Neuropilin-1-VEGFR-2 complexing requires the PDZ-binding domain of neuropilin-1

被引：109

作者：

Prahst, Claudia ^{[1
,2
]}

Heroult, Melanie ^{[1
,2
]}

Lanahan, Anthony A. ^{[3
,4
]}

Uziel, Noa ^{[5
]}

Kessler, Ofra ^{[5
]}

Shraga-Heled, Niva ^{[5
]}

Simons, Michael ^{[3
,4
]}

Neufeld, Gera ^{[5
]}

Augustin, Hellmut G. ^{[1
,2
]}

机构：

[1] Univ Heidelberg, Med Fac Mannheim CBTM, Joint Res Div Vasc Biol, D-69120 Heidelberg, Germany

[2] DKFZ, D-69120 Heidelberg, Germany

[3] Dartmouth Med Sch, Dept Med, Angiogenesis Res Ctr, Lebanon, NH 03756 USA

[4] Dartmouth Med Sch, Dept Med, Cardiol Sect, Lebanon, NH 03756 USA

[5] Technion Israel Inst Technol, Bruce Rappaport Fac Med, Rappaport Res Inst Med Sci, Canc & Vasc Biol Res Ctr, IL-31096 Haifa, Israel

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2008年 / 283卷 / 37期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1074/jbc.C800137200

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Vascular endothelial growth factor (VEGF) acts as a hierarchically high switch of the angiogenic cascade by interacting with its high affinity VEGF receptors and with neuropilin co-receptors. VEGF(165) binds to both Neuropilin-1 (NP-1) and VEGFR-2, and it is believed that ligand binding forms an extracellular bridge between both molecules. This leads to complex formation, thereby enhancing VEGFR-2 phosphorylation and subsequent signaling. We found that inhibition of VEGF receptor (VEGFR) phosphorylation reduced complex formation between NP-1 and VEGFR-2, suggesting a functional role of the cytoplasmic domain of VEGFR-2 for complex formation. Correspondingly, deleting the PDZ-binding domain of NP-1 decreased complex formation, indicating that extracellular VEGF165 binding is not sufficient for VEGFR-2-NP-1 interaction. Synectin is an NP-1 PDZ-binding domain-interacting molecule. Experiments in Synectin-deficient endothelial cells revealed reduced VEGFR-2-NP-1 complex formation, suggesting a role for Synectin in VEGFR-2-NP-1 signaling. Taken together, the experiments have identified a novel mechanism of NP-1 interaction with VEGFR-2, which involves the cytoplasmic domain of NP-1.

引用

页码：25110 / 25114

页数：5

共 29 条

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