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:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neurofibromatosis type 2 (NF2) gene was recently cloned, and the protein it encodes (merlin) was revealed to belong to a family of proteins that link cytoskeletal components with proteins in the cell membrane. To elucidate the biological function of merlin, we produced a bacterial fusion protein consisting of glutathione S-transferase and merlin and used it to detect five merlin-binding cellular proteins, designated p165, p145, p125, p85 and p70, by a protein-binding assay. p165 and merlin were phosphorylated on serine/threonine residues, and immunoprecipitation showed that p85 bound the native form of merlin. Although the entire merlin-ezrin-radixin-moesin (MERM) homology domain of merlin was found to be essential for binding to all five proteins, the MERM homology domains of ezrin and moesin did not bind to any of the five proteins. Since most reported NF2 mutations are in the region we determined was necessary for binding, the mutations probably impair binding. Therefore, the formation of the protein complex is probably crucial for tumor suppression.
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PMID:Detection of cellular proteins that interact with the NF2 tumor suppressor gene product. 803 98

During activation, T lymphocytes become motile cells, switching from a spherical to a polarized shape. Chemokines and other chemotactic cytokines induce lymphocyte polarization with the formation of a uropod in the rear pole, where the adhesion receptors intercellular adhesion molecule-1 (ICAM-1), ICAM-3, and CD44 redistribute. We have investigated membrane-cytoskeleton interactions that play a key role in the redistribution of adhesion receptors to the uropod. Immunofluorescence analysis showed that the ERM proteins radixin and moesin localized to the uropod of human T lymphoblasts treated with the chemokine RANTES (regulated on activation, normal T cell expressed, and secreted), a polarization-inducing agent; radixin colocalized with arrays of myosin II at the neck of the uropods, whereas moesin decorated the most distal part of the uropod and colocalized with ICAM-1, ICAM-3, and CD44 molecules. Two other cytoskeletal proteins, beta-actin and alpha-tubulin, clustered at the cell leading edge and uropod, respectively, of polarized lymphocytes. Biochemical analysis showed that moesin coimmunoprecipitates with ICAM-3 in T lymphoblasts stimulated with either RANTES or the polarization- inducing anti-ICAM-3 HP2/19 mAb, as well as in the constitutively polarized T cell line HSB-2. In addition, moesin is associated with CD44, but not with ICAM-1, in polarized T lymphocytes. A correlation between the degree of moesin-ICAM-3 interaction and cell polarization was found as determined by immunofluorescence and immunoprecipitation analysis done in parallel. The moesin-ICAM-3 interaction was specifically mediated by the cytoplasmic domain of ICAM-3 as revealed by precipitation of moesin with a GST fusion protein containing the ICAM-3 cytoplasmic tail from metabolically labeled Jurkat T cell lysates. The interaction of moesin with ICAM-3 was greatly diminished when RANTES-stimulated T lymphoblasts were pretreated with the myosin-disrupting drug butanedione monoxime, which prevents lymphocyte polarization. Altogether, these data indicate that moesin interacts with ICAM-3 and CD44 adhesion molecules in uropods of polarized T cells; these data also suggest that these interactions participate in the formation of links between membrane receptors and the cytoskeleton, thereby regulating morphological changes during cell locomotion.
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PMID:Moesin interacts with the cytoplasmic region of intercellular adhesion molecule-3 and is redistributed to the uropod of T lymphocytes during cell polarization. 929 94

Chemokines as well as the signaling through the adhesion molecules intercellular adhesion molecule (ICAM)-3 and CD43 are able to induce in T lymphocytes their switching from a spherical to a polarized motile morphology, with the formation of a uropod at the rear of the cell. We investigated here the role of CD43 in the regulation of T-cell polarity, CD43-cytoskeletal interactions, and lymphocyte aggregation. Pro-activatory anti-CD43 monoclonal antibody (MoAb) induced polarization of T lymphocytes with redistribution of CD43 to the uropod and the CCR2 chemokine receptor to the leading edge of the cell. Immunofluorescence analysis showed that all three ezrin-radixin-moesin (ERM) actin-binding proteins localized in the uropod of both human T lymphoblasts stimulated with anti-CD43 MoAb and tumor-infiltrating T lymphocytes. Radixin localized at the uropod neck, whereas ezrin and moesin colocalized with CD43 in the uropod. Biochemical analyses showed that ezrin and moesin coimmunoprecipitated with CD43 in T lymphoblasts. Furthermore, in these cells, the CD43-associated moesin increased after stimulation through CD43. The interaction of moesin and ezrin with CD43 was specifically mediated by the cytoplasmic domain of CD43, as shown by precipitation of both ERM proteins with a GST-fusion protein containing the CD43 cytoplasmic tail. Videomicroscopy analysis of homotypic cell aggregation induced through CD43 showed that cellular uropods mediate cell-cell contacts and lymphocyte recruitment. Immunofluorescence microscopy performed in parallel showed that uropods enriched in CD43 and moesin localized at the cell-cell contact areas of cell aggregates. The polarization and homotypic cell aggregation induced through CD43 was prevented by butanedione monoxime, indicating the involvement of myosin cytoskeleton in these phenomena. Altogether, these data indicate that CD43 plays an important regulatory role in remodeling T-cell morphology, likely through its interaction with actin-binding proteins ezrin and moesin. In addition, the redistribution of CD43 to the uropod region of migrating lymphocytes and during the formation of cell aggregates together with the enhancing effect of anti-CD43 antibodies on lymphocyte cell recruitment suggest that CD43 plays a key role in the regulation of cell-cell interactions during lymphocyte traffic.
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PMID:CD43 interacts with moesin and ezrin and regulates its redistribution to the uropods of T lymphocytes at the cell-cell contacts. 1018 2

In response to the chemoattractants interleukin 8, C5a, N-formyl-methionyl-leucyl-phenylalanine, and interleukin 15, adhesion molecules P-selectin glycoprotein ligand 1 (PSGL-1), intercellular adhesion molecule 3 (ICAM-3), CD43, and CD44 are redistributed to a newly formed uropod in human neutrophils. The adhesion molecules PSGL-1 and ICAM-3 were found to colocalize with the cytoskeletal protein moesin in the uropod of stimulated neutrophils. Interaction of PSGL-1 with moesin was shown in HL-60 cell lysates by isolating a complex with glutathione S-transferase fusions of the cytoplasmic domain of PSGL-1. Bands of 78- and 81-kd were identified as moesin and ezrin by Western blot analysis. ICAM-3 and moesin also coeluted from neutrophil lysates with an anti-ICAM-3 immunoaffinity assay. Direct interaction of the cytoplasmic domains of ICAM-3 and PSGL-1 with the amino-terminal domain of recombinant moesin was demonstrated by protein-protein binding assays. These results suggest that the redistribution of PSGL-1 and its association with intracellular molecules, including the ezrin-radixin-moesin actin-binding proteins, regulate functions mediated by PSGL-1 in leukocytes stimulated by chemoattractants.
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PMID:Polarization and interaction of adhesion molecules P-selectin glycoprotein ligand 1 and intercellular adhesion molecule 3 with moesin and ezrin in myeloid cells. 1073 15

The Protein 4.1 family contains at least two members that function as tumour suppressors, the neurofibromatosis 2 gene product merlin and the recently identified differentially expressed in adenocarcinoma of the lung (DAL-1)/Protein 4.1B molecule. DAL-1/Protein 4.1B loss is observed in a variety of tumours, including breast and lung cancers as well as meningiomas. We have previously demonstrated that DAL-1/Protein 4.1B interacts with some but not all merlin-binding proteins, raising the possibility that DAL-1/Protein 4.1B associates with additional unique proteins specific to its function as a negative growth regulator. Using yeast two-hybrid interaction cloning, we identified three 14-3-3 isoforms, beta, gamma and eta, to be DAL-1/Protein 4.1B-binding proteins. These interactions were verified by using glutathione S-transferase affinity chromatography in vitro and co-immunoprecipitation in vivo. The interaction of 14-3-3 with DAL-1/Protein 4.1B was specific, as 14-3-3 did not bind to the related Protein 4.1 family members merlin, ezrin or radixin. The DAL-1/Protein 4.1B domain that mediates 14-3-3 binding was mapped to residues Pro(244) and Leu(280) within the 4.1/ezrin/radixin/moesin domain. The identification of this novel DAL-1/Protein 4.1B-interacting protein represents the first step towards elucidating its potentially unique mechanism of action.
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PMID:The 4.1/ezrin/radixin/moesin domain of the DAL-1/Protein 4.1B tumour suppressor interacts with 14-3-3 proteins. 1199 70

Caspr/paranodin is an essential neuronal component of paranodal axoglial junctions, associated with contactin/F3. Its short intracellular domain contains a conserved motif (GNP motif) capable of binding protein 4.1 domains [FERM domains (four point one, ezrin, radixin, moesin)]. Schwannomin/merlin is a tumour suppressor expressed in many cell types, including in neurons, the function and partners of which are still poorly characterized. We show that the FERM domain of schwannomin binds to the paranodin GNP motif in glutathione S-transferase (GST)-pull down assays and in transfected COS-7 cells. The two proteins co-immunoprecipitated in brain extracts. In addition, paranodin and schwannomin were associated with integrin beta1 in transfected cells and in brain homogenates. The presence of paranodin increased the association between integrin beta1 and schwannomin or its N-terminal domain, suggesting that the interactions between these proteins are interdependent. In jimpy mutant mice, which display a severe dysmyelination with deficient paranodal junctions, the interactions between paranodin, schwannomin and integrin beta1 were profoundly altered. Our results show that schwannomin and integrin beta1 can be associated with paranodin in the central nervous system. Since integrin beta1 and schwannomin do not appear to be enriched in paranodes they may be quantitatively minor partners of paranodin in these regions and/or be associated with paranodin at other locations.
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PMID:Association of Caspr/paranodin with tumour suppressor schwannomin/merlin and beta1 integrin in the central nervous system. 1255 84

To identify proteins interacting with the C-terminal cytoplasmic tail of the dopamine D(3) receptor (D(3)R), we used the two-hybrid system to screen a rat brain cDNA library. We isolated three partial cDNAs encoding, respectively, for the MUPP1 multi-PDZ protein, for the N-terminal region of radixin, for GIPC and for a 160-amino acid open reading frame sharing high homology with the human CLIC6, also identified as parchorin in rabbit. In the two-hybrid system, CLIC6 was also able to interact with the D(2)R and D(4)R. The interaction between D(3)R and CLIC6 was confirmed by the use of a GST-D(3)R C-terminus fusion protein and COS cell extracts transiently expressing epitope-tagged CLIC6. In adult rat brain, CLIC6 mRNA expression was restricted to the choroid plexus, the striatal proliferative subventricular zone and the cerebellum where it is co-expressed with the D(3)R in the Purkinje cells of the lobules IX and X. CLIC6 mRNA was also detected in the pituitary in the posterior lobe and in cells co-expressing the D(2)R at the border between the intermediate and anterior lobes. In transfected HEK293 cells, D(3)R and CLIC6 co-localized at the plasma-membrane. No effect of CLIC6 transfection was observed on either intracellular chloride concentration or D(3)R/D(2)R-mediated response. In two-hybrid system, CLIC6 also interacted with MUPP1 and radixin but not GIPC, suggesting it could take part in a complex with D(2)-like receptors, not only by direct interaction with their C-termini, but also through interactions with scaffolding proteins.
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PMID:CLIC6, a member of the intracellular chloride channel family, interacts with dopamine D(2)-like receptors. 1449 80

The mechanisms underlying targeted sorting of endocytosed receptors for recycling to the plasma membrane or degradation in lysosomes are poorly understood. In this report, the C-terminal tails of the five dopamine receptors (D1-D5) were expressed as glutathione S-transferase (GST) fusion proteins and studied for their interaction with ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) and N-ethylmaleimide-sensitive factor (NSF), which are known to be involved in post-endocytic recycling of receptors back to the plasma membrane, and with sorting nexin 1 (SNX1), known to be involved in targeting receptors to lysosomal degradation. EBP50 did not bind any of the dopamine receptor tails. NSF bound strongly to D1 and D5 and only weakly to D2, D3 and D4. However, SNX1 clearly distinguished between D1 and D5, as only D5 bound strongly to this protein. This report shows that there are distinct interaction patterns for NSF and SNX1 to the various dopamine receptor subtypes.
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PMID:Distinct in vitro interaction pattern of dopamine receptor subtypes with adaptor proteins involved in post-endocytotic receptor targeting. 1470 63

We previously showed that Na(+)/H(+)-exchanger regulatory factor-1/Ezrin-radixin-moesin-binding phosphoprotein-50 (NHERF-1/EBP50) co-immunoprecipitated with the human kappa opioid receptor (hKOR) and that its overexpression blocked the kappa agonist U50,488H-induced hKOR down-regulation by enhancing recycling. Here, we show that glutathione S-transferase (GST)-hKOR C-tail interacted with purified NHERF-1/EBP50, whereas GST or GST-C-tails of micro or delta opioid receptors did not. GST-hKOR C-tail, but not GST, bound HA-NHERF-1/EBP50 transfected into Chinese hamster ovary cells and endogenous NHERF-1/EBP50 in opossum kidney proximal tubule epithelial cells (OK cells). The PDZ domain I, but not II, of NHERF-1/EBP50 was involved in the interaction. Association of NHERF-1/EBP50 with hKOR C-tail enhanced oligomerization of NHERF-1/EBP50. NHERF-1/EBP50 was previously shown to regulate Na(+)/H(+)-exchanger 3 (NHE3) activities in OK cells. We found stimulation of OK cells with U50,488H significantly enhanced Na(+)/H(+) exchange, which was blocked by naloxone but not by pertussis toxin pretreatment, indicating it is mediated by KORs but independent of G(i)/G(o) proteins. In OKH cells, a subclone of OK cells expressing a much lower level of NHERF-1/EBP50, U50,488H had no effect on Na(+)/H(+) exchange, although it enhanced p44/42 mitogen-activated protein kinase phosphorylation via G(i)/G(o) proteins similar to that in OK cells. Stable transfection of NHERF-1/EBP50 into OKH cells restored the stimulatory effect of U50,488H upon Na(+)/H(+) exchange. Thus, NHERF-1/EBP50 binds directly to KOR, and this association plays an important role in accelerating Na(+)/H(+) exchange. We hypothesize that binding of the KOR to NHERF-1/EBP50 facilitates oligomerization of NHERF-1/EBP50, leading to stimulation of NHE3. This study provides the first direct evidence that a G protein-coupled receptor through association with NHERF-1/EBP-50 stimulates NHE3.
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PMID:kappa Opioid receptor interacts with Na(+)/H(+)-exchanger regulatory factor-1/Ezrin-radixin-moesin-binding phosphoprotein-50 (NHERF-1/EBP50) to stimulate Na(+)/H(+) exchange independent of G(i)/G(o) proteins. 1507 Sep 4

The neurofibromatosis type 2 gene-encoded protein, merlin, is related to the ERM (ezrin, radixin, and moesin) family of membrane-cytoskeleton-associated proteins. Recent studies suggest that the loss of neurofibromatosis type 2 function contributes to tumor development and metastasis. Although the cellular functions of merlin as a tumor suppressor are relatively well characterized, the cellular mechanism whereby merlin controls cell proliferation from membrane locations is still poorly understood. During our efforts to find potential merlin modulators through protein-protein interactions, we identified transactivation-responsive RNA-binding protein (TRBP) as a merlin-binding protein in a yeast two-hybrid screen. The interaction between TRBP and merlin was confirmed by glutathione S-transferase pull-down assays, co-immunoprecipitation, and co-localization experiments. The carboxyl-terminal regions of each protein were responsible for their interaction. Cells overexpressing TRBP showed enhanced cell growth in cell proliferation assays and also exhibited transformed phenotypes, such as anchorage-independent cell growth and tumor development in mouse xenografts. Merlin efficiently inhibited these oncogenic activities of TRBP in our experiments. These results provide the first clue to the functional interaction between TRBP and merlin and suggest a novel mechanism for the tumor suppressor function of merlin both in vitro and in vivo.
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PMID:Merlin, a tumor suppressor, interacts with transactivation-responsive RNA-binding protein and inhibits its oncogenic activity. 1512 92


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