Neuropilin-1 functions as a VEGFR2 co-receptor to guide developmental angiogenesis independent of ligand binding

Gelfand, Maria V.; Hagan, Nellwyn; Tata, Aleksandra; Oh, Won-Jong; Lacoste, Baptiste; Kang, Kyu‐Tae; Kopycińska, Justyna; Bischoff, Joyce; Wang, Jia-Huai; Gu, Chenghua

doi:10.7554/elife.03720

Cited by 125 publications

(137 citation statements)

References 35 publications

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“…This mechanism may even occur in the absence of VEGF-A121a binding to NRP1, as it would be the interaction between VEGFR2 and NRP1 that would be key. Sequence-specific contacts at the transmembrane and intracellular domains in VEGFR2-NRP interactions 29 , 48 - 50 can provide a mechanistic interpretation for the Shraga-Heled et al results demonstrating enhancement of VEGFR2 activation by VEGF-A165a, VEGF-A121a, and VEGF-A165aKF (a VEGF-A165a mutant with impaired VEGFR binding but intact NRP and HSPG binding).…”

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

confidence: 90%

“…Interactions of NRP1 with VEGFR2 via transmembrane (TM) and intracellular (IC) domain contacts are a strong possibility. 9 , 15 , 48 Evidence of functional cytoplasmic interactions between VEGFR2 and NRP1 was presented by Prahst et al in 2008. Blockade of VEGFR2 phosphorylation disrupts formation of VEGFR2-NRP1 complexes, and removal of the IC domain of NRP1 reduces the number of VEGFR/NRP/VEGF-A165a complexes.…”

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

confidence: 99%

“…The NRP cytoplasmic domain has 40 residues and allows binding of the PDZ domain-containing protein GIPC1 (or synectin) 49 . NRP1 can form ligand-independent homodimers 29 , and heterodimers with NRP2 63-65 and with VEGFR2 48 , 49 in the cellular plasma membrane. NRP1 (but not NRP2) has one covalent GAG (HS/CS) attachment in the EC domain at Serine 612 30 (conserved across species 66 ); The GAG modification of NRP1 enhances VEGFR2 signaling in endothelial cells by multiple mechanisms, including enhancement of VEGF-A165a binding and delayed degradation of VEGFR2 bound to VEGF 30 . …”

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

confidence: 99%

“…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%

“…Prahst et al and others have shown by co-immunoprecipitation that NRP1 and VEGFR2 heterodimerize in the absence and presence of VEGFs. 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.…”

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

confidence: 90%

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

confidence: 99%

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

confidence: 99%

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%

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VEGF-A121a binding to Neuropilins – A concept revisited

Sarabipour

Gabhann

2017

Cell Adhesion & Migration

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Molecular and Cellular Mechanisms of Vascular Development

Bolton¹,

Naylor²,

Ruhrberg³

2019

Encyclopedia of Life Sciences

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Blood vessels form an extensive organ system that enables gas exchange, delivers nutrients and removes waste products from tissues and is, therefore, essential for vertebrate life. Blood vessels additionally regulate leukocyte trafficking to support immune system function and transport endocrine hormones for the systemic regulation of physiological processes. During embryonic development, blood vessels also secrete cues that regulate the formation of other organs. To ensure that functional vasculature forms in the embryo, a large number of molecules regulate a wide range of cellular mechanisms that collectively act on the endothelial cells that form the inner lining of all blood vessels. These molecular and cellular mechanisms may be reactivated after birth to induce blood vessel growth that is beneficial by countering tissue ischemia or pathological if excessive or dysfunctional. Understanding developmental blood vessel growth, therefore, provides knowledge that may be used to develop new therapeutic strategies for a range of diseases. Key Concepts The circulatory system is the first organ to form during vertebrate embryogenesis and is required for the subsequent development of other organs. The circulatory system is the first organ to form during vertebrate embryogenesis. Proper blood vessel growth and remodeling is required for the subsequent development of other organs. Blood vessel development can be studied using the embryonic mouse hindbrain and perinatal mouse retina. Many molecular pathways synergise to regulate blood vessel growth. Elucidating the mechanisms of vascular development may advance novel therapies to treat vascular insufficiency in ischemic diseases.

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Neuropilin‐1‐Mediated SARS‐CoV‐2 Infection in Bone Marrow‐Derived Macrophages Inhibits Osteoclast Differentiation

et al. 2022

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As of January 25, 2022, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has caused more than 340 million infections with over 5.5 million deaths. [1] Coronavirus disease 2019 (COVID-19) patients may develop various clinical manifestations, including severe acute pulmonary disease, [2][3][4] hepatic dysfunction, [3,4] kidney injury, [4] heart damage, [3,4] gastrointestinal, [5] pancreatic symptoms, [6] and olfactory dysfunction. [7] However, due to the lagged, yet possibly long-lasting effects, [8] the impact of COVID-19 on the skeleton system has not been well characterized. Bone is the major reservoir for body calcium and phosphorus. [9] Preliminary clinical data have uncovered COVID-19-associated calcium metabolic disorders and osteoporosis. [10,11] Importantly, severe COVID-19 patients are found to have decreased blood calcium and phosphorus levels, in comparison with moderate COVID-19 patients. [12] These observations suggest a possible link between SARS-CoV-2 infection and damage in the skeleton system. In humans, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause medical complications across various tissues and organs. Despite the advances to understanding the pathogenesis of SARS-CoV-2, its tissue tropism and interactions with host cells have not been fully understood. Existing clinical data have revealed disordered calcium and phosphorus metabolism in Coronavirus Disease 2019 (COVID-19) patients, suggesting possible infection or damage in the human skeleton system by SARS-CoV-2. Herein, SARS-CoV-2 infection in mouse models with wildtype and beta strain (B.1.351) viruses is investigated, and it is found that bone marrow-derived macrophages (BMMs) can be efficiently infected in vivo. Single-cell RNA sequencing (scRNA-Seq) analyses of infected BMMs identify distinct clusters of susceptible macrophages, including those related to osteoblast differentiation. Interestingly, SARS-CoV-2 entry on BMMs is dependent on the expression of neuropilin-1 (NRP1) rather than the widely recognized receptor angiotensin-converting enzyme 2 (ACE2). The loss of NRP1 expression during BMM-to-osteoclast differentiation or NRP1 neutralization and knockdown can significantly inhibit SARS-CoV-2 infection in BMMs. Importantly, it is found that authentic SARS-CoV-2 infection impedes BMM-to-osteoclast differentiation. Collectively, this study provides evidence for NRP1-mediated SARS-CoV-2 infection in BMMs and establishes a potential link between disturbed osteoclast differentiation and disordered skeleton metabolism in COVID-19 patients.

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Neuropilin-1 functions as a VEGFR2 co-receptor to guide developmental angiogenesis independent of ligand binding

Cited by 125 publications

References 35 publications

VEGF-A121a binding to Neuropilins – A concept revisited

VEGF-A121a binding to Neuropilins – A concept revisited

Molecular and Cellular Mechanisms of Vascular Development

Neuropilin‐1‐Mediated SARS‐CoV‐2 Infection in Bone Marrow‐Derived Macrophages Inhibits Osteoclast Differentiation

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