Endothelial NO Synthase-Dependent S-Nitrosylation of β-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 β-catenin by eNOS-derived NO has been shown to influence intercellular contacts between endothelial cells. However, the implication of SNO in the regulation of β-catenin transcriptional activity is ill defined. Here, we report that NO inhibits the transcriptional activity of β-catenin and endothelial cell proliferation induced by activation of Wnt/β-catenin signaling. Interestingly, induction by Wnt3a of β-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 β-catenin as a target for SNO by eNOS-derived NO and as the critical residue for the repressive effects of NO on β-catenin transcriptional activity. Furthermore, we observed that Cys466 of β-catenin, located at the binding interface of the β-catenin-TCF4 transcriptional complex, is essential for disruption of this complex by NO. Importantly, Cys466 of β-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 β-catenin and link eNOS-derived NO to the modulation by VEGF of Wnt/β-catenin-induced endothelial cell proliferation.
Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.|Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
Ying
Y
Zhang
Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.|Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
Rony
R
Chidiac
Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
Chantal
C
Delisle
Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada jean-philippe.gratton@umontreal.ca.
Jean-Philippe
JP
Gratton
D000818:Animals; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D003545:Cysteine / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D015538:Nitrosation / Q000187:drug effects; D058118:Transcription Factor 7-Like 2 Protein / Q000378:metabolism*; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism*
C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D042461:Vascular Endothelial Growth Factor A; D060509:Wnt3A Protein; D051176:beta Catenin; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D003545:Cysteine
S-nitrosylation; VEGF; Wnts; cell signaling; endothelial cells; nitric oxide; nitric oxide synthase