Phosphorylation of Tyrosine 801 of Vascular Endothelial Growth Factor Receptor-2 Is Necessary for Akt-dependent Endothelial Nitric-oxide Synthase Activation and Nitric Oxide Release from Endothelial Cells

Blanes, Mariela Garcia; Oubaha, Malika; Rautureau, Yohann; Gratton, Jean‐Philippe

doi:10.1074/jbc.m609048200

Cited by 65 publications

(21 citation statements)

References 50 publications

(76 reference statements)

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“…NO production plays a prominent role in VEGF-induced angiogenesis and vascular permeability [4, 5]. Thus, we assessed the effect of syntenin knockdown on VEGF-induced NO production and permeability of EC monolayers.…”

Section: Resultsmentioning

confidence: 99%

Syntenin promotes VEGF-induced VEGFR2 endocytosis and angiogenesis by increasing ephrin-B2 function in endothelial cells

et al. 2017

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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.

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Section: Resultsmentioning

confidence: 99%

Syntenin promotes VEGF-induced VEGFR2 endocytosis and angiogenesis by increasing ephrin-B2 function in endothelial cells

et al. 2017

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“…2E). To determine whether VEGFR2 kinase activity is required for VEGFR3 signaling, we expressed either a control (wild type) or a dominant-negative “kinase-dead” VEGFR2 mutant (K868R) construct 23 in HDLECs (Fig. SII).…”

Section: Resultsmentioning

confidence: 99%

Molecular Controls of Lymphatic VEGFR3 Signaling

Deng

Zhang

Simons

2015

ATVB

115

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Objectives Vascular endothelial growth factor receptor 3 (VEGFR3) plays important roles both in lymphangiogenesis and angiogenesis. Upon stimulation by its ligand VEGF-C, VEGFR3 is able to form both homodimers as well as heterodimers with VEGFR2 and activates several downstream signal pathways including ERK1/2 and AKT. Despite certain similarities with VEGFR2, molecular features of VEGFR3 signaling are still largely unknown. Approach and Results Human dermal lymphatic endothelial cells (HDLECs) were used to examine VEGF-C-driven activation of signaling. Compared to VEGF-A activation of VEGFR2, VEGF-C-induced VEGFR3 activation led to a more extensive AKT activation while activation of ERK1/2 displayed a distinctly different kinetics. Furthermore, VEGF-C, but not VEGF-A, induced formation of VEGFR3/VEGFR2 complexes. Silencing VEGFR2 or its partner neuropilin-1 (NRP1) specifically abolished VEGF-C-induced AKT but not ERK activation, while silencing of NRP2 had little effect on either signaling pathway. Finally, suppression of vascular endothelial phosphotyrosine phosphatase (VE-PTP) but not other PTPs enhanced VEGF-C-induced activation of both ERK and AKT pathways. Functionally, both ERK and AKT pathways are important for LECs migration. Conclusions VEGF-C activates AKT signaling via formation of VEGFR3/VEGFR2 complex while ERK is activated by VEGFR3 homodimer. NRP1 and VE-PTP are involved in regulation of VEGFR3 signaling.

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“…VEGF increases VEGFR-2 phosphorylation on Tyr 1175 for activation [29-31]. Although DIF-1 decreased the phosphorylation level of Tyr 1175 on VEGFR-2 in a time-dependent manner, it was parallel with the time course of the VEGFR-2 protein amount, indicating that DIF-1 had no significant effects on the level of VEGFR-2 phosphorylation (Figure 6B).…”

Section: Resultsmentioning

confidence: 99%

Anti-angiogenic effects of differentiation-inducing factor-1 involving VEGFR-2 expression inhibition independent of the Wnt/β-catenin signaling pathway

et al. 2010

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BackgroundDifferentiation-inducing factor-1 (DIF-1) is a putative morphogen that induces cell differentiation in Dictyostelium discoideum. DIF-1 inhibits proliferation of various mammalian tumor cells by suppressing the canonical Wnt/β-catenin signaling pathway. To assess the potential of a novel cancer chemotherapy based on the pharmacological effect of DIF-1, we investigated whether DIF-1 exhibits anti-angiogenic effects in vitro and in vivo.ResultsDIF-1 not only inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) by restricting cell cycle in the G0/G1 phase and degrading cyclin D1, but also inhibited the ability of HUVECs to form capillaries and migrate. Moreover, DIF-1 suppressed VEGF- and cancer cell-induced neovascularization in Matrigel plugs injected subcutaneously to murine flank. Subsequently, we attempted to identify the mechanism behind the anti-angiogenic effects of DIF-1. We showed that DIF-1 strongly decreased vascular endothelial growth factor receptor-2 (VEGFR-2) expression in HUVECs by inhibiting the promoter activity of human VEGFR-2 gene, though it was not caused by inhibition of the Wnt/β-catenin signaling pathway.ConclusionThese results suggested that DIF-1 inhibits angiogenesis both in vitro and in vivo, and reduction of VEGFR-2 expression is involved in the mechanism. A novel anti-cancer drug that inhibits neovascularization and tumor growth may be developed by successful elucidation of the target molecules for DIF-1 in the future.

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Phosphorylation of Tyrosine 801 of Vascular Endothelial Growth Factor Receptor-2 Is Necessary for Akt-dependent Endothelial Nitric-oxide Synthase Activation and Nitric Oxide Release from Endothelial Cells

Cited by 65 publications

References 50 publications

Syntenin promotes VEGF-induced VEGFR2 endocytosis and angiogenesis by increasing ephrin-B2 function in endothelial cells

Syntenin promotes VEGF-induced VEGFR2 endocytosis and angiogenesis by increasing ephrin-B2 function in endothelial cells

Molecular Controls of Lymphatic VEGFR3 Signaling

Anti-angiogenic effects of differentiation-inducing factor-1 involving VEGFR-2 expression inhibition independent of the Wnt/β-catenin signaling pathway

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