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)

We have recently documented that the vast majority of patients with glioblastoma multiforme (GBM) over-express a receptor (R) for interleukin 13 (IL13) in situ. We have now evaluated further the degree of relative specificity of the binding of IL13 to GBM when compared with other growth factor receptors. Tumor samples of 11 patients with GBM, 7 various normal brain samples, and several cell lines in culture were examined. Same patient tissue sections were incubated with 125I-labeled: IL13, monoclonal antibody HB21 against human transferrin (Tf) receptor, epidermal growth factor (EGF), and an IL4 antagonist, IL4.Y124D. All 11 GBMs stained specifically, densely, and relatively homogeneously for both IL13R and TfR. Seven GBM specimens showed specific binding for 125I-EGF, but it was less homogeneous when compared with IL13R or TfR. Two of the GBMs studied demonstrated extremely high density of the EGFR. Furthermore, we did not detect significant presence of the IL4R in the studied GBM specimens in situ. All sections of non-malignant brain tissues examined showed avid binding by the TfR with lack of consistent and specific binding of 125I-IL13 or -EGF. Thus, it appears that the GBM-associated IL13R is considerably more specific to GBM that the one for Tf and more frequently and homogeneously expressed than the EGFR. These results render further support for the hIL13R being a new unique candidate for delivery of variety of anti-GBM therapies.
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PMID:Receptor for interleukin 13 is abundantly and specifically over-expressed in patients with glioblastoma multiforme. 1042 28

The rapid internalization of receptor tyrosine kinases after ligand binding has been assumed to be a negative modulation of signal transduction. However, accumulating data indicate that signal transduction from internalized cell surface receptors also occurs from endosomes. We show that a substantial fraction of tyrosine-phosphorylated epidermal growth factor receptor (EGFR) and Shc, Grb2 and Cbl after internalization relocates from early endosomes to compartments which are negative for the early endosomes, recycling vesicle markers EEA1 and transferrin in EGF-stimulated cells. These compartments contained the multivesicular body and late endosome marker CD63, and the late endosome and lysosome marker LAMP-1, and showed a multivesicular morphology. Subcellular fractionation revealed that activated EGFR, adaptor proteins and activated ERK 1 and 2 were located in EEA1-negative and LAMP-1-positive fractions. Co-immunoprecipitations showed EGFR in complex with both Shc, Grb2 and Cbl. Treatment with the weak base chloroquine or inhibitors of lysosomal enzymes after EGF stimulation induced an accumulation of tyrosine-phosphorylated EGFR and Shc in EEA1-negative and CD63-positive vesicles after a 120-min chase period. This was accompanied by a sustained activation of ERK 1 and 2. These results suggest that EGFR signaling is not spatially restricted to the plasma membrane, primary vesicles and early endosomes, but is continuing from late endocytic trafficking organelles maturing from early endosomes.
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PMID:Re-localization of activated EGF receptor and its signal transducers to multivesicular compartments downstream of early endosomes in response to EGF. 1137 Jul 43

Human diploid fibroblasts (HDF) do not divide indefinitely and eventually lead to an arrest of cell division by a process termed cellular or replicative senescence. Irreversible growth arrest of senescent cells is strongly related to the attenuated response to growth factors. Recently, we reported that up-regulation of caveolin in the senescent cells is responsible for the attenuated response to growth factors. Senescent cells did not phosphorylate Erk-1/2 after EGF stimulation, whereas young cells did. In those senescent cells, we found an increased level of caveolin proteins and strong interactions between caveolin-1 and EGFR. When we overexpressed caveolin-1 in young HDF, the activation of Erk-1/2 on EGF stimulation was significantly suppressed. These results suggest that the hyporesponsiveness of senescent fibroblasts to EGF stimulation might be due to the overexpression of caveolin. In addition, the clathrin-dependent endocytosis system plays the more active and dominant role over the caveolae system. Therefore, we monitored the efficiency of clathrin-dependent receptor-mediated endocytosis in the senescent cells in order to elucidate the exact mode of the attenuated response to growth factors in the senescent cells. Using a transferrin-uptake assay and Western blot analysis of endocytosis-related proteins, we found a significant decrease of amphiphysin-1 in human diploid fibroblasts of multipassages. By adjusting the level of amphiphysin, we could modulate the efficiency of receptor-mediated endocytosis either in young or old cells toward growth factors: that is, a dominant negative mutant of amphiphysin-1 blocked the endocytosis in the young cells, while microinjection of the gene resumed its activity in the old cells. Taken together, we conclude that the loss of endocytotic activity of senescent cells is directly related to the down-regulation of amphiphysin-1 and/or up-regulation of caveolins. This opens a new field of functional recovery of the senescent cells simply through adjusting the receptor-mediated endocytosis capacity.
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PMID:Down-regulation of receptor-mediated endocytosis is responsible for senescence-associated hyporesponsiveness. 1197 84

In order to determine the interrelationship between dietary iron and zinc levels, the effects of dietary iron levels (2, 10, 20, and 40 microg/g) on changes in iron and zinc status and zinc enzyme activities (aminolevulinic acid dehydratase ALA-D EC 4.2.1.24 and alkaline phosphatase ALK-P EC 3.1.3.1) in male Wistar rats were investigated using adequate and marginally deficient zinc diets (25 and 5 microg/g). When rats were fed 5 microg Zn/g diets, body weight gain and food intake remained unchanged at a Fe diet intake of 20 microg/g or greater. Similar tendencies were obtained for hemoglobin, hematocrit, plasma iron, and transferrin saturation. In contrast, liver, spleen, and femur iron concentrations increased gradually with increased iron intake. Feeding diets containing 25 microg Zn/g did not alter these parameters. The percentages of apparent iron absorption in both dietary zinc groups tended to increase with decreasing dietary iron and attained maximum levels at an Fe intake of 10 microg/g. However, In the case of rats fed Fe at concentrations of 2 microg/g Iron absorption decreased. Regardless of the dietary zinc level, rats fed diets with an Fe concentration of 2 microg/g had decreased zinc absorption and plasma ALK-P activity. However, ALA-D activity was not influenced by dietary iron.
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PMID:The effect of dietary iron levels on changes in iron status and zinc-dependent enzyme activities in rats fed two levels of dietary zinc. 1277 12

Various immunotoxins have been developed for the treatment of cancer. The toxin is internalized by target cells through cell-surface receptors, and it is essential for these receptors to be expressed for the immunotoxin to have specific anti-tumor activity. Radiation therapy is one of the main treatment modalities for primary malignant brain tumors. The purpose of this study was to determine whether radiation influences the expression of cell-surface receptors. Cells of one human medulloblastoma (Daoy) and two glioblastoma (U373-MG and T98-G) cell lines were tested by exposing the cells to a single dose of 5 Gy gamma rays. Expression of transferrin receptors, type-1 insulin-like growth factor receptors (IGF1R), and interleukin 4 receptors (IL4R) was measured by flow cytometry analysis on unirradiated cells and on cells 3 to 120 h after irradiation. In Daoy cells, the absolute expression index of transferrin receptors increased during the 24 h after irradiation with the greatest change of 26% above control at 9 h. The absolute expression index of IGF1R increased 26.5% above control at 12 h. The absolute expression index of IL4R decreased 9 h after irradiation. In U373-MG cells the absolute expression index of transferrin receptors increased during the 24 h after irradiation, and the greatest increase was 45% above control at 9 h. The absolute expression index of IGF1R increased during the 12 h after irradiation with a maximum increase of 33% above control at 6 h. The absolute expression index of IL4R decreased with time after irradiation. In T98-G cells, the absolute expression index of both transferrin receptors and IL4R decreased after irradiation. The results suggest that the expression of growth factor receptors on brain tumor cells may be influenced by radiation. The effect of ionizing radiation on receptor expression should be considered when administration of targeted toxin is combined with radiation. Similar studies with other growth factor receptors used in targeted toxin therapy are recommended.
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PMID:Changes in expression of transferrin, insulin-like growth factor 1, and interleukin 4 receptors after irradiation of cells of primary malignant brain tumor cell lines. 1285 34

Intersectin (ITSN) is a molecular scaffold involved in regulating endocytosis and mitogenic signaling. We previously demonstrated that ITSN transformed rodent fibroblasts, accelerated hormone-induced maturation of Xenopus oocytes, and activated the Elk-1 transcription factor through an MEK- and Erk-independent mechanism. We now demonstrate that ITSN complexes with the Ras guanine nucleotide exchange factor Sos1 leading to increased RasGTP levels. Using fluorescence resonant energy transfer analysis, we demonstrate that ITSN complexes with Ras in living cells leading to Ras activation on intracellular vesicles. These vesicles contain epidermal growth factor receptor but are distinct from transferrin-positive vesicles. However, Ras is not required for ITSN stimulation of transcription. Rather, we demonstrate that ITSN signals through JNK to activate Elk-1. Although ITSN activation of Elk-1 was Ras-independent, ITSN cooperates with Ras to synergistically activate JNK. These findings indicate that ITSN activates multiple intracellular signaling pathways and suggest that this adaptor protein may coordinately regulate the activity of these pathways in vivo.
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PMID:Intersectin activates Ras but stimulates transcription through an independent pathway involving JNK. 1297 Mar 66

Effects of the development of Fe deficiency on changes in Fe and Zn metabolism and its possible interactions with dietary Zn were determined. Adequate (25 microg/g) and marginally deficient (5 microg/g) Zn diets containing a sufficient (40 microg/g) dietary Fe levels were fed for 2 wk. Thereafter, both dietary Zn groups were fed an Fe-deficient (2.2 microg/g) diet for 4 wk. It was found that the effects of an Fe-deficient diet began to occur 7 and 14 d after feeding the Fe-deficient diet. At this time, tissue Fe concentrations were depleted and rats were unable to maintain hemoglobin levels. The Fe-deficient diet also induced an immediate fall in plasma Fe concentration, transferrin saturation, and apparent Fe absorption, while the concentrations of liver cytochrome c increased as Fe deficiency developed. Decreases in liver and spleen Fe levels, as well as the activities of blood and bone marrow aminolevulinic acid dehydratase (ALA-D, EC 4.2.1.24) were observed 3, 7, and 14 d after feeding the Fe-deficient diet, and thereafter they were increased. On the other hand, the activity of plasma alkaline phosphatase (ALK-P, EC 3.1.3.1) decreased continuously as Fe deficiency progressed. With severe development of Fe deficiency, rats fed the Zn-adequate diet had increased levels of Zn concentration in the plasma, liver, spleen, kidney, and femur, whereas apparent Zn absorption was decreased. The decrease in apparent Zn absorption and the increase in tissue Zn concentration of rats might be related to the lowered Zn requirement, which is associated with the depressed Zn metabolism caused by feeding Fe-deficient diets.
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PMID:Development of iron deficiency decreases zinc requirement of rats. 1459 9

Nonviral vectors should undergo "virus-like" changes compatible with the steps of gene delivery. Poly(ethylene) glycol (PEG) shielding of DNA/polycation polyplexes protects from nonspecific interactions with the extracellular environment. pH-triggered removal of the shield within the endosome may be advantageous. Polycation and PEG were linked via acylhydrazides or pyridylhydrazines. The pyridylhydrazone prepared from polylysine and propionaldehyde-PEG showed the greatest acid-dependent hydrolysis; at pH 5, 37 degrees C for 10 min, 90% hydrolyzed, while at pH 7.4 the half-life was 1.5 h. Particle size and zeta potential measurements of the polyplexes showed complete deshielding within 1 h at pH 5, while at pH 7.4 the shield remained at 4 h, 37 degrees C. For gene transfection a targeting conjugate was also included in the polyplex, transferrin as ligand for K562 and Neuro2A cells and epidermal growth factor for HUH-7 and Renca-EGFR cells. Marker gene expression showed that the reversibly shielded polyplexes exhibited up to 2 log orders of magnitude higher gene expression in vitro and 1 log magnitude higher gene expression in an in vivo mouse model, compared to the stably shielded control polyplexes. Engineering of polyplexes with more dynamic domains is an encouraging new direction in nonviral vector design.
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PMID:Toward synthetic viruses: endosomal pH-triggered deshielding of targeted polyplexes greatly enhances gene transfer in vitro and in vivo. 1572 38

Many growth factors and cytokines bind to more than one receptor, but in many cases the different roles of the separate receptors in signal transduction are unclear. Intracellular sorting of ligand-receptor complexes may modulate the signalling, and we have here studied the intracellular trafficking of ligand bound to receptors for fibroblast growth factors (FGFs). For this purpose, we transfected HeLa cells with any one of the four tyrosine kinase FGF receptors (FGFR1-4). In cells expressing any one of these receptors, externally added FGF1 was localized to sorting/early endosomes after 15 minutes at 37 degrees C. After longer incubation times, FGF1 internalized in cells expressing FGFR1 was localized mainly to late endosomes/lysosomes, similarly to EGF. By contrast, FGF1 internalized in cells expressing FGFR4 followed largely the same intracellular pathway as the recycling ligand, transferrin. In cells expressing FGFR2 or FGFR3, sorting of FGF1 to lysosomes was somewhat less efficient than that observed for FGFR1. Furthermore, FGF1 was more slowly degraded in cells expressing FGFR4 than in cells expressing FGFR1-3 and in addition, internalized FGFR4 as such was more slowly degraded than the other receptors. The data indicate that after endocytosis, FGFR4 and its bound ligand are sorted mainly to the recycling compartment, whereas FGFR1-3 with ligand are sorted mainly to degradation in the lysosomes. Alignment of the amino acid sequence of the intracellular part of the four FGFRs revealed several lysines conserved in FGFR1-3 but absent in FGFR4. Lysines are potential ubiquitylation sites and could thus target a receptor to lysosomes for degradation. Indeed, we found that FGFR4 is less ubiquitylated than FGFR1, which could be the reason for the different sorting of the receptors.
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PMID:Different intracellular trafficking of FGF1 endocytosed by the four homologous FGF receptors. 1609 23

Lysosomal degradation of signalling receptors such as the epidermal growth factor (EGF) receptor (EGFR) is an important mechanism for termination of cell signalling. Such degradation involves the endosomal sorting of ubiquitylated receptors into intralumenal vesicles (ILVs) of multivesicular endosomes (MVEs) that move along microtubules to fuse with perinuclear lysosomes. The Rab7-interacting lysosomal protein RILP is interesting in this context as it interacts with Vps22 (also known as EAP30) and Vps36 (also known as EAP45), subunits of the endosomal sorting complex required for transport II (ESCRT-II), as well as with the dynein-dynactin motor complex. Because previous functional studies of RILP have been based on its overexpression, we have asked here whether RILP is required for endocytic trafficking of receptors. Depletion of RILP caused elevated levels of four late-endosomal molecules, lyso-bisphosphatidic acid, Lamp1, CD63 and cation-independent mannose-6-phosphate receptors. Electron microscopy showed that endosomes of RILP-depleted cells were morphologically distinct from normal late endosomes and had a strongly reduced content of ILVs. As in Vps22-depleted cells, ligand-mediated degradation of EGFRs was strongly inhibited in RILP-depleted cells, in which endocytosed EGFRs were found to accumulate in early endosomes. By contrast, endocytosis and recycling of transferrin receptors occurred normally in RILP-depleted cells. These results establish that RILP, like the ESCRT proteins, is required for biogenesis of MVEs and degradative trafficking of EGFRs but not for trafficking of transferrin receptors through early endosomes. We propose that RILP might coordinate the biogenesis of MVEs with dynein-mediated motility.
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PMID:RILP is required for the proper morphology and function of late endosomes. 1795 29


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