Disease relevance of NRP1

• These findings indicate that GAG modification of NRP1 plays a critical role in modulating VEGF signaling, and may provide new insights into physiological and pathological angiogenesis [1].
• Carcinomas express NRP1, whereas neuronal tumors and melanomas predominantly express NRP2 [2].
• The higher grade of glioma overexpressed the NRP1 gene significantly (p=0.0015) [3].
• Vascular endothelial growth factor (VEGF)-like protein from orf virus NZ2 binds to VEGFR2 and neuropilin-1 [4].
• Indeed, VEGF(145) does not bind to MDA-MB-231 breast cancer cells, which predominantly express np-1 [5].
• Knockdown of NRP1 suppressed cancer cell migration, invasion, filopodia formation, tumorigenesis, angiogenesis, and in vivo metastasis [6].

High impact information on NRP1

• In addition, Vegf165 promoted survival of motor neurons during hypoxia through binding to Vegf receptor 2 and neuropilin 1 [7].
• Sema3A treatment leads to the redistribution of growth cone NP-1 and plexin into clusters [8].
• Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor [9].
• Conversely, inhibition of VEGF165 binding to neuropilin-1 inhibits its binding to KDR and its mitogenic activity for endothelial cells [9].
• Next, we validated the motif PQPRPL as a novel chimeric ligand mimic that binds specifically to VEGF receptor-1 and to neuropilin-1 [10].

Chemical compound and disease context of NRP1

• Chemosensitivity to gemcitabine or 5-fluorouracil (5-FU) was assessed by MTT assay in pancreatic cancer cells following NRP-1 overexpression or siRNA-induced downregulation of NRP-1 [11].
• Overexpression of vascular endothelial growth factor164 and its co-receptor neuropilin-1 in estrogen-induced rat pituitary tumors and GH3 rat pituitary tumor cells [12].

Biological context of NRP1

• Glycosylation increased VEGF binding in both cell types, but the differential GAG composition of NRP1 mediates opposite responsiveness to VEGF in ECs and SMCs [1].
• Down-regulation of NRP1 by NRSF overexpression reduced Sema3A activity [13].
• Using NRP1 promoter constructs in HaCaT cells, a keratinocyte cell line, we could demonstrate that a neuron restrictive silencer element (NRSE) was implicated in transcriptional repression of the NRP1 gene [13].
• The NRP1 and NRP2 genes span over 120 and 112 kb, respectively, and are composed of 17 exons [14].
• With the use of this rate, our model gives predictions in good quantitative agreement with several independent in vitro experiments involving VEGF(121) and VEGF(165) isoforms, confirming that VEGFR2-NRP1 coupling through VEGF(165) can fully explain the observed differences in receptor binding and phosphorylation in response to these isoforms [15].

Anatomical context of NRP1

• It was concluded that NRSF is a transcription factor that silences NRP1 expression and thereby diminishes the Sema3A mediated inhibition of HaCaT keratinocyte migration [13].
• The functions of NRP1 and NRP2 have been extensively studied in neurons where they act in axon guidance and in endothelial cells where they promote angiogenesis and cell migration [16].
• During avian blood vessel development NRP1 is expressed only in arteries whereas NRP2 is expressed in veins [17].
• Overexpression of NRP1 results in the formation of excess capillaries and hemorrhaging [17].
• NRP1(Delta exon16) is expressed in endothelial cells, astrocytes, and various tumor cell lines, and accounts for 30% of the total NRP1 transcript [18].

Associations of NRP1 with chemical compounds

• Here we show that a substantial fraction of NRP1 is proteoglycan modified with either heparan sulfate or chondroitin sulfate on a single conserved Ser [1].
• Furthermore, the histone deacetylase inhibitor trichostatin A, an inhibitor of NRSF silencing activity, also increased NRP1 levels [13].
• The affinity of VEGF165 for the NP-1 ECD was greatly enhanced either by increasing the density of immobilized NP-1 (K(d) = 113 nm) or by the addition of heparin (K(d) = 25 nm) [19].
• The selected peptide, ATWLPPR, inhibited the VEGF(165) binding to NRP-1 but not to tyrosine kinase receptors, VEGFR-1 (flt-1) and KDR; nor did it bind to heparin [20].
• Here we report the identification of a new NP1 transcript (designated NRP1(Delta exon16)) that contains an arginine codon in place of exon 16-derived sequences at a locus between the c-domain and membrane spanning domain [18].

Physical interactions of NRP1

• Neuropilin-1 binds only the isoform of VEGF responsible for pathological angiogenesis (VEGF165), and is thus a potential target for inhibiting VEGF signaling [21].
• These results suggest that VEGF and SEMA3F compete for binding to their common neuropilin receptor [22].
• The NRP1 binding of VEGF-B could be competed by an excess of VEGF(165) [23].
• In competition experiments, VEGF165 competed PlGF-2 binding to the NRP1 b1b2 domain, suggesting that the binding sites of VEGF165 and PlGF-2 overlap [24].
• The neuropilin (NP)/plexin (Plex) Rc complex binds Sema [25].

Regulatory relationships of NRP1

• Reducing SEMA3A or NP1 expression by RNA interference or inhibiting plexin-A1 signaling enhanced migration [26].
• VEGF165 also mediated the binding of a soluble NRP1 dimer to cells expressing KDR only, confirming the formation of such complexes [27].
• The binding of VEGF-B(167) was mediated by the heparin binding domain, whereas the binding of VEGF-B(186) to NRP1 was regulated by exposure of a short COOH-terminal proline-rich peptide upon its proteolytic processing [23].
• CONCLUSIONS: These data show that exogenous CypA downregulates NRP-1 and VEGF expression in pancreatic cancer cells [28].
• Blockade of the phosphatidylinositol-3 kinase (PI-3K)/Akt, mitogen-activated protein kinase (MAPK)/Erk, or P-38 pathways abrogated EGF-induced NRP-1 expression [29].

Other interactions of NRP1

• Lastly, neuropilin-1 can homomultimerize and form heteromultimers with neuropilin-2 [30].
• In normal pituitaries, VEGFR-1 was detected in endocrine cells, whereas VEGFR-2 and NRP-1 were exclusively expressed in endothelial cells [31].
• Neuropilin-1 is a receptor for Sema III [30].
• We examined the expression of NRP-1 mRNA and EGF-R protein in seven human gastric cancer cell lines [32].
• These results suggest that regulation of NRP-1 expression in human gastric cancer is intimately associated with the EGF/EGF-R system [32].
• Targeted depletion of NRP2 using small hairpin RNA revealed that NRP2 can function in the absence of NRP1 to mediate endothelial tube formation in hypoxia [33].

Analytical, diagnostic and therapeutic context of NRP1

• Double in situ hybridization reveals that six-somite embryos contain intermingled extraembryonic blood island (BI) subpopulations that express np1 or np2 as well as a BI subpopulation that coexpresses both neuropilins [34].
• RT-PCR demonstrated significantly greater expression of neuropilin-1 in normal vein compared with arterialized vein (P <0.05) [35].
• Expression of VEGF and NP-1 in OFPAE cells and fetal placentas was confirmed by Northern and Western blot analyses [36].
• NRP protein expression was detected by immunocytochemistry and Western blotting [37].
• Although gene-targeting studies documenting embryonic lethality in NRP-1 null mice have demonstrated a critical role for NRP-1 in vascular development, the activities of NRP-1 in mature endothelial cells have been incompletely defined [38].

References