Valvular dystrophy associated filamin A mutations reveal a new role of its first repeats in small-GTPase regulation
| Autor: | H. Le Marec, Russell A. Norris, Ross L. Levine, Jean Mérot, Delphine Duval, Aurélie Lardeux, V. Sauzeau, Roger R. Markwald, Jean-Jacques Schott, Vincent Probst, T. Le Tourneau |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Repetitive Sequences
Amino Acid RHOA GTPase-activating protein Filamins Heart Valve Diseases 030204 cardiovascular system & hematology Filamin Article Mesoderm 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine Cell Movement Cell Line Tumor Cell Adhesion FLNA Humans Small GTPase Actin-binding protein Molecular Biology Cell Shape 030304 developmental biology Cell Size Genetics 0303 health sciences biology GTPase-Activating Proteins RhoA Cell Biology Actin cytoskeleton Cell biology Filamin A rac GTP-Binding Proteins Rac GTP-Binding Proteins FilGAP Mutation biology.protein Mutant Proteins rhoA GTP-Binding Protein Mitral valve prolapse Rac1 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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