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 MCF-7 cell line is a hormone-responsive human breast-cancer cell line, which has been extensively used in studies of estrogen regulation of cell growth. These studies have indicated that the growth stimulation of the MCF-7 cells by estrogens may be effected by an autocrine mechanism involving several growth factors, such as EGF, TGF alpha and IGF-I and their receptors. We have amplified and cloned tyrosine-kinase-related sequences from the MCF-7 cell mRNA using the polymerase chain reaction and characterized the partial cDNAs obtained by nucleic acid sequencing. Nine tyrosine kinase cDNAs and one serine/threonine kinase cDNA were identified among the amplified sequences. Four different tyrosine kinase genes encoding receptors for fibroblast growth factors (FGFs) were found to be expressed by the MCF-7 cells. In addition, differences were observed in the expression of these members of FGF receptor family in different breast-cancer cells. A putative tyrosine-kinase receptor and a novel serine/threonine kinase were preferentially expressed in estrogen-responsive tumor cell lines. However, no estrogen-dependent regulation of any of the novel tyrosine-kinase receptor mRNAs was found in any of the cell lines including the MCF-7 or ZR-75-I cells, where the expression of the neu proto-oncogene mRNA was decreased during estrogen treatment. The expression of several FGF receptors by breast-cancer cells suggests that FGFs may be involved in their growth regulation and tumorigenesis.
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PMID:Analysis of tyrosine kinase mRNAs including four FGF receptor mRNAs expressed in MCF-7 breast-cancer cells. 131 Dec 87

Many oncogenes encode proteins with a tyrosine kinase activity that appears to be directly involved in the process of transformation. Because these kinases are themselves activated for transformation by tyrosine phosphorylation, proteins which remove phosphate from tyrosine residues, protein tyrosine phosphatases (also termed phosphotyrosine phosphatases and protein phosphotyrosyl phosphatases), are intuitive candidate transformation suppressors. The human PTP1B gene, previously cloned in our laboratory and encoding the low molecular weight protein tyrosine phosphatase PTPase 1B, was introduced into NIH 3T3 cells. Subsequent transformation of these PTPase 1B-expressing cells by an oncogenic form of the human neu gene was suppressed relative to control NIH 3T3 cells. This suppression of transformation was observed in assays for focus formation, anchorage-independent growth, and tumorigenicity. Tumorigenicity assays indicated a complex effect of PTPase 1B expression on transformation.
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PMID:Effect of protein tyrosine phosphatase 1B expression on transformation by the human neu oncogene. 134 14

The neu proto-oncogene may be converted into a dominantly transforming oncogene by a single point mutation. Substitution of a valine residue at position 664 in the transmembrane region with glutamic acid activates the tyrosine kinase of the molecule and is associated with increased receptor dimerization. Previously we have proposed a model in which the glutamic acid side chain stabilizes receptor dimerization by hydrogen bonding. Other models have been proposed in which the mutation leads to a conformational change in the transmembrane region mimicking that assumed to occur following binding of a natural ligand. Synthetic peptides representing part of the transmembrane region were prepared. Some residues were replaced with serine in order to improve peptide solubility to allow purification and analysis. Both the peptides containing valine and glutamic acid dissolved in water and in an artificial lipid monolayer. The structures of the peptides were determined by NMR spectroscopy to be alpha-helical. No significant difference in conformation was observed between the two peptides. This result does not support the model proposing a conformational change. The receptor structures determined experimentally do allow alternative models involving receptor transmembrane region packing.
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PMID:Three dimensional structure of the transmembrane region of the proto-oncogenic and oncogenic forms of the neu protein. 134 63

The neu proto-oncogene encodes a protein highly homologous to the epidermal growth factor receptor. The neu protein (p185) has a molecular weight of 185,000 Daltons and, like the EGF receptor, possesses tyrosine kinase activity. neu is activated in chemically induced rat neuro/glioblastomas by substitution of valine 664 with glutamic acid within the transmembrane domain. The activated neu* protein (p185*) has an elevated tyrosine kinase activity and a higher propensity to dimerize, but the mechanism of this activation is still unknown. We have used site-directed mutagenesis to explore the role of specific amino acids within the transmembrane domain in this activation. We found that the lateral position and rotational orientation of the glutamic acid in the transmembrane domain does not correlate with transformation. However, the primary structure in the vicinity of Glu664 plays a significant role in this activation. Our results suggest that the Glu664 activation involves highly specific interactions in the transmembrane domain of p185.
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PMID:A subdomain in the transmembrane domain is necessary for p185neu* activation. 134 45

Ligand-induced dimerization of growth factor receptors is crucial for stimulation of their intrinsic protein tyrosine kinase activity promoting receptor autophosphorylation by an intermolecular mechanism. Moreover, the suppressive and negative dominant action of defective epidermal growth factor receptor (EGFR) was shown to be caused by formation of inactive heterodimers with normal EGFR leading to diminished biological signaling. In this report we explore the structural requirements and functional significance of heterodimerization between EGFR and HER2. HER2 (also called c-erbB-2 or neu) is a member of the EGFR family whose natural ligand is still unknown. We show that in response to EGF, wild type EGFR and various EGFR mutants were able to undergo heterodimerization with HER2. Addition of EGF to transfected cells co-expressing HER2 with a kinase negative point mutant of EGFR (K721A) stimulated heterodimer formation, tyrosine phosphorylation of K721A and HER2, and tyrosine phosphorylation of one of their known substrates, phospholipase C gamma. However, the binding of EGF to transfected cells co-expressing HER2 together with another EGFR mutant CD533 (a deletion mutant lacking most of the cytoplasmic domain of EGFR) caused heterodimerization and inhibition of tyrosine kinase activity. It appears therefore that EGF-induced heterodimerization of EGFR and HER2 can promote either stimulatory or inhibitory influences on kinase activity. We propose that the nature of receptor interactions on the cell surface can either activate or inhibit the initiation of growth factor-controlled cellular signaling.
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PMID:Heterodimerization of c-erbB2 with different epidermal growth factor receptor mutants elicits stimulatory or inhibitory responses. 134 15

The c-erbB-2/neu gene encodes a transmembrane protein of 185 kDa (p185) with tyrosine kinase activity and extensive sequence homology to epidermal growth factor receptor. Amplification and overexpression of the c-erbB-2/neu gene has been shown in certain human tumors and is postulated to be important in human carcinogenesis. High levels of expression of the c-erbB-2/neu gene have been reported in non-small-cell lung cancer (NSCLC) cell lines and primary tumors from the United States. Since geographical and cultural factors may contribute to the development of certain types of cancer, we examined p185 examined p185 expression in 120 tumors from Chinese patients with lung cancers of different cell types and used immunohistochemical staining to determine the extent and general significance of p185 expression in human primary lung cancer. Our results demonstrate that 58.8% of the NSCLCs expressed p185 and that expression of p185 was observed only in NSCLC and not in small-cell lung cancers. Thirty-three of 41 adenocarcinomas and 24 of 55 squamous cell carcinomas among the NSCLCs examined were found to express p185 at levels different from those of normal lung. For the squamous cell carcinomas, p185 expression was correlated with lymph node metastasis (P less than 0.01), but for the adenocarcinomas, it was not (P greater than 0.05). In addition, expression of p185 in NSCLC was significantly more frequent in patients in advanced clinical stages. Our findings indicate that p185 expression is a frequent event and a general phenomenon in NSCLC and is correlated with poor clinical prognostic indicators, suggesting that expression of p185 may be of potential prognostic importance in NSCLC.
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PMID:Overexpression of the c-erbB-2/neu-encoded p185 protein in primary lung cancer. 135 Jan 98

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

In this work, we have used Xenopus oocyte maturation as a read-out for examining the ability of the neu tyrosine kinase (p185neu) to participate with the epidermal growth factor (EGF) receptor in a common signal transduction pathway. We find that unlike the case for the EGF receptor, which elicits EGF-dependent maturation of these oocytes as reflected by their germinal vesicle breakdown (GVBD), neither the normal neu tyrosine kinase (p185val664) nor the oncogenic form of neu (p185glu664) are able to effectively trigger this maturation event. However, expression of p185glu664 causes a specific and significant promotion of the progesterone-induced GVBD, reducing the half-time for this maturation even from approximately 9 h to approximately 5 h. Stimulation of the progesterone-induced GVBD did not occur following the expression of a kinase-deficient p185neu protein (in which a lysine residue at position 758 was changed to alanine). Essentially identical results were obtained when the mRNAs coding for fusion proteins comprised of the extracellular domain of the receptor for immunoglobulin E (IgE), and the membrane-spanning and tyrosine kinase domains of normal or oncogenic p185neu (designated IgER/p185val664 and IgER/p185glu664, respectively), were injected into oocytes. Antigen-induced crosslinking of IgER/p185val164 proteins expressed in oocytes caused a reduction in the half-time for the progesterone-stimulated GVBD from approximately 9 h to approximately 7 h. Thus, the aggregation of the membrane-spanning and/or tyrosine kinase domains of p185val664 partially mimics the effects of the oncogenic forms of p185neu. Overall, the results of these studies suggest that the activation of the p185neu tyrosine kinase by a point mutation within its membrane-spanning helix, or an aggregation event, can result in the facilitation of oocyte maturation events that are elicited by other factors (e.g. progesterone). However, the activated p185neu tyrosine kinases are not able to mimic the EGF-stimulated EGF receptor tyrosine kinase in triggering oocyte maturation, which suggests that the EGF receptor and the p185neu tyrosine kinase do not input into identical signal transduction pathways in these cells.
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PMID:The effects of the normal and oncogenic forms of the neu tyrosine kinase, and the corresponding forms of an immunoglobulin E receptor/neu tyrosine kinase fusion protein, on Xenopus oocyte maturation. 135 69

To examine the role of the transmembrane domain (TM) of the insulin receptor in insulin-induced receptor kinase activation, we prepared four mutated insulin receptors: 1) a Val938----Asp substitution (IR/TMv----D), 2) insertion of a 3-amino acid repeat (Val938-Phe939-Leu940) (IR/TM+3), or the entire TM was replaced by the corresponding domain of either the 3) platelet-derived growth factor (PDGF) receptor (IR/TMPDGFR) or 4) c-neu/erbB2 proto-oncogene product (IR/TMc-neu). Each mutant receptor was stably expressed in Chinese hamster ovary cells, assessed by fluorescence-activated cell sorting, insulin binding, and biosynthetic labeling. All mutant receptors exhibited normal affinity for insulin. Pulse-chase experiments showed that each proreceptor was processed into alpha- and beta-subunits, although the rate of IR/TMV----D conversion was reduced approximately 3-fold. With IR/TMPDGFR, IR/TMV----D, and IR/TM+3 basal and insulin-stimulated levels of autophosphorylation and tyrosine kinase activation were normal, both in wheat germ agglutinin (WGA)-purified receptor preparations and intact cells. By contrast, following WGA purification or isolation of crude membranes, IR/TMc-neu was a constitutively active autokinase and substrate kinase in vitro. However, in intact cells insulin-stimulated autophosphorylation and kinase activity appeared normal. We conclude that although there is considerable latitude in acceptable structure, residues within the insulin receptor transmembrane domain can play a functional role in regulation of insulin receptor tyrosine kinase activity.
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PMID:Substitution of the insulin receptor transmembrane domain with the c-neu/erbB2 transmembrane domain constitutively activates the insulin receptor kinase in vitro. 135 86


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