title: Comparative Phosphoproteomics Analysis of VEGF and Angiopoietin-1 Signaling Reveals ZO-1 as a Critical Regulator of Endothelial Cell Proliferation.
abstract: VEGF and angiopoietin-1 (Ang-1) are essential factors to promote angiogenesis through regulation of a plethora of signaling events in endothelial cells (ECs). Although pathways activated by VEGF and Ang-1 are being established, the unique signaling nodes conferring specific responses to each factor remain poorly defined. Thus, we conducted a large-scale comparative phosphoproteomic analysis of signaling pathways activated by VEGF and Ang-1 in ECs using mass spectrometry. Analysis of VEGF and Ang-1 networks of regulated phosphoproteins revealed that the junctional proteins ZO-1, ZO-2, JUP and p120-catenin are part of a cluster of proteins phosphorylated following VEGF stimulation that are linked to MAPK1 activation. Down-regulation of these junctional proteins led to MAPK1 activation and accordingly, increased proliferation of ECs stimulated specifically by VEGF, but not by Ang-1. We identified ZO-1 as the central regulator of this effect and showed that modulation of cellular ZO-1 levels is necessary for EC proliferation during vascular development of the mouse postnatal retina. In conclusion, we uncovered ZO-1 as part of a signaling node activated by VEGF, but not Ang-1, that specifically modulates EC proliferation during angiogenesis.
authors: From the ‡Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada; §Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada;
authors: Rony
authors: R
authors: Chidiac
authors: From the ‡Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada; §Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada;
authors: Ying
authors: Y
authors: Zhang
authors: ¶Proteomics discovery platform, Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada.
authors: Sylvain
authors: S
authors: Tessier
authors: ¶Proteomics discovery platform, Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada.
authors: Denis
authors: D
authors: Faubert
authors: From the ‡Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada;
authors: Chantal
authors: C
authors: Delisle
authors: From the ‡Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada; jean-philippe.gratton@umontreal.ca.
authors: Jean-Philippe
authors: JP
authors: Gratton
mesh_terms: D042683:Angiopoietin-1 / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002460:Cell Line; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D018919:Neovascularization, Physiologic; D010750:Phosphoproteins / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D012160:Retina / Q000254:growth & development* / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein / Q000378:metabolism*
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D010750:Phosphoproteins; C569042:TJP1 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D062826:Zonula Occludens-1 Protein