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9 results on '"MESH : Cell Adhesion"'

1. Sex differences in the GSK3β-mediated survival of adherent leukemic progenitors

Author

Jessica Bertrand, Bernard Payrastre, N Gallay, Nathalie Vergnolle, Véronique Maguer-Satta, Mathieu Despeaux, Cécile Demur, Ezzeddine Bourogaa, S Joly, P Bonnevialle, F Louache, Claire Racaud-Sultan, ANDRA, Laboratoire d'Hématologie [Purpan], Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Equipe 11, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Physiopathologie Toulouse Purpan, Université Paul Sabatier - Toulouse 3 ( UPS ) -IFR30-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Departement /u563 : Oncogenèse, Signalisation et Innovation thérapeutique, Université Paul Sabatier - Toulouse 3 ( UPS ) -Institut Claudius Regaud-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Claudius Regaud

Subjects
Male, MESH : Aged, Antigens, CD34, MESH : Blotting, Western, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Glycogen Synthase Kinase 3, 0302 clinical medicine, MESH : Indoles, MESH : Tumor Cells, Cultured, GSK-3, Tumor Cells, Cultured, Protein Phosphatase 2, MESH : GTP-Binding Proteins, Cells, Cultured, MESH: Glycogen Synthase Kinase 3, MESH: Etoposide, Etoposide, MESH: Indoles, MESH : Maleimides, Aged, 80 and over, MESH : Cell Survival, 0303 health sciences, education.field_of_study, MESH: Middle Aged, MESH: Protein Phosphatase 2, Neoplasm Proteins, MESH: Cell Survival, MESH: Young Adult, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, RNA Interference, MESH: Cells, Cultured, MESH : Protein Phosphatase 2, MESH : Glycogen Synthase Kinase 3, MESH: Antineoplastic Agents, Phytogenic, Blotting, Western, MESH : Young Adult, Receptors, Cell Surface, MESH: Cell Adhesion, 03 medical and health sciences, MESH : Neoplasm Proteins, MESH: Sex Factors, Genetics, MESH: Blotting, Western, Humans, MESH : Middle Aged, MESH: Tumor Cells, Cultured, Progenitor cell, MESH : Aged, 80 and over, Clonogenic assay, education, Molecular Biology, Aged, MESH: Interleukin-3 Receptor alpha Subunit, MESH: Humans, Glycogen Synthase Kinase 3 beta, MESH : Hematopoietic Stem Cells, MESH : Humans, MESH : Leukemia, MESH: Adult, MESH: Antigens, CD34, Protein phosphatase 2, Hematopoietic Stem Cells, MESH: Neoplastic Stem Cells, Immunology, MESH: Female, MESH: Neoplasm Proteins, Cancer Research, Indoles, MESH : Receptors, Cell Surface, MESH : Interleukin-3 Receptor alpha Subunit, MESH : Antineoplastic Agents, Phytogenic, MESH: Hematopoietic Stem Cells, Maleimides, MESH: Aged, 80 and over, MESH : Female, MESH: Maleimides, MESH: Receptors, Cell Surface, MESH: Aged, Leukemia, Myeloid leukemia, MESH : Adult, Middle Aged, medicine.anatomical_structure, MESH : Antigens, CD34, Female, Stem cell, Adult, MESH: GTP-Binding Proteins, Cell Survival, MESH : Male, MESH : Sex Factors, MESH: RNA Interference, Population, Interleukin-3 Receptor alpha Subunit, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : Etoposide, Biology, Receptors for Activated C Kinase, Young Adult, MESH : Neoplastic Stem Cells, Sex Factors, GTP-Binding Proteins, MESH: Leukemia, MESH : Cells, Cultured, Cell Adhesion, medicine, 030304 developmental biology, Antineoplastic Agents, Phytogenic, MESH: Male, MESH : Cell Adhesion, Cancer research, Bone marrow, MESH : RNA Interference
Abstract

International audience; Therapeutic resistance of acute myeloid leukemia stem cells, enriched in the CD34(+)38(-)123(+) progenitor population, is supported by extrinsic factors such as the bone marrow niche. Here, we report that when adherent onto fibronectin or osteoblast components, CD34(+)38(-)123(+) progenitors survive through an integrin-dependent activation of glycogen synthase kinase 3β (GSK3β) by serine 9-dephosphorylation. Strikingly, GSK3β-mediated survival was restricted to leukemic progenitors from female patients. GSK3β inhibition restored sensitivity to etoposide, and impaired the clonogenic capacities of adherent leukemic progenitors from female patients. In leukemic progenitors from female but not male patients, the scaffolding protein RACK1, activated downstream of α(5)β(1)-integrin engagement, was specifically upregulated and controlled GSK3β activation through the phosphatase protein phosphatase 2A (PP2A). In a mirrored manner, survival of adherent progenitors (CD34(+)38(-)) from male but not female healthy donors was partially dependent on this pathway. We conclude that the GSK3β-dependent survival pathway might be sex-specific in normal immature population and flip-flopped upon leukemogenesis. Taken together, our results strengthen GSK3β as a promising target for leukemic stem cell therapy and reveal gender differences as a new parameter in anti-leukemia therapy.

Published
2011
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2. Candida albicans is able to use M cells as a portal of entry across the intestinal barrier in vitro

Author

Albac, Sandrine, Schmitz, Antonin, Lopez-Alayon, Carolina, d'Enfert, Christophe, Sautour, Marc, Ducreux, Amandine, Labruère-Chazal, Catherine, Laue, Michael, Holland, Gudrun, Bonnin, Alain, Dalle, Frederic, Agroécologie [Dijon], Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Biologie et Pathogénicité fongiques, Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), Laboratoire de parasitologie mycologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Mathématiques de Bourgogne [Dijon] (IMB), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Bourgogne (UB), Robert Koch Institute [Berlin] (RKI), Agence Nationale de la Recherche. Grant Number: ANR-08-MIEN- 033-01 BIOASTER-Sanofi-Alliance pour les Sciences de la Vie et de la Santé (AVIESAN) Investissement d'Avenir. Grant Number: ANR-10-AIRT-03, ANR-08-MIEN-0033,KANJI,Colonisation et invasion de la muqueuse digestive par le champignon pathogène de l'homme Candida albicans(2008), ANR-10-AIRT-0005,NANOELEC,NANOELEC(2010), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris], Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), ANR: ANR-10-AIRT-05,Programme Investissements d’Avenir, Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut National de la Recherche Agronomique ( INRA ) -Institut Pasteur [Paris], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Institut de Mathématiques de Bourgogne [Dijon] ( IMB ), Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), Robert Koch Institute [Berlin] ( RKI ), ANR-08-MIEN-0033,KANJI,Colonisation et invasion de la muqueuse digestive par le champignon pathogène de l'homme Candida albicans ( 2008 ), ANR : ANR-10-AIRT-05,Programme Investissements d’Avenir, Biologie et Pathogénicité fongiques (BPF), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP), and Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH : Cell Line, MESH : Coculture Techniques, MESH : Microscopy, Fluorescence, [SDV]Life Sciences [q-bio], MESH: Microscopy, Fluorescence, MESH: Candidemia, Peyer's Patches, Mucosal immunity, Invasion, Candida albicans, MESH : Host-Pathogen Interactions, [ SDV.MP.MYC ] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, B-Lymphocytes, Endocytosis, MESH : Epithelial Cells, MESH : Peyer's Patches, MESH: Epithelial Cells, Host-Pathogen Interactions, MESH: Endocytosis, Adhesion, Transcytosis, Infection, MESH : Microscopy, Electron, Scanning, MESH : Candida albicans, MESH: Microscopy, Electron, Scanning, MESH : Endocytosis, MESH : B-Lymphocytes, Cell Line, MESH: Cell Adhesion, MESH: Coculture Techniques, MESH: B-Lymphocytes, Cell Adhesion, MESH : Candidemia, Humans, MESH: Humans, [ SDV ] Life Sciences [q-bio], MESH: Candida albicans, MESH : Humans, MESH: Host-Pathogen Interactions, Candidemia, Epithelial Cells, Coculture Techniques, MESH: Cell Line, Gastrointestinal Tract, MESH : Cell Adhesion, Microscopy, Fluorescence, Microscopy, Electron, Scanning, MESH: Peyer's Patches, MESH: Gastrointestinal Tract, MESH : Gastrointestinal Tract
Abstract

International audience; Candida albicans is the most frequent yeast responsible for systemic infections in humans. These infections mainly originate from the gastrointestinal tract where C. albicans can invade the gut epithelial barrier to gain access to the bloodstream. Along the gut, pathogens can use Microfold (M) cells as a portal of entry to cross the epithelial barrier. M cells are specialized cells mainly located in the follicule-associated epithelium of Peyer patches. In this study, we used scanning electron and fluorescence microscopy, adhesion and invasion assays and fungal mutants to investigate the interactions of C. albicans with M cells obtained in an established in vitro model whereby enterocyte-like Caco-2 cells co-cultured with the Raji B cell line undergo a phenotypic switch to morphologically and functionally resembling M cells. Our data demonstrate that C. albicans co-localizes with and invades preferentially M cells, providing evidence that the fungus can use M cells as a portal of entry into the intestinal barrier. In addition to active penetration, F-actin dependent endocytosis contributes to internalization of the fungus into M cells through a mechanism involving hypha-associated invasins including Ssa1 and Als3.

Published
2016
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3. A protocol to quantify mammary early common progenitors from long-term mammosphere culture

Author

Véronique Maguer-Satta, Emmanuel Delay, Elodie Bachelard-Cascales, Marion Chapellier, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), and Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
MESH: Neoplasm Proteins, Time Factors, Cellular differentiation, Cell Culture Techniques, MESH : Aged, MESH : Receptors, Cell Surface, MESH : Blotting, Western, MESH : Interleukin-3 Receptor alpha Subunit, MESH : Antineoplastic Agents, Phytogenic, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Hematopoietic Stem Cells, Mice, 0302 clinical medicine, MESH: Aged, 80 and over, MESH : Indoles, MESH : Tumor Cells, Cultured, MESH : Female, MESH : GTP-Binding Proteins, MESH: Glycogen Synthase Kinase 3, MESH: Maleimides, MESH: Receptors, Cell Surface, MESH: Etoposide, MESH : Maleimides, MESH: Aged, MESH: Indoles, MESH : Cell Survival, 0303 health sciences, MESH: Middle Aged, Stem Cells, MESH: Protein Phosphatase 2, Cell Differentiation, General Medicine, MESH : Adult, Cell biology, MESH: Cell Survival, MESH: Young Adult, 030220 oncology & carcinogenesis, MESH : Antigens, CD34, Stem cell, MESH: Cells, Cultured, Adult, MESH: GTP-Binding Proteins, MESH : Protein Phosphatase 2, MESH : Glycogen Synthase Kinase 3, MESH : Male, MESH : Sex Factors, MESH: RNA Interference, MESH: Antineoplastic Agents, Phytogenic, MESH : Young Adult, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : Etoposide, Biology, MESH: Cell Adhesion, Colony-Forming Units Assay, 03 medical and health sciences, MESH : Neoplasm Proteins, MESH : Neoplastic Stem Cells, MESH: Sex Factors, Spheroids, Cellular, MESH : Cells, Cultured, MESH: Leukemia, Animals, Humans, MESH: Blotting, Western, MESH : Middle Aged, MESH: Tumor Cells, Cultured, Progenitor cell, Mammary Glands, Human, MESH : Aged, 80 and over, 030304 developmental biology, Progenitor, MESH: Interleukin-3 Receptor alpha Subunit, MESH: Humans, MESH : Hematopoietic Stem Cells, Stem cell population, MESH : Humans, MESH : Leukemia, MESH: Adult, Cell Biology, MESH: Antigens, CD34, MESH: Neoplastic Stem Cells, MESH: Male, MESH : Cell Adhesion, Cell culture, Immunology, NIH 3T3 Cells, MESH : RNA Interference, MESH: Female, Developmental Biology
Abstract

International audience; Here we describe a protocol established in our laboratory to quantify early common progenitors/stem cells grown as spheres in non-adherent culture conditions. This protocol is based on the combination of two functional tests: the mammosphere assay to maintain and enrich early mammary progenitors/stem cells, and the epithelial colony-forming cells (E-CFC) assay to identify and quantify further differentiated epithelial progenitors. Primary spheres mainly contain progenitors and rare stem/early common progenitor cells while secondary and tertiary spheres contain progenitor cells derived from the early common progenitor/stem cell population maintained through passages and partially differentiated. Spheres are enzymatically and mechanically dissociated; the derived cells are subsequently plated on irradiated NIH-3T3 fibroblasts for further processing, as in the E-CFC assay. The principle of this assay is to quantify the number of epithelial colonies generated by cells present in the different sequential spheres. This assay has therefore been named ECP-DC, standing for Early Common Progenitor-Derived Colonies assay.

Published
2012
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4. Myrip couples the capture of secretory granules by the actin-rich cell cortex and their attachment to the plasma membrane

Author

Tim Zeiske, François Darchen, Patricia Meireles, Sébastien Huet, Nathanael Larochette, Isabelle Fanget, Ouardane Jouannot, Claire Desnos, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de dynamique membranaire et maladies neurologiques (UMR 8192), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de dynamique membranaire et maladies neurologiques ( UMR 8192 ), Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ), and De Villemeur, Hervé

Subjects
MESH : Vesicular Transport Proteins, MESH: Vesicular Transport Proteins, MESH: Secretory Vesicles, Vesicular Transport Proteins, MESH : Actins, 0302 clinical medicine, Myosin, MESH : Secretory Vesicles, 0303 health sciences, MESH: Exocytosis, General Neuroscience, MESH : Protein Binding, Articles, Cell biology, Biochemistry, Protein Binding, MESH: Cell Line, Tumor, MESH : Cell Membrane, Exocyst, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Actins, MESH : Exocytosis, Exocytosis, MESH: Cell Adhesion, 03 medical and health sciences, stomatognathic system, MESH : Enterochromaffin Cells, Microtubule, Cell Line, Tumor, Cell cortex, Cell Adhesion, Enterochromaffin Cells, Molecular motor, Humans, MESH: Protein Binding, MESH: Enterochromaffin Cells, RAB27, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Actin, 030304 developmental biology, MESH: Humans, MESH : Cell Line, Tumor, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Secretory Vesicles, MESH : Humans, Cell Membrane, Actins, MESH : Cell Adhesion, 030217 neurology & neurosurgery, MESH: Cell Membrane
Abstract

International audience; Exocytosis of secretory granules (SGs) requires their delivery to the actin-rich cell cortex followed by their attachment to the plasma membrane (PM). How these reactions are executed and coordinated is still unclear. Myrip, which is also known as Slac-2c, binds to the SG-associated GTPase Rab27 and is thought to promote the delivery of SGs to the PM by recruiting the molecular motor myosin Va. Myrip also interacts with actin and the exocyst complex, suggesting that it may exert multiple roles in the secretory process. By combining total internal reflection fluorescence microscopy, single-particle tracking, a photoconversion-based assay, and mathematical modeling, we show that, in human enterochromaffin cells, Myrip (1) inhibits a class of SG motion characterized by fast and directed movement, suggesting that it facilitates the dissociation of SGs from microtubules; (2) enhances their motion toward the PM and the probability of SG attachment to the PM; and (3) increases the characteristic time of immobilization at the PM, indicating that it is a component of the molecular machinery that tether SGs to the PM. Remarkably, while the first two effects of Myrip depend on its ability to recruit myosin Va on SGs, the third is myosin Va independent but relies on the C-terminal domain of Myrip. We conclude that Myrip couples the retention of SGs in the cell cortex, their transport to the PM, and their attachment to the PM, and thus promotes secretion. These three steps of the secretory process are thus intimately coordinated.

Published
2012
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5. Foxp3+ T cells induce perforin-dependent dendritic cell death in tumor-draining lymph nodes

Author

Tim Sparwasser, Alexandre Boissonnas, Luc Fetler, Alix Scholer-Dahirel, Bernard Malissen, Adrien Kissenpfennig, Luigia Pace, Fabien Valet, Virginie Simon-Blancal, Sebastian Amigorena, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hannover Medical School [Hannover] (MHH), Physico-Chimie-Curie (PCC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), MINES ParisTech - École nationale supérieure des mines de Paris-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE, Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Hannover Medical School [Hannover] ( MHH ), Physico-Chimie-Curie ( PCC ), and Centre National de la Recherche Scientifique ( CNRS ) -INSTITUT CURIE-Université Pierre et Marie Curie - Paris 6 ( UPMC )

Subjects
MESH: Cell Death, MESH : Fibrosarcoma, Fibrosarcoma, Priming (immunology), MESH: Lymph Nodes, MESH: T-Lymphocyte Subsets, Lymphocyte Activation, T-Lymphocytes, Regulatory, MESH: Mice, Knockout, MESH : T-Lymphocytes, Regulatory, Interleukin 21, Mice, 0302 clinical medicine, Cell Movement, T-Lymphocyte Subsets, MESH : Cell Movement, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Cytotoxic T cell, MESH : Female, MESH: Animals, MOLIMMUNO, MESH: Cell Movement, MESH : Lymph Nodes, Mice, Knockout, 0303 health sciences, Cell Death, MESH: Dendritic Cells, MESH: Fibrosarcoma, Forkhead Transcription Factors, hemic and immune systems, MESH : Mice, Transgenic, 3. Good health, MESH : Forkhead Transcription Factors, Infectious Diseases, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Cell Line, Tumor, MESH: Mice, Transgenic, T cell, Immunology, Mice, Transgenic, chemical and pharmacologic phenomena, MESH : Mice, Inbred C57BL, Biology, TREG CELLS, MESH: Cell Adhesion, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH: Forkhead Transcription Factors, Cell Line, Tumor, MESH : Mice, medicine, Lymph node stromal cell, Cell Adhesion, MESH : Neoplasm Transplantation, Animals, MESH : Perforin, Antigen-presenting cell, MESH: Lymphocyte Activation, MESH: Mice, MESH : Lymphocyte Activation, 030304 developmental biology, MESH : Cell Line, Tumor, Perforin, MESH: T-Lymphocytes, Regulatory, Dendritic cell, Dendritic Cells, MESH : T-Lymphocyte Subsets, MESH: Perforin, Mice, Inbred C57BL, MESH : Cell Adhesion, CELLIMMUNO, MESH : Cell Death, MESH : Dendritic Cells, Cancer research, MESH : Mice, Knockout, MESH : Animals, Lymph Nodes, MESH: Female, CD8, Neoplasm Transplantation, MESH: Neoplasm Transplantation, 030215 immunology
Abstract

International audience; Regulatory T (Treg) cells limit the onset of effective antitumor immunity, through yet-ill-defined mechanisms. We showed the rejection of established ovalbumin (OVA)-expressing MCA101 tumors required both the adoptive transfer of OVA-specific CD8(+) T cell receptor transgenic T cells (OTI) and the neutralization of Foxp3(+) T cells. In tumor-draining lymph nodes, Foxp3(+) T cell neutralization induced a marked arrest in the migration of OTI T cells, increased numbers of dendritic cells (DCs), and enhanced OTI T cell priming. Using an in vitro cytotoxic assay and two-photon live microscopy after adoptive transfer of DCs, we demonstrated that Foxp3(+) T cells induced the death of DCs in tumor-draining lymph nodes, but not in the absence of tumor. DC death correlated with Foxp3(+) T cell-DC contacts, and it was tumor-antigen and perforin dependent. We conclude that Foxp3(+) T cell-dependent DC death in tumor-draining lymph nodes limits the onset of CD8(+) T cell responses.

Published
2010
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6. Autophosphorylation-independent and -dependent functions of focal adhesion kinase during development

Author

Corsi, Jean-Marc, Houbron, Christophe, Billuart, Pierre, Brunet, Isabelle, Bouvrée, Karine, Eichmann, Anne, Girault, Jean-Antoine, Enslen, Hervé, Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Angiogénèse embryonnaire et pathologique, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), ARC 3746, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Mutation, MESH: Mice, Transgenic, MESH : Male, proliferation, MESH : Focal Adhesion Protein-Tyrosine Kinases, MESH : Mice, Inbred C57BL, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Cell Adhesion, MESH : Phosphorylation, vascularization, MESH: Mice, Inbred C57BL, MESH : Mice, MESH : Embryo, Mammalian, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BDD ] Life Sciences [q-bio]/Development Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, development, MESH: Mice, [SDV.BDD]Life Sciences [q-bio]/Development Biology, MESH: Focal Adhesion Protein-Tyrosine Kinases, MESH: Phosphorylation, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, MESH: Biological Markers, MESH: Embryo, Mammalian, tyrosine kinase, MESH: Integrins, MESH : Mice, Transgenic, MESH: Male, MESH : Biological Markers, MESH : Cell Adhesion, Adhesion, MESH : Animals, MESH : Mutation, MESH : Integrins
Abstract

International audience; Focal adhesion kinase (FAK) regulates numerous cellular functions and is critical for processes ranging from embryo development to cancer progression. Although autophosphorylation on Tyr-397 appears required for FAK functions in vitro, its role in vivo has not been established. We addressed this question using a mutant mouse (fakDelta) deleted of exon 15, which encodes Tyr-397. The resulting mutant protein FAKDelta is an active kinase expressed at normal levels. Our results demonstrate that the requirement for FAK autophosphorylation varies during development. FAK(Delta/Delta) embryos developed normally up to embryonic day (E) 12.5, contrasting with the lethality at E8.5 of FAK-null embryos. Thus, autophosphorylation on Tyr-397 is not required for FAK to achieve its functions until late mid-gestation. However, FAK(Delta/Delta) embryos displayed hemorrhages, edema, delayed artery formation, vascular remodeling defects, multiple organ abnormalities, and overall developmental retardation at E13.5-14.5, and died thereafter demonstrating that FAK autophosphorylation is also necessary for normal development. Fibroblasts derived from mutant embryos had a normal stellate morphology and expression of focal adhesion proteins, Src family members, p53, and Pyk2. In contrast, in FAK(Delta/Delta) fibroblasts and endothelial cells, spreading and lamellipodia formation were altered with an increased size and number of focal adhesions, enriched in FAKDelta. FAK mutation also decreased fibroblast proliferation. These results show that the physiological functions of FAK in vivo are achieved through both autophosphorylation-independent and autophosphorylation-dependent mechanisms.

Published
2009
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7. Erk5 controls Slug expression and keratinocyte activation during wound healing

Author

Pierre Savagner, Valérie Arnoux, Annie L'Helgoualc'h, Mayssaa Nassour, Robert A. Hipskind, Genotypes et Phenotypes Tumoraux, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Ligue Regionale contre le Cancer (Languedoc-Roussillon), Groupement des Entreprises Francaises dans la Lutte contre le Cancer, the Fondation de France and the Association pour la Recherche sur le Cancer (VA and RAH)., Université Montpellier 1 ( UM1 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Le Ster, Yves, and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], MESH : Wound Healing, MESH : Promoter Regions, Genetic, MESH : RNA, Small Interfering, migration, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, MESH : Phosphorylation, MESH : Cytoskeleton, 0302 clinical medicine, Desmosome organization, MESH: Cricetulus, MESH : CHO Cells, MESH: Animals, Cytoskeleton, Mitogen-Activated Protein Kinase 1, 0303 health sciences, Mitogen-Activated Protein Kinase 3, MESH : Gene Expression Regulation, MESH : Cricetinae, Keratinocyte activation, MESH: Transcription Factors, Cell biology, ErbB Receptors, 030220 oncology & carcinogenesis, MESH: Mitogen-Activated Protein Kinase 7, MESH: Mitogen-Activated Protein Kinase 3, MESH: Mitogen-Activated Protein Kinase 1, Slug, MESH : Cricetulus, MESH: Receptor, Epidermal Growth Factor, MESH: Cell Adhesion, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: CHO Cells, MESH: Promoter Regions, Genetic, Humans, Cell adhesion, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, EGF, MESH: Humans, Epidermal Growth Factor, MESH: Phosphorylation, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, HaCaT, MESH : Humans, MAPK, MESH : Epithelium, MESH: Wound Healing, MESH: Epithelium, Wound healing, [ SDV.MHEP.DERM ] Life Sciences [q-bio]/Human health and pathology/Dermatology, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Transcription Factors, Keratinocytes, MESH: Epidermal Growth Factor, Cytoskeleton organization, MESH : Transcription Factors, MESH: Cricetinae, Epithelium, MESH : Receptor, Epidermal Growth Factor, Cricetinae, MESH: RNA, Small Interfering, Phosphorylation, RNA, Small Interfering, Keratinocyte migration, Promoter Regions, Genetic, MESH : Epidermal Growth Factor, MESH : Mitogen-Activated Protein Kinase 1, biology, MESH : Mitogen-Activated Protein Kinase 3, ERK1/2, MESH : Keratinocytes, [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Articles, MESH: Gene Expression Regulation, MESH: Keratinocytes, MESH : Mitogen-Activated Protein Kinase 7, Motility, [SDV.CAN]Life Sciences [q-bio]/Cancer, CHO Cells, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Cricetulus, MESH : Mice, Cell Adhesion, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Cytoskeleton, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, Mitogen-Activated Protein Kinase 7, 030304 developmental biology, Wound Healing, Cell Biology, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, biology.organism_classification, MESH : Cell Adhesion, Gene Expression Regulation, Cancer research, Snail Family Transcription Factors, MESH : Animals
Abstract

International audience; Reepithelialization during cutaneous wound healing involves numerous signals that result in basal keratinocyte activation, spreading, and migration, all linked to a loosening of cell-cell adhesion structures. The transcription factor Slug is required for this process, and EGF treatment of human keratinocytes induced activating phosphorylation of Erk5 that coincides with slug transcription. Accordingly, ectopic activation of Erk5 led to increased Slug mRNA levels and faster wound healing, whereas keratinocyte migration was totally blocked by Erk5 pathway inhibition. Expression of a shRNA specific for Erk5 strongly diminished Erk5 levels in keratinocytes and significantly decreased their motility response to EGF, along with induction of Slug expression. These Erk5-deprived keratinocytes showed an altered, more compact morphology, along with disruption of desmosome organization. Accordingly, they displayed an altered ability to form cell aggregates. These results implicate a novel EGFR/Erk5/Slug pathway in the control of cytoskeleton organization and cell motility in keratinocytes treated with EGF.

Published
2008
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8. Transforming growth factor beta controls the directional migration of hepatocyte cohorts by modulating their adhesion to fibronectin

Author

Urszula Hibner, Fabien Binamé, Patrice Lassus, Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique Moléculaire de Montpellier (IGMM), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)

Subjects
rac1 GTP-Binding Protein, MESH : Cell Line, MESH : Protein Subunits, Apoptosis, Cell Communication, Integrin alpha5, MESH : Hepatocytes, Epithelium, Mesoderm, MESH: Hepatocytes, Mice, 0302 clinical medicine, Cell Movement, Transforming Growth Factor beta, MESH: Fibronectins, MESH : Cell Movement, MESH : Fibronectins, MESH: Animals, MESH: Cell Movement, MESH: Mesoderm, 0303 health sciences, MESH : Gene Expression Regulation, MESH: Cell Surface Extensions, MESH : Mesoderm, Articles, Adhesion, MESH: Protein Subunits, MESH: Gene Expression Regulation, Cell biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Hepatocyte, MESH: Integrin alpha5, MESH : Cell Communication, MESH : Cell Membrane, MESH : Cell Surface Extensions, Biology, Cell Line, MESH: Cell Adhesion, MESH: Gene Expression Profiling, 03 medical and health sciences, MESH : rac1 GTP-Binding Protein, MESH : Integrin alpha5, MESH: Cell Communication, MESH : Mice, Cell Adhesion, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH: Humans, MESH: rac1 GTP-Binding Protein, Gene Expression Profiling, MESH: Apoptosis, MESH : Gene Expression Profiling, Cell Membrane, MESH : Humans, Cell Biology, MESH : Epithelium, Fibronectins, MESH: Cell Line, Fibronectin, Protein Subunits, MESH: Epithelium, MESH : Cell Adhesion, MESH : Transforming Growth Factor beta, Gene Expression Regulation, Hepatocytes, biology.protein, Cell Surface Extensions, MESH : Animals, MESH : Apoptosis, MESH: Cell Membrane, Transforming growth factor
Abstract

International audience; Transforming growth factor beta (TGF-beta) has a strong impact on liver development and physiopathology, exercised through its pleiotropic effects on growth, differentiation, survival, and migration. When exposed to TGF-beta, the mhAT3F cells, immortalized, highly differentiated hepatocytes, maintained their epithelial morphology and underwent dramatic alterations of adhesion, leading to partial or complete detachment from a culture plate, followed by readhesion and spreading. These alterations of adhesive behavior were caused by sequential changes in expression of the alpha5beta1 integrin and of its ligand, the fibronectin. The altered specificity of anchorage to the extracellular matrix gave rise to changes in cells' collective motility: cohorts adhering to fibronectin maintained a persistent, directional motility, with ezrin-rich pathfinder cells protruding from the tips of the cohorts. The absence of adhesion to fibronectin prevented the appearance of polarized pathfinders and lead to random, oscillatory motility. Our data suggest a novel role for TGF-beta in the control of collective migration of epithelial cohorts.

Published
2008
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9. Extracellular matrix-bound angiopoietin-like 4 inhibits endothelial cell adhesion, migration, and sprouting and alters actin cytoskeleton

Author

Nicolas Bréchot, Ariane Galaup, Clémence Chomel, Laurent Muller, Marine Bignon, Stéphane Germain, Catherine Monnot, Pierre Corvol, Aurélie Cazes, Holger Weber, Sébastien Le Jan, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Departement of Vascular Biology and Angiogenesis Research, Tumor Biology Center, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mouret, Sandrine, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale, Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'hématologie A [CHU HEGP], and Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP )

Subjects
MESH: Heparin, MESH : Biological Availability, Physiology, Angiogenesis, MESH: Anoxia, MESH : Actins, Extracellular matrix, MESH : Cytoskeleton, Mice, 0302 clinical medicine, Cell Movement, Ischemia, MESH: Blood Proteins, MESH : Cell Movement, MESH: Animals, MESH: Endothelial Cells, Hypoxia, Cytoskeleton, MESH: Cell Movement, Cells, Cultured, MESH: Biological Availability, Tube formation, 0303 health sciences, MESH : Neovascularization, Physiologic, MESH: Hindlimb, MESH : Extracellular Matrix, Blood Proteins, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH : Proteoglycans, Extracellular Matrix, Hindlimb, Cell biology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Endothelial stem cell, Biochemistry, 030220 oncology & carcinogenesis, MESH: Proteoglycans, Proteoglycans, Cardiology and Cardiovascular Medicine, MESH: Neovascularization, Physiologic, MESH: Cells, Cultured, MESH : Blood Proteins, MESH : Anoxia, Biological Availability, Neovascularization, Physiologic, MESH : Mice, Inbred C57BL, Angiopoietin-like 4 Protein, In Vitro Techniques, Biology, MESH: Extracellular Matrix, MESH: Actins, Article, MESH: Cell Adhesion, Angiopoietin, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH : Ischemia, MESH: Mice, Inbred C57BL, MESH : Mice, MESH : Cells, Cultured, Cell Adhesion, MESH: Cytoskeleton, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Angiopoietin-Like Protein 4, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH : Hindlimb, MESH : Endothelial Cells, Heparin, Endothelial Cells, Actin cytoskeleton, Actins, Mice, Inbred C57BL, MESH : Cell Adhesion, MESH : Heparin, MESH : Animals, MESH: Ischemia, Angiopoietins
Abstract

Angiopoietin-like 4 (ANGPTL4) is a secreted protein that belongs to the angiopoietin family and is involved in angiogenesis and metabolism regulation. We previously reported the induction of angptl4 by hypoxia in endothelial cells and in human ischemic tissues from peripheral artery disease. We here observed in a mouse model of hindlimb ischemia that the mRNA upregulation in the vessels correlates with the accumulation of the full-length protein in ischemic tissues. We then investigated its functions in endothelial cells. In response to hypoxia, endogenous ANGPTL4 accumulates in the subendothelial extracellular matrix (ECM). Although the secreted protein undergoes proteolysis leading to truncated fragments present in the medium, only full-length ANGPTL4 interacts with the ECM. Competition and direct binding assays indicate that the strong interaction of ANGPTL4 with the ECM is heparin/heparan sulfate proteoglycan dependent. The balance between matrix-associated and soluble forms of ANGPTL4 points to the role of the ECM in the regulation of its bioavailability. The angiogenic function of the ECM-bound full-length protein was investigated using either the form associated with the conditioned ECM from ANGPTL4-transfected HEK293 cells or the purified immobilized protein. We show that matrix-associated and immobilized ANGPTL4 limit the formation of actin stress fibers and focal contacts in the adhering endothelial cells and inhibit their adhesion. Immobilized ANGPTL4 also decreases motility of endothelial cells and inhibits the sprouting and tube formation. Altogether, these findings show that hypoxic endothelial cells accumulate ANGPTL4 in the ECM, which in turn negatively regulates their angiogenic capacities through an autocrine pathway.

Published
2006
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