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)

Stimulation of human fibroblasts by platelet-derived growth factor (PDGF)-BB leads to a down-regulation of PDGF beta-receptors and a concomitant appearance of intracellular granular accumulations of receptors, as determined by stainings with the mAb PDGFR-B2. The granules contained both the ligand and PDGF beta-receptors, as revealed by double-immunofluorescence staining, and were formed in response to PDGF-BB but not in response to other cytokines tested. The formation of intracellular PDGF beta-receptor granules was dependent on PDGF-BB concentration and time of stimulation. The granular PDGF beta-receptor staining on cells treated with PDGF-BB for 1 h at 37 degrees C was used to investigate the effects of macrophage-derived cytokines on PDGF beta-receptor expression. The number of PDGF beta-receptor granules was found to be reduced in fibroblasts grown for 48 h in the presence of PDGF-BB, TNF-alpha, or IL-1; PDGF-AA under the same conditions had no effect. The reduction observed was paralleled by a decrease in cell surface expression of PDGF beta-receptors, measured as binding of 125I-PDGF-BB and of the PDGFR-B2 antibody. Furthermore, both TNF-alpha and IL-1 decreased the detergent-extractable pool of PDGF-beta receptors in the fibroblasts, as revealed by immunoblotting of detergent cell extracts. Finally, the decrease in PDGF beta-receptors after culturing of the cells in the presence of TNF-alpha and IL-1 was accompanied by a decreased incorporation of [3H]thymidine in response to PDGF-BB stimulation. In conclusion, our data suggest that certain macrophage-derived cytokines can modulate the expression of PDGF beta-receptors by cultured fibroblasts, which may contribute in part to their reduced responsiveness to PDGF.
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PMID:Expression of platelet-derived growth factor-beta receptors on human fibroblasts. Regulation by recombinant platelet-derived growth factor-BB, IL-1, and tumor necrosis factor-alpha. 130 61

A truncated form of the type 1 fibroblast growth factor receptor (FGFR1) lacking most of its cytoplasmic domain was tested for its ability to inhibit signal transduction by each of three different wild-type FGFRs (FGFR1, 2, and 3). When the truncated FGFR1 was expressed in Xenopus oocytes in excess of each wild-type FGFR, mobilization of intracellular calcium mediated by the wild-type FGFRs was completely blocked. The truncated FGFR did not inhibit signal transduction by the co-expressed platelet-derived growth factor beta-receptor. A form of truncated FGFR1 which lacked the first immunoglobulin-like domain also inhibited signal transduction by wild-type FGFRs. Truncated FGFR formed complexes with wild-type FGFR in the presence of basic FGF in intact cells. These observations were consistent with the hypothesis that the truncated FGFR interacted with wild-type FGFRs to form nonfunctional heterodimers, thus eliminating the signaling by the wild-type FGFRs. The observation that signaling by multiple types of FGFR can be blocked by a single type of truncated FGFR suggests that the different types of FGFR can interact with each other in ligand-mediated complexes. These findings provide a molecular basis for inhibiting the actions of FGFs in vivo.
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PMID:A truncated form of fibroblast growth factor receptor 1 inhibits signal transduction by multiple types of fibroblast growth factor receptor. 130 84

Carcinoid tumors are slowly growing neuroendocrine neoplasms which often present pronounced fibrosis around the tumor cells. We have previously shown by immunohistochemistry that carcinoid tumors express platelet-derived growth factor (PDGF) beta-receptors on surrounding stromal cells. In this report, 22 midgut carcinoids and 5 endocrine pancreatic tumors were examined for the presence of PDGF with a monoclonal antibody raised against a peptide corresponding to a part of the B-chain of PDGF which reacts strongly with the B-chain and weakly with the A-chain. They were also examined for PDGF alpha-receptors with an affinity-purified polyclonal peptide antibody and for PDGF beta-receptor with the monoclonal antibody PDGFR-B2. PDGF was expressed on tumor cells and on adjacent stroma. PDGF alpha-receptor was seen on clusters of tumor cells and occasionally on adjacent stroma, whereas beta-receptors were seen only in the stroma. Tissue sections from some of these midgut carcinoids were also investigated by in situ hybridization for mRNA of PDGF A- and B-chains as well as alpha- and beta-receptors. By in situ hybridization, abundant expression of mRNA for PDGF beta-receptor and PDGF A-chain was observed in stromal cells adjacent to carcinoid tumor cell clusters, but the mRNA expression in the tumor cells themselves was at a low level. A few clustered tumor cells and stromal cells expressed mRNA for the PDGF alpha-receptor, thus consolidating the immunohistochemical findings. mRNA for the PDGF B-chain was detected in both tumor cells and stroma, but only at low levels. Our data suggest that PDGF is involved in the growth stimulation of the carcinoid tumor cells in an autocrine fashion and in the stimulation of stromal cell growth through paracrine and possibly autocrine mechanisms. Moreover, remarkably strong immunostaining of PDGF and the PDGF alpha-receptor was seen on peripheral nerve fibers.
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PMID:Expression of platelet-derived growth factor and its receptors in neuroendocrine tumors of the digestive system. 131 Jun 35

Tyrphostins, which block protein tyrosine kinase activity, were studied for their inhibitory action on platelet-derived growth factor (PDGF)-induced proliferation of human bone marrow fibroblasts. Of the seven tryphostins examined, tyrphostin AG370 was found to be the most potent blocker against PDGF-induced mitogenesis (IC50 = 20 microM). This PTK blocker also blocks mitogenesis induced by epidermal growth factor (IC50 = 50 microM) and human serum (IC50 = 50 microM), but with lower efficacy. In digitonin-permeabilized fibroblasts as well as in intact fibroblasts, tyrphostin AG370 inhibits PDGF receptor autophosphorylation and the tyrosine phosphorylation of intracellular protein substrates (pp120, pp85, and pp75) which coprecipitate with the PDGF receptor. In comparison to AG370, AG18, a potent EGF receptor blocker, was less efficient in inhibiting PDGF-induced proliferation of fibroblasts and phosphorylation of the intracellular protein substrates. Under the conditions in which AG370 inhibits PDGF-induced mitogenesis and phosphorylation, it does not affect [125I]PDGF internalization and enhance [125I]PDGF binding. These findings suggest that AG370, which is an indole tyrphostin, may serve as a model for developing analogues with a therapeutic potential for treatment of diseases which involve abnormal cellular proliferation induced by PDGF.
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PMID:Inhibition of platelet-derived growth factor-induced mitogenesis and tyrosine kinase activity in cultured bone marrow fibroblasts by tyrphostins. 131 7

This study was undertaken to characterize the expression of a chimeric growth factor receptor composed of the extracellular and transmembrane domains of the platelet-derived growth factor (PDGF) beta-receptor (PDGFR-beta) fused to the intracellular domain of the fibroblast growth factor receptor-1 (FGFR-1) and to assess its effect on the growth potential of pancreatic islet cells. For this purpose rat pancreatic islets or monolayers of pancreatic islet cells were transfected with recombinant DNA constructs coding for the PDGF B-chain, the PDGFR-beta, the FGFR-1 and the chimera between PDGFR-beta and FGFR-1. DNA synthesis, monitored as the percentage of labelled nuclei and [3H]thymidine incorporation, was stimulated in pancreatic islet cells cotransfected with the constructs coding for the PDGF B-chain and the PDGFR-beta or the chimeric PDGFR-beta/FGFR-1 as compared with that determined after transfection with control plasmid. PDGF-BB stimulated DNA synthesis when islet cells had been transfected with PDGFR-beta or PDGFR-beta/FGFR-1. Cotransfection of the PDGFR-beta and the chimeric PDGFR-beta/FGFR-1 constructs attenuated the stimulation of DNA synthesis in response to PDGF-BB. Receptor binding studies showed binding with a Kd of 0.7 nM to the chimeric receptor. The present findings show that when the chimeric PDGFR-beta/FGFR-1 construct is expressed in beta-cells it is efficient in increasing DNA synthesis when stimulated with ligand.
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PMID:A chimera between platelet-derived growth factor beta-receptor and fibroblast growth factor receptor-1 stimulates pancreatic beta-cell DNA synthesis in the presence of PDGF-BB. 131 68

The expression of platelet-derived growth factor (PDGF) and its receptors was analyzed in 14 gliomas of various degrees of malignancy and compared with three gliosis cases by in situ hybridization and immunohistochemistry techniques. Expression of both PDGF A- and B-chains was higher in glioblastomas than in astrocytomas. The PDGF A-chain mRNA was predominantly found in cell-rich areas in glioblastomas. The cognate PDGF-alpha receptor (PDGFR-alpha) mRNA was heterogeneously distributed in gliomas of all grades, and PDGFR-alpha expression was higher in gliomas than in gliosis. Within some glioblastomas probed with PDGFR-alpha complementary RNA, cells heavily loaded with grains were intermingled with others containing low or moderate signals. The heavily labeled cells were often found in the vicinity of proliferating capillaries. Immunostaining with an anti-PDGF antibody and an affinity-purified antiserum against the PDGFR-alpha showed strong staining of most tumor cells with both antibodies in glioblastoma. In addition, the PDGFR-alpha antibodies yielded a strong staining of scattered cells, and the anti-PDGF antibody yielded staining of a few cells within the astrocytoma. Furthermore, high levels of the PDGF-beta receptor (PDGFR-beta) and PDGF B-chain mRNA as well as the beta receptor protein were found in hyperplastic capillaries. These results suggest the presence of autocrine and paracrine loops in glioma, activating the PDGFR-alpha in glioma cells and the PDGFR-beta in endothelial cells.
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PMID:Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. 131 61

Epidermal growth factor (EGF) or platelet-derived growth factor binding to their receptor on fibroblasts induces tyrosine phosphorylation of PLC gamma 1 and stable association of PLC gamma 1 with the receptor protein tyrosine kinase. Similarly in lymphocytes, cross-linking of antigen receptors induces the formation of molecular complexes incorporating PLC gamma 1; however, associated kinase activity is thought to be mediated through cytoplasmic protein tyrosine kinase(s). In this report, we generated a fusion protein containing the SH2 domains of human PLC gamma 1 and human IgG1 heavy chain constant region to identify lymphocyte phosphoprotein-binding PLC gamma 1 SH2 domains following cellular activation. As in EGF- or platelet-derived growth factor-stimulated fibroblasts, PLC gamma 1 is coprecipitated in activated lymphocytes, complexed with associated tyrosine-phosphorylated proteins. One of these, a 35/36-kDa protein found prominently in T cells and at lower levels in B cells, bound to the fusion protein in immunoprecipitation experiments. The fusion protein showed lineage restricted association with a 74-kDa phosphoprotein in T cells and a 93-kDa phosphoprotein in B cells. It bound to activated EGF receptor in fibroblasts as expected, and protein tyrosine kinase activity was precipitated from EGF-stimulated cells. However, PLC gamma 1-associated protein tyrosine kinase activity was not detected in activated lymphocytes. These data suggest that lymphocyte PLC gamma 1 SH2-binding proteins are cell lineage specific and may be transiently associated with activated PLC gamma 1.
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PMID:Lymphocyte lineage-restricted tyrosine-phosphorylated proteins that bind PLC gamma 1 SH2 domains. 132 23

Signal transduction by tyrosine kinase growth factor receptors involves ligand-induced phosphorylation of substrates for the kinase, resulting in mediation of common or receptor-specific biological signals. We have compared signal transduction pathways for the fibroblast growth factor receptor-1 (FGFR-1), the platelet-derived growth factor beta-receptor (PDGFR-beta), and a chimeric FGFR-1 molecule, FGFRchim, in which the FGFR-1 kinase insert was replaced with that of the PDGFR-beta. The different receptors were characterized and found to be functional as ligand-stimulatable kinases, after expression of the respective human cDNAs in porcine aortic endothelial cells. Substrates for the receptors were analyzed by ligand stimulation of [32P]orthophosphate-labeled cells and immunoprecipitation with phosphotyrosine antiserum. A number of phosphoproteins were induced in all the different types of cells, but components specifically induced after stimulation of FGFR-1 and PDGFR-beta expressing cells could also be detected. Examination of receptor-associated substrates by in vitro kinase assays revealed phosphoproteins of 65 and 85 kDa, which were associated with PDGFR-beta and FGFRchim, but not with FGFR-1. The 85-kDa phosphoprotein could correspond to the regulatory subunit of phosphatidylinositol 3' kinase (PI3-K), since phosphatidylinositol 3' kinase activity was detected after ligand stimulation of FGFRchim- and PDGFR-beta- but not FGFR-1-expressing cells. In addition, ligand stimulation of FGFRchim- and PDGFR-beta-expressing cells, but not FGFR-1-expressing cells, led to induction of actin reorganization in the form of circular membrane ruffling. Thus, replacement of a discrete segment of the intracellular domain of the FGFR-1 with the corresponding stretch from the PDGFR-beta resulted in transfer of PDGFR-beta-specific signaling properties to the chimeric molecule.
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PMID:The platelet-derived growth factor beta-receptor kinase insert confers specific signaling properties to a chimeric fibroblast growth factor receptor. 132 30

To document over-expression of proto-oncogenes in tumors, it is necessary to determine the level of expression in the progenitor normal tissue. These studies compare the levels of nuclear transcription of a series of growth-factor related genes and proto-oncogenes in human glioblastoma cell lines with those in three normal glial cell populations. The unusual finding was that levels in the three normal glial cell populations varied considerably for several genes and thus overexpression of a specific gene in a tumor cell when compared to just one normal glial cell population would not necessarily represent overexpression. In this study, we compared the level of 17 genes in 7 tumors to the highest level of each gene found in any of three normal glial cell populations. Over-expression of PDGF-B in 4/7 glioblastoma cell lines, EGFR in 1/7, neu in 1/7 IGF-2 in 1/7 and ros in 2/7 was observed. The variation observed in the normal glial cell populations emphasizes the possibility that the normal glial cell populations represent different glial cell lineages and/or stages of differentiation and that the tumors could have arisen from different normal glial cells. Matching lineages of normal and tumor cells, probably by monoclonal antibody reactions, may be required to accurately define over-expression.
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PMID:Transcriptional patterns of growth factors and proto-oncogenes in human glioblastomas and normal glial cells. 132 85

Circular dichroism and fluorescence spectroscopy were used to investigate the structure of the p85 alpha subunit of the PI 3-kinase, a closely related p85 beta protein, and a recombinant SH2 domain-containing fragment of p85 alpha. Significant spectral changes, indicative of a conformational change, were observed on formation of a complex with a 17 residue peptide containing a phosphorylated tyrosine residue. The sequence of this peptide is identical to the sequence surrounding Tyr751 in the kinase-insert region of the platelet-derived growth factor beta-receptor (beta PDGFR). The rotational correlation times measured by fluorescence anisotropy decay indicated that phosphopeptide binding changed the shape of the SH2 domain-containing fragment. The CD and fluorescence spectroscopy data support the secondary structure prediction based on sequence analysis and provide evidence for flexible linker regions between the various domains of the p85 proteins. The significance of these results for SH2 domain-containing proteins is discussed.
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PMID:Interaction of the p85 subunit of PI 3-kinase and its N-terminal SH2 domain with a PDGF receptor phosphorylation site: structural features and analysis of conformational changes. 133 May 35


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