Year: 2015
Type: article
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.
DOI: 10.3390/jcdd2030233
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,258
Funders: National Science Foundation, American Heart Association, Medical University of South Carolina, Institut National de la Santé et de la Recherche Médicale, Fédération Française de Cardiologie, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Center for Research Resources
Awards: ISCHEMIC MITRAL REGURGITATION: FROM MECHANISM TO THERAPY, G299210616, G3023051777, G350062807, 2009 Research Infrastructure Improvement Grant, G5103928679, G5305657220, G5690318517, G5710227431, G5743453972, SC COBRE for Developmentally Based Cardiovascular Diseases, EXTRAMURAL RESEARCH FACILITIES CONSTRUCTION, G6728956057, G7175419485, G7306917086, Bioengineering Center of Regeneration and Formation of Tissues (SC BioCRAFT), Mucopolysaccharide Metabolism in Cardiac Anomalies, Improving Mitral Compensation in Ischemic Regurgitation, G9000054258, G9000135001, G9000210174
OpenAlex ID: W2117160158