Endothelial NO Synthase-Dependent S-Nitrosylation of ?-Catenin Prevents Its Association with TCF4 and Inhibits Proliferation of Endothelial Cells Stimulated by Wnt3a.
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.
Mesh Terms:
Animals, Cattle, Cell Proliferation, Cysteine, Endothelial Cells, HEK293 Cells, Humans, Mice, Nitric Oxide, Nitric Oxide Synthase Type III, Nitrosation, Transcription Factor 7-Like 2 Protein, Transcription, Genetic, Vascular Endothelial Growth Factor A, Wnt Signaling Pathway, Wnt3A Protein, beta Catenin
Animals, Cattle, Cell Proliferation, Cysteine, Endothelial Cells, HEK293 Cells, Humans, Mice, Nitric Oxide, Nitric Oxide Synthase Type III, Nitrosation, Transcription Factor 7-Like 2 Protein, Transcription, Genetic, Vascular Endothelial Growth Factor A, Wnt Signaling Pathway, Wnt3A Protein, beta Catenin
Mol Cell Biol
Date: Jun. 15, 2017
PubMed ID: 28320874
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