title: Valvular dystrophy associated filamin A mutations reveal a new role of its first repeats in small-GTPase regulation.
abstract: Filamin A (FlnA) is a ubiquitous actin binding protein which anchors various transmembrane proteins to the cell cytoskeleton and provides a scaffold to many cytoplasmic signaling proteins involved in actin cytoskeleton remodeling in response to mechanical stress and cytokines stimulation. Although the vast majority of FlnA binding partners interact with the carboxy-terminal immunoglobulin like (Igl) repeats of FlnA, little is known on the role of the amino-N-terminal repeats. Here, using cardiac mitral valvular dystrophy associated FlnA-G288R and P637Q mutations located in the N-terminal Igl repeat 1 and 4 respectively as a model, we identified a new role of FlnA N-terminal repeats in small Rho-GTPases regulation. Using FlnA-deficient melanoma and HT1080 cell lines as expression systems we showed that FlnA mutations reduce cell spreading and migration capacities. Furthermore, we defined a signaling network in which FlnA mutations alter the balance between RhoA and Rac1 GTPases activities in favor of RhoA and provided evidences for a role of the Rac1 specific GTPase activating protein FilGAP in this process. Together our work ascribed a new role to the N-terminal repeats of FlnA in Small GTPases regulation and supports a conceptual framework for the role of FlnA mutations in cardiac valve diseases centered around signaling molecules regulating cellular actin cytoskeleton in response to mechanical stress.
authors.affiliation: Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, 8 Quai Moncousu 44007 Nantes Cedex, France. Electronic address: damien.duval@etu.univ-nantes.fr.
authors.forename: D
authors.initials: D
authors.lastname: Duval
authors.affiliation: Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, 8 Quai Moncousu 44007 Nantes Cedex, France. Electronic address: aurelie.lardeux@gmail.com.
authors.forename: A
authors.initials: A
authors.lastname: Lardeux
authors.affiliation: Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, 8 Quai Moncousu 44007 Nantes Cedex, France. Electronic address: thletourneau@yahoo.fr.
authors.forename: T
authors.initials: T
authors.lastname: Le Tourneau
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Cardiovascular Developmental Biology Center, Children's Research Institute, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA. Electronic address: norrisra@musc.edu.
authors.forename: R A
authors.initials: RA
authors.lastname: Norris
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Cardiovascular Developmental Biology Center, Children's Research Institute, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA. Electronic address: markwald@musc.edu.
authors.forename: R R
authors.initials: RR
authors.lastname: Markwald
authors.affiliation: Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, 8 Quai Moncousu 44007 Nantes Cedex, France. Electronic address: vincent.sauzeau@inserm.fr.
authors.forename: V
authors.initials: V
authors.lastname: Sauzeau
authors.affiliation: Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, 8 Quai Moncousu 44007 Nantes Cedex, France. Electronic address: vincent.probst@chu-nantes.fr.
authors.forename: V
authors.initials: V
authors.lastname: Probst
authors.affiliation: Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, 8 Quai Moncousu 44007 Nantes Cedex, France. Electronic address: herve.lemarec@univ-nantes.fr.
authors.forename: H
authors.initials: H
authors.lastname: Le Marec
authors.affiliation: Noninvasive Cardiac Laboratory, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: RLEVINE@PARTNERS.ORG.
authors.forename: R
authors.initials: R
authors.lastname: Levine
authors.affiliation: Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, 8 Quai Moncousu 44007 Nantes Cedex, France. Electronic address: jjschott@univ-nantes.fr.
authors.forename: J J
authors.initials: JJ
authors.lastname: Schott
authors.affiliation: Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, 8 Quai Moncousu 44007 Nantes Cedex, France. Electronic address: jean.merot@univ-nantes.fr.
authors.forename: J
authors.initials: J
authors.lastname: Merot
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D048430:Cell Shape; D048429:Cell Size; D064448:Filamins / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics*; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006349:Heart Valve Diseases / Q000235:genetics*; D006801:Humans; D008648:Mesoderm / Q000473:pathology; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D020449:Repetitive Sequences, Amino Acid; D013329:Structure-Activity Relationship; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D064448:Filamins; D020690:GTPase-Activating Proteins; D050505:Mutant Proteins; D020744:rac GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: FilGAP; Filamin A; Mitral valve prolapse; Rac1; RhoA