Oncotarget

Research Papers:

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

Nara Tae, Suhyun Lee, Okwha Kim, Juhee Park, Sunghun Na and Jeong-Hyung Lee _

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Oncotarget. 2017; 8:38886-38901. https://doi.org/10.18632/oncotarget.16452

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Abstract

Nara Tae1, Suhyun Lee1, Okwha Kim1, Juhee Park1, Sunghun Na2 and Jeong-Hyung Lee1

1Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 243-41, Republic of Korea

2Department of Obstetrics and Gynecology, Kangwon National University Hospital, school of Medicine, Kangwon National University, Chuncheon, Gangwon-Do 243-41, Republic of Korea

Correspondence to:

Jeong-Hyung Lee, email: jhlee36@kangwon.ac.kr

Keywords: syntenin, VEGFR2 endocytosis, ephrin-B2, endothelial cell, angiogenesis

Received: July 04, 2016    Accepted: February 27, 2017    Published: March 22, 2017

ABSTRACT

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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