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J. Cardiovasc. Dev. Dis. 2015, 2(3), 233-247; doi:10.3390/jcdd2030233

MVP-Associated Filamin A Mutations Affect FlnA-PTPN12 (PTP-PEST) Interactions

1
Institut du thorax, Inserm UMR 1087, CNRS UMR 6291, 8 Quai Moncousu, Nantes F-44007, France
2
Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, SC 29425, USA
3
Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114-2696 USA
*
Author to whom correspondence should be addressed.
Academic Editor: Cheryl L. Maslen
Received: 18 May 2015 / Revised: 1 September 2015 / Accepted: 3 September 2015 / Published: 8 September 2015
(This article belongs to the Special Issue Genetics and Cardiovascular Development and Disease)
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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. View Full-Text
Keywords: Filamin-A; PTPN12; mitral valve prolapse; p190RhoGAP; Src Filamin-A; PTPN12; mitral valve prolapse; p190RhoGAP; Src
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Duval, D.; Labbé, P.; Bureau, L.; Tourneau, T.L.; Norris, R.A.; Markwald, R.R.; Levine, R.; Schott, J.-J.; Mérot, J. MVP-Associated Filamin A Mutations Affect FlnA-PTPN12 (PTP-PEST) Interactions. J. Cardiovasc. Dev. Dis. 2015, 2, 233-247.

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J. Cardiovasc. Dev. Dis. EISSN 2308-3425 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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