Vascular Endothelial Growth Factor Receptor-2 and Neuropilin-1 Form a Receptor Complex That Is Responsible for the Differential Signaling Potency of VEGF165 and VEGF121

Whitaker, G. Brian; Limberg, Brian J.; Rosenbaum, Jan S.

doi:10.1074/jbc.m102315200

Cited by 265 publications

(232 citation statements)

References 63 publications

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“…The new model explains these downstream effects by proposing two key concepts: 1) binding of VEGF-A121a to NRP1; and 2) stabilization of both VEGFR2-NRP1-VEGF-A121a (and VEGFR2-NRP1-VEGF-A165a) complexes by transmembrane and intracellular domain contacts between VEGFR2 and NRP1. In this new model: (D) VEGFR2 and NRP1 form complexes (low activity homo- and hetero-dimers) in the absence of VEGFs 15 , 29 , 48 , 50 , 59 . These dimers are stabilized by specific ECD, TMD and ICD contacts in the absence of VEGFs.…”

Section: Evidence That the Exon 8a Domain Which Vegf-a121a Has Is Rmentioning

confidence: 99%

“…48 , 49 A number of studies have used other techniques to report evidence for spontaneously formed (pre-formed) VEGFR2-NRP1 complexes. 15 , 48 , 59 In addition, NRP1 D320K (NRP1 with impaired VEGF binding) is found to be capable of regulating VEGFR2 activation 48 , and NRP1 modulates VEGFR2 levels independent of VEGF binding to NRP1. 15 , 49 , 59 Dimerization propensity of NRP1 TM domains has been measured using reporter genes in ToxLuc and FRET assays in detergent micelles.…”

Section: A New Model: Vegfr-nrp Interactions Outside Of the Extracellmentioning

confidence: 99%

“…15 , 48 , 59 In addition, NRP1 D320K (NRP1 with impaired VEGF binding) is found to be capable of regulating VEGFR2 activation 48 , and NRP1 modulates VEGFR2 levels independent of VEGF binding to NRP1. 15 , 49 , 59 Dimerization propensity of NRP1 TM domains has been measured using reporter genes in ToxLuc and FRET assays in detergent micelles. Roth et al demonstrated that the TM domain drives NRP1 homodimerization as mutation of the GxxxG motifs in the TM domains diminished NRP1-induced Sema3A activation.…”

Section: A New Model: Vegfr-nrp Interactions Outside Of the Extracellmentioning

confidence: 99%

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VEGF-A121a binding to Neuropilins – A concept revisited

Sarabipour

Gabhann

2017

Cell Adhesion & Migration

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All known splice isoforms of vascular endothelial growth factor A (VEGF-A) can bind to the receptor tyrosine kinases VEGFR-1 and VEGFR-2. We focus here on VEGF-A121a and VEGF-A165a, two of the most abundant VEGF-A splice isoforms in human tissue1, and their ability to bind the Neuropilin co-receptors NRP1 and NRP2. The Neuropilins are key vascular, immune, and nervous system receptors on endothelial cells, neuronal axons, and regulatory T cells respectively. They serve as co-receptors for the Plexins in Semaphorin binding on neuronal and vascular endothelial cells, and for the VEGFRs in VEGF binding on vascular and lymphatic endothelial cells, and thus regulate the initiation and coordination of cell signaling by Semaphorins and VEGFs.2 There is conflicting evidence in the literature as to whether only heparin-binding VEGF-A isoforms – that is, isoforms with domains encoded by exons 6 and/or 7 plus 8a – bind to Neuropilins on endothelial cells. While it is clear that VEGF-A165a binds to both NRP1 and NRP2, published studies do not all agree on the ability of VEGF-A121a to bind NRPs. Here, we review and attempt to reconcile evidence for and against VEGF-A121a binding to Neuropilins. This evidence suggests that, in vitro, VEGF-A121a can bind to both NRP1 and NRP2 via domains encoded by exons 5 and 8a; in the case of NRP1, VEGF-A121a binds with lower affinity than VEGF-A165a. In in vitro cell culture experiments, both NRP1 and NRP2 can enhance VEGF-A121a-induced phosphorylation of VEGFR2 and downstream signaling including proliferation. However, unlike VEGFA-165a, experiments have shown that VEGF-A121a does not ‘bridge’ VEGFR2 and NRP1, i.e. it does not bind both receptors simultaneously at their extracellular domain. Thus, the mechanism by which Neuropilins potentiate VEGF-A121a-mediated VEGFR2 signaling may be different from that for VEGF-A165a. We suggest such an alternate mechanism: interactions between NRP1 and VEGFR2 transmembrane (TM) and intracellular (IC) domains.

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Section: Evidence That the Exon 8a Domain Which Vegf-a121a Has Is Rmentioning

confidence: 99%

Section: A New Model: Vegfr-nrp Interactions Outside Of the Extracellmentioning

confidence: 99%

Section: A New Model: Vegfr-nrp Interactions Outside Of the Extracellmentioning

confidence: 99%

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VEGF-A121a binding to Neuropilins – A concept revisited

Sarabipour

Gabhann

2017

Cell Adhesion & Migration

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“…Vascular endothelial growth factor's effects are mediated primarily through two tyrosine kinase receptors: VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1/KDR). More recently, two additional nontyrosine kinase receptors for the VEGF family have been identified, neuropilin-1 (NRP-1) and neuropilin-2, which are believed to function as co-receptors for VEGFR-1 and VEGFR-2 (Fuh et al, 2000;Whitaker et al, 2001). Although the VEGF receptors have been described as endothelial cell-specific, emerging evidence has documented their presence on tumour cells (Itakura et al, 2000;Masood et al, 2001).…”

mentioning

confidence: 99%

Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells

et al. 2005

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Neuropilin-1 (NRP-1) is a novel co-receptor for vascular endothelial growth factor (VEGF). Neuropilin-1 is expressed in pancreatic cancer, but not in nonmalignant pancreatic tissue. We hypothesised that NRP-1 expression by pancreatic cancer cells contributes to the malignant phenotype. To determine the role of NRP-1 in pancreatic cancer, NRP-1 was stably transfected into the human pancreatic cancer cell line FG. Signal transduction was assessed by Western blot analysis. Susceptibility to anoikis (detachment induced apoptosis) was evaluated by colony formation after growth in suspension. Chemosensitivity to gemcitabine or 5-fluorouracil (5-FU) was assessed by MTT assay in pancreatic cancer cells following NRP-1 overexpression or siRNA-induced downregulation of NRP-1. Differential expression of apoptosis-related genes was determined by gene array and further evaluated by Western blot analysis. Neuropilin-1 overexpression increased constitutive mitogen activated protein kinase (MAPK) signalling, possibly via an autocrine loop. Neuropilin-1 overexpression in FG cells enhanced anoikis resistance and increased survival of cells by 430% after exposure to clinically relevant levels of gemcitabine and 5-FU. In contrast, downregulation of NRP-1 expression in Panc-1 cells markedly increased chemosensitivity, inducing 450% more cell death at clinically relevant concentrations of gemcitabine. Neuropilin-1 overexpression also increased expression of the antiapoptotic regulator, MCL-1. Neuropilin-1 overexpression in pancreatic cancer cell lines is associated with (a) increased constitutive MAPK signalling, (b) inhibition of anoikis, and (c) chemoresistance. Targeting NRP-1 in pancreatic cancer cells may downregulate survival signalling pathways and increase sensitivity to chemotherapy.

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“…The difference between these two proteins is the ability of the longer isoform to bind to both glycosaminoglycans (GAGs) in the interstitial space and Neuropilin co-receptors on endothelial cells. 57,66 Due to the dual effects of VEGF as mitogen and chemoattractant, the angiogenic response to VEGF depends on both: VEGF concentration (and the resulting formation of VEGF-VEGF receptor complexes on endothelial cells); and the formation of extracellular gradients of VEGF concentration. These are the two primary quantities that we report in this computational study.…”

Section: Introductionmentioning

confidence: 99%

Multi-scale Computational Models of Pro-angiogenic Treatments in Peripheral Arterial Disease

Gabhann

Popel

2007

Ann Biomed Eng

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Vascular Endothelial Growth Factor Receptor-2 and Neuropilin-1 Form a Receptor Complex That Is Responsible for the Differential Signaling Potency of VEGF165 and VEGF121

Abstract: The two most abundant secreted isoforms of vascular endothelial growth factor A (VEGF 165

Cited by 265 publications

References 63 publications

VEGF-A121a binding to Neuropilins – A concept revisited

VEGF-A121a binding to Neuropilins – A concept revisited

Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells

Multi-scale Computational Models of Pro-angiogenic Treatments in Peripheral Arterial Disease

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