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Comparative Phosphoproteomics Analysis of VEGF and Angiopoietin-1 Signaling
Reveals ZO-1 as a Critical Regulator of Endothelial Cell Proliferation
#MMPMID26846344
Chidiac R
; Zhang Y
; Tessier S
; Faubert D
; Delisle C
; Gratton JP
Mol Cell Proteomics
2016[May]; 15
(5
): 1511-25
PMID26846344
show ga
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.
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