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Pierre Jalinot - One of the best experts on this subject based on the ideXlab platform.
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human papillomavirus type 18 e6 Protein binds the cellular PDZ Protein tip 2 gipc which is involved in transforming growth factor β signaling and triggers its degradation by the proteasome
Journal of Virology, 2005Co-Authors: Arnaud Favrebonvin, Caroline Reynaud, Carole Kretzremy, Pierre JalinotAbstract:Several viral Proteins expressed by DNA or RNA transforming viruses have the particular property of binding via their C-terminal end to various cellular Proteins with PDZ domains. This study is focused on the PDZ Protein TIP-2/GIPC, which was originally identified in two-hybrid screens performed with two different baits: the human T-cell leukemia virus type 1 Tax oncoProtein and the regulator of G signaling RGS-GAIP. Further studies have shown that TIP-2/GIPC is also able to associate with the cytoplasmic domains of various transmembrane Proteins. In this report we show that TIP-2/GIPC interacts with the E6 Protein of human papillomavirus type 18 (HPV-18). This event triggers polyubiquitination and proteasome-mediated degradation of the cellular Protein. In agreement with this observation, silencing of E6 by RNA interference in HeLa cells causes an increase in the intracellular TIP-2/GIPC level. This PDZ Protein has been previously found to be involved in transforming growth factor β (TGF-β) signaling by favoring expression of the TGF-β type III receptor at the cell membrane. In line with this activity of TIP-2/GIPC, we observed that depletion of this Protein in HeLa cells hampers induction of the Id3 gene by TGF-β treatment and also diminishes the antiproliferative effect of this cytokine. Conversely, silencing of E6 increases the expression of Id3 and blocks proliferation of HeLa cells. These results support the notion that HPV-18 E6 renders cells less sensitive to the cytostatic effect of TGF-β by lowering the intracellular amount of TIP-2/GIPC.
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Human papillomavirus type 18 E6 Protein binds the cellular PDZ Protein TIP-2/GIPC, which is involved in transforming growth factor beta signaling and triggers its degradation by the proteasome.
Journal of Virology, 2005Co-Authors: Arnaud Favre-bonvin, Caroline Reynaud, Carole Kretz-remy, Pierre JalinotAbstract:Several viral Proteins expressed by DNA or RNA transforming viruses have the particular property of binding via their C-terminal end to various cellular Proteins with PDZ domains. This study is focused on the PDZ Protein TIP-2/GIPC, which was originally identified in two-hybrid screens performed with two different baits: the human T-cell leukemia virus type 1 Tax oncoProtein and the regulator of G signaling RGS-GAIP. Further studies have shown that TIP-2/GIPC is also able to associate with the cytoplasmic domains of various transmembrane Proteins. In this report we show that TIP-2/GIPC interacts with the E6 Protein of human papillomavirus type 18 (HPV-18). This event triggers polyubiquitination and proteasome-mediated degradation of the cellular Protein. In agreement with this observation, silencing of E6 by RNA interference in HeLa cells causes an increase in the intracellular TIP-2/GIPC level. This PDZ Protein has been previously found to be involved in transforming growth factor beta (TGF-beta) signaling by favoring expression of the TGF-beta type III receptor at the cell membrane. In line with this activity of TIP-2/GIPC, we observed that depletion of this Protein in HeLa cells hampers induction of the Id3 gene by TGF-beta treatment and also diminishes the antiproliferative effect of this cytokine. Conversely, silencing of E6 increases the expression of Id3 and blocks proliferation of HeLa cells. These results support the notion that HPV-18 E6 renders cells less sensitive to the cytostatic effect of TGF-beta by lowering the intracellular amount of TIP-2/GIPC.
Pascale Zimmermann - One of the best experts on this subject based on the ideXlab platform.
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The characterization of the nuclear dynamics of syntenin-2, a PIP2 binding PDZ Protein.
Cytometry. Part A : the journal of the International Society for Analytical Cytology, 2013Co-Authors: Annelies Geeraerts, Pascale Zimmermann, Fan Hsiu-fang, Yves EngelborghsAbstract:Cellular signaling is largely dependent on the presence, that is, assembly/disassembly, of supramolecular complexes. Postsynaptic density Protein, Discs-large, Zona occludens (PDZ) domains play important roles in the assembly of various signaling complexes. Syntenin-2 (S2) is a PDZ Protein that interacts with nuclear phosphatidylinositol 4,5-bisphosphate (PIP2 ). Although nuclear lipids emerge as key players in nuclear processes, the global significance of nuclear phosphoinositide-Protein interactions is still poorly understood. Those phosphoinositide-Protein interactions that have been studied in detail appear to have profound physiological effects. To our knowledge none of these were investigated by dynamic studies such as Fluorescence Correlation Spectroscopy (FCS), Fluorescence Cross-Correlation Spectroscopy (FCCS), or Fluorescence Recovery After Photobleaching (FRAP). Although the exact function of S2 is unknown, siRNA experiments suggest that this PDZ Protein plays a role in the organization of nuclear PIP2 , cell division, and cell survival. As a consequence of its PIP2 interaction, its reported self-association in a yeast two-hybrid study and its speculated interaction with many, yet unidentified, Proteins one can hypothesize that S2 plays an important role in cell signaling. Therefore, we studied the dynamics of S2 using FCS, FCCS, and FRAP, utilizing an active truncated form deleted for the first 94 amino acids (S2-ΔN). We showed that S2-ΔN self-associates and is distributed in three groups. One immobile group, one slow diffusing group, which interacts with the nuclear environment and one fast diffusing group, which is not incorporated in high molecular weight complexes. In addition, our FCS and FRAP measurements on S2-ΔN mutants affected in their PIP2 binding showed that PIP2 plays an important role in the distribution of S2-ΔN among these groups, and favors the enrichment of S2-ΔN in the slow diffusing and immobile group. This work indicates that S2 relies on nuclear PIP2 to interact with practically immobile structures, possibly chromatin.
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Extensions of PSD‐95/discs large/ZO‐1 (PDZ) domains influence lipid binding and membrane targeting of syntenin‐1
FEBS Letters, 2012Co-Authors: Anna Anna Maria Wawrzyniak, Elke Vermeiren, Pascale Zimmermann, Ylva IvarssonAbstract:Abstract Syntenin-1 is a PDZ Protein involved in receptor recycling and clustering. Its two PDZ domains interact with various receptors and phosphoinositides, and are flanked by N- and C-terminal regions. Here, we report the identification of an autoinhibitory peptide stretch in the N-terminus that might be regulated by phosphorylation. We further establish that basic residues in the C-terminal region mediate electrostatic interactions with reconstituted liposomes and contribute to the plasma membrane targeting. Our study adds new components to the multi-dentate membrane targeting mechanism and highlights the role of N- and C-terminal PDZ extensions in the regulation of syntenin-1 plasma membrane localization. Structured summary of Protein interactions PDZ1-PDZ2 and peptide bind by fluorescence technology (View Interaction: 1 , 2 , 3 , 4 ).
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abstract 5347 disruption of PDZ Protein Protein interactions inhibits tax transformation and htlv 1 infection capacities
Cancer Research, 2010Co-Authors: Jeanclaude Twizere, Naoaki Fujii, Pascale Zimmermann, Jeanfrancois Dewulf, Sebastien Legros, Mathieu Boxus, Richard KettmannAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Approximately 15 to 25 million people worldwide are infected with human T-cell leukaemia virus type 1 (HTLV-1) or type 2 (HTLV-2). One of the viral regulatory Proteins, Tax, is critical for viral transcription and replication and has been clearly implicated in T-lymphocyte transformation in vitro and oncogenesis in vivo. Elucidation of the metabolic processes involved in Tax activity is thus of prime importance for understanding the pathogenesis induce by HTLV. Interactions between Tax and a selected group of PDZ containing Proteins are associated with the transforming activities of Tax1 as well as persistent HTLV-1 infection. We demonstrate that the PDZ-containing Protein syntenin-1 and −2, known to interact with Heparan sulfate proteoglycan receptor syndecan-1 and to connect cytoskeletal Proteins, interact with HTLV-1 Tax and with the HTLV-1 receptor GLUT-1 but not with HTLV-2 Tax. Both PDZ1 and 2 domains of syntenins are required for Tax binding. We also show that syntenin-2 co-localizes with Tax in nuclear speckles. Furthermore, we demonstrate that an antagonist for PDZ Protein- Protein interaction suppresses Tax-induced transformation and prevents T cell infection by HTLV-1. Thus, disruption of PDZ Protein-Protein interaction may provide new therapeutic opportunities for HTLV-1 induced diseases. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5347.
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Characterization of syntenin, a syndecan-binding PDZ Protein, as a component of cell adhesion sites and microfilaments.
Molecular biology of the cell, 2001Co-Authors: Pascale Zimmermann, Daniela Tomatis, Marcela Rosas, Johan Grootjans, Iris Leenaerts, Gisèle Degeest, Gunter Reekmans, Christien Coomans, Guido DavidAbstract:Syntenin is a PDZ Protein that binds the cytoplasmic C-terminal FYA motif of the syndecans. Syntenin is widely expressed. In cell fractionation experiments, syntenin partitions between the cytosol ...
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Characterization of syntenin, a syndecan-binding PDZ Protein, as a component of cell adhesion sites and microfilaments.
Molecular biology of the cell, 2001Co-Authors: Pascale Zimmermann, Daniela Tomatis, Marcela Rosas, Johan Grootjans, Iris Leenaerts, Gisèle Degeest, Gunter Reekmans, Christien Coomans, Guido DavidAbstract:Syntenin is a PDZ Protein that binds the cytoplasmic C-terminal FYA motif of the syndecans. Syntenin is widely expressed. In cell fractionation experiments, syntenin partitions between the cytosol and microsomes. Immunofluorescence microscopy localizes endogenous and epitope-tagged syntenin to cell adhesion sites, microfilaments, and the nucleus. Syntenin is composed of at least three domains. Both PDZ domains of syntenin are necessary to target reporter tags to the plasma membrane. The addition of a segment of 10 amino acids from the N-terminal domain of syntenin to these PDZ domains increases the localization of the tags to stress fibers and induces the formation of long, branching plasma membrane extensions. The addition of the complete N-terminal region, in contrast, reduces the localization of the tags to plasma membrane/adhesion sites and stress fibers, and reduces the morphotypical effects. Recombinant domains of syntenin with the highest plasma membrane localization display the lowest nuclear localization. Syndecan-1, E-cadherin, β-catenin, and α-catenin colocalize with syntenin at cell-cell contacts in epithelial cells, and coimmunoprecipitate with syntenin from extracts of these cells. These results suggest a role for syntenin in the composition of adherens junctions and the regulation of plasma membrane dynamics, and imply a potential role for syntenin in nuclear processes.
Guido David - One of the best experts on this subject based on the ideXlab platform.
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Characterization of syntenin, a syndecan-binding PDZ Protein, as a component of cell adhesion sites and microfilaments.
Molecular biology of the cell, 2001Co-Authors: Pascale Zimmermann, Daniela Tomatis, Marcela Rosas, Johan Grootjans, Iris Leenaerts, Gisèle Degeest, Gunter Reekmans, Christien Coomans, Guido DavidAbstract:Syntenin is a PDZ Protein that binds the cytoplasmic C-terminal FYA motif of the syndecans. Syntenin is widely expressed. In cell fractionation experiments, syntenin partitions between the cytosol ...
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Characterization of syntenin, a syndecan-binding PDZ Protein, as a component of cell adhesion sites and microfilaments.
Molecular biology of the cell, 2001Co-Authors: Pascale Zimmermann, Daniela Tomatis, Marcela Rosas, Johan Grootjans, Iris Leenaerts, Gisèle Degeest, Gunter Reekmans, Christien Coomans, Guido DavidAbstract:Syntenin is a PDZ Protein that binds the cytoplasmic C-terminal FYA motif of the syndecans. Syntenin is widely expressed. In cell fractionation experiments, syntenin partitions between the cytosol and microsomes. Immunofluorescence microscopy localizes endogenous and epitope-tagged syntenin to cell adhesion sites, microfilaments, and the nucleus. Syntenin is composed of at least three domains. Both PDZ domains of syntenin are necessary to target reporter tags to the plasma membrane. The addition of a segment of 10 amino acids from the N-terminal domain of syntenin to these PDZ domains increases the localization of the tags to stress fibers and induces the formation of long, branching plasma membrane extensions. The addition of the complete N-terminal region, in contrast, reduces the localization of the tags to plasma membrane/adhesion sites and stress fibers, and reduces the morphotypical effects. Recombinant domains of syntenin with the highest plasma membrane localization display the lowest nuclear localization. Syndecan-1, E-cadherin, β-catenin, and α-catenin colocalize with syntenin at cell-cell contacts in epithelial cells, and coimmunoprecipitate with syntenin from extracts of these cells. These results suggest a role for syntenin in the composition of adherens junctions and the regulation of plasma membrane dynamics, and imply a potential role for syntenin in nuclear processes.
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Syntenin, a PDZ Protein that binds syndecan cytoplasmic domains
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Jan-johannes Grootjans, Pascale Zimmermann, Gisèle Degeest, Gunter Reekmans, Anne Smets, Joachim Dürr, Guido DavidAbstract:The syndecans are transmembrane proteoglycans that place structurally heterogeneous heparan sulfate chains at the cell surface and a highly conserved polypeptide in the cytoplasm. Their versatile heparan sulfate moieties support various processes of molecular recognition, signaling, and trafficking. Here we report the identification of a Protein that binds to the cytoplasmic domains of the syndecans in yeast two-hybrid screens, surface plasmon resonance experiments, and ligand-overlay assays. This Protein, syntenin, contains a tandem repeat of PDZ domains that reacts with the FYA C-terminal amino acid sequence of the syndecans. Recombinant enhanced green fluorescent Protein (eGFP)–syntenin fusion Proteins decorate the plasmamembrane and intracellular vesicles, where they colocalize and cosegregate with syndecans. Cells that overexpress eGFP–syntenin show numerous cell surface extensions, suggesting effects of syntenin on cytoskeleton–membrane organization. We propose that syntenin may function as an adaptor that couples syndecans to cytoskeletal Proteins or cytosolic downstream signal-effectors.
Ana Carmena - One of the best experts on this subject based on the ideXlab platform.
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The PDZ Protein Canoe regulates the asymmetric division of Drosophila neuroblasts and muscle progenitors.
Current biology : CB, 2008Co-Authors: Stephan Speicher, Anja Fischer, Juergen A. Knoblich, Ana CarmenaAbstract:Summary Asymmetric cell division is a conserved mechanism to generate cellular diversity during animal development and a key process in cancer and stem cell biology [1, 2]. Despite the increasing number of Proteins characterized, the complex network of Proteins interactions established during asymmetric cell division is still poorly understood. This suggests that additional components must be contributing to orchestrate all the events underlying this tightly modulated process. The PDZ Protein Canoe (Cno) and its mammalian counterparts AF-6 and Afadin are critical to regulate intracellular signaling and to organize cell junctions throughout development [3–13]. Here, we show that Cno functions as a new effector of the apical Proteins Inscuteable (Insc)-Partner of Inscuteable (Pins)-Gαi during the asymmetric division of Drosophila neuroblasts (NBs) [2]. Cno localizes apically in metaphase NBs and coimmnunoprecipitates with Pins in vivo. Furthermore, Cno functionally interacts with the apical Proteins Insc, Gαi, and Mushroom body defect (Mud) to generate correct neuronal lineages. Failures in muscle and heart lineages are also detected in cno mutant embryos. Our results strongly support a new function for Cno regulating key processes during asymmetric NB division: the localization of cell-fate determinants, the orientation of the mitotic spindle, and the generation of unequal-sized daughter cells.
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the PDZ Protein canoe af 6 links ras mapk notch and wingless wnt signaling pathways by directly interacting with ras notch and dishevelled
PLOS ONE, 2006Co-Authors: Stephan Speicher, Ana Carmena, Mary K BayliesAbstract:Over the past few years, it has become increasingly apparent that signal transduction pathways are not merely linear cascades; they are organized into complex signaling networks that require high levels of regulation to generate precise and unique cell responses. However, the underlying regulatory mechanisms by which signaling pathways cross-communicate remain poorly understood. Here we show that the Ras-binding Protein Canoe (Cno)/AF-6, a PDZ Protein normally associated with cellular junctions, is a key modulator of Wingless (Wg)/Wnt, Ras-Mitogen Activated Protein Kinase (MAPK) and Notch (N) signaling pathways cross-communication. Our data show a repressive effect of Cno/AF-6 on these three signaling pathways through physical interactions with Ras, N and the cytoplasmic Protein Dishevelled (Dsh), a key Wg effector. We propose a model in which Cno, through those interactions, actively coordinates, at the membrane level, Ras-MAPK, N and Wg signaling pathways during progenitor specification.
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The PDZ Protein Canoe/AF-6 Links Ras-MAPK, Notch and Wingless/Wnt Signaling Pathways by Directly Interacting with Ras, Notch and Dishevelled
PloS one, 2006Co-Authors: Ana Carmena, Stephan Speicher, Mary K BayliesAbstract:Over the past few years, it has become increasingly apparent that signal transduction pathways are not merely linear cascades; they are organized into complex signaling networks that require high levels of regulation to generate precise and unique cell responses. However, the underlying regulatory mechanisms by which signaling pathways cross-communicate remain poorly understood. Here we show that the Ras-binding Protein Canoe (Cno)/AF-6, a PDZ Protein normally associated with cellular junctions, is a key modulator of Wingless (Wg)/Wnt, Ras-Mitogen Activated Protein Kinase (MAPK) and Notch (N) signaling pathways cross-communication. Our data show a repressive effect of Cno/AF-6 on these three signaling pathways through physical interactions with Ras, N and the cytoplasmic Protein Dishevelled (Dsh), a key Wg effector. We propose a model in which Cno, through those interactions, actively coordinates, at the membrane level, Ras-MAPK, N and Wg signaling pathways during progenitor specification.
Hiromu Sugino - One of the best experts on this subject based on the ideXlab platform.
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regulation of endocytosis of activin type ii receptors by a novel PDZ Protein through ral ral binding Protein 1 dependent pathway
Journal of Biological Chemistry, 2002Co-Authors: Takashi Matsuzaki, Kunihiro Tsuchida, Hisashi Kishi, Zhong Hui Liu, Sayuri Hanai, Yongli Bao, Akira Kikuchi, Hiromu SuginoAbstract:Using yeast two-hybrid screening, we have identified a mouse Postsynaptic density 95/Discs large/Zona occludens-1 (PDZ) Protein that interacts with activin type II receptors (ActRIIs). We named the Protein activin receptor-interacting Protein 2 (ARIP2). ARIP2 was found to have one PDZ domain in the NH2-terminal region and interact specifically with ActRIIs among the receptors for the transforming growth factor β family by the PDZ domain. Interestingly, overexpression of ARIP2 enhances endocytosis of ActRIIs and reduces activin-induced transcription in Chinese hamster ovary K1 cells. In addition, immunofluorescence co-localization studies indicated the direct involvement of ARIP2 in the intracellular translocation of ActRIIs by PDZ domain-mediated interaction. Moreover, we have identified that the COOH-terminal region of ARIP2 interacts with Ral-binding Protein 1 (RalBP1). RalBP1 is a potential effector Protein of small GTP-binding Protein Ral and regulates endocytosis of epidermal growth factor and insulin receptors. The studies using deletion mutants of RalBP1 and constitutively GTP and GDP binding forms of Ral indicate that ARIP2 regulates endocytosis of ActRIIs through the Ral/RalBP1-dependent pathway, and the GDP-GTP exchange of Ral is critical for this regulation.
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Regulation of Endocytosis of Activin Type II Receptors by a Novel PDZ Protein through Ral/Ral-binding Protein 1-dependent Pathway
The Journal of biological chemistry, 2002Co-Authors: Takashi Matsuzaki, Kunihiro Tsuchida, Hisashi Kishi, Zhong Hui Liu, Sayuri Hanai, Yongli Bao, Akira Kikuchi, Hiromu SuginoAbstract:Using yeast two-hybrid screening, we have identified a mouse Postsynaptic density 95/Discs large/Zona occludens-1 (PDZ) Protein that interacts with activin type II receptors (ActRIIs). We named the Protein activin receptor-interacting Protein 2 (ARIP2). ARIP2 was found to have one PDZ domain in the NH2-terminal region and interact specifically with ActRIIs among the receptors for the transforming growth factor β family by the PDZ domain. Interestingly, overexpression of ARIP2 enhances endocytosis of ActRIIs and reduces activin-induced transcription in Chinese hamster ovary K1 cells. In addition, immunofluorescence co-localization studies indicated the direct involvement of ARIP2 in the intracellular translocation of ActRIIs by PDZ domain-mediated interaction. Moreover, we have identified that the COOH-terminal region of ARIP2 interacts with Ral-binding Protein 1 (RalBP1). RalBP1 is a potential effector Protein of small GTP-binding Protein Ral and regulates endocytosis of epidermal growth factor and insulin receptors. The studies using deletion mutants of RalBP1 and constitutively GTP and GDP binding forms of Ral indicate that ARIP2 regulates endocytosis of ActRIIs through the Ral/RalBP1-dependent pathway, and the GDP-GTP exchange of Ral is critical for this regulation.
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Identification and Characterization of a PDZ Protein That Interacts with Activin Type II Receptors
The Journal of biological chemistry, 2000Co-Authors: Hiroki Shoji, Kunihiro Tsuchida, Hisashi Kishi, Norio Yamakawa, Takashi Matsuzaki, Zhong Hui Liu, Takanori Nakamura, Hiromu SuginoAbstract:Abstract We have identified a mouse PDZ Protein that interacts with the activin type IIA receptor (ActRIIA), which we named activin receptor-interacting Protein 1 (ARIP1). By using yeast two-hybrid screening, we isolated a cDNA clone of ARIP1 from a mouse brain cDNA library. We detected two forms of ARIP1, ARIP1-long and ARIP1-short, which may be produced by alternative splicing. ARIP1-long had one guanylate kinase domain in the NH2-terminal region, followed by two WW domains and five PDZ domains (PDZ1–5). ARIP1-short had a deletion in the NH2-terminal region and lacked the guanylate kinase domain. Both forms interacted with ActRIIA through PDZ5. The COOH-terminal residues of ActRIIA (ESSL) agree with a PDZ-binding consensus motif, and ARIP1 recognized the consensus sequence. ARIP1 interacts specifically with ActRIIA among the receptors for the transforming growth factor β family. Interestingly, ARIP1 also interacted with Smad3, which is an activin/transforming growth factor β intracellular signaling molecule. The mRNA of ARIP1 was more abundant in the brain than in other tissues. Overexpression of ARIP1 controls activin-induced and Smad3-induced transcription in activin-responsive cell lines. These findings suggest that ARIP1 has a significant role in assembling activin signaling molecules at specific subcellular sites and in regulating signal transduction in neuronal cells.