PMID- 24200678 OWN - NLM STAT- MEDLINE DCOM- 20140320 LR - 20211021 IS - 0006-3002 (Print) IS - 0006-3002 (Linking) VI - 1843 IP - 2 DP - 2014 Feb TI - Valvular dystrophy associated filamin A mutations reveal a new role of its first repeats in small-GTPase regulation. PG - 234-44 LID - S0167-4889(13)00367-4 [pii] LID - 10.1016/j.bbamcr.2013.10.022 [doi] AB - 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. CI - Copyright (c) 2013 Elsevier B.V. All rights reserved. FAU - Duval, D AU - Duval D AD - Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, 8 Quai Moncousu 44007 Nantes Cedex, France. Electronic address: damien.duval@etu.univ-nantes.fr. FAU - Lardeux, A AU - Lardeux A AD - Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, 8 Quai Moncousu 44007 Nantes Cedex, France. Electronic address: aurelie.lardeux@gmail.com. FAU - Le Tourneau, T AU - Le Tourneau T AD - Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, 8 Quai Moncousu 44007 Nantes Cedex, France. Electronic address: thletourneau@yahoo.fr. FAU - Norris, R A AU - Norris RA AD - 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. FAU - Markwald, R R AU - Markwald RR AD - 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. FAU - Sauzeau, V AU - Sauzeau V AD - Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, 8 Quai Moncousu 44007 Nantes Cedex, France. Electronic address: vincent.sauzeau@inserm.fr. FAU - Probst, V AU - Probst V AD - Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, 8 Quai Moncousu 44007 Nantes Cedex, France. Electronic address: vincent.probst@chu-nantes.fr. FAU - Le Marec, H AU - Le Marec H AD - Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, 8 Quai Moncousu 44007 Nantes Cedex, France. Electronic address: herve.lemarec@univ-nantes.fr. FAU - Levine, R AU - Levine R AD - Noninvasive Cardiac Laboratory, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: RLEVINE@PARTNERS.ORG. FAU - Schott, J J AU - Schott JJ AD - Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, 8 Quai Moncousu 44007 Nantes Cedex, France. Electronic address: jjschott@univ-nantes.fr. FAU - Merot, J AU - Merot J AD - Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, 8 Quai Moncousu 44007 Nantes Cedex, France. Electronic address: jean.merot@univ-nantes.fr. LA - eng GR - K24 HL067434/HL/NHLBI NIH HHS/United States GR - P20 GM103444/GM/NIGMS NIH HHS/United States GR - K24 HL67434/HL/NHLBI NIH HHS/United States GR - R01 HL033756/HL/NHLBI NIH HHS/United States GR - P30 GM103342/GM/NIGMS NIH HHS/United States GR - 8P20 GM103444/GM/NIGMS NIH HHS/United States GR - R01-HL33756/HL/NHLBI NIH HHS/United States GR - 1 P30 GM103342/GM/NIGMS NIH HHS/United States GR - R01 HL109506/HL/NHLBI NIH HHS/United States GR - C06 RR018823/RR/NCRR NIH HHS/United States GR - HL109506/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20131104 PL - Netherlands TA - Biochim Biophys Acta JT - Biochimica et biophysica acta JID - 0217513 RN - 0 (Filamins) RN - 0 (GTPase-Activating Proteins) RN - 0 (Mutant Proteins) RN - EC 3.6.5.2 (rac GTP-Binding Proteins) RN - EC 3.6.5.2 (rhoA GTP-Binding Protein) SB - IM MH - Cell Adhesion MH - Cell Line, Tumor MH - Cell Movement MH - Cell Shape MH - Cell Size MH - Filamins/*chemistry/deficiency/*genetics MH - GTPase-Activating Proteins/metabolism MH - Heart Valve Diseases/*genetics MH - Humans MH - Mesoderm/pathology MH - Mutant Proteins/metabolism MH - Mutation/*genetics MH - *Repetitive Sequences, Amino Acid MH - Structure-Activity Relationship MH - rac GTP-Binding Proteins/*metabolism MH - rhoA GTP-Binding Protein/*metabolism PMC - PMC3928473 MID - NIHMS537874 OTO - NOTNLM OT - FilGAP OT - Filamin A OT - Mitral valve prolapse OT - Rac1 OT - RhoA EDAT- 2013/11/10 06:00 MHDA- 2014/03/22 06:00 PMCR- 2015/02/01 CRDT- 2013/11/09 06:00 PHST- 2013/07/10 00:00 [received] PHST- 2013/10/26 00:00 [revised] PHST- 2013/10/28 00:00 [accepted] PHST- 2013/11/09 06:00 [entrez] PHST- 2013/11/10 06:00 [pubmed] PHST- 2014/03/22 06:00 [medline] PHST- 2015/02/01 00:00 [pmc-release] AID - S0167-4889(13)00367-4 [pii] AID - 10.1016/j.bbamcr.2013.10.022 [doi] PST - ppublish SO - Biochim Biophys Acta. 2014 Feb;1843(2):234-44. doi: 10.1016/j.bbamcr.2013.10.022. Epub 2013 Nov 4.