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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)

There is a critical need for new targets, in addition to DNA, for anticancer drug development. A recently discovered target is the intracellular signalling pathways that mediate the actions of growth factors and oncogenes on cell proliferation. Two important pathways, the myo-inositol and protein tyrosine kinase signalling pathways are reviewed. Three classes of compounds that modulate myo-inositol signalling are discussed. These are: 1) the D-3-substituted-3-deoxy-myo-inositol analogues that act as antimetabolites of myo-inositol and show selective growth inhibition of some transformed cells; 2) the alkaloid staurosporine that acts as a potent inhibitor of protein kinase C and of platelet-derived growth factor (PDGF) receptor protein tyrosine kinase activity; 3) the ether lipid analogues that block growth factor signalling at several points by acting as inhibitors of protein kinase C, phosphoinositide specific phospholipase C and inositol(1,4,5)trisphosphate-induced Ca2+ release. It is suggested that inhibition of signalling pathways may explain the growth inhibitory effects of these compounds. Other potential signalling target sites for anticancer drug development are discussed.
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PMID:Growth factor and oncogene signalling pathways as targets for rational anticancer drug development. 176 Aug 77

Several steps implicated in platelet-derived growth factor (PDGF) receptor-coupled signaling are activated by PDGF exposure at 0-4 degrees C. These include receptor self-phosphorylation, physical association with and phosphorylation of phospholipase C gamma (PLC gamma). Reduced temperature blocks PDGF internalization, making it possible to dissociate bound PDGF after PLC gamma tyrosine phosphorylation. We addressed the functional consequences of PDGF dissociation from intact cell PDGF receptors. PDGF exposure at 0-4 degrees C for 15 min stimulated self-phosphorylation of a subpopulation of BALB/c 3T3 cell PDGF beta-type receptors (35%) and initiated subsequent inositol phosphate production. A small fraction of cellular PLC gamma (1-3%) coprecipitated with ligand-activated PDGF receptors; 3-5% of cellular PLC gamma acquired phosphotyrosine. The PLC gamma coprecipitating with PDGF receptors did not contain detectible phosphotyrosine. Phosphotyrosine antibody recovered similar amounts of PLC gamma from soluble and particulate fractions of PDGF-stimulated cells. Acid dissociation of bound PDGF from receptor caused rapid dephosphorylation of PDGF receptors and PCL gamma, and interrupted PLC gamma-PDGF receptor coprecipitation. Orthovanadate blocked tyrosine dephosphorylation of both PDGF receptors and PLC gamma and stabilized coprecipitation. Orthovanadate reversed the acid wash effect to abrogate PDGF-stimulated inositol phosphate production. PDGF receptor remains competent to coprecipitate with PLC gamma and stimulate PLC-mediated inositol phosphate production if PDGF-induced receptor phosphorylation is maintained. Formation of a coprecipitable PDGF receptor-PLC gamma complex appears required for PDGF-stimulated inositol phosphate production.
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PMID:Phospholipase C gamma complexes with ligand-activated platelet-derived growth factor receptors. An intermediate implicated in phospholipase activation. 184 94

For the determination of LDL receptor expression on living human cells two monoclonal antibodies specific for the extracellular domain of LDL receptor were established using affinity-purified LDL receptor and carrier-conjugated LDL receptor peptide 163-174 as immunizing antigens. The 125I-labeled antibodies were used to quantify increases in LDL receptor expression on human cells grown in the presence of increasing concentrations of various growth factors. Growth factor-mediated increase of LDL receptor expression was entirely different in various cell lines with respect to a distinct growth factor and for different growth factors when tested with one and the same cell line. An increased LDL receptor expression was observed on A431 epidermoid carcinoma cells of the vulva in the presence of epidermal growth factor (EGF) or insulin but not with platelet-derived growth factor (PDGF), on HUV-EC primary endothelial cells in the presence of insulin or PDGF but not with EGF, and on MRC-5 diploid fetal lung cells only in the presence of PDGF. HEP-3B hepatoma cells did not respond to any of the three growth factors essentially maintaining the original level of LDL receptor expression.
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PMID:Expression of LDL receptor on tumor cells induced by growth factors. 185 Feb 20

It is known that the receptor for platelet-derived growth factor (PDGF) activates phospholipase C (PLC) by phosphorylating the gamma 1 isoform of PLC with the receptor protein-tyrosine kinase (PTK), whereas a guanine nucleotide-binding protein participates as a transducer in the PLC activation through the receptors for vasopressin, bombesin and prostaglandin F2 alpha (PGF2 alpha). We have shown in a rat fibroblast line that staurosporine is a potent PTK inhibitor capable of clearly discriminating the two types of receptor-stimulated Ca2+ mobilization and, by inference, PLC activations the response triggered by PDGF was completely inhibited, whereas the responses triggered by vasopressin, bombesin and PGF2 alpha were not affected at all. The Ca2+ mobilization in human T and B cell lines induced by anti-CD3 and anti-immunoglobulins (Ig) was completely suppressed by staurosporine. The results indicate that the PTK activity plays an essential role in the PLC activation through the T cell receptor/CD3 complex and through membrane Ig.
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PMID:Suppression by staurosporine of Ca(2+)-mobilization triggered by ligation of antigen-specific receptors on t and B lymphocytes. An essential role of protein tyrosine kinase in the signal transduction. 187 63

The neu proto-oncogene product has been found to exist in two interconvertible forms in G8/DHFR mouse fibroblasts. The 185-kilodalton form (p185) present in growing cells is replaced by a 175-kilodalton form (p175) under conditions of serum starvation. This low molecular weight form accounts almost exclusively for the phosphotyrosine content of the receptor and is associated with increased tyrosine kinase activity. Addition of serum, platelet-derived growth factor or tumor promoter induces conversion of p175 to p185 within minutes, and this increase in molecular weight is associated with phosphorylation of serine and threonine; removal of serum growth factors is followed by replacement of p185 with p175 over several hours. Unlike G8/DHFR cells, the human breast cancer cell line SK-Br-3 expresses a high molecular weight neu/HER2 receptor with unchanged phosphotyrosine content in both serum-starved and serum-stimulated cultures. These findings indicate that activation of the neu proto-oncogene product in G8/DHFR cells may be regulated in part by protein kinase C-mediated receptor transmodulation rather than by ligand availability alone.
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PMID:Modulation of a Mr 175,000 c-neu receptor isoform in G8/DHFR cells by serum starvation. 197 80

Human esophageal and gastric carcinomas express multi-autocrine growth factors and hormones including epidermal growth factor (EGF), transforming growth factor (TGF)-alpha and beta, platelet-derived growth factor (PDGF), insulin-like growth factor (IGF) and sex hormones. Overexpression of EGF, TGF-alpha and EGF receptor (EGFR) by tumor cells is closely correlated with the tumor invasion and patient prognosis. This is substantiated by the facts that EGF and TGF-alpha act as autocrine growth factors and then induce the expression of mRNAs for multi-growth factors and their receptors (EGF, TGF-alpha, EGFR, ERBB2, PDGF). Moreover, they stimulate the expression of metalloproteinase genes suggesting that EGF and TGF-alpha successively evoke cascade phenomena which are most convenient for tumor progression, invasion and metastasis. On the other hand, multiple oncogene alterations take place in the process of tumor progression. HST-1 and INT-2 genes which is a member of fibroblast growth factor gene family, are amplified in approximately 50% of primary tumors and all the metastatic tumors of esophageal carcinomas. The amplification of ERBB2 gene in metastatic gastric carcinomas is detected more frequently than in primary carcinomas. Overexpression of multi-growth factor-receptor systems might lead to genetical alterations. Scirrhous gastric carcinoma has vast fibrous stroma with rapid and extensive growth and exhibits high malignancy. Its fibrous stroma may account for synchronous overexpression of EGF, TGF-alpha, PDGF, IGF and TGF-beta by tumor cells. Most of well differentiated adenocarcinomas show overexpression of p 185ERBB2 and coexpression of p 185ERBB2, and EGFR evidently correlates with high malignancy. In conclusion, the accumulation and interaction of several growth factors produced by tumor cells are necessary for the progression of human esophageal and gastric carcinomas. They may be attributed to genetic changes including activation of oncogenes, inactivation and deletion of anti-oncogenes and transcriptional regulatory sequences.
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PMID:Growth factors in progression of human esophageal and gastric carcinomas. 209 74

Carcinoid tumors of the midgut type are slowly growing neoplasms which often present clinically and histologically pronounced fibrosis around the tumors. Cryosections from 41 neuroendocrine tumors (31 midgut carcinoid tumors, 8 endocrine pancreatic carcinomas, 1 parathyroid carcinoma, and 1 pheochromocytoma) and 22 nonneuroendocrine carcinomas were examined for the presence of platelet-derived growth factor (PDGF) beta-receptor by immunohistochemistry using the monoclonal antibody PDGFR-B2. Twenty midgut carcinoid tumor tissues (66%) and 4 endocrine pancreatic carcinomas (50%) and the parathyroid carcinoma stained positively with the antibody. In contrast, only 2 nonneuroendocrine tumor tissues (10%) were stained, and the staining in these cases was weak. The immunoreaction in the carcinoid tumors was observed in connective tissue cells adjacent to tumor cell clusters but not in the tumor cells themselves. The degree of positive PDGF beta-receptor expression in the carcinoid tissues seems to correlate positively with the presence of macrophages as determined by the monoclonal antibody anti-Leu-M5, but not with other infiltrated lymphocytes identified with the monoclonal antibody anti-Leu-4, or with anti-HLA-DR antibodies. Stromal cells adjacent to tumor cells, including small capillaries, stained more strongly than the stromal cells which were distant from tumor cell clusters. Furthermore, carcinoid tumor metastases from lymph nodes as well as from liver showed stronger immunoreactivity in the stromal cells with the PDGF beta-receptor antibody than the corresponding primary tumors. Our data suggest that carcinoid tumor cells may directly or indirectly induce expression of PDGF beta-receptor on adjacent stromal cells in the tumor tissue, which may contribute to the fibrosis that is often seen around carcinoid tumors.
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PMID:Expression of platelet-derived growth factor beta-receptors on stromal tissue cells in human carcinoid tumors. 215 46

Synthetic peptides derived from the sequence surrounding tyrosine-857 in the human platelet-derived growth factor (PDGF) beta-receptor were used to elucidate the requirement for length and presence of negative and positively charged amino acids in substrates of the PDGF beta-receptor protein tyrosine kinase. The measured Km for the different peptides were all in the range 1-10 mM. A peptide of only five amino acids, lacking acidic amino acid residues, were found to be substrates for the receptor kinase. Ligand binding was found to stimulate the phosphorylation of peptides mainly by lowering the Km both for peptide and for ATP. Only minor changes in the Vmax occurred upon stimulation with PDGF. The reaction mechanism was found to be sequential, i.e. both the peptide and ATP have to bind to the enzyme before any product is released.
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PMID:Characterization of the platelet-derived growth factor beta-receptor kinase activity by use of synthetic peptides. 215 30

Several HTLV-I-infected T-cell lines express the two genes encoding platelet-derived growth factor (PDGF). Therefore, we examined the question of a possible self-stimulatory mechanism of proliferation involving PDGF in these cells. Using a nucleic acid probe and an antibody specific for the PDGF-B receptor (PDGFR-B), we examined four established human T-cell lines infected with HTLV-I, as well as several noninfected T-cell lines for expression of the PDGF-B receptor. Previous reports indicate that lymphocytes do not display receptors for PDGF; our results show that two noninfected T-cell lines (HUT-78, CCRF-HSB-2) expressed the canonical 5.5-kb PDGFR mRNA, and two HTLV-I-infected T-cell lines (C10/MJ, MT-2) expressed a novel PDGFR mRNA of 4.8 kb. Concomitantly, the cell lines expressing PDGFR mRNA also synthesize PDGFR proteins immunoprecipitated by the antibody to PDGFR-B. Differences were observed in the molecular weight of PDGFR molecules immunoprecipitated from uninfected and HTLV-infected T-cells. Immunofluorescence studies demonstrated that the PDGFR-B proteins are localized primarily on the cell external membrane. The results suggest that the HTLV-I-infected T-cells acquire an autostimulatory mechanism of cell proliferation that involves PDGF.
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PMID:Coexpression of the genes for platelet-derived growth factor and its receptor in human T-cell lines infected with HTLV-I. 216 Feb 60

The interferons (IFNs) have been shown to be antagonistic to the growth stimulatory effects of mitogens on cultured cells. A report of the interactions of IFN-beta and platelet-derived growth factor on BALB/c-3T3 mouse cells established that IFN itself induced the secretion of a limited number of proteins from this cell line. The present work was undertaken to determine if other murine cell lines treated with homologous IFN-beta also secreted new or additional protein(s) in response to this agent and if this response correlated with other phenotypic properties of the cells. The cell lines examined included L929 cells and two derivatives of this line (GM347 and WDIFN), CAK-TK-, Swiss-3T3, and BALB/c-3T3. Each line was exposed to [35S]methionine in the absence and in the presence of IFN-beta, the supernatant fluids collected, and the radioactive, secreted proteins examined by fluorography after electrophoresis through SDS-containing polyacrylamide gels. Two cell lines (GM347 and Swiss-3T3) did not appear to secrete new or additional proteins after IFN treatment. However, four lines (L929, WDIFN, CAK-TK-, and BALB/c-3T3) did secrete new or additional proteins in response to IFN. Thus IFN-induced secretion of protein appeared to be a common but not universal phenomenon. In addition, although the number and apparent size(s) of the IFN-induced, secreted proteins were different in these various lines, one protein (Mr = 89-90,000) appeared to be secreted by each of them. In this respect it was unique. Moreover the IFN-induced secretion of protein did not appear to correlate with the antiviral or antiproliferative effects of IFN.
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PMID:Effect of interferon on secretion of proteins by various murine cell lines. 245 71


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