Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neu proto-oncogene product, p185neu (HER2, c-ErbB-2), encodes a cell-surface tyrosine kinase receptor with high oncogenic potential, which correlates with increased tyrosine kinase activity and a rapid receptor internalization rate. To investigate the interactions and signal(s) leading to the endocytosis of Neu receptors, we employed lateral mobility and internalization studies. Fluorescence photobleaching recovery measurements revealed that activation of Neu receptors (induced by mutation or by agonistic antibodies) markedly reduced their mobile fractions. To elucidate the signals involved, other mutants, all carrying a constitutively dimerizing oncogenic mutation, were analyzed. A kinase-negative mutant and a mutant lacking all cytoplasmic tyrosine phosphorylation consensus sequences exhibited high mobile fractions, similar to nonactivated Neu. Retention of a single tyrosine autophosphorylation site (Tyr-1253) out of the five known such sites was sufficient to immobilize a large fraction of the receptor. For all mutants, internalization correlated with receptor immobilization and was blocked by treatments that interfere with coated pit structure, indicating that the immobilization is due to interactions with coated pits. This was supported by the coimmunoprecipitation of alpha-adaptin only with the constitutively activated Neu mutants. We conclude that activated Neu receptors become stably associated with coated pits via plasma membrane adaptor complexes (AP-2). Efficient Neu receptor endocytosis requires activation, a functional kinase domain, and at least one tyrosine autophosphorylation site.
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PMID:Roles for a cytoplasmic tyrosine and tyrosine kinase activity in the interactions of Neu receptors with coated pits. 770 44

The neu oncogene encodes a 185 kDa receptor tyrosine kinase. A single point mutation (Val664-->Glu) within the p185neu transmembrane region results in higher efficiency of receptor dimerization, constitutive activity of tyrosine kinase and cellular transformation. The oncogenic potential of this mutated form of p185neu (termed Tneu) can be inactivated by site-directed alteration of a lysine residue in the conserved catalytic domain. In this report, we have utilized the physical and functional interaction of a full-length kinase-deficient neu protein (T757) and truncated kinase-active Tneu forms to determine critical protein domains for Tneu oligomerization and the resultant biological consequences. Analysis of various truncated Tneu mutants confirmed that the transmembrane region was crucial for p185 dimerization. Receptor association facilitates intermolecular phosphorylation of kinase-deficient mutant T757 by truncated kinase-active p185 proteins, and the trans-phosphorylated kinase-deficient T757 was able to associate in vitro with proteins containing SH2 domains. Receptor-receptor interactions resulted in enhanced signal transduction potential and transformation of cell-lines co-expressing different neu-kinase forms. These studies emphasize a novel feature of protein-protein interaction and the functional significance of p185 dimerization, intermolecular phosphorylation and signaling which may result in cellular transformation.
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PMID:Intermolecular association and trans-phosphorylation of different neu-kinase forms permit SH2-dependent signaling and oncogenic transformation. 782 75

Structure and function of p185neu receptor tyrosine kinase were found to be regulated in a cell cycle-dependent manner. In M phase, p185neu is hyperphosphorylated at serine and/or threonine residues. The phosphotyrosine [Tyr(P)] content of p185neu is at its highest level in G0/G1 phase, decreases through S and G2 phases, and reaches its lowest level in M phase. Phospholipase C-gamma (PLC-gamma) and GTPase-activating protein (GAP), substrates of p185neu, also have a similar profile of Tyr(P) content during the cell cycle. These results, along with in vitro immune complex kinase assays, suggest that the tyrosine kinase activity of p185neu is least active in M phase. Interestingly, the mutation-activated neu oncogene (neu*)-encoded protein product, p185neu* escaped from cell cycle regulation. Taken together, we demonstrate in this report that the structure and function of p185neu are regulated in a cell cycle-dependent manner, yet p185neu* escapes from this regulation and remains active through the cell cycle. Disruption of this cell cycle regulation may define a mechanism for p185neu*-mediated cellular transformation.
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PMID:Cell cycle-dependent regulation of p185neu: a relationship between disruption of this regulation and transformation. 786 40

Growth factor receptors such as the epidermal growth factor receptor (EGFR) and the p185c-neu protein serve vital roles in the transduction of differentiation, developmental, or mitogenic signaling within normal cells. Two methods of analysis suggest that the inappropriately high expression of either protein tyrosine kinase promotes malignant transformation. First, data from in vitro experiments indicate that overexpression of either EGFR or p185c-neu (or the human homolog c-erbB-2) transforms cell-lines. Second, analysis of primary tumors and tumor cell-lines derived from many epithelial tissues (breast, stomach, ovary, and pancreas) show growth factor receptor gene amplification and elevated protein levels. The physical and functional interaction of p185c-neu and EGFR leads to the formation of a highly active, heterodimeric tyrosine kinase complex which synergistically activates cellular transformation. Anti-receptor antibodies have shown potential utility for the down modulation of these cell-surface proteins and suppression of the malignant phenotype. Design of organic antibody "mimetics" based on the structure of antireceptor antibodies may provide useful therapies and biological reagents to affect growth factor receptor function.
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PMID:Interaction of the neu/p185 and EGF receptor tyrosine kinases: implications for cellular transformation and tumor therapy. 790 Dec 29

Amplification and overexpression of the neu (c-erbB2) proto-oncogene has been implicated in the pathogenesis of 20 to 30% of human breast cancers. Although the activation of Neu receptor tyrosine kinase appears to be a pivotal step during mammary tumorigenesis, the mechanism by which Neu signals cell proliferation is unclear. Molecules bearing a domain shared by the c-Src proto-oncogene (Src homology 2) are thought to be involved in signal transduction from activated receptor tyrosine kinases such as Neu. To test whether c-Src was implicated in Neu-mediated signal transduction, we measured the activity of the c-Src tyrosine kinase in tissue extracts from either mammary tumors or adjacent mammary epithelium derived from transgenic mice expressing a mouse mammary tumor virus promoter/enhancer/unactivated neu fusion gene. The Neu-induced mammary tumors possessed six- to eightfold-higher c-Src kinase activity than the adjacent epithelium. The increase in c-Src tyrosine kinase activity was not due to an increase in the levels of c-Src but rather was a result of the elevation of its specific activity. Moreover, activation of c-Src was correlated with its ability to complex tyrosine-phosphorylated Neu both in vitro and in vivo. Together, these observations suggest that activation of the c-Src tyrosine kinase during mammary tumorigenesis may occur through a direct interaction with activated Neu.
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PMID:Mammary tumors expressing the neu proto-oncogene possess elevated c-Src tyrosine kinase activity. 790 21

RNA and DNA viruses can be transforming and tumourigenic agents. The transformation is a consequence of the ability of viruses to integrate into the host cell's DNA and to produce transforming proteins. These proteins are mainly produced by specific integral parts of the viral genome, the oncogenes. Comparison between RNA/DNA sequence of viral oncogenes and normal human genome of non-transformed cells revealed high sequence similarities in specific genomic areas, which were named cellular proto-oncogens. They are important components of the growth regulatory pathways in normal cells. The accumulation of genetic alterations of some proto-oncogens, like the erbB-family, may be part of the mechanism, by which malignant cells can acquire a selective growth advantage. The epidermal growth factor receptor (EGF-R, c-erbB1), Her-2/neu (c-erbB2), and c-erbB3 are members of the erbB-family. The detection of increased abundance of EGF-R or Her-2/neu proteins in human tumours can provide additional information on the disease-free survival and overall survival for patients with breast, ovarian, endometrial or cervical cancer. Molecular and cell-physiological analyses have improved the understanding of tumour biology and provide the opportunity for new therapeutic approaches. Monoclonal antibody targeted therapy directed against EGF-R or Her-2/neu, the use of anti-sense oligonucleotides and oligodeoxynucleotides, and the application of tyrosine kinase and protein C-kinase inhibitors are currently being investigated.
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PMID:[The erbB gene family: significance for tumor development, prognosis and new therapeutic modalities]. 790 70

One hundred and eighty thousand new cases of invasive breast cancer were diagnosed in 1992 within the United States. This disease affects approximately 1 out of 8 women in the US. Chemotherapy and/or hormonal therapy have shown some improved disease-free and/or overall survival rates. Unfortunately, this type of therapy is not directed specifically to the malignant cells, and systemic toxicities are observed. In order to develop site-specific treatment, the biology of the disease must be understood such that certain genes or their products which are involved in the pathogenesis of the disease can be targeted. Two structurally related tyrosine kinase growth factors, the epidermal growth factor receptor (EGFR) and c-erbB-2 (neu) have been identified in human breast cancer tissue and, in many instances, may function as oncogenes. The clinical data related to these two growth factor receptors as prognostic factors for the disease have been critically evaluated. Several problems with the critical studies were identified, and solutions were proposed to clarify the conflicting results reported in the studies which have attempted to examine whether c-erbB-2 (neu), in particular, is a prognostic indicator for breast cancer. In addition, data related to the structure of, ligands for and interaction between the proteins have been reviewed and presented with respect to their role in breast cancer development. A more thorough understanding of the genetic changes which contribute to the development of breast cancer will lead to more specific and less toxic treatment for this disease.
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PMID:neu(c-erbB-2/HER2) and the epidermal growth factor receptor (EGFR) in breast cancer. 790 69

The neu protooncogene (also known as c-erbB2, NGL, and HER2) encodes a 185-kDa transmembrane glycoprotein with intrinsic tyrosine kinase activity that resembles the receptor for epidermal growth factor. The p185 gene and protein were originally identified in the brain and are thought to play a critical role in neurogenesis. Aberrant c-erbB2 protein overexpression also occurs in several human adenocarcinomas. A ligand for p185, neu-activating factor (NAF), specifically binds to neu receptor and increases the p185c-neu tyrosine phosphorylation in vitro and in vivo in a dose-dependent manner. We now show that NAF specifically binds to purified p185 expressed in baculovirus. Direct binding analysis showed that NAF binds with high affinity (Kd = 1.3 nM). We have investigated changes in the structure and association state of baculovirus-produced neu holoreceptor that are induced by ligand binding. In this study, we used sucrose gradients to show that purified p185c-neu exists mainly in the monomeric form at low concentrations, whereas at higher concentrations p185c-neu exists as dimers or multimers. At low concentrations, but in the presence of ligand, p185c-neu sediments as a dimeric or multimeric form. Monomer-oligomer interconversion is absolutely ligand dependent at low receptor concentrations. The high molecular weight form of the receptor is enzymatically more active, as a consequence of ligand-driven activation of the receptor kinase. Oncogenic p185neu receptors sediment predominantly as high molecular weight forms and have constitutively active kinases.
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PMID:Ligand and p185c-neu density govern receptor interactions and tyrosine kinase activation. 790 21

Expression of rat oncogenic neu receptor, p185T-neu (a growth factor receptor with constitutive tyrosine kinase activity), causes cells to become transformed. Treatment with anti-neu receptor monoclonal antibodies reverts the transformed phenotype by down-modulation of p185T-neu. Monoclonal antibody treatment of cells expressing normal neu receptor, p185C-neu (which lacks constitutive tyrosine kinase activity), does not result in down-modulation of p185C-neu. To understand further the role the biochemical activity of p185T-neu plays in transformation and endocytosis, we created a series of mutations in p185T-neu. We found that fibroblasts expressing the tyrosine kinase-defective mutants cannot form foci in culture, colonies in soft agar, or tumors in immunocompromised mice. To follow the antibody-induced endocytosis of neu receptors expressed in these transfectants, we developed a novel two-color flow cytometric assay and confirmed receptor localization by electron microscopy. Cells were treated with mAb7.16.4 over time. After 4 hr of antibody treatment, less than 50% of full-length p185T-neu and of mutant T691 remained on the cell surface, whereas internal expression of the neu receptors within these cells initially increased and then decreased to the original internal receptor level. In contrast, the level of kinase-deficient mutated neu receptors remaining on the cell surface initially decreased by 35%, but, after 4 hr of antibody treatment, the cell surface expression level returned to approximately the original level. Concurrently, fluctuations in expression levels were seen internally over time as well. These cell lines were also treated with gold-conjugated mAb7.16.4. Using electron microscopy, we consistently found the gold particles within multivesicular bodies of cell lines expressing full-length or mutated neu receptor. These data strongly suggest that the fate of the neu receptor, once internalized, is directed by its tyrosine kinase activity. When the kinase activity of the neu receptor is disrupted, the receptor is internalized but recycled to the cell surface, whereas neu receptors which have constitutive kinase activity are internalized and presumably degraded when engaged with anti-neu receptor mAb. Understanding the regulation of receptor endocytosis, degradation, and recycling will contribute to the development of novel therapeutic protocols to combat human malignancies, particularly those associated with the overexpression of the human homologue of the neu receptor, c-erbB2.
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PMID:Demonstration by two-color flow cytometry that tyrosine kinase activity is required for down-modulation of the oncogenic neu receptor. 791 24

While some tumor cells are sensitive to the antiproliferative effects of tumor necrosis factor (TNF), others are resistant. The molecular basis for cellular resistance to TNF is not completely understood. Previously we have shown that transfection of cells with an oncogene HER2/neu/erb B2, a receptor tyrosine kinase, leads to resistance to the anticellular effects of TNF [(1988) Proc. Natl. Acad. Sci. USA 85, 5102-5106]. In the present study, we demonstrate that the overexpression of another oncogenic tyrosine kinase, pp60v-src also induces resistance to TNF. In contrast to HER2, however, pp60v-src transfection of cells did not lead to down-modulation of TNF receptors but rather to decreased intracellular glutathione levels. The pp60v-src-induced cellular resistance to TNF could be abrogated by interferon-gamma. Thus, these results indicate that the resistance of certain tumors to TNF may also be due in part to the overexpression of pp60v-src oncogene.
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PMID:pp60v-src kinase overexpression leads to cellular resistance to the antiproliferative effects of tumor necrosis factor. 791 Oct 89


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