title: Annexin II-dependent actin remodelling evoked by hydrogen peroxide requires the metalloproteinase/sphingolipid pathway.
abstract: Actin remodeling is a dynamic process associated with cell shape modification occurring during cell cycle and proliferation. Oxidative stress plays a role in actin reorganization via various systems including p38MAPK. Beside, the mitogenic response evoked by hydrogen peroxide (H2O2) in fibroblasts and smooth muscle cells (SMC) involves the metalloproteinase (MMPs)/sphingomyelinase 2 (nSMase2) signaling pathway. The aim of this work was to investigate whether this system plays a role in actin remodeling induced by H2O2. Low H2O2 dose (5µM) rapidly triggered a signaling cascade leading to nSMase2 activation, src and annexin 2 (AnxA2) phosphorylation, and actin remodeling, in fibroblasts and SMC. These events were blocked by pharmacological inhibitors of MMPs (Ro28-2653) and p38MAPK (SB203580), and were lacking in MMP2(-/-) and in nSMase2-mutant (fro) fibroblasts. Likewise, H2O2 was unable to induce actin remodeling in fro and MMP2(-/-) fibroblasts or in cells pretreated with p38MAPK, or MMP inhibitors. Finally we show that nSMase2 activation by H2O2, depends on MMP2 and p38MAPK, and is required for the src-dependent phosphorylation of AnxA2, and actin remodeling. Taken together, these findings indicate for the first time that AnxA2 phosphorylation and actin remodeling evoked by oxidative stress depend on the sphingolipid pathway, via MMP2 and p38MAPK.
authors.affiliation: INSERM UMR-1048, Toulouse, France; Dept de Biochimie, CHU Rangueil, Toulouse, France; Université Paul Sabatier, Toulouse, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Cinq-Frais
authors.affiliation: INSERM UMR-1048, Toulouse, France; Dept de Biochimie, CHU Rangueil, Toulouse, France; Université Paul Sabatier, Toulouse, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Coatrieux
authors.affiliation: INSERM UMR-1048, Toulouse, France; Dept de Biochimie, CHU Rangueil, Toulouse, France; Université Paul Sabatier, Toulouse, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Savary
authors.affiliation: INSERM UMR-1048, Toulouse, France.
authors.forename: Romina
authors.initials: R
authors.lastname: D'Angelo
authors.affiliation: INSERM UMR-1048, Toulouse, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Bernis
authors.affiliation: INSERM UMR-1048, Toulouse, France; Dept de Biochimie, CHU Rangueil, Toulouse, France; Université Paul Sabatier, Toulouse, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Salvayre
authors.affiliation: INSERM UMR-1048, Toulouse, France; Université Paul Sabatier, Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Nègre-Salvayre
authors.affiliation: INSERM UMR-1048, Toulouse, France; Université Paul Sabatier, Toulouse, France. Electronic address: nathalie.auge@inserm.fr.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Augé
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D017306:Annexin A2 / Q000096:biosynthesis / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D013107:Sphingolipids / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D000199:Actins; D017306:Annexin A2; D013107:Sphingolipids; D006861:Hydrogen Peroxide; D048051:p38 Mitogen-Activated Protein Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
keywords: Actin; Fibroblasts; Oxidative stress; Smooth muscle cells; Sphingolipids; Vasculo-proliferative diseases