1. Interaction of the coiled‐coil domain with glycosaminoglycans protects angiopoietin‐like 4 from proteolysis and regulates its antiangiogenic activity
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Sylvie Ricard-Blum, Clément Faye, Corinne Ardidie-Robouant, Clémence Chomel, Laurent Muller, Stéphane Germain, Aurélie Cazes, A. Barret, Catherine Monnot, Elisa Gomez, Marine Bignon, 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), Service d'anatomo-pathologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), 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), This work was supported by the European Vascular Genomics Network (http://www.evgn.org) (contract LSHMCT-2003-503254), ANR-06-JCJC-0160,ANGPTL4,Role of ANGPTL4 during development and ischemic heart disease(2006), Pathologie vasculaire et endocrinologie rénale, Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Experimental Medicine Unit, Collège de France ( CdF ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Institut de biologie et chimie des protéines [Lyon] ( IBCP ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Service d'hématologie A [CHU HEGP], and ANR-06-JCJC-0160,ANGPTL4,Role of ANGPTL4 during development and ischemic heart disease ( 2006 )
- Subjects
MESH : Cell Line ,MESH : Angiopoietins ,Protein Conformation ,Angiogenesis ,MESH: Cricetinae ,Biochemistry ,Extracellular matrix ,angiogenesis ,MESH: Protein Structure, Tertiary ,MESH: Protein Conformation ,0302 clinical medicine ,MESH : Lipid Metabolism ,Cricetinae ,MESH: Animals ,MESH : Protein Conformation ,Glycosaminoglycans ,MESH: Lipid Metabolism ,0303 health sciences ,MESH : Neovascularization, Physiologic ,medicine.diagnostic_test ,Chemistry ,MESH : Cricetinae ,MESH : Extracellular Matrix ,MESH : Protein Binding ,MESH: Glycosaminoglycans ,[ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,3. Good health ,Cell biology ,Endothelial stem cell ,030220 oncology & carcinogenesis ,endothelial cell ,MESH : Mutation ,MESH : Protein Structure, Tertiary ,MESH: Neovascularization, Physiologic ,Protein Binding ,Biotechnology ,MESH: Mutation ,extracellular matrix ,Proteolysis ,Neovascularization, Physiologic ,Angiopoietin-like 4 Protein ,MESH: Extracellular Matrix ,Cell Line ,Angiopoietin ,03 medical and health sciences ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,MESH : Glycosaminoglycans ,Genetics ,medicine ,Animals ,Humans ,MESH: Protein Binding ,Molecular Biology ,030304 developmental biology ,MESH: Humans ,hypoxia ,MESH : Humans ,Lipid Metabolism ,Protein Structure, Tertiary ,MESH: Cell Line ,Cell culture ,MESH: Angiopoietins ,Mutation ,MESH : Animals ,Proprotein Convertases ,Angiopoietins - Abstract
International audience; Angiopoietin-like 4 (ANGPTL4) is involved in angiogenesis and lipid metabolism. It is secreted by liver and adipose tissues and cleaved to generate circulating coiled-coil domain (CCD) and fibrinogen-like domain (FLD) fragments. The full-length ANGPTL4 produced by hypoxic endothelial cells interacts with the extracellular matrix (ECM). The ECM-bound and soluble forms of ANGPTL4 have antiangiogenic properties. We carried out a structure-function analysis to investigate the regulation of ANGPTL4 bioactivity in endothelial cells. We found that the recombinant CCD binds to the ECM, whereas the FLD is released into the medium. The CCD, like the full-length ANGPTL4, binds to heparan and dermatan sulfates in surface plasmon resonance assays and inhibits endothelial cell adhesion, motility, and tubule-like formation. In endothelial cells, ANGPTL4 is processed in the secretion medium after release from the ECM. This processing is altered by the proprotein convertases inhibitor alpha1-PDX and abolished by the mutation of the (161)RRKR(164) cleavage site without modification of the ECM binding and release. These data suggest that the full-length form, which interacts with heparan sulfate proteoglycans via its CCD, is protected from proteolysis by proprotein convertases and constitutes the major active pool of ANGPTL4 in hypoxic endothelial cells.
- Published
- 2008
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