Papier de Donald Martin 2025

L'article intitulé "Efficient Fine-Tuning of Endothelial Gene Expression by a Single Tyrosine (Y685) to Phenylalanine Point Mutation in the VE-Cadherin Gene" a été publié dans Arteriosclerosis, Thrombosis, and Vascular Biology

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Ici vous trouverez l'article de Donald Martin
"VE (vascular endothelial)-cadherin is an endothelial cell-surface receptor that lacks intrinsic tyrosine kinase activity but can be tyrosine phosphorylated in cancer and inflammation. Previous studies have uncovered the molecular underpinnings of phosphorylation events; however, there is a need for a comprehensive analysis of the transcriptome of endothelial cells. Using a tyrosine-to-phenylalanine (Y->F) transgenic mouse (KI), we provide the first experimental evidence that tyrosine-to phenylalanine at the site 685 (Y685F)-VE-cadherin induces a specific transcriptional program in vivo in lung tissue.

RNA-sequencing analysis revealed a total of 884 differentially expressed genes (766 downregulated and 118 upregulated in endothelial cells from KI) involved in cell-cell adhesion, vascular development, and angiogenesis. The heatmap of the top 30 differentially expressed genes clearly shows 22 downregulated genes (including cell signaling enzymes, anion transport, and lipid metabolism) and 8 upregulated genes that confer significantly reduced migration, proliferation, and outgrowth capabilities to endothelial cells from KI. A central pathway in signal transduction revealed a notable increase in phosphorylation of site tyrosine 731 (Y731) in Y685F-VE-cadherin in KI (P=0.041). This further compromised the binding of β-catenin, which was preferentially located in the nuclear fraction in KI (P=0.034) with increased transcriptional activity. One of the genes of particular interest was s1pr1 (sphingosine-1-phosphate receptor 1), which had the highest mean expression level in KI. We identified the lung endothelial–specific transcription factor FOXF1 (forkhead box protein F1) that binds to the s1pr1 promoter with a significantly higher intensity in KI (7-fold; P=0.023), as shown by chromatin immunoprecipitation assay. Consequently, increased s1pr1 expression was confirmed by reverse transcription polymerase chain reaction and Western blotting. Importantly, quantitative analysis of the pulmonary vasculature of KI revealed a significant decrease in the number of capillaries (P=0.036), with less fibrosis and no edema.

Overall, our results indicate a novel regulatory mechanism for transcriptional signatures in lung tissue, involving the critical site Y685 of VE-cadherin. This finding offers future insights for precision medicine applications.."