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 protooncogene encodes a tyrosine kinase receptor that is involved in the regulation of normal growth and malignant transformation. To circumvent the use of the incompletely characterized ligand of Neu, we constructed a chimeric protein composed of the ligand-binding domain of the epidermal growth factor receptor and the transmembrane and cytoplasmic portions of Neu. By expressing this Neu-epidermal growth factor receptor chimera (termed NEC), we found that following stimulation by the heterologous ligand, the tyrosine kinase of Neu became associated with a phosphatidylinositol (PI) kinase activity. The association was dependent on the concentration of the ligand and was almost maximal within 30 s after ligand binding. The lipid kinase was identified as a type I PI 3'-kinase on the basis of its inhibition by Nonidet P-40 and high pressure liquid chromatography of the phosphorylated product. To confirm the identification of PI 3'-kinase as an effector of Neu, we raised antibodies to the alpha-isoform of the regulatory subunit of PI 3'-kinase (p85). Using these antibodies, it was possible to directly demonstrate ligand-dependent formation of a tyrosine-phosphorylated complex of NEC and PI 3'-kinase. Apparently, both PI 3'-kinase and phospholipase C gamma, another substrate of the Neu kinase, simultaneously associated with the same activated NEC molecule. Nevertheless, immunofluorescence localization of PI 3'-kinase revealed no significant cellular redistribution of the enzyme after activation of the Neu kinase. Interestingly, PI 3'-kinase was localized primarily to the cell nucleus and to confined regions of the plasma membrane. Analysis of mutants of the Neu protein indicated that the oncogenic point-mutated Neu (Glu664) was permanently coupled to PI 3'-kinase; but two nontransforming versions of the oncoprotein, a kinase-defective protein and a carboxyl-terminally deleted Neu, were devoid of the constitutive association with PI 3'-kinase. Hence, we concluded that phosphatidylinositol 3'-kinase is a physiological substrate of the Neu receptor, but the regulation of this coupling is released upon oncogenic activation.
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PMID:Regulated coupling of the Neu receptor to phosphatidylinositol 3'-kinase and its release by oncogenic activation. 135 Oct 56

Explants of synovial cells in rheumatoid arthritis display a transformed phenotype with focus formation and anchorage-independent growth. Many of the cytokines that activate these fibroblasts mediate their action through tyrosine kinase growth factor receptors. Mechanisms of signal transduction via such tyrosine kinases are therefore relevant to the pathogenesis of rheumatoid lesions. Data are presented using the neu oncogene product p185neu as a model system to explore signal transduction by receptor tyrosine kinases. Evidence is shown that increased tyrosine kinase activity in the oncogenic form of this protein may result from dimerization of the tyrosine kinase receptor. In the normal cellular counterpart of p185neu, dimerization appears to be mediated by the action of an as yet unidentified ligand. Dimerization also appears to be important in signal transduction mediated by epidermal growth factor, platelet-derived growth factor, and colony-stimulating factor 1. These cytokines also alter the phenotype of rheumatoid synovial fibroblasts to resemble transformed fibroblasts. Additionally, preliminary data that suggest increased tyrosine kinase activity in rheumatoid arthritis synovia compared with osteoarthritis synovia are presented. Molecular characterization of tyrosine kinase receptors will be an important direction for future studies of the pathogenesis of rheumatoid disease.
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PMID:Tyrosine kinase signal transduction in rheumatoid synovitis. 135 18

The neu oncogene product, p185neu, is a tyrosine kinase receptor with structural similarity to the epidermal growth factor (EGF) receptor. We have recently described that coexpression of EGF receptors and high levels of normal p185c-neu lead to transformation of rodent fibroblasts. Anti-EGF receptor and anti-p185neu monoclonal antibodies inhibited tumorigenic growth of these transformants implanted into nude mice. These monoclonal antibodies also suppressed focus formation of the cells transformed by the synergistic action of these receptor proteins in vitro. However, EGF enhanced focus formation and stimulated cell growth when added to cells transfected just with the EGF receptor encoding cDNA. These data suggest that receptor specific effectors may have potentially useful applications in cancer therapy for neoplasms which demonstrate increased receptor densities. In addition the data suggest novel differences in the actions of tyrosine kinases when acting alone or in concert with other receptors.
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PMID:Anti-receptor antibodies reverse the phenotype of cells transformed by two interacting proto-oncogene encoded receptor proteins. 197 Jan 51

p185neu, the protein product of the neu gene, is a tyrosine kinase receptor with structural similarity to the epidermal growth factor (EGF) receptor. The cognate ligand for the p185neu receptor remains unknown. We have defined: 1) stage and tissue-specific expression patterns of the neu gene product in developing tissues; 2) p185neu phosphorylation and the regulation of p185neu tyrosine kinase activity by EGF. 3) Synergistic interactions of cellular rat p185neu and EGF receptor leading to cell transformation; 4) structural and functional differences of normal and oncogenic p185neu. These observations explain some features of how p185neu is involved in normal development and neoplastic transformation.
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PMID:The role of the neu oncogene product in cell transformation and normal development. 290 55

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

Overexpression of human-specific c-neu proto-oncogene transmembrane tyrosine kinase receptor protein (p185) is an index of cell transformation and of poor patient survival in several malignancies. The authors studied this protein in low- and high-grade human malignant astrocytomas before and after xenografting into aspiration pockets in rat cortex. Human-specific p185c-neu-positive cells were found in tumor specimens from all grades of astrocytoma. Significantly fewer p185c-neu-positive cells were observed in the low-grade versus the high-grade astrocytomas examined (p < 0.05). Human specific p185c-neu-positive cells were also positive for the human major histocompatibility complex, human leukocyte antigen (HLA)-DR, as well as glial fibrillary acidic protein and S-100 protein. Fresh suspensions of tumor tissue were prelabeled with the plant lectin Phaseolus vulgaris leukoagglutinin and xenografted into pockets in rat cortex. A class of human p185c-neu-positive cells found in tissue samples from all grades of astrocytoma migrated in the rat brain along parallel and intersecting nerve fibre bundles and basement membrane-lined surfaces. Migrated p185c-neu-positive cells were also positive for HLA-DR, Phaseolus vulgaris leukoagglutinin, glial fibrillary acidic protein, and S-100 protein, suggesting that they were in fact human astrocytoma cells. Simultaneous expression of human p185c-neu, HLA-DR, and glial fibrillary acidic protein was observed in a class of human malignant astrocytoma cells in both tumor tissue and xenografted cells that migrated into rat brain. These molecules are signature proteins for the study of the spread of human malignant astrocytomas in an animal model, and indicate that transformed human malignant astrocytoma cells can migrate within the parenchyma of the central nervous system and could play a role in the development of multifocal tumors.
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PMID:Human-specific c-neu proto-oncogene protein overexpression in human malignant astrocytomas before and after xenografting. 809 25

HER2/neu, a Mr 185,000 tyrosine kinase receptor that is overexpressed in breast cancer, undergoes proteolytic cleavage of its extracellular domain (ECD). In contrast with other membrane-bound proteins, including growth factor receptors, that are cleaved by a common machinery system, we show that HER2 cleavage is a slow process and is not activated by protein kinase C. Pervanadate, a general inhibitor of protein-tyrosine phosphatases, induces a rapid and potent shedding of HER2 ECD. The shedding of HER2 ECD is inhibited by the broad-spectrum metalloprotease inhibitors EDTA, TAPI-2, and batimastat. The tissue inhibitor of metalloproteases-1; an inhibitor of matrix metalloproteases that does not inhibit cleavage by the general protein kinase C-dependent shedding machinery, also inhibited HER2 ECD shedding, whereas tissue inhibitor of metalloproteases-2 did not. These data suggest that HER2 cleavage is a process regulated by an as-yet-unidentified distinct protease.
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PMID:Cleavage of the HER2 ectodomain is a pervanadate-activable process that is inhibited by the tissue inhibitor of metalloproteases-1 in breast cancer cells. 1009 47

The neu (c-erbB-2) proto-oncogene encodes a tyrosine kinase receptor that is overexpressed in 20 to 30% of human breast tumors. Herein, cyclin D1 protein levels were increased in mammary tumors induced by overexpression of wild-type Neu or activating mutants of Neu in transgenic mice and in MCF7 cells overexpressing transforming Neu. Analyses of 12 Neu mutants in MCF7 cells indicated important roles for specific C-terminal autophosphorylation sites and the extracellular domain in cyclin D1 promoter activation. Induction of cyclin D1 by NeuT involved Ras, Rac, Rho, extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38, but not phosphatidylinositol 3-kinase. NeuT induction of the cyclin D1 promoter required the E2F and Sp1 DNA binding sites and was inhibited by dominant negative E2F-1 or DP-1. Neu-induced transformation was inhibited by a cyclin D1 antisense or dominant negative E2F-1 construct in Rat-1 cells. Growth of NeuT-transformed mammary adenocarcinoma cells in nude mice was blocked by the cyclin D1 antisense construct. These results demonstrate that E2F-1 mediates a Neu-signaling cascade to cyclin D1 and identify cyclin D1 as a critical downstream target of neu-induced transformation.
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PMID:Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. 1061 Dec 46

Trk immunoreactivity is expressed by a discrete population of cortical neurons, primarily those with cell bodies in layer Vb and dendrites in supragranular cortex. We tested the hypothesis that neurons co-express multiple isoforms of trk receptors. The distribution of neurons expressing specific high affinity neurotrophin receptors was determined immunohistochemically. Multiple antibodies directed against each trk isoform and an antibody directed against an epitope shared by all three trk isoforms were used. The distribution of neurons expressing each of the three receptors was virtually identical. Each anti-trk antibody primarily labeled neurons with cell bodies in layer V. More than one-third of layer V neurons was positive for a high affinity trk receptor. Few immunoreactive somata (1%-5%) were in the other layers. In addition, the neuropil in the supragranular laminae was immunopositive for each trk isoform. Recent data show that layer V neurons in the mature somatosensory cortex express the tyrosine kinase receptor c-erbB2, also known as c-neu. Immunofluorescence double labeling shows that approximately 80% of the c-neu-immunolabeled neurons in layer V co-expressed pan-trk immunoreactivity and two-thirds of all c-neu-positive neurons expressed a specific trk isoform. We concluded from these data that there is significant co-expression of trk isoforms in layer V neurons. In summary, trkA, trkB, trkC, and c-neu were primarily expressed by cortical projection neurons in layer V and co-expression among these receptors was common. This implies that cortical growth factor systems are redundant and that cortical neurons are responsive to more than one growth factor.
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PMID:Neurotrophin receptors in the somatosensory cortex of the mature rat: co-localization of p75, trk, isoforms and c-neu. 1067 63

High quality purification of membrane-spanning peptides and proteins remains a challenging problem. In this work we describe a tailored chromatographic purification of a synthetic 35-residue peptide corresponding to the transmembrane region of the tyrosine kinase receptor c-erb2/neu. Composed to over 70% by the amino acids alanine, isoleucine, leucine, phenylalanine and valine, this peptide presents a very hydrophobic character. Product isolation from the complex peptide mixture, obtained after acid cleavage of the resin matrix used during the solid-phase synthesis, represents a difficult task. We propose a three step strategy based on gel permeation and reversed-phase high-performance liquid chromatography, using aprotic polar solvent mixtures. The challenge consisted in obtaining a sufficient amount of an extremely pure sample, in order to allow structural analysis by NMR spectroscopy. Keeping trace of the synthetic peptide throughout the different purification steps was assured by MALDI TOF mass spectrometry, and the final product purity was checked by coupled liquid chromatography-ESI TOF mass spectrometry.
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PMID:Purification of the c-erbB2/neu membrane-spanning segment: a hydrophobic challenge. 1068 Oct 41


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