Selective Binding of VEGF121 to One of the Three Vascular Endothelial Growth Factor Receptors of Vascular Endothelial Cells

Gitay-Goren, Hela; Cohen, Tzafra; Tessler, Shoshana; Söker, Shay; Gengrinovitch, Stela; Rockwell, Patricia; Klagsbrun, Michael; Levi, Ben‐Zion; Neufeld, Gera

doi:10.1074/jbc.271.10.5519

Cited by 187 publications

(167 citation statements)

References 31 publications

(22 reference statements)

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“…2 of their paper 13 , bands corresponding to the molecular weight of NRP1+ 125 I-VEGF-A121a did not appear with excess VEGF-A121a (10–20 ng.mL −1 ∼ 0.25–0.52 nM). Furthermore, treatment with an excess of VEGF-A121a did not inhibit formation of NRP1+ 125 I-VEGF-A165a complexes 13 or does so to a small extent. 10 The authors concluded that either VEGF-A121a does not bind to NRPs, or that the affinity of VEGF-A121a to these receptors is lower 13 ; competition experiments are not always sufficiently sensitive to detect low affinity ligand binding.…”

Section: Evidence Against Binding Of Vegf-a121a To Neuropilinsmentioning

confidence: 91%

“…As noted above, this one exception (VEGF-A111a) is likely due to the lack of part of exon 5 encoded sequence on the VEGF-A111a isoform. The authors suggest that the lack of observed NRP1-binding by VEGF-A121a in earlier publications 11-13 is due to degradation of exon 8a encoded sequence during expression and preparation of the ligand or during the experiments. They also showed that VEGF-A xxx b isoform failing to bind NRP1 is due to lack of exon 8a encoded sequence/tertiary fold and is not due to the presence of exon 8b encoded sequence/tertiary fold.…”

Section: Evidence Supporting Direct Vegf-a121a Binding To Neuropilinsmentioning

confidence: 91%

“…13 In Fig. 2 of their paper 13 , bands corresponding to the molecular weight of NRP1+ 125 I-VEGF-A121a did not appear with excess VEGF-A121a (10–20 ng.mL −1 ∼ 0.25–0.52 nM). Furthermore, treatment with an excess of VEGF-A121a did not inhibit formation of NRP1+ 125 I-VEGF-A165a complexes 13 or does so to a small extent.…”

Section: Evidence Against Binding Of Vegf-a121a To Neuropilinsmentioning

confidence: 94%

“…11-14 The authors used cross-linking to fix 125 I-VEGF-A121a and 125 I-VEGF-A165a to human umbilical endothelial (HUE) cells that express VEGFR1, VEGFR2, NRP1 and NRP2 at densities detectable by western blotting. 13 They used western blotting to assess the appearance of 125 I-VEGF-A121a-bound or 125 I-VEGF-A165a-bound NRP and VEGFR complexes by bands corresponding to their combined molecular weight. 13 In Fig.…”

Section: Evidence Against Binding Of Vegf-a121a To Neuropilinsmentioning

confidence: 99%

“…13 They used western blotting to assess the appearance of 125 I-VEGF-A121a-bound or 125 I-VEGF-A165a-bound NRP and VEGFR complexes by bands corresponding to their combined molecular weight. 13 In Fig. 2 of their paper 13 , bands corresponding to the molecular weight of NRP1+ 125 I-VEGF-A121a did not appear with excess VEGF-A121a (10–20 ng.mL −1 ∼ 0.25–0.52 nM).…”

Section: Evidence Against Binding Of Vegf-a121a To Neuropilinsmentioning

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 Against Binding Of Vegf-a121a To Neuropilinsmentioning

confidence: 91%

Section: Evidence Supporting Direct Vegf-a121a Binding To Neuropilinsmentioning

confidence: 91%

Section: Evidence Against Binding Of Vegf-a121a To Neuropilinsmentioning

confidence: 94%

Section: Evidence Against Binding Of Vegf-a121a To Neuropilinsmentioning

confidence: 99%

Section: Evidence Against Binding Of Vegf-a121a To Neuropilinsmentioning

confidence: 99%

See 3 more Smart Citations

VEGF-A121a binding to Neuropilins – A concept revisited

Sarabipour

Gabhann

2017

Cell Adhesion & Migration

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Concomitant over-expression of vascular endothelial growth factor and its receptors in pancreatic cancer

Itakura

Ishiwata

Shen³

et al. 2000

Int. J. Cancer

218

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Vascular endothelial growth factors VEGF-B and VEGF-C

et al. 1997

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Vascular endothelial growth factor, which was iden-heart cDNA library, respectively, by using a serendipitously found partial mouse cDNA clone as a probe tified almost 10 years ago, has so far been considered as the only growth factor relatively specific for endothelial (20,24). Independently, another group found the same gene when attempting to identify candidate genes for cells. VEGF is an important regulator of endothelial cell proliferation, migration, and permeability during multiple endocrine neoplasia type 1 (MEN1). The product of this alternatively spliced gene was designated as embryonic vasculogenesis and in physiological and pathological angiogenesis [reviewed in (1 -3)]. The piv-VRF (21).The two currently known isoforms of VEGF-B are otal role of VEGF in embryogenesis is emphasized by the unprecedented result that the inactivation of even a generated by alternative splicing of mRNA from the VEGF-B gene, spanning about 4 kb of DNA. The human single VEGF allele results in embryonic lethality (4,5). VEGF acts through its two known high-affinity recep-and murine VEGF-B genes are composed of 7 exons, and their exon -intron organization resembles that of tors Flt1, vascular endothelial growth factor receptor 1 (VEGFR-1) and KDR/Flk1, or VEGFR-2 (6 -10). A VEGF and PlGF genes (21,24,25). The mature VEGF-B proteins (devoid of signal sequence) have 167 (VEGF-third receptor tyrosine kinase homologous with VEGFR-1 and VEGFR-2, designated Flt4, was cloned B 167 ) and 186 (VEGF-B 186 ) amino acid residues, respectively. VEGF-B 186 is generated by using an alternative as an orphan receptor by two research groups and was shown not to bind VEGF (11 -14). Additional VEGF splice acceptor site in exon 6, resulting in an insertion of 101 bp between nucleotides 410 and 411 in the coding receptors of unknown nature also exist on endothelial and tumor cells (15,16).sequence of VEGF-B167. This insertion introduces a frame shift and a stop codon at the position correspond-The second member of the VEGF family of growth factors, placenta growth factor (PlGF), is 53% identical ing to nucleotides 521 -523 of the coding region of VEGF-B 167 cDNA (Fig. 1). Thus, the two VEGF-B iso-with VEGF within its platelet-derived growth factorlike region and binds only VEGFR-1 (17 -19). Both forms have an identical NH2-terminal domain of 115 aa and different COOH-terminal domains. Although VEGF and PlGF are dimeric glycoproteins related in structure to the platelet-derived growth factors A and the C-terminus of VEGF-B 167 is highly basic, that of VEGF-B 186 is rich in alanine, proline, serine, and threo-B (PDGF-A and PDGF-B). This relation is based on the presence of several conserved amino acid residues nine amino acid residues and has no significant similarity with amino acid sequences of known proteins including 8 equally spaced cysteines. Compared with VEGF, the mitogenic or permeability-enhancing activi- (21,24). Unlike other growth factors of the VEGF-family, both isoforms of human and mouse VEGF-B lack ties of PlGF are weak; however, Pl...

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Selective Binding of VEGF121 to One of the Three Vascular Endothelial Growth Factor Receptors of Vascular Endothelial Cells

Cited by 187 publications

References 31 publications

VEGF-A121a binding to Neuropilins – A concept revisited

VEGF-A121a binding to Neuropilins – A concept revisited

Concomitant over-expression of vascular endothelial growth factor and its receptors in pancreatic cancer

Vascular endothelial growth factors VEGF-B and VEGF-C

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