Signaling properties of VEGF receptor-1 and -2 homo- and heterodimers

Huang, Kui; Andersson, Charlotte; Roomans, Godfried M.; Ito, Nobuyuki; Claesson‐Welsh, Lena

doi:10.1016/s1357-2725(01)00019-x

Cited by 116 publications

(86 citation statements)

References 24 publications

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“…50 VEGFRs form heterodimers as well: intact VEGFR2/VEGFR3 and VEGFR2/VEGFR1 dimers form as demonstrated by a number of biochemical techniques including PLA and co-immunoprecipitation. 53-56 NRP1, though not an RTK, homodimerizes in the absence of VEGFs 29 , and the transmembrane domain plays a role in NRP-NRP interactions. The NRP1 transmembrane domain includes two GxxxG dimerization motifs in the form of GxxxGxxxG, (where G is an amino acid with a small side chain such as Glycine, Serine or Alanine); this motif is long recognized to promote higher order structures of alpha-helical transmembrane domains 57 , 58 .…”

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

confidence: 98%

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

confidence: 98%

VEGF-A121a binding to Neuropilins – A concept revisited

Sarabipour

Gabhann

2017

Cell Adhesion & Migration

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“…Heterodimerization between VEGFR-1 and VEGFR-2 subunits in preassembled complexes has been identified in cell-free systems 13 and in porcine 32 , bovine 33 and murine 19 endothelial cell lines. We confirmed VEGF receptor subunit heterodimerization in porcine aortic endothelial cells (PAEC) overexpressing human VEGFR-1 and VEGFR-2 (PAER-1:R-2), by immunoprecipitation ( Fig.…”

Section: Vegfr-1 and Vegfr-2 Form Heterodimers In Endothelial Cellsmentioning

confidence: 99%

“…Activation of VEGFR-2 mobilizes calcium from intracellular stores 48 , and evidence derived from cell lines expressing specific VEGF receptor subtypes indicated that the heterodimer mediated induction of calcium release in a biphasic manner 32 . In our study, VEGF-A caused a rapid, but transient calcium release in HUVEC (Fig.…”

Section: Neuropilins Have No Role In Vegf-e:plgf-1-induced Signallingmentioning

confidence: 99%

“…Pre-assembled heterodimer receptors of VEGFR-2 and VEGFR-3 subunits have been isolated from primary lymphatic endothelial cells 28,29 and detected in situ on angiogenic sprouts 30 . Heterodimerization between VEGFR-1 and VEGFR-2 subunits (VEGFR 1 − 2 ) has been detected in cell-free systems 13 and in endothelial cell lines 19,[31][32][33] . A computational model of VEGF receptor subunit dimerization concluded that a tenfold excess of one VEGF receptor subunit would result in minimal homodimerization of the less abundant receptor 34 .…”

mentioning

confidence: 99%

“…Therefore, dissection of VEGFR 1 − 2 heterodimerspecific function has been challenging. Receptor subunit knockdown and use of cell lines expressing specific receptors indicate that prostacyclin release 33 and biphasic calcium induction 32 is likely to be the result of VEGFR 1 − 2 activation.…”

mentioning

confidence: 99%

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