NADPH oxidase 1 controls the persistence of directed cell migration by a Rho-dependent switch of alpha2/alpha3 integrins.
NADPH oxidase 1 (Nox1) is expressed mainly in colon epithelial cells and produces superoxide ions as a primary function. We showed that Nox1 knockdown inhibits directional persistence of migration on collagen I. This paper dissects the mechanism by which Nox1 affects the direction of colonic epithelial cell migration in a two-dimensional model. Transient activation of Nox1 during cell spreading on collagen 1 temporarily inactivated RhoA and led to efficient exportation of alpha2beta1 integrin to the cell surface, which supported persistent directed migration. Nox1 knockdown led to a loss of directional migration which takes place through a RhoA-dependent alpha2/alpha3 integrin switch. Transient RhoA overactivation upon Nox1 inhibition led to transient cytoskeletal reorganization and increased cell-matrix contact associated with a stable increase in alpha3 integrin cell surface expression. Blocking of alpha3 integrin completely reversed the loss of directional persistence of migration. In this model, Nox1 would represent a switch between random and directional migration through RhoA-dependent integrin cell surface expression modulation.
Sadok
Amine
A
INSERM UMR 911, Centre de Recherche en Oncologie biologique et en Oncopharmacologie, Faculté de Pharmacie, Aix-Marseille Université, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 5, France.
Pierres
Anne
A
Dahan
Laetitia
L
Prévôt
Charles
C
Lehmann
Maxime
M
Kovacic
Hervé
H
D002448:Cell Adhesion / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D024042:Collagen Type I / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D039421:Integrin alpha2 / Q000378:metabolism*; D039422:Integrin alpha3 / Q000378:metabolism*; D008954:Models, Biological; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D024042:Collagen Type I; D039421:Integrin alpha2; D039422:Integrin alpha3; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C066737:RHOA protein, human; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; D054460:rho-Associated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein