Synergistic Binding of Vascular Endothelial Growth Factor-A and Its Receptors to Heparin Selectively Modulates Complex Affinity

Teran, Madelane; Nugent, Matthew A.

doi:10.1074/jbc.m114.627372

Cited by 65 publications

(92 citation statements)

References 52 publications

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“…Indeed, GFR molecules commonly exhibit high specificity toward the ligands they bind allowing them, thus, to be characterized as 'strict gatekeepers' responsible for the interpretation and further processing of incoming signals [50]. The binding of ligands and resulting function of GFRs, however, are further finely modulated through interaction with respective coreceptors [60,61]. A number of elegant early reports attributed to syndecans the ability to act as coreceptors for GFs.…”

Section: Syndecans As Co-receptors In Cooperation With Gfrs In Cell Smentioning

confidence: 99%

Syndecans – key regulators of cell signaling and biological functions

et al. 2016

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Syndecans are a small family of four transmembrane proteoglycans in mammals. They have similar structural organization, consisting of an Nterminal ectodomain, single transmembrane domain and C-terminal cytoplasmic domain. Over the years, the association between syndecans and the actin cytoskeleton has been established, which has consequences for the regulation of cell adhesion and migration. Specifically, ecto-and cytoplasmic domains are responsible for the interaction with extracellular matrix molecules and intracellular kinases, respectively. These interactions indicate syndecans as key molecules during cancer initiation and progression. Particularly syndecans interact with other cell surface receptors, such as growth factor receptors and integrins, which lead to activation of downstream signaling pathways, which are critical for the cellular behavior. Moreover, this review describes the key role of syndecans in intracellular calcium regulation and homeostasis. The syndecan-mediated regulation of calcium metabolism is highly correlated with cells' adhesion phenotype through the actin cytoskeleton and formation of junctions, with implications during differentiation and disease progression.

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Section: Syndecans As Co-receptors In Cooperation With Gfrs In Cell Smentioning

confidence: 99%

Syndecans – key regulators of cell signaling and biological functions

et al. 2016

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“…1) that confer on those isoforms an ability to bind to, and be sequestered by, proteoglycans of the extracellular matrix 5 or cell surface (HSPGs). 3 , 6 , 7 Second, the ‘xxxa’ isoforms contain the short C-terminal exon 8a-encoded sequence, which can confer the ability to bind to the Neuropilin coreceptors (Fig. 1, 2), while the ‘xxxb’ isoforms, containing the exon 8b-encoded sequence, cannot.…”

Section: Vegf-a Isoforms Exhibit Differential Binding To Vegfrs and Nrpsmentioning

confidence: 99%

“…A complete picture of differential VEGFR2 phosphorylation and signaling induced by VEGF-A121a and VEGF-A165a is yet to be elucidated, and is complicated by the inclusion of HSPGs and NRPs in the signal initiation macrocomplex. The old model proposed that: (A) receptors exist only as monomers in the absence of ligands; (B) upon VEGF-A165a binding, two VEGFR2 monomers and two NRP1 monomers are bridged by the ligand, which results in formation of a macrocomplex 6 efficient in VEGFR2 transphosphorylation; and (C) VEGF-A121a binds only to two VEGFR2 monomers to form dimers and to activate the receptor's tyrosine kinase domain. Since VEGF-A121a does not bind to NRPs to bridge VEGFR2 and NRP1 extracellular domains in this model, it does not explain the observed modulation of VEGF-A121a signaling by NRP1.…”

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

confidence: 99%

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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“…However, it is well established that, in addition to participating in VEGF–ECM interactions, heparin increases the affinity of VEGF for endothelial receptors, including VEGFR2. Indeed, this was clearly and elegantly demonstrated by Teran and Nugent (), co‐authors of the Sack et al paper. Although such interactions are mentioned in the discussion, they are not taken into account in interpreting the data presented in this study.…”

mentioning

confidence: 76%

Further Support for ECM Control of Receptor Trafficking and Signaling

Clegg

Gabhann

2016

J. Cell. Physiol

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Recently, Sack et al. (2016) presented an interesting, novel data set in Journal of Cellular Physiology examining the effect of substrate stiffness on VEGF processing and signaling. The data represent a clear contribution to the field. However, the authors' conclusion that "extracellular matrix binding is essential for VEGF internalization" conflicts with other knowledge in the field, and is not supported by their data. Instead, their data demonstrate the effect of heparin addition and changing ECM stiffness on both VEGF binding to fibronectin and VEGF binding to endothelial receptors. This is consistent with other work showing that matrix binding reduces VEGF-VEGFR internalization, shifting downstream signaling. J. Cell. Physiol. 232: 36-37, 2017. © 2016 Wiley Periodicals, Inc.

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Synergistic Binding of Vascular Endothelial Growth Factor-A and Its Receptors to Heparin Selectively Modulates Complex Affinity

Cited by 65 publications

References 52 publications

Syndecans – key regulators of cell signaling and biological functions

Syndecans – key regulators of cell signaling and biological functions

VEGF-A121a binding to Neuropilins – A concept revisited

Further Support for ECM Control of Receptor Trafficking and Signaling

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