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  1. Article ; Online: Modest Interference with Actin Dynamics in Primary T Cell Activation by Antigen Presenting Cells Preferentially Affects Lamellal Signaling.

    Roybal, Kole T / Mace, Emily M / Clark, Danielle J / Leard, Alan D / Herman, Andrew / Verkade, Paul / Orange, Jordan S / Wülfing, Christoph

    PloS one

    2015  Volume 10, Issue 8, Page(s) e0133231

    Abstract: Dynamic subcellular distributions of signaling system components are critical regulators of cellular signal transduction through their control of molecular interactions. Understanding how signaling activity depends on such distributions and the cellular ... ...

    Abstract Dynamic subcellular distributions of signaling system components are critical regulators of cellular signal transduction through their control of molecular interactions. Understanding how signaling activity depends on such distributions and the cellular structures driving them is required for comprehensive insight into signal transduction. In the activation of primary murine T cells by antigen presenting cells (APC) signaling intermediates associate with various subcellular structures, prominently a transient, wide, and actin-associated lamellum extending from an interdigitated T cell:APC interface several micrometers into the T cell. While actin dynamics are well established as general regulators of cellular organization, their role in controlling signaling organization in primary T cell:APC couples and the specific cellular structures driving it is unresolved. Using modest interference with actin dynamics with a low concentration of Jasplakinolide as corroborated by costimulation blockade we show that T cell actin preferentially controls lamellal signaling localization and activity leading downstream to calcium signaling. Lamellal localization repeatedly related to efficient T cell function. This suggests that the transient lamellal actin matrix regulates T cell signaling associations that facilitate T cell activation.
    MeSH term(s) Actins/metabolism ; Animals ; Antigen-Presenting Cells/drug effects ; Antigen-Presenting Cells/immunology ; Antigen-Presenting Cells/metabolism ; Calcium Signaling/drug effects ; Calcium Signaling/immunology ; Depsipeptides/pharmacology ; Lymphocyte Activation/drug effects ; Lymphocyte Activation/immunology ; Mice ; Phosphorylation/drug effects ; Signal Transduction/drug effects ; Signal Transduction/immunology ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
    Chemical Substances Actins ; Depsipeptides ; jasplakinolide (102396-24-7)
    Language English
    Publishing date 2015-08-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0133231
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Co-ordinate regulation of distinct host cell signalling pathways by multifunctional enteropathogenic Escherichia coli effector molecules.

    Kenny, Brendan / Ellis, Sarah / Leard, Alan D / Warawa, Jonathan / Mellor, Harry / Jepson, Mark A

    Molecular microbiology

    2002  Volume 44, Issue 4, Page(s) 1095–1107

    Abstract: Enteropathogenic Escherichia coli (EPEC) is a major cause of paediatric diarrhoea and a model for the family of attaching and effacing (A/E) pathogens. A/E pathogens encode a type III secretion system to transfer effector proteins into host cells. The ... ...

    Abstract Enteropathogenic Escherichia coli (EPEC) is a major cause of paediatric diarrhoea and a model for the family of attaching and effacing (A/E) pathogens. A/E pathogens encode a type III secretion system to transfer effector proteins into host cells. The EPEC Tir effector protein acts as a receptor for the bacterial surface protein intimin and is involved in the formation of Cdc42-independent, actin-rich pedestal structures beneath the adhered bacteria. In this paper, we demonstrate that EPEC binding to HeLa cells also induces Tir-independent, cytoskeletal rearrangement evidenced by the early, transient formation of filopodia-like structures at sites of infection. Filopodia formation is dependent on expression of the EPEC Map effector molecule - a protein that targets mitochondria and induces their dysfunction. We show that Map-induced filopodia formation is independent of mitochondrial targeting and is abolished by cellular expression of the Cdc42 inhibitory WASP-CRIB domain, demonstrating that Map has at least two distinct functions in host cells. The transient nature of the filopodia is related to an ability of EPEC to downregulate Map-induced cell signalling that, like pedestal formation, was dependent on both Tir and intimin proteins. The ability of Tir to downregulate filopodia was impaired by disrupting a putative GTPase-activating protein (GAP) motif, suggesting that Tir may possess such a function, with its interaction with intimin triggering this activity. Furthermore, we also found that Map-induced cell signalling inhibits pedestal formation, revealing that the cellular effects of Tir and Map must be co-ordinately regulated during infection. Possible implications of the multifunctional nature of EPEC effector molecules in pathogenesis are discussed.
    MeSH term(s) Actins/metabolism ; Adhesins, Bacterial/metabolism ; Bacterial Adhesion ; Carrier Proteins/metabolism ; Cytoskeleton/metabolism ; Cytoskeleton/microbiology ; Diarrhea/metabolism ; Diarrhea/microbiology ; Down-Regulation ; Epithelial Cells/metabolism ; Epithelial Cells/microbiology ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Escherichia coli/pathogenicity ; Escherichia coli/ultrastructure ; Escherichia coli Infections/metabolism ; Escherichia coli Infections/microbiology ; Escherichia coli Proteins ; HeLa Cells ; Humans ; Models, Biological ; Protein Binding ; Pseudopodia/physiology ; Receptors, Cell Surface/metabolism ; Signal Transduction ; cdc42 GTP-Binding Protein/metabolism
    Chemical Substances Actins ; Adhesins, Bacterial ; Carrier Proteins ; Escherichia coli Proteins ; Receptors, Cell Surface ; Tir protein, E coli ; eaeA protein, E coli (147094-99-3) ; cdc42 GTP-Binding Protein (EC 3.6.5.2)
    Language English
    Publishing date 2002-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 619315-8
    ISSN 1365-2958 ; 0950-382X
    ISSN (online) 1365-2958
    ISSN 0950-382X
    DOI 10.1046/j.1365-2958.2002.02952.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2502: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article: Synergistic roles for the Map and Tir effector molecules in mediating uptake of enteropathogenic Escherichia coli (EPEC) into non-phagocytic cells.

    Jepson, Mark A / Pellegrin, Stephanie / Peto, Leon / Banbury, David N / Leard, Alan D / Mellor, Harry / Kenny, Brendan

    Cellular microbiology

    2003  Volume 5, Issue 11, Page(s) 773–783

    Abstract: Enteropathogenic Escherichia coli (EPEC) are a major cause of paediatric diarrhoea and a model for the family of attaching and effacing (A/E) pathogens. Enteropathogenic Escherichia coli encode a type III secretion system (TTSS) to transfer effector ... ...

    Abstract Enteropathogenic Escherichia coli (EPEC) are a major cause of paediatric diarrhoea and a model for the family of attaching and effacing (A/E) pathogens. Enteropathogenic Escherichia coli encode a type III secretion system (TTSS) to transfer effector proteins into host cells, a process which is essential for virulence. In addition to generation of A/E lesions, the TTSS is also implicated in the ability of EPEC to invade cultured cells but the effector proteins responsible for promoting invasion have not been identified. In this paper we confirm the requirement of TTSS in EPEC invasion and demonstrate important roles for the Map and Tir effector molecules. Whereas in trans expression of Tir in the tir mutant restored invasion to wild-type levels, similar complementation of the map mutation by in trans expression of Map results in a hyperinvasive phenotype. The Map effector protein has two distinct functions within host cells, mediating Cdc42-dependent filopodia formation and targeting mitochondria to elicit dysfunction. The former function appears to be related to Map's ability to promote invasion as this was inhibited by interference with Cdc42 signalling. Conversely, Map targeting to mitochondria is not necessary for invasion. Promotion of EPEC invasion by Tir appears to involve interaction with intimin but is independent of pedestal formation, and intimin-Tir interaction is neither necessary nor sufficient for invasion. Comparison of the invasiveness of strains lacking Tir and/or Map with wild-type or mutant strains expressing the effectors in trans provides evidence that Map and Tir stimulate invasion by synergistic mechanisms. This synergism, which is in stark contrast to the antagonistic actions of Map and Tir in regulating filopodia and pedestal formation, further illustrates the complex interplay between EPEC effectors.
    MeSH term(s) Adhesins, Bacterial/genetics ; Adhesins, Bacterial/metabolism ; Animals ; Biological Transport ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Escherichia coli/metabolism ; Escherichia coli/pathogenicity ; Escherichia coli/ultrastructure ; Escherichia coli Proteins/genetics ; Escherichia coli Proteins/metabolism ; HeLa Cells ; Humans ; Phagocytes/metabolism ; Proteins/genetics ; Proteins/metabolism ; Pseudopodia/metabolism ; Pseudopodia/ultrastructure ; RNA, Small Interfering/metabolism ; Receptors, Cell Surface/genetics ; Receptors, Cell Surface/metabolism ; Recombinant Fusion Proteins/metabolism ; Wiskott-Aldrich Syndrome Protein ; cdc42 GTP-Binding Protein/genetics ; cdc42 GTP-Binding Protein/metabolism ; rac1 GTP-Binding Protein/genetics ; rac1 GTP-Binding Protein/metabolism
    Chemical Substances Adhesins, Bacterial ; Carrier Proteins ; Escherichia coli Proteins ; Proteins ; RNA, Small Interfering ; Receptors, Cell Surface ; Recombinant Fusion Proteins ; Tir protein, E coli ; WAS protein, human ; Wiskott-Aldrich Syndrome Protein ; eaeA protein, E coli (147094-99-3) ; cdc42 GTP-Binding Protein (EC 3.6.5.2) ; rac1 GTP-Binding Protein (EC 3.6.5.2)
    Language English
    Publishing date 2003-10-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1468320-9
    ISSN 1462-5822 ; 1462-5814
    ISSN (online) 1462-5822
    ISSN 1462-5814
    DOI 10.1046/j.1462-5822.2003.00315.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5288: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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