The erbB-3 gene encodes a transmembrane protein that is related to the epidermal growth factor (EGF) receptor and erbB-2. We compared erbB-3 expression in the normal human pancreas, human pancreatic carcinomas, and cultured human pancreatic cancer cell lines. Northern blot analysis of total RNA revealed the anticipated 6.2-kb mRNA transcript in all 19 normal pancreatic samples. In 17 of 27 pancreatic cancers, there was a 6.7-fold increase (P < 0.001) in erbB-3 mRNA levels. Southern blot analysis did not reveal erbB-3 gene amplification. Four of six pancreatic cancer cell lines exhibited the 6.2-kb erbB-3 mRNA transcript, and all four cell lines coexpressed the epidermal growth factor receptor and erbB-2. Using a highly specific antibody, we determined that faint to moderate erbB-3 immunoreactivity was present in the ductal cells in the normal pancreas. In 47% (27/58) of the pancreatic cancers, there were many cancer cells with intense erbB-3 immunostaining. The presence of erbB-3 in the cancer cells was associated with advanced tumor stage and shorter survival postoperatively. These data indicate that a significant proportion of human pancreatic cancers overexpress erbB-3, and that erbB-3 may contribute to disease progression in this disorder.
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PMID:Enhanced erbB-3 expression in human pancreatic cancer correlates with tumor progression. 981 39

We are developing strategies to use naive T lymphocytes in cancer therapy. For this purpose, we are deriving T cells with specificity of recognition for defined tumor cells. To direct effector lymphocytes toward tumor cells, we have manipulated the recognition specificity of naive rat and mouse T lymphocytes and a mouse T-cell line. The cells were stably transduced with a chimeric T-cell receptor (TCR) component. The zeta chain of the TCR consists of a single transmembrane protein with a short extracellular domain and an intracellular domain for TCR signaling. We provided an extracellular tumor cell recognition domain to the zeta chain. Human heregulin beta1 (ligand to the erbB-3 and erbB-4 receptors) and three different single-chain antibodies specific for the human and rat Neu/erbB-2 receptors were used. One single-chain antibody (C11) is directed against the rat Neu protein, and one single-chain antibody (FRP5) is directed against the human erbB-2 receptor. The single-chain antibody (R-AK) directed against the Mr 14,000 fusion protein of orthopox viruses served as a control. An efficient procedure was devised to introduce the chimeric genes into primary rat and mouse T lymphocytes. Retrovirus-producing packaging cell lines were cocultured with the T cells activated by phytohemagglutinin and interleukin 2. T-cell lines were transduced by exposure to retrovirus-containing supernatants from helper cell lines. Expression of the fusion genes was determined by fluorescence-activated cell sorting analysis. More than 80% of the naive rat and mouse T cells and 85-100% of the cells from the established T-cell lines expressed the fusion genes within 48 h after infection. The expression of the fusion genes was maintained for at least 10 days after infection. Target cells expressing Neu/erbB-2, erbB-3, or erbB-4 were lysed in vitro with high specificity by T cells expressing the corresponding recognition proteins. No selection of a marker gene is necessary to confer a predetermined recognition specificity. The described experiments are important for a gene therapy approach to cancer treatment with autologous T cells.
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PMID:Cytolysis of tumor cells expressing the Neu/erbB-2, erbB-3, and erbB-4 receptors by genetically targeted naive T lymphocytes. 981 61

The c-erbB-2 proto-oncogene encodes a transmembrane protein tyrosine kinase receptor of 185 kDa (p185) and has been associated with several types of human cancers. In human breast cancer, overexpression of p185 occurs in 15-30% of cases, correlates with poor prognostic factors and characterizes breast cancers with a more aggressive behavior. Overexpression of p185 is usually associated with c-erbB-2 amplification, though it may occur independently and thus define subpopulations of breast cancers which might be of clinical interest. p185 expression is usually detected by immunohistochemistry (IHC) and few studies have been carried out to evaluate the p185 content of breast cancers with an ELISA technique. In this context, we showed, in 106 breast cancer samples, that p185 was expressed at high levels in 13.2%, intermediate levels in 55.7% and negative ones in 31.1% of cases. All p185 positive samples showed a c-erbB-2 oncogene amplification while none of the p185 negative samples and only 4% of p185 imtermediate samples had an amplification of c-erbB-2. p185 expression is significantly correlated with the negativity of estrogen and progestrone receptors, with high levels of cathepsin D and in some conditions with axillary nodal involvement. Thus, using the p185 ELISA assay, the c-erbB-2 status of breast cancers can be defined and moreover a subset can be discriminated which is characterized by intermediate levels of p185 and absence of c-erbB-2 amplification. The quantitative approach towards p185 in breast cancers affords the possibility of identifying more appropriately patients with high or low risk and thus permits adaptation of therapeutic regimens.
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PMID:Relevance of p185 HER-2/neu oncoprotein quantification in human primary breast carcinoma. 1109 92

The human proto-oncogene c-erbB-2/neu gene, which is structurally similar to the epidermal growth factor receptor gene, encodes a transmembrane protein of 185 kDa (p185) with tyrosine kinase activity. Paraffin-embedded sections from 42 cases with lung carcinoma were stained immunohistochemically using the Avidin-Biotin Horseradish Peroxidase method to search for c-erbB-2 reaction. Results were evaluated semiquantitatively. The c-erbB-2 expression from each case was compared according to tumor type, grade, mitotic activity, clinical stage and lymph node metastasis. Results were statistically analyzed by using chi-square tests. We were unable to detect a significant relation between c-erbB-2 expression and histological grade, nodal metastasis, number of mitotic figures or tumor type, but we did observe a statistically significant correlation between clinical stage and increased c-erbB-2 expression (p < 0.05). In our opinion, c-erbB-2 expression in human lung carcinomas may be useful for determining clinical outcome.
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PMID:Prognostic factors and c-erbB-2 expression in non-small-cell lung carcinoma (c-erbB-2 in non-small cell lung carcinoma). 1184 6

The molecular mechanisms by which mammalian receptor tyrosine kinases are negatively regulated remain largely unexplored. Previous genetic and biochemical studies indicate that Kekkon-1, a transmembrane protein containing leucine-rich repeats and an immunoglobulin-like domain in its extracellular region, acts as a feedback negative regulator of epidermal growth factor (EGF) receptor signaling in Drosophila melanogaster development. Here we tested whether the related human LRIG1 (also called Lig-1) protein can act as a negative regulator of EGF receptor and its relatives, ErbB2, ErbB3, and ErbB4. We observed that in co-transfected 293T cells, LRIG1 forms a complex with each of the ErbB receptors independent of growth factor binding. We further observed that co-expression of LRIG1 with EGF receptor suppresses cellular receptor levels, shortens receptor half-life, and enhances ligand-stimulated receptor ubiquitination. Finally, we observed that co-expression of LRIG1 suppresses EGF-stimulated transformation of NIH3T3 fibroblasts and that the inducible expression of LRIG1 in PC3 prostate tumor cells suppresses EGF- and neuregulin-1-stimulated cell cycle progression. Our observations indicate that LRIG1 is a negative regulator of the ErbB family of receptor tyrosine kinases and suggest that LRIG1-mediated receptor ubiquitination and degradation may contribute to the suppression of ErbB receptor function.
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PMID:The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases. 1534 10

The human epidermal growth factor receptor, type 2 (HER-2/neu or c-erbB-2) is a 185 kDa transmembrane protein that is phosphorylated upon ligand binding and dimerization with members of the HER/c-erbB family and regulates cell growth and differentiation. Its overexpression is strongly associated with advanced disease, metastasis and poor clinical outcome. To better understand the mechanisms underlying the poor prognosis of breast tumors with HER-2/neu-positive status, parallel proteomic analyses were performed on estrogen receptor-negative and node-positive breast tumors with or without overexpression of the HER-2/neu oncogene, using laser capture microdissection and two-dimensional gel electrophoresis. The differentially expressed proteins were identified by peptide mass fingerprinting using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Cytokeratin 19 (CK19), one of the identified proteins, was highly expressed in the HER-2/neu-positive breast tumors when compared with HER-2/neu-negative breast tumors. The enhanced overexpression of CK19 in HER-2/neu-positive tumors was further analyzed using semiquantitative reverse-transcription polymerase chain reaction, Western blotting and reverse-phase protein arrays. Immunohistochemical staining of sections from a breast tumor tissue microarray of 97 tumors showed moderate to strong staining against anti-CK19 antibody in 20 (5 with moderate and 15 with strong staining) of the 26 HER-2/neu-positive tumors (76.9%) and in 22 (12 with moderate and 10 with strong staining) of 52 HER-2/neu-negative tumors (48%) (p = 0.002). Our results indicate that CK19, an intermediate fragment of the cytoskeleton, and other proteins showing differential expression, are likely to be intricately involved in intra- and intercellular molecular events driving the more aggressive tumor proliferation, invasion and metastasis associated with HER-2/neu-positive tumors.
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PMID:Proteomics of breast cancer: enhanced expression of cytokeratin19 in human epidermal growth factor receptor type 2 positive breast tumors. 1582 49

Uterine papillary serous carcinoma (UPSC) is a highly aggressive variant of endometrial cancer with features similar to high-grade ovarian cancer. Patients tend to be elderly, thin, have a high grade tumor with extensive extrauterine disease at the time of diagnosis. The transmembrane receptor encoded by the HER-2 cellular oncogene is amplified in several types of human carcinomas and provides an attractive therapeutic target. HER-2/neu, the transmembrane receptor encoded by the c-erbB2 gene, is overexpressed by immunohistochemistry in <25% of ovarian cancers and 20-30% of breast cancers, and <10% of endometrial cancer. There are prognostic and therapeutic implications associated with the overexpression of this transmembrane protein. Herceptin, a humanized murine monoclonal antibody directed against the extracellular domain of the HER-2/neu protein, is being used to treat breast cancer that overexpresses HER-2/neu. We reviewed all patients diagnosed with UPSC between 1999-2001. Twenty-six patients were identified, and 19 patients had specimens available for evaluation. We performed immunohistochemical analysis (Herceptest, Dako, Carpinteria, CA) on 19 paraffin embedded blocks of UPSC tumors looking for HER-2/neu over expression. Five out of 19 (26%) stained heavily (3+) for HER-2/neu receptor protein. Four of these five patients had advanced disease at diagnosis. Two of these patients were subsequently treated with Herceptin; one with complete response and one with stable disease based on CT scan and CA-125 findings. Targeting HER-2/neu may be beneficial for a select group of patients with UPSC. We are continuing to evaluate samples for HER-2/neu over expression by fluorescence in situ hybridization (FISH).
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PMID:HER-2/neu overexpression in uterine papillary serous cancers and its possible therapeutic implications. 1700 89

The rhomboid gene was discovered in Drosophila, where it encodes a seven transmembrane protein that is the signal-generating component of epidermal growth factor (EGF) receptor signaling during development. Although metazoan developmental regulators are rarely conserved outside the animal kingdom, rhomboid proteins are conserved in all kingdoms of life, but the significance of this remains unclear. Recent biochemical reconstitution and high-resolution crystal structures have provided proof that rhomboid proteins function as novel intramembrane proteases, with a serine protease-like catalytic apparatus embedded within the membrane bilayer, buried in a hydrophilic cavity formed by a protein ring. A thorough consideration of all known examples of rhomboid function suggests that, despite biochemical similarity in mechanism and specificity, rhomboid proteins function in diverse processes including quorum sensing in bacteria, mitochondrial membrane fusion, apoptosis, and stem cell differentiation in eukaryotes; rhomboid proteins are also now starting to be linked to human disease, including early-onset blindness, diabetes, and parasitic diseases. Regulating cell signaling is at the heart of rhomboid protein function in many, but not all, of these processes. Further study of these novel enzymes promises to reveal the evolutionary path of rhomboid protein function, which could provide insights into the forces that drive the molecular evolution of regulatory mechanisms.
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PMID:Rhomboid proteins: conserved membrane proteases with divergent biological functions. 1711 79

Elastomers based on poly(dimethylsiloxane) (PDMS) are promising materials for fabrication of a wide range of microanalytical systems due to their mechanical and optical properties and ease of processing. To date, however, quantitative studies that demonstrate reliable and reproducible methods for attachment of binding groups that capture complex receptor proteins of relevance to biomedical applications of PDMS microsystems have not been reported. Herein we describe methods that lead to the reproducible capture of a transmembrane protein, the human epidermal growth factor (EGF) receptor, onto PDMS surfaces presenting covalently immobilized antibodies for EGF receptor, and subsequent isolation of the captured receptor by mechanical transfer of the receptor onto a chemically functionalized surface of a gold film for detection. This result is particularly significant because the physical properties of transmembrane proteins make this class of proteins a difficult one to analyze. We benchmark the performance of antibodies to the human EGF receptor covalently immobilized on PDMS against the performance of the same antibodies physisorbed to conventional surfaces utilized in ELISA assays through the use of EGF receptor that was (32)P-radiolabeled in its autophosphorylation domain. These results reveal that two pan-reactive antibodies for the EGF receptor (clones H11 and 111.6) and one phosphospecific EGF receptor antibody (clone pY1068) capture the receptor on both PDMS and ELISA plates. When using H11 antibody to capture EGF receptor and subsequent treatment with a stripping buffer (NaOH and sodium dodecylsulfate) to isolate the receptor, the signal-to-background obtained using the PDMS surface was 82 : 1, exceeding the signal-to-background measured on the ELISA plate (<48 : 1). We also characterized the isolation of captured EGF receptor by mechanical contact of the PDMS surface with a chemically functionalized gold film. The efficiency of mechanical transfer of the transmembrane protein from the PDMS surface was found to be 75-81%. However, the transfer of non-specifically bound protein was substantially less than 75%, thus leading to the important finding that mechanical transfer of the EGF receptor leads to an approximately four-fold increase in signal-to-background from 20 : 1 to 88 : 1. The signal-to-background obtained following mechanical transfer is also better than that obtained using ELISA plates and stripping buffer (<48 : 1). The EGF receptor is a clinically important protein and the target of numerous anticancer agents and thus these results, when combined, provide guidance for the design of PDMS-based microanalytical systems for the capture and isolation of complex and clinically important transmembrane proteins.
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PMID:Engineering of PDMS surfaces for use in microsystems for capture and isolation of complex and biomedically important proteins: epidermal growth factor receptor as a model system. 1865 Oct 79


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