Endothelial NO Synthase-Dependent S-Nitrosylation of ?-Catenin Prevents Its Association with TCF4 and Inhibits Proliferation of Endothelial Cells Stimulated by Wnt3a.

ABSTRACT: Nitric oxide (NO) produced by endothelial NO synthase (eNOS) modulates many functions in endothelial cells. S-nitrosylation (SNO) of cysteine residues on ?-catenin by eNOS-derived NO has been shown to influence intercellular contacts between endothelial cells. However, the implication of SNO in the regulation of ?-catenin transcriptional activity is ill defined. Here, we report that NO inhibits the transcriptional activity of ?-catenin and endothelial cell proliferation induced by activation of Wnt/?-catenin signaling. Interestingly, induction by Wnt3a of ?-catenin target genes, such as the axin2 gene, is repressed in an eNOS-dependent manner by vascular endothelial growth factor (VEGF). We identified Cys466 of ?-catenin as a target for SNO by eNOS-derived NO and as the critical residue for the repressive effects of NO on ?-catenin transcriptional activity. Furthermore, we observed that Cys466 of ?-catenin, located at the binding interface of the ?-catenin-TCF4 transcriptional complex, is essential for disruption of this complex by NO. Importantly, Cys466 of ?-catenin is necessary for the inhibitory effects of NO on Wnt3a-stimulated proliferation of endothelial cells. Thus, our data define the mechanism responsible for the repressive effects of NO on the transcriptional activity of ?-catenin and link eNOS-derived NO to the modulation by VEGF of Wnt/?-catenin-induced endothelial cell proliferation.

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC5452725 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature