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  1. Article ; Online: Peak BMP Responses in the Drosophila Embryo Are Dependent on the Activation of Integrin Signaling.

    Sawala, Annick / Scarcia, Margherita / Sutcliffe, Catherine / Wilcockson, Scott G / Ashe, Hilary L

    Cell reports

    2015  Volume 12, Issue 10, Page(s) 1584–1593

    Abstract: Within a 3D tissue, cells need to integrate signals from growth factors, such as BMPs, and the extracellular matrix (ECM) to coordinate growth and differentiation. Here, we use the Drosophila embryo as a model to investigate how BMP responses are ... ...

    Abstract Within a 3D tissue, cells need to integrate signals from growth factors, such as BMPs, and the extracellular matrix (ECM) to coordinate growth and differentiation. Here, we use the Drosophila embryo as a model to investigate how BMP responses are influenced by a cell's local ECM environment. We show that integrins, which are ECM receptors, are absolutely required for peak BMP signaling. This stimulatory effect of integrins requires their intracellular signaling function, which is activated by the ECM protein collagen IV. Mechanistically, integrins interact with the BMP receptor and stimulate phosphorylation of the downstream Mad transcription factor. The BMP-pathway-enhancing function of integrins is independent of focal adhesion kinase, but it requires conserved NPXY motifs in the β-integrin cytoplasmic tail. Furthermore, we show that an α-integrin subunit is a BMP target gene, identifying positive feedback between integrin signaling and BMP pathway activity that may contribute to robust cell fate decisions.
    MeSH term(s) Animals ; Bone Morphogenetic Proteins/physiology ; Cell Line ; Collagen Type IV/genetics ; Collagen Type IV/metabolism ; Drosophila Proteins/physiology ; Drosophila melanogaster/embryology ; Drosophila melanogaster/metabolism ; Embryo, Nonmammalian/metabolism ; Embryonic Development ; Feedback, Physiological ; Gene Expression ; Gene Expression Regulation, Developmental ; Integrins/physiology ; Signal Transduction
    Chemical Substances Bone Morphogenetic Proteins ; Collagen Type IV ; Drosophila Proteins ; Integrins
    Language English
    Publishing date 2015-09-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2015.08.012
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Peak BMP Responses in the Drosophila Embryo Are Dependent on the Activation of Integrin Signaling.

    Sawala, Annick / Scarcia, Margherita / Sutcliffe, Catherine / Wilcockson, Scott G / Ashe, Hilary L

    Cell reports

    2015  Volume 13, Issue 7, Page(s) 1519–1520

    Language English
    Publishing date 2015-11-17
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2015.10.079
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Chemically induced neurite-like outgrowth reveals a multicellular network function in patient-derived glioblastoma cells.

    da Silva, Barbara / Irving, Bronwyn K / Polson, Euan S / Droop, Alastair / Griffiths, Hollie B S / Mathew, Ryan K / Stead, Lucy F / Marrison, Joanne / Williams, Courtney / Williams, Jennifer / Short, Susan C / Scarcia, Margherita / O'Toole, Peter J / Allison, Simon J / Mavria, Georgia / Wurdak, Heiko

    Journal of cell science

    2019  Volume 132, Issue 19

    Abstract: Tumor stem cells and malignant multicellular networks have been separately implicated in the therapeutic resistance of glioblastoma multiforme (GBM), the most aggressive type of brain cancer in adults. Here, we show that small-molecule inhibition of RHO- ... ...

    Abstract Tumor stem cells and malignant multicellular networks have been separately implicated in the therapeutic resistance of glioblastoma multiforme (GBM), the most aggressive type of brain cancer in adults. Here, we show that small-molecule inhibition of RHO-associated serine/threonine kinase proteins (ROCKi) significantly promoted the outgrowth of neurite-like cell projections in cultures of heterogeneous patient-derived GBM stem-like cells. These projections formed
    MeSH term(s) Calcium Signaling/physiology ; Cell Line, Tumor ; Cell Movement/physiology ; Glioblastoma/metabolism ; Humans ; Immunoblotting ; Lysosomes/metabolism ; Mitochondria/metabolism ; Neoplastic Stem Cells/metabolism ; Neurites/metabolism ; Neuronal Outgrowth/physiology ; Phenotype ; Protein Serine-Threonine Kinases/metabolism
    Chemical Substances Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2019-10-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2993-2
    ISSN 1477-9137 ; 0021-9533
    ISSN (online) 1477-9137
    ISSN 0021-9533
    DOI 10.1242/jcs.228452
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1200: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 14: Show issues

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  4. Article ; Online: Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor.

    Liakouli, Vasiliki / Elies, Jacobo / El-Sherbiny, Yasser Mohamed / Scarcia, Margherita / Grant, Gary / Abignano, Giuseppina / Derrett-Smith, Emma C / Esteves, Filomena / Cipriani, Paola / Emery, Paul / Denton, Christopher P / Giacomelli, Roberto / Mavria, Georgia / Del Galdo, Francesco

    Annals of the rheumatic diseases

    2017  Volume 77, Issue 3, Page(s) 431–440

    Abstract: Objectives: Systemic sclerosis (SSc) is characterised by tissue fibrosis and vasculopathy with defective angiogenesis. Transforming growth factor beta (TGF-β) plays a major role in tissue fibrosis, including downregulation of caveolin-1 (Cav-1); however, ...

    Abstract Objectives: Systemic sclerosis (SSc) is characterised by tissue fibrosis and vasculopathy with defective angiogenesis. Transforming growth factor beta (TGF-β) plays a major role in tissue fibrosis, including downregulation of caveolin-1 (Cav-1); however, its role in defective angiogenesis is less clear. Pigment epithelium-derived factor (PEDF), a major antiangiogenic factor, is abundantly secreted by SSc fibroblasts. Here, we investigated the effect of TGF-β and Cav-1 on PEDF expression and the role of PEDF in the ability of SSc fibroblasts to modulate angiogenesis.
    Methods: PEDF and Cav-1 expression in fibroblasts and endothelial cells were evaluated by means of immunohistochemistry on human and mouse skin biopsies. PEDF and Cav-1 were silenced in cultured SSc and control fibroblasts using lentiviral short-hairpin RNAs. Organotypic fibroblast-endothelial cell co-cultures and matrigel assays were employed to assess angiogenesis.
    Results: PEDF is highly expressed in myofibroblasts and reticular fibroblasts with low Cav-1 expression in SSc skin biopsies, and it is induced by TGF-β in vitro. SSc fibroblasts suppress angiogenesis in an organotypic model. This model is reproduced by silencing Cav-1 in normal dermal fibroblasts. Conversely, silencing PEDF in SSc fibroblasts rescues their antiangiogenic phenotype. Consistently, transgenic mice with TGF-β receptor hyperactivation show lower Cav-1 and higher PEDF expression levels in skin biopsies accompanied by reduced blood vessel density.
    Conclusions: Our data reveal a new pathway by which TGF-β suppresses angiogenesis in SSc, through decreased fibroblast Cav-1 expression and subsequent PEDF secretion. This pathway may present a promising target for new therapeutic interventions in SSc.
    MeSH term(s) Animals ; Caveolin 1/metabolism ; Cells, Cultured ; Endothelial Cells/metabolism ; Eye Proteins/metabolism ; Female ; Fibroblasts/metabolism ; Humans ; Immunohistochemistry ; Male ; Mice ; Mice, Transgenic ; Neovascularization, Pathologic/metabolism ; Nerve Growth Factors/metabolism ; Real-Time Polymerase Chain Reaction ; Scleroderma, Systemic/metabolism ; Scleroderma, Systemic/pathology ; Serpins/metabolism ; Skin/pathology ; Transforming Growth Factor beta/metabolism
    Chemical Substances Caveolin 1 ; Eye Proteins ; Nerve Growth Factors ; Serpins ; Transforming Growth Factor beta ; pigment epithelium-derived factor
    Language English
    Publishing date 2017-12-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 7090-7
    ISSN 1468-2060 ; 0003-4967
    ISSN (online) 1468-2060
    ISSN 0003-4967
    DOI 10.1136/annrheumdis-2017-212120
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.114: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 167: Show issues

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  5. Article ; Online: RhoJ/TCL regulates endothelial motility and tube formation and modulates actomyosin contractility and focal adhesion numbers.

    Kaur, Sukhbir / Leszczynska, Katarzyna / Abraham, Sabu / Scarcia, Margherita / Hiltbrunner, Sabina / Marshall, Christopher J / Mavria, Georgia / Bicknell, Roy / Heath, Victoria L

    Arteriosclerosis, thrombosis, and vascular biology

    2010  Volume 31, Issue 3, Page(s) 657–664

    Abstract: Objective: RhoJ/TCL was identified by our group as an endothelial-expressed Rho GTPase. The aim of this study was to determine its tissue distribution, subcellular localization, and function in endothelial migration and tube formation.: Methods and ... ...

    Abstract Objective: RhoJ/TCL was identified by our group as an endothelial-expressed Rho GTPase. The aim of this study was to determine its tissue distribution, subcellular localization, and function in endothelial migration and tube formation.
    Methods and results: Using in situ hybridization, RhoJ was localized to endothelial cells in a set of normal and cancerous tissues and in the vasculature of mouse embryos; endogenous RhoJ was localized to focal adhesions by immunofluorescence. The proangiogenic factor vascular endothelial growth factor activated RhoJ in endothelial cells. Using either small interfering (si)RNA-mediated knockdown of RhoJ expression or overexpression of constitutively active RhoJ (daRhoJ), RhoJ was found to positively regulate endothelial motility and tubule formation. Downregulating RhoJ expression increased focal adhesions and stress fibers in migrating cells, whereas daRhoJ overexpression resulted in the converse. RhoJ downregulation resulted in increased contraction of a collagen gel and increased phospho-myosin light chain, indicative of increased actomyosin contractility. Pharmacological inhibition of Rho-kinase (which phosphorylates myosin light chain) or nonmuscle myosin II reversed the defective tube formation and migration of RhoJ knockdown cells.
    Conclusions: RhoJ is endothelial-expressed in vivo, activated by vascular endothelial growth factor, localizes to focal adhesions, regulates endothelial cell migration and tube formation, and modulates actomyosin contractility and focal adhesion numbers.
    MeSH term(s) Actomyosin/metabolism ; Animals ; Cell Movement/drug effects ; Cell Shape ; Cells, Cultured ; Endothelial Cells/drug effects ; Endothelial Cells/enzymology ; Fluorescent Antibody Technique ; Focal Adhesions/metabolism ; GTP Phosphohydrolases/genetics ; GTP Phosphohydrolases/metabolism ; Humans ; In Situ Hybridization ; Mice ; Myosin Light Chains/metabolism ; Neovascularization, Physiologic/drug effects ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; RNA Interference ; Stress Fibers/metabolism ; Transfection ; Vascular Endothelial Growth Factor A/metabolism ; rho GTP-Binding Proteins/genetics ; rho GTP-Binding Proteins/metabolism ; rho-Associated Kinases/antagonists & inhibitors ; rho-Associated Kinases/metabolism
    Chemical Substances Myosin Light Chains ; Protein Kinase Inhibitors ; Rhoj protein, mouse ; Vascular Endothelial Growth Factor A ; Actomyosin (9013-26-7) ; rho-Associated Kinases (EC 2.7.11.1) ; GTP Phosphohydrolases (EC 3.6.1.-) ; RHOJ protein, human (EC 3.6.1.-) ; rho GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2010-12-09
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1221433-4
    ISSN 1524-4636 ; 1079-5642
    ISSN (online) 1524-4636
    ISSN 1079-5642
    DOI 10.1161/ATVBAHA.110.216341
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1705: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  6. Article ; Online: A Rac/Cdc42 exchange factor complex promotes formation of lateral filopodia and blood vessel lumen morphogenesis.

    Abraham, Sabu / Scarcia, Margherita / Bagshaw, Richard D / McMahon, Kathryn / Grant, Gary / Harvey, Tracey / Yeo, Maggie / Esteves, Filomena O G / Thygesen, Helene H / Jones, Pamela F / Speirs, Valerie / Hanby, Andrew M / Selby, Peter J / Lorger, Mihaela / Dear, T Neil / Pawson, Tony / Marshall, Christopher J / Mavria, Georgia

    Nature communications

    2015  Volume 6, Page(s) 7286

    Abstract: During angiogenesis, Rho-GTPases influence endothelial cell migration and cell-cell adhesion; however it is not known whether they control formation of vessel lumens, which are essential for blood flow. Here, using an organotypic system that ... ...

    Abstract During angiogenesis, Rho-GTPases influence endothelial cell migration and cell-cell adhesion; however it is not known whether they control formation of vessel lumens, which are essential for blood flow. Here, using an organotypic system that recapitulates distinct stages of VEGF-dependent angiogenesis, we show that lumen formation requires early cytoskeletal remodelling and lateral cell-cell contacts, mediated through the RAC1 guanine nucleotide exchange factor (GEF) DOCK4 (dedicator of cytokinesis 4). DOCK4 signalling is necessary for lateral filopodial protrusions and tubule remodelling prior to lumen formation, whereas proximal, tip filopodia persist in the absence of DOCK4. VEGF-dependent Rac activation via DOCK4 is necessary for CDC42 activation to signal filopodia formation and depends on the activation of RHOG through the RHOG GEF, SGEF. VEGF promotes interaction of DOCK4 with the CDC42 GEF DOCK9. These studies identify a novel Rho-family GTPase activation cascade for the formation of endothelial cell filopodial protrusions necessary for tubule remodelling, thereby influencing subsequent stages of lumen morphogenesis.
    MeSH term(s) Animals ; Cytoskeleton/metabolism ; GTPase-Activating Proteins/physiology ; Guanine Nucleotide Exchange Factors/metabolism ; Human Umbilical Vein Endothelial Cells ; Humans ; Mice, Inbred C57BL ; Mice, Knockout ; Neovascularization, Pathologic ; Neovascularization, Physiologic ; Pseudopodia/physiology ; Vascular Endothelial Growth Factor A/metabolism ; cdc42 GTP-Binding Protein/metabolism ; rho GTP-Binding Proteins/metabolism
    Chemical Substances DOCK4 protein, human ; DOCK9 protein, human ; GTPase-Activating Proteins ; Guanine Nucleotide Exchange Factors ; Vascular Endothelial Growth Factor A ; RHOG protein, human (147605-13-8) ; cdc42 GTP-Binding Protein (EC 3.6.5.2) ; rho GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2015-07-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/ncomms8286
    Database MEDical Literature Analysis and Retrieval System OnLINE

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