Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

p185c-neu and epidermal growth factor receptor (EGFR) associate into an active heterodimer, and overexpression of these two receptors leads to a transformed phenotype. However, the association of EGFR and kinase-deficient Neu proteins (point mutant N757 or cytoplasmic domain deletion mutant N691stop) results in a defective or inactive heterodimeric complex. In this report we explore the biological consequences of heterodimerization between EGFR and wild-type (WT) or kinase-deficient mutant Neu proteins in living cells. We show that co-expression of EGFR and kinase-deficient Neu proteins abolished the synergistic transformation and tumorigenicity. Moreover, the normal responses of EGFR to ligand were significantly suppressed, e.g., loss of EGF-dependent transformation, reduced rate of receptor endocytosis and turnover, diminished DNA synthesis, and decreased EGF binding affinity. These results provide the first evidence that kinase-deficient Neu proteins suppress normal EGFR function and display a dominant negative mutant phenotype. Together with the stimulatory effects observed in cells forming active heterodimers, these studies provide a role for heterodimerization of EGFR and Neu/c-erbB2 in interreceptor activation and synergistic signaling which may be responsible for the transition from normal receptor function into oncogenesis.
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PMID:Kinase-deficient neu proteins suppress epidermal growth factor receptor function and abolish cell transformation. 790 33

The epidermal growth factor receptor, EGFR, has been implicated in cell transformation in both mammalian and avian species. The v-ErbB oncoprotein is an oncogenic form of the chicken EGFR. The tyrosine kinase activity of this oncoprotein is required for transformation, but no transformation-specific cellular substrates have been described to date. Recently activation of the ras signal transduction pathway by the EGFR has been shown to involve the Shc and Grb2 proteins. In this communication, we demonstrate that the Shc proteins are phosphorylated on tyrosine residues and are complexed with Grb2 and the chicken EGFR following ligand activation of this receptor. In fibroblasts and erythroid cells transformed by the avian erythroblastosis virus (AEV) strains H and ES4, the Shc proteins are found to be constitutively phosphorylated on tyrosine residues. The tyrosine-phosphorylated forms of the AEV strain H v-ErbB protein are found in a complex with Shc and Grb2, but the Shc proteins do not bind to the AEV strain ES4 v-ErbB protein. Mutant forms of the v-ErbB protein (in which several of the tyrosines that become autophosphorylated have been deleted by truncation) are unable to transform erythroid cells but can still transform fibroblasts. Analysis of cells transformed by one of these mutants revealed that the truncated v-ErbB protein could no longer bind to either Shc or Grb2, but this oncoprotein still gave rise to tyrosine-phosphorylated Shc proteins that complexed with Grb2 and led to activation of mitogen-activated protein (MAP) kinase. The results suggest that stable binding of Grb2 and Shc to the v-ErbB protein is not necessary to activate this signal transduction pathway and assuming that the mutant activate MAP kinase in erythroid cells in a manner similar to that of fibroblasts, that activation of this pathway is not sufficient to transform erythroid cells.
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PMID:Analysis of the role of the Shc and Grb2 proteins in signal transduction by the v-ErbB protein. 790 55

The Neu proto-oncogene (also called ErbB-2 and HER-2) encodes a tyrosine kinase transmembrane receptor homologous to the epidermal growth factor receptor (EGF-R). Overexpression, a point-mutation, and co-expression with EGF-R activate the oncogenic potential of the Neu protein by permanent coupling to signal transducing pathways. The search for ligands that elevate tyrosine phosphorylation of Neu led to the discovery of a 44-kDa glycoprotein that acts either as a differentiation factor or as a mitogen for mammary tumor cells. This protein, termed Neu differentiation factor (NDF), is derived from a transmembrane precursor that contains an EGF-like motif and an immunoglobulin-like domain. Alternative splicing generates a dozen NDF-related proteins that are expressed in a variety of mesenchymal and neuronal tissues. This unprecedented multiplicity raises the possibility that different isoforms fulfill distinct biological roles.
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PMID:Neu differentiation factors: a family of alternatively spliced neuronal and mesenchymal factors. 791 39

A cell line, GBM, was established from a human malignant glioblastoma and was characterized with particular reference to its response to conventional drugs. The GBM cell line exhibited a 73 +/- 7 h doubling time in monolayer cultures. Expression of glial fibrillary acidic and S-100 proteins was observed. Karyotype analysis of GBM cells at early passages revealed the presence of two near-triploid clones (A and B) with multiple chromosome rearrangements; a 100% frequency for clone B was observed in the established cell line. GBM cells had tumorigenic properties, since the s.c. injection of cultured cells into nude mice gave rise to slowly growing tumors. The morphology of GBM cells was retained during in vitro and in vivo passages, as judged by light microscopy. GBM cells were relatively resistant to most conventional drugs; among the tested drugs, only taxol exhibited a marked cytotoxic effect comparable to that found in cells of a different tumor type. GBM cells were found positive for the epidermal growth factor receptor, HER2-neu and P-glycoprotein by flow cytometry of cells labelled with monoclonal antibodies. In spite of the expression of relatively high gamma-glutamyltransferase activity, the intracellular glutathione level was comparable to that of other chemosensitive tumor cells. This glioblastoma cell line is a suitable model for the identification and preclinical studies of new agents and provides an additional system to explore the molecular basis of the intrinsic drug resistance of glioblastoma.
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PMID:Characterization of an established human, malignant, glioblastoma cell line (GBM) and its response to conventional drugs. 792 29

A novel class of tyrosine kinase blockers represented by the tyrphostins AG1295 and AG1296 is described. These compounds inhibit selectively the platelet-derived growth factor (PDGF) receptor kinase and the PDGF-dependent DNA synthesis in Swiss 3T3 cells and in porcine aorta endothelial cells with 50% inhibitory concentrations below 5 and 1 microM, respectively. The PDGF receptor blockers have not effect on epidermal growth factor receptor autophosphorylation; weak effects on DNA synthesis stimulated by insulin, by epidermal growth factor, or by a combination of both; and over an order of magnitude weaker blocking effect on fibroblast growth factor-dependent DNA synthesis. AG1296 potently inhibits signaling of human PDGF alpha- and beta-receptors as well as of the related stem cell factor receptor (c-Kit) but has no effect on autophosphorylation of the vascular endothelial growth factor receptor KDR or on DNA synthesis induced by vascular endothelial growth factor in porcine aortic endothelial cells. Treatment by AG1296 reverses the transformed phenotype of sis-transfected NIH 3T3 cells but has no effect on src-transformed NIH 3T3 cells or on the activity of the kinase p60c-src(F527) immunoprecipitated from these cells. These potent and selective compounds represent leads for the development of novel agents to combat tumors driven by PDGF or to inhibit PDGF action in other diseases in which PDGF plays a key role, such as restenosis.
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PMID:Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation. 795 56

Current cancer chemotherapy treatments generally act by affecting rapidly growing malignant cells. Unfortunately, they are relatively nonspecific and thus have a tendency to affect other rapidly growing normal cells in a deleterious manner. Triplex-forming oligodeoxyribonucleotides (TFOs) promise to be a new class of sequence-specific DNA-binding drugs which will target malignancies at the transcriptional level. The formation of an intermolecular triplex (triple helix) has been shown to block the binding of transcription factors and repress transcription in genes such as c-myc and that encoding the epidermal growth factor receptor. The rat neu oncogene promoter contain promoter-enhancer elements which are purine/pyrimidine rich. These enhancer elements are amenable to targeting by TFOs. the human counterpart of rat neu, HER2, is often found to be amplified or overexpressed in a variety of malignancies, such as those of the breast, lungs, ovary, colon and stomach. TFOs may proved to be the basis of effective chemotherapy drugs for these cancers. TFO binding at the "GTG" element (5'GGTGGGGGGG) and at the 'GA' element (5'GGAGGAGGAGGG) has been characterized by gel mobility shift analysis and DNase 1 footprinting. Binding has been shown to occur at a Kd as low as 10(-8) M and has been shown to be sequence specific.
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PMID:Triplex formation at the rat neu oncogene promoter. 795 74

Amplifications of cellular oncogenes and growth factor genes have previously been reported in gliomas. Here we have evaluated 21 gliomas for amplification of tumor related genes including NMYC, EGFR, TGFalpha, MET, CMYC, SRC, HRAS, NRAS, SEC, ROS1, JUN, and WNT1. Five amplifications were observed. The epidermal growth factor receptor (EGFR) gene was amplified in 4 glioblastomas. The oncogene MET was amplified in a glioblastoma which showed no EGFR gene amplification. Importantly, both genes are located on chromosome 7 and belong to a family with tyrosine kinase activity. There was no amplification found for TGFalpha which was previously reported to be amplified in gliomas. The finding of MET and EGFR independently amplified in glioma lends further support to a crucial role of chromosome 7 in the development of gliomas.
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PMID:Two independent amplification events on chromosome 7 in glioma: amplification of the epidermal growth factor receptor gene and amplification of the oncogene MET. 801 63

A series of 63 3-substituted quinoline derivatives has been prepared and tested for inhibition of cell-free platelet derived growth factor receptor tyrosine kinase (PDGF-RTK) activity. The compounds were generally prepared either by a Friedlander condensation between an aryl-acetaldehyde and an o-aminobenzaldehyde or by a palladium-catalyzed coupling between an aryl bromide or triflate and an organostannane or organozinc chloride. The presence of 6,7-dimethoxy groups on the quinoline ring was found to be advantageous although not essential for potent inhibition of PDGF-RTK. A lipophilic group attached to the quinoline 3-position contributed substantially to activity. The lipophilic groups generally consisted of monocyclic aromatics or small alkynyl, alkenyl, and alkyl groups. Optimum activity of ca. < or = 20 nM (IC50) was observed when 6,7-dimethoxyquinoline was substituted in the 3-position with 4-methoxyphenyl (15d), 3-fluoro-4-methoxyphenyl (17m), 3-fluorophenyl (17b), 4-hydroxyphenyl (24), 6-methoxypyridin-3-yl (15o), 5-pyridin-2(1H)-one (23), trans-beta-styryl (15e), thiophene-3-yl (2e), 5-chlorothiophene-2-yl (15f), or cyclopentenyl (17n) groups. Most of the compounds in the series were tested for inhibition of cell-free epidermal growth factor receptor tyrosine kinase activity and found to be inactive.
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PMID:A new series of PDGF receptor tyrosine kinase inhibitors: 3-substituted quinoline derivatives. 803 19

Nine cases of malignant gliomas were selected for the presence of double minutes (dmin) or homogeneously staining regions (hsr) detected by conventional cytogenetics. Analyses were performed on fresh (2 cases) or xenografted (5 cases) tumors or both (2 cases). A modified comparative genomic hybridization technique (mCGH) was applied exhibiting a single amplified locus in 8 tumors and 4 amplified loci in one tumor. Recurrent sites of amplification were detected in 7p11-p12 (5 cases) and 1q32.1 (2 cases). Signals were also observed in 4q11-q12, 5p15.1, 7q31, 8q24.1 and 9p2 in one tumor each. Southern blotting demonstrated that the genes for EGFR (epidermal growth factor receptor), PDGFRA (platelet derived growth factor receptor alpha), MET and MYC oncogenes were involved in 7p11-p12, 4q11-q12, 7q31 and 8q24.1 amplifications, respectively. These amplifications were found by in situ hybridization on tumor spreads, in dmin or episomes for EGFR, dmin for PDGFRA and MET, and hsr and dmin for MYC genes. Other mCGH signals, for which no target genes could be proposed, were confirmed by chromosome paintings on tumor metaphases. In one of the tumors, the coamplification of DNA from 5p15.1 and 9p2 bands in the same dmin was demonstrated.
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PMID:Oncogene amplification in human gliomas: a molecular cytogenetic analysis. 805 36


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