Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SH2 domains function to bind proteins containing phosphotyrosine and are components of proteins that are important signal transducers for tyrosine kinases. We have cloned SH2 domain proteins by screening bacterial expression libraries with the tyrosine phosphorylated carboxyterminus of the epidermal growth factor (EGF) receptor. Here we report the identification of a new SH2 domain protein, Grb10. Grb10 is highly related to Grb7, an SH2 domain protein that we have previously identified. In addition to an SH2 domain, Grb7 and Grb10 have a central domain with similarity to a putative C. elegans gene likely to be involved in neuronal migration. At least three forms of Grb10 exist in fibroblasts apparently due to alternate translational start sites. Grb10 undergoes serine but not tyrosine phosphorylation after EGF treatment resulting in a shift mobility in a large fraction of Grb10 molecules. However Grb10 appears to bind poorly to EGF-Receptor and the true binding partner for the Grb10 SH2 domain is unclear. Grb10 maps to mouse chromosome 11 very close to the EGF-Receptor which is remarkably similar to Grb7 that maps near the EGF-Receptor related HER2 receptor. The finding of multiple family members with evolutionarily conserved domains indicates that these SH2 domain proteins are likely to have an important, although as of yet, unidentified function.
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PMID:The cloning of Grb10 reveals a new family of SH2 domain proteins. 773 17

The proto-oncogene HER2/neu encodes for a 185 kDa transmembrane protein with extensive homology to the epidermal growth factor (EGF) receptor. We have previously shown a correlation between HER2/neu expression and the level of in vitro cytotoxicity of tumour-associated lymphocytes (TAL) versus autologous tumour. In addition, we have recently demonstrated that tumour-associated cytotoxic T-lymphocytes (CTL) from ovarian and breast cancer patients can recognize a HER2/neu derived peptide epitope when presented in the context of HLA-A2. Since repeated tumour stimulation of CTL enhances both proliferation and cytotoxicity against autologous tumour, we hypothesized that repeated peptide antigen stimulation would have a similar effect. To be therapeutically useful, the peptide antigen must meet the following conditions: (1) the peptide must be immunogenic and cause a proliferation of CTL to adequate therapeutic numbers, and (2) the peptide-specific CTL which are generated must be cytotoxic against autologous tumour. To test our hypothesis, T-lymphocytes isolated from the ascites of four consecutive HER2/neu+ ovarian cancer patients were initially stimulated with solid phase anti-CD3 antibody and divided into three groups: (1) treatment with recombinant interleukin-2 (IL-2) alone, (2) IL-2 plus weekly stimulation with irradiated autologous tumour cells, and (3) IL-2 plus weekly stimulation with a HER2/neu derived peptide. Peptide-stimulated and tumour-stimulated CTL showed similar increases in proliferation with both groups consistently reaching therapeutic numbers. Peptide-stimulated CTL demonstrated significantly enhanced cytotoxicity against autologous tumour in 4-h chromium release assays as compared to the IL-2 alone group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro stimulation of ovarian tumour-associated lymphocytes with a peptide derived from HER2/neu induces cytotoxicity against autologous tumour. 778 Jun 12

Shc is a ubiquitously expressed Src homology 2 (SH2) domain protein that can transform fibroblasts and differentiate PC12 cells in a Ras-dependent fashion. Shc binds a variety of tyrosine-phosphorylated growth factor receptors presumably via its carboxyl-terminal SH2 domain. We cloned a fragment of Shc when screening a bacterial expression library with tyrosine-phosphorylated epidermal growth factor (EGF) receptor. Surprisingly, this fragment encodes the amino terminus of Shc, a region that has no significant similarity to an SH2 domain. When expressed as a glutathione S-transferase fusion protein, this amino-terminal domain binds to autophosphorylated EGF receptor, as well as HER2/neu and TrkA receptors. This fragment acts like an SH2 domain in that it does not bind non-phosphorylated EGF receptor or EGF receptor with all tyrosine phosphorylation sites mutated or deleted. Our data define a novel domain in Shc that has the potential to interact with growth factor receptors and other tyrosine-phosphorylated proteins.
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PMID:A region in Shc distinct from the SH2 domain can bind tyrosine-phosphorylated growth factor receptors. 779 94

Overexpression of the c-erbB-2/HER2 protooncogene in breast carcinoma is controlled not only by the degree of amplification of the gene but also at the level of gene transcription. Thus, whether or not the gene is amplified, the activity of the c-erbB-2 promoter is enhanced in overexpressing cells through the binding of an additional transcription factor, OB2-1, whose activity is increased in these lines. Here we describe further characterization of OB2-1 and show that it is identical to the developmentally regulated transcription factor AP-2. Functional assays confirm that AP-2 is able to regulate c-erbB-2 expression in mammary-derived cell lines. Furthermore, although AP-2 is barely detectable in cells with the low c-erbB-2 expression phenotype, protein levels are clearly elevated in a panel of c-erbB-2-overexpressing lines. These findings demonstrate an important role for this transcription factor in human cancer.
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PMID:The developmentally regulated transcription factor AP-2 is involved in c-erbB-2 overexpression in human mammary carcinoma. 784 46

The c-erbB-2 (HER-2, neu) oncogene has been implicated frequently in many human tumors. This oncogene codes for a 185-kDa protein that functions as a transmembrane growth factor receptor. Overexpression of the normal protein or point mutations in the transmembrane domain of the protein have been shown to have a transforming effect. Molecular structure studies of the transmembrane domain provide a plausible explanation for this transforming effect in both cases and relate this to the process of receptor dimerization in the membrane, degradation of the protein with release of the extracellular domain (ECD) into the extracellular environment, and aberrant signal transduction. The release of the ECD into the extracellular environment provides a potential biomarker for the study of signal transduction at the molecular level in vivo. The ECD can be quantitated immunologically in the serum of individuals with cancers associated with p185 overexpression and in individuals at risk for the development of such cancers and can be used to distinguish these individuals from normal, healthy controls. Identification of such individuals by their serum ECD levels combined with specific chemotherapeutic/chemoprophylactic interventions could allow for improvement treatment and prevention of c-erbB-2-related cancers.
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PMID:The c-erbB-2 protein in oncogenesis: molecular structure to molecular epidemiology. 784 90

The HER4/ERBB4 gene encodes a 180K transmembrane protein (HER4/p180erbB4) that is structurally related to the 185K product (HER2/p185erbB2) of the HER2/ERBB2 proto-oncogene. A 45K heparin-binding glycoprotein (p45) has been characterized that specifically activates the intrinsic tyrosine kinase activity of HER4 (ref. 2). This HER4 ligand shares several features with the heregulin family of proteins, including molecular mass, ability to induce differentiation of breast cancer cells, activation of tyrosine phosphorylation in MDA-MB453 cells, and amino-terminal protein sequence. Heregulin exists as multiple isoforms and all are presumed to interact directly with HER2 (refs 3-6). We have used binding and phosphorylation studies with recombinant ligand on cell lines expressing recombinant receptors, and report here that heregulin, like p45, is a specific ligand for HER4. Furthermore, heregulin fails to induce phosphorylation of HER2 in the absence of HER4. These findings suggest that activation of the HER4 receptor is involved in signal transduction by heregulin.
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PMID:Heregulin induces tyrosine phosphorylation of HER4/p180erbB4. 790 37

Four monoclonal antibodies (MAbs) specific for the extracellular domain of the human erbB-2/HER2 protein (FRP5, FSP16, FWP51 and FSP77) have been isolated (Harwerth et al., J. Biol. Chem., 267, 15160-15167, 1992). In this paper we describe the effects of erbB-2 specific MAb administration on the tumorigenic growth of human erbB-2 transformed NIH3T3 cells implanted into athymic nude mice. Two antibodies, FWP51 and FSP77, inhibited the onset of tumour growth, while the administration of FRP5 and FSP16 did not affect tumour growth. In addition, administration of MAbs FWP51 and FSP77 led to a retardation in the growth of established tumours. Treatment was not curative in that tumours regrew within two weeks of the final treatment. The administration of a combination of MAbs FWP51 and FSP77 which react with two distinct regions on the erbB-2 molecule was more effective than treatment with either MAb alone. The two growth-inhibitory antibodies were also effective in the treatment of tumours established from SKOV3 cells, a human ovarian tumour cell line with high levels of the erbB-2 protein. The effect of the MAbs on the anchorage-independent growth of erbB-2 transformed cells and on erbB-2 receptor turnover was also measured.
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PMID:Monoclonal antibodies directed to the erbB-2 receptor inhibit in vivo tumour cell growth. 790 53

SH2 domain proteins are important components of the signal transduction pathways activated by growth factor receptor tyrosine kinases. We have been cloning SH2 domain proteins by bacterial expression cloning using the tyrosine phosphorylated C-terminus of the epidermal growth factor receptor as a probe. One of these newly cloned SH2 domain proteins, GRB-7, was mapped on mouse chromosome 11 to a region which also contains the tyrosine kinase receptor, HER2/erbB-2. The analogous chromosomal locus in man is often amplified in human breast cancer leading to overexpression of HER2. We find that GRB-7 is amplified in concert with HER2 in several breast cancer cell lines and that GRB-7 is overexpressed in both cell lines and breast tumors. GRB-7, through its SH2 domain, binds tightly to HER2 such that a large fraction of the tyrosine phosphorylated HER2 in SKBR-3 cells is bound to GRB-7. GRB-7 can also bind tyrosine phosphorylated SHC, albeit at a lower affinity than GRB2 binds SHC. We also find that GRB-7 has a strong similarity over > 300 amino acids to a newly identified gene in Caenorhabditis elegans. This region of similarity, which lies outside the SH2 domain, also contains a pleckstrin homology domain. The presence of evolutionarily conserved domains indicates that GRB-7 is likely to perform a basic signaling function. The fact that GRB-7 and HER2 are both overexpressed and bound tightly together suggests that this basic signaling pathway is greatly amplified in certain breast cancers.
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PMID:The SH2 domain protein GRB-7 is co-amplified, overexpressed and in a tight complex with HER2 in breast cancer. 790 78

Transmembrane receptor tyrosine kinases that bind to peptide factors transmit essential growth and differentiation signals. A growing list of orphan receptors, of which some are oncogenic, holds the promise that many unknown ligands may be discovered by tracking the corresponding surface molecules. The neu gene (also called erbB-2 and HER-2) encodes such a receptor tyrosine kinase whose oncogenic potential is released in the developing rodent nervous system through a point mutation. Amplification and overexpression of neu are thought to contribute to malignancy of certain human adenocarcinomas. The search for soluble factors that interact with the Neu receptor led to the discovery of a 44 kDa glycoprotein that induces phenotypic differentiation of cultured mammary tumor cells to growth-arrested and milk-producing cells. The Neu differentiation factor (NDF or heregulin), however, also acts as a mitogen for epithelial, Schwann and glial cells. Multiple forms of the factor are produced by alternative splicing and their expression is confined predominantly to the central and to the peripheral nervous systems. One identified neuronal function of this family of polypeptides is to control the formation of neuromuscular junctions, but their physiological role in secretory epithelia is still unknown. Other open questions relate to the transmembrane topology of various precursors, the identity of a putative coreceptor, the possible existence of additional ligands of Neu and the functional significance of the interaction between Neu and at least three highly related receptor tyrosine kinases.
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PMID:Neu and its ligands: from an oncogene to neural factors. 790 91

Transformed cells, such as those found in breast cancer, often overexpress a variety of cell surface receptors and antigens. Antibodies or growth factors that specifically recognize these membrane-bound structures can be linked with protein toxins, resulting in cell-specific cytotoxic reagents. Many of these cytotoxic molecules have been produced and are referred to as oncotoxins, mitotoxins, or immunotoxins, depending on the components of the chimeric molecule. These bifunctional reagents are constructed as either chemical conjugates or fusion proteins between a ligand/antibody and a toxin. This report focuses on the use of cytotoxic proteins targeted to epidermal growth factor receptors, fibroblast growth factor receptors, erbB-2/HER-2, and tumor-associated carbohydrate antigens. Using immunotoxin therapy, total regression of established tumors in animal xenograft models have been demonstrated. These results suggest that immunotoxin molecules offer exciting opportunities for the treatment of human cancer.
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PMID:Targeted toxins as anticancer agents. 791 61


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