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2017 ; 8
(24
): 38886-38901
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Syntenin promotes VEGF-induced VEGFR2 endocytosis and angiogenesis by increasing
ephrin-B2 function in endothelial cells
#MMPMID28418925
Tae N
; Lee S
; Kim O
; Park J
; Na S
; Lee JH
Oncotarget
2017[Jun]; 8
(24
): 38886-38901
PMID28418925
show ga
Syntenin, a tandem PDZ-domain-containing scaffold protein, is involved in the
regulation of diverse biological functions, including protein trafficking,
exosome biogenesis, and cancer metastasis. Here, we present the first study to
explore the significance of syntenin in endothelial cells. Syntenin knockdown in
human umbilical vein endothelial cells (HUVECs) impaired vascular endothelial
growth factor (VEGF)-mediated proliferation, migration, invasion, vascular
permeability, and nitric oxide (NO) production. Syntenin knockdown also
suppressed expression of the VEGFR2 target genes VEGF, MMP2, and Nurr77 as well
as VEGF-induced angiogenesis in vitro and in vivo. And it decreased cell-surface
levels of ephrin-B2. Biochemical analyses revealed that syntenin exists in
complex with VEGFR2 and ephrin-B2. Syntenin knockdown abolished the association
between VEGFR2 and ephrin-B2, suggesting syntenin functions as a scaffold protein
facilitating their association in HUVECs. Consistent with these observations,
knocking down syntenin or ephrin-B2 abolished VEGF-induced endocytosis and VEGFR2
phosphorylation and activation of its downstream signaling molecules. Treatment
with MG132, a proteasome inhibitor, rescued the downregulation of ephrin-B2 and
VEGFR2 signaling induced by syntenin knockdown. These findings demonstrate that
syntenin promotes VEGF signaling and, through its PDZ-dependent interaction with
ephrin-B2, enhances VEGF-mediated VEGFR2 endocytosis and subsequent downstream
signaling and angiogenesis in endothelial cells.