학술논문
MVP-Associated Filamin A Mutations Affect FlnA-PTPN12 (PTP-PEST) Interactions.
Document Type
Academic Journal
Author
Duval D; Institut du thorax, Inserm UMR 1087, CNRS UMR 6291, 8 Quai Moncousu, Nantes F-44007, France; damien.duval@etu.univ-nantes.fr (D.D.); pauline.labbe@etu.univ-nantes.fr (P.L.); bureau.lea@gmail.com (L.B.); thletourneau@yahoo.fr (T.L.T.); jjschott@univ-nantes.fr (J.-J.S.).; Labbé P; Institut du thorax, Inserm UMR 1087, CNRS UMR 6291, 8 Quai Moncousu, Nantes F-44007, France; damien.duval@etu.univ-nantes.fr (D.D.); pauline.labbe@etu.univ-nantes.fr (P.L.); bureau.lea@gmail.com (L.B.); thletourneau@yahoo.fr (T.L.T.); jjschott@univ-nantes.fr (J.-J.S.).; Bureau L; Institut du thorax, Inserm UMR 1087, CNRS UMR 6291, 8 Quai Moncousu, Nantes F-44007, France; damien.duval@etu.univ-nantes.fr (D.D.); pauline.labbe@etu.univ-nantes.fr (P.L.); bureau.lea@gmail.com (L.B.); thletourneau@yahoo.fr (T.L.T.); jjschott@univ-nantes.fr (J.-J.S.).; Le Tourneau T; Institut du thorax, Inserm UMR 1087, CNRS UMR 6291, 8 Quai Moncousu, Nantes F-44007, France; damien.duval@etu.univ-nantes.fr (D.D.); pauline.labbe@etu.univ-nantes.fr (P.L.); bureau.lea@gmail.com (L.B.); thletourneau@yahoo.fr (T.L.T.); jjschott@univ-nantes.fr (J.-J.S.).; Norris RA; Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, SC 29425, USA; norrisra@musc.edu (R.A.N.); markwald@musc.edu (R.R.M.).; Markwald RR; Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, SC 29425, USA; norrisra@musc.edu (R.A.N.); markwald@musc.edu (R.R.M.).; Levine R; Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114-2696 USA; rlevine@partners.org.; Schott JJ; Institut du thorax, Inserm UMR 1087, CNRS UMR 6291, 8 Quai Moncousu, Nantes F-44007, France; damien.duval@etu.univ-nantes.fr (D.D.); pauline.labbe@etu.univ-nantes.fr (P.L.); bureau.lea@gmail.com (L.B.); thletourneau@yahoo.fr (T.L.T.); jjschott@univ-nantes.fr (J.-J.S.).; Mérot J; Institut du thorax, Inserm UMR 1087, CNRS UMR 6291, 8 Quai Moncousu, Nantes F-44007, France; damien.duval@etu.univ-nantes.fr (D.D.); pauline.labbe@etu.univ-nantes.fr (P.L.); bureau.lea@gmail.com (L.B.); thletourneau@yahoo.fr (T.L.T.); jjschott@univ-nantes.fr (J.-J.S.).
Source
Publisher: MDPI AG Country of Publication: Switzerland NLM ID: 101651414 Publication Model: Print Cited Medium: Print ISSN: 2308-3425 (Print) Linking ISSN: 23083425 NLM ISO Abbreviation: J Cardiovasc Dev Dis Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
2308-3425
Abstract
Although the genetic basis of mitral valve prolapse (MVP) has now been clearly established, the molecular and cellular mechanisms involved in the pathological processes associated to a specific mutation often remain to be determined. The FLNA gene (encoding Filamin A; FlnA) was the first gene associated to non-syndromic X-linked myxomatous valvular dystrophy, but the impacts of the mutations on its function remain un-elucidated. Here, using the first repeats (1-8) of FlnA as a bait in a yeast two-hybrid screen, we identified the tyrosine phosphatase PTPN12 (PTP-PEST) as a specific binding partner of this region of FlnA protein. In addition, using yeast two-hybrid trap assay pull down and co-immunoprecipitation experiments, we showed that the MVP-associated FlnA mutations (G288R, P637Q, H743P) abolished FlnA/PTPN12 interactions. PTPN12 is a key regulator of signaling pathways involved in cell-extracellular matrix (ECM) crosstalk, cellular responses to mechanical stress that involve integrins, focal adhesion transduction pathways, and actin cytoskeleton dynamics. Interestingly, we showed that the FlnA mutations impair the activation status of two PTPN12 substrates, the focal adhesion associated kinase Src, and the RhoA specific activating protein p190RhoGAP. Together, these data point to PTPN12/FlnA interaction and its weakening by FlnA mutations as a mechanism potentially involved in the physiopathology of FlnA-associated MVP.