NF2 signaling pathway plays a pro-apoptotic role in β-adrenergic receptor stimulated cardiac myocyte apoptosis
Year: 2018
Type: article
Abstract: β-adrenergic receptor (β-AR) stimulation induces cardiac myocyte apoptosis in vitro and in vivo.Neurofibromin 2 (NF2) is a member of the ezrin/radixin/moesin (ERM) family of proteins.Post-translational modifications such as phosphorylation and sumoylation affect NF2 activity, subcellular localization and function.Here, we tested the hypothesis that β-AR stimulation induces post-translational modifications of NF2, and NF2 plays a pro-apoptotic role in β-AR-stimulated myocyte apoptosis. Methods and resultsTreatment of adult rat ventricular myocytes (ARVMs) with β-AR agonist (isoproterenol) for 15 min increased phosphorylation (serine-518) and sumoylation of NF2.Co-immunoprecipitation assay confirmed β-AR-stimulated sumoylation of NF2.β-AR stimulation enhanced nuclear translocation of phosphorylated and sumoylated NF2.Specific inhibition of β 1 -AR and protein kinase A (PKA) decreased β-AR-stimulated increase in NF2 post-translational modifications, while inhibition of β 2 -AR had no effect.Activation of adenylyl cyclase using forskolin (FSK) mimicked the effects of β-AR stimulation.β-AR stimulation and expression of wild-type (WT)-NF2 using adenoviruses increased phosphorylation of mammalian sterile like kinase-1/2 (MST1/2) and yes activated protein (YAP), downstream targets of NF2.Knockdown of NF2 using siRNA in H9C2 cardiomyocytes decreased β-AR-stimulated increase in NF2 and YAP phosphorylation.siRNA-mediated knockdown of NF2 decreased β-AR-stimulated increase in apoptosis, while expression of WT-NF2 induced apoptosis in ARVMs.Expression of WT-NF2 stimulated the mitochondrial death pathway as evidenced by activation of c-Jun N-terminal Kinases (JNKs), and increase in cytosolic cytochrome c levels and Bax expression. Conclusionβ-AR stimulation affects post-translational modifications of NF2 via the involvement β 1 -AR/PKA/cAMP pathway, and NF2 plays a pro-apoptotic role in β-AR-stimulated myocyte
Source: PLoS ONE
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,382
OpenAlex ID: W2803043374