Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding

Appleton, B.A.; Wu, Ping; Maloney, Janice; Yin, Jianping; Liang, Wei-Ching; Stawicki, Scott; Mortara, Kyle; Bowman, Krista K.; Elliott, J. Michael; Desmarais, William; Bazán, J. Fernando; Bagri, Anil; Tessier‐Lavigne, Marc; Koch, Alexander W.; Wu, Yan; Watts, Ryan J.; Wiesmann, Christian

doi:10.1038/sj.emboj.7601906

Cited by 198 publications

(206 citation statements)

References 63 publications

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“…Hence, it was initially suggested that Sema3s compete for the binding to Nrp1 with VEGF, thus inhibiting VEGF-induced angiogenesis. However, recent reports have shown that Sema3s and VEGF use different domains on Nrp1 for binding [40]. Consistent with a separate function of Sema3A on Nrp1, Sema3A increases vascular permeability, inhibits endothelial cell proliferation, and induces apoptosis even in the absence of VEGF [34,41], suggesting Sema3A activates its own signaling routes.…”

Section: Sema3amentioning

confidence: 78%

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

2011

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Angiogenesis, the formation of new blood vessels from preexisting vasculature, is essential for many physiological processes, and aberrant angiogenesis contributes to some of the most prevalent human diseases, including cancer. Angiogenesis is controlled by delicate balance between pro-and anti-angiogenic signals. While pro-angiogenic signaling has been extensively investigated, how developmentally regulated, naturally occurring anti-angiogenic molecules prevent the excessive growth of vascular and lymphatic vessels is still poorly understood. In this review, we summarize the current knowledge on how semaphorins and their receptors, plexins and neuropilins, control normal and pathological angiogenesis, with an emphasis on semaphorin-regulated anti-angiogenic signaling circuitries in vascular and lymphatic endothelial cells. This emerging body of information may afford the opportunity to develop novel anti-angiogenic therapeutic strategies.

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Section: Sema3amentioning

confidence: 78%

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

2011

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“…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%

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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“…16). The MAM domain has been suggested to have a role in dimerization of NRPs (31); however, other reports suggest the importance of the CUB and F5/8 domains as well as the transmembrane region in NRP dimerization (32)(33)(34). Recently, Rollenhagen et al (35) showed that NRP-2 is polysialylated on O-glycans located in the linker region between the second F5/8 (F5/8-2) and MAM domains.…”

Section: Resultsmentioning

confidence: 99%

Sequence Requirements for Neuropilin-2 Recognition by ST8SiaIV and Polysialylation of Its O-Glycans

Bhide

Fernandes

Colley

2016

Journal of Biological Chemistry

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Polysialic acid is an oncofetal glycopolymer, added to the glycans of a small group of substrates, that controls cell adhesion and signaling. One of these substrates, neuropilin-2, is a VEGF and semaphorin co-receptor that is polysialylated on its O-glycans in mature dendritic cells and macrophages by the polysialyltransferase ST8SiaIV. To understand the biochemical basis of neuropilin-2 polysialylation, we created a series of domain swap chimeras with sequences from neuropilin-1, a protein for which polysialylation had not been previously reported. To our surprise, we found that membrane-associated neuropilin-1 is polysialylated at ϳ50% of the level of neuropilin-2 but not polysialylated when it lacks its cytoplasmic tail and transmembrane region and is secreted from the cell. This was not the case for neuropilin-2, which is polysialylated when either membraneassociated or soluble. Evaluation of the soluble chimeric proteins demonstrated that the meprin A5 antigen-tyrosine phosphatase (MAM) domain and the O-glycan-containing linker region of neuropilin-2 are necessary and sufficient for its polysialylation and serve as better recognition and acceptor sites in the polysialylation process than those regions of neuropilin-1. In addition, specific acidic residues on the surface of the MAM domain are critical for neuropilin-2 polysialylation. Based on these data and pull-down experiments, we propose a model where ST8SiaIV recognizes and docks on an acidic surface of the neuropilin-2 MAM domain to polysialylate O-glycans on the adjacent linker region. These results together with those related to neural cell adhesion molecule polysialylation establish a paradigm for the process of protein-specific polysialylation. Polysialic acid (polySia)2 is a glycopolymer consisting of 8 to Ͼ100 ␣2,8-linked sialic acid residues (1). It is synthesized on the N-linked or O-linked glycans of a very specific set of cell surface proteins by two Golgi-localized polysialyltransferases (polySTs), ST8SiaII and ST8SiaIV (2, 3). Polysialylated proteins include the neural cell adhesion molecule (NCAM) (4), neuropilin-2 (NRP-2) (5), synaptic cell adhesion molecule 1 (6), the CD36 scavenger receptor in human milk (7), the ␣ subunit of the voltage-dependent sodium channel (8), and the polySTs themselves (9).PolySia has been shown to be crucially important for the development of the nervous system, synaptic plasticity and cell migration in the adult nervous system, and the regeneration of damaged nerves and tissues, and it is also up-regulated in many types of late stage cancers, where it is suggested to promote cancer metastasis (reviewed in Refs. 2, 3, and 10). Notably, work by Tanaka et al. (11) demonstrates that a substantial proportion of late stage non-small cell lung cancers express polySia, but not NCAM, suggesting that other substrates are polysialylated in these cancers. These functions of polySia are due to its abilities to serve as an anti-adhesive, a reservoir for biologically significant ligands, and a signaling modulator (reviewed ...

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Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding

Cited by 198 publications

References 63 publications

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

VEGF-A121a binding to Neuropilins – A concept revisited

Sequence Requirements for Neuropilin-2 Recognition by ST8SiaIV and Polysialylation of Its O-Glycans

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