{"gene":"NRP1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2011,"finding":"VEGF binding to NRP1 requires residues Y297 and D320 in the b1 domain; mutations at these sites abolish high-affinity VEGF binding, disrupt NRP1-VEGFR2 (KDR) complex formation, reduce FAK Tyr407 phosphorylation, and impair endothelial cell migration and angiogenesis. NRP1 non-binding mutants can act dominantly negative by heterodimerizing with wild-type NRP1 and NRP2.","method":"Site-directed mutagenesis, VEGF binding assays, co-immunoprecipitation, phosphorylation assays, migration assays, coculture angiogenesis model, overexpression in HUVECs","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro mutagenesis with multiple orthogonal functional readouts (binding, Co-IP, phosphorylation, migration, angiogenesis) in a single rigorous study","pmids":["21653826"],"is_preprint":false},{"year":2014,"finding":"NRP1 promotes brain angiogenesis cell-autonomously in endothelium and specifically in tip cells. Endothelial NRP1-expressing cells preferentially attain the tip cell position over NRP1-negative cells in chimeric vessel sprouts. Neural progenitor- and macrophage-derived NRP1 are dispensable for this process.","method":"Conditional endothelial-specific Nrp1 knockout, genetic mosaic analysis in chimeric mice, in vivo brain vessel imaging","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional knockouts with mosaic genetic analysis, replicated across multiple lineage-specific models","pmids":["23315162"],"is_preprint":false},{"year":2015,"finding":"NRP1 suppresses the stalk-cell phenotype during sprouting angiogenesis by limiting Smad2/3 activation through ALK1 and ALK5 (TGF-β/BMP receptors). Notch signaling downregulates NRP1, thereby relieving ALK1/ALK5 inhibition and driving stalk-cell behavior. NRP1 levels act as the pivot for endothelial cell heterogeneity in the Dll4/Notch lateral feedback loop.","method":"Genetic epistasis in zebrafish and mouse, endothelial-specific NRP1 knockout, Smad2/3 phosphorylation assays, ALK inhibitor experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis in two model organisms plus biochemical phosphorylation readouts, multiple orthogonal approaches","pmids":["26081042"],"is_preprint":false},{"year":2014,"finding":"NRP1 presented in trans (on a different cell than VEGFR2) arrests VEGFR2 endocytosis, prolonging phosphorylation of PLCγ and ERK2 while reducing ERK1 phosphorylation, and suppresses tumor initiation and vascularization. In cis, VEGF induces rapid VEGFR2/NRP1 complex formation and co-internalization. The trans effect requires high-affinity VEGF binding and the NRP1 C-terminal domain.","method":"Co-culture cis/trans cell systems, VEGFR2 internalization assays, phosphorylation time courses, NRP1 domain-deletion constructs, mouse fibrosarcoma/melanoma tumor models","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstituted cis vs trans systems with domain mutants, multiple signaling readouts, and in vivo tumor validation","pmids":["24656741"],"is_preprint":false},{"year":2017,"finding":"VEGF165-induced vascular permeability requires both VEGFR2 and NRP1, specifically the VEGF164-binding site of NRP1 and the NRP1 cytoplasmic domain (NCD). The NCD promotes ABL kinase activation within the receptor complex, which in turn activates VEGFR2-recruited SRC family kinases (SFKs). GIPC1, a known NCD interactor, is not required for this permeability response.","method":"In vivo vascular leakage assays (Miles assay), NRP1 cytoplasmic domain knock-in mice, ABL and SFK kinase assays, tissue culture signaling experiments, choroidal neovascularization mouse model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo knock-in mouse model combined with in vitro kinase hierarchy dissection and domain-specific mutants","pmids":["28289053"],"is_preprint":false},{"year":2007,"finding":"SEMA3A is required for axon patterning of limb nerves but not for angiogenesis; VEGF164 (not SEMA3A) controls NRP1-dependent angiogenesis in vivo. There is no genetic interaction between SEMA3A and VEGF164 during vasculogenesis, angiogenesis, or limb axon patterning, arguing against ligand competition at NRP1 controlling neurovascular congruence.","method":"Mouse knockouts of Sema3a and Vegf isoforms, genetic interaction analysis, in vivo axon and vessel patterning assays","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple mouse knockout models with epistasis analysis across both vascular and neural compartments","pmids":["17428830"],"is_preprint":false},{"year":2011,"finding":"NRP1 (via an autocrine VEGF loop) promotes cancer stem cell (CSC) stemness and symmetric division in skin papillomas. Conditional deletion of Nrp1 in tumor epithelial cells blocks VEGF's ability to promote cancer stemness and renewal. NRP1 deletion in normal epidermis also prevents skin tumor initiation.","method":"Conditional Nrp1 knockout in tumor epithelial cells (mouse model), CSC functional assays (symmetric division, self-renewal), VEGFR2 blockade, VEGF overexpression/deletion","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional in vivo knockout with multiple functional CSC readouts and corroborating VEGF gain/loss experiments","pmids":["22012397"],"is_preprint":false},{"year":2018,"finding":"VEGF upregulates NRP1 proteolytic cleavage via ADAM9 and ADAM10 metalloproteinases, generating C-terminal NRP1 fragments (lacking ligand-binding A and B regions) that inhibit VEGF-induced VEGFR2 phosphorylation, endothelial cell motility, and angiogenesis.","method":"siRNA knockdown of ADAM9/10, pharmacological ADAM10 inhibitor, adenoviral overexpression of NRP1 C-terminal constructs, VEGFR2 phosphorylation assays, aortic ring sprouting assay, coculture angiogenesis model","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal approaches (genetic KD, pharmacological inhibition, domain overexpression) with functional readouts in single lab","pmids":["29880492"],"is_preprint":false},{"year":2015,"finding":"VEGF-A/NRP1 signaling induces formation of a GIPC1-Syx complex that activates RhoA, leading to degradation of the CDK inhibitor p27 and cancer cell proliferation. The NRP1 cytoplasmic domain is required for this effect. RhoA/ROCK inhibition blocks VEGF-A-induced proliferation.","method":"Co-immunoprecipitation (GIPC1-NRP1, GIPC1-Syx), RhoA activity assays, shRNA knockdown, NRP1 cytoplasmic deletion mutants, C3 exoenzyme/Y27632 inhibition, p27 western blot, proliferation assays","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with multiple knockdowns and rescue experiments, single lab","pmids":["26209534"],"is_preprint":false},{"year":2018,"finding":"NRP-1 forms a complex with GIPC1 and α6/β4-integrin to activate FAK/Src signaling, which stabilizes a YAP1/ΔNp63α complex to enhance epidermal cancer stem cell survival, invasion, and angiogenesis. Loss of NRP-1 reduces tumor vascularization and tumor growth.","method":"Co-immunoprecipitation (NRP1-GIPC1-integrin), FAK/Src kinase assays, YAP1/ΔNp63α western blot, NRP-1 knockout xenograft model, constitutively active YAP1/ΔNp63α rescue","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and rescue experiments with in vivo validation, single lab","pmids":["29755126"],"is_preprint":false},{"year":2018,"finding":"NRP-1/GIPC1/Syx complex activates RhoA-dependent p38 MAPK signaling to enhance epidermal cancer stem cell spheroid formation, invasion, migration, and angiogenic potential. Pharmacological inhibition of VEGF-A/NRP-1 interaction or RhoA reduces p38 activity and tumor growth.","method":"Co-immunoprecipitation, RhoA/p38 kinase assays, NRP1 knockout cells, constitutively active RhoA/p38 rescue, tumor growth assays","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Co-IPs and rescue assays, same lab as PMID:29755126","pmids":["30456845"],"is_preprint":false},{"year":2012,"finding":"SEMA3A signaling through NRP1 has multiple cell-autonomous roles in sympathetic nervous system development, including neuronal cell body positioning, aggregation, and axon guidance during sympathetic chain assembly and heart/aorta innervation. Loss of NRP1 in the sympathetic lineage causes sinus bradycardia, similar to Sema3a-null mice.","method":"Lineage-specific conditional Nrp1 knockout (sympathetic vs. vascular), Sema3a and NRP1/NRP2 compound mutant mice, cardiac function assessment","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional knockouts with genetic epistasis and functional cardiac phenotype","pmids":["22790009"],"is_preprint":false},{"year":2014,"finding":"VEGF189 can bind NRP1 and promote NRP1-dependent neuronal migration, survival, and axon guidance responses, demonstrating that VEGF189 (in addition to VEGF165) is a biologically active NRP1 ligand in the nervous system.","method":"In situ ligand-binding assays, NRP1 mutant mice, in vitro neuronal migration and survival assays, VEGF isoform knock-in mouse models","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding assays combined with genetic mouse models and in vitro functional assays, single lab","pmids":["25519242"],"is_preprint":false},{"year":2020,"finding":"Reelin's C-terminal region (CTR) binds NRP1, which forms a complex with VLDLR (a canonical Reelin receptor) in superficial neocortical layers. NRP1 acts as a co-receptor for VLDLR, augments Reelin signaling (reducing Dab1 accumulation), and is required for normal dendritic development in superficial-layer neurons. Proteolytic removal of the 6 C-terminal Reelin residues abolishes NRP1 binding.","method":"Co-immunoprecipitation (NRP1-VLDLR), in utero electroporation NRP1 knockdown, Dab1 accumulation assays, dendritic morphology analysis, binding studies with Reelin CTR mutants","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — Co-IP complex formation plus in vivo knockdown with defined neuronal phenotype and biochemical Reelin signaling readout, single lab with multiple methods","pmids":["33009002"],"is_preprint":false},{"year":2021,"finding":"CMT2N-causing mutations in the aminoacylation domain of AlaRS (including R329H) cause structural loosening of the domain and enable aberrant interaction with the b1b2 domains of NRP1. Wild-type AlaRS does not interact with NRP1. The aberrant AlaRS-NRP1 interaction is confirmed in patient samples.","method":"X-ray crystallography, SAXS, hydrogen-deuterium exchange, switchSENSE hydrodynamic measurements, protease digestion, co-immunoprecipitation in patient samples, in vitro binding assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus multiple orthogonal biophysical methods, patient sample validation","pmids":["33753480"],"is_preprint":false},{"year":2016,"finding":"In endothelium, VEGF requires NRP-1 to inhibit LPS-dependent dendritic cell maturation. NRP-1-deficient BMDCs are completely insensitive to VEGF-mediated suppression of LPS-induced maturation. Mechanistically, NRP-1 directly interacts with TLR4 in the presence of VEGF and suppresses downstream ERK and NF-κB signaling, resulting in inhibition of MHC II, CD40, CD86 expression, and proinflammatory cytokine production.","method":"Conditional NRP-1 knockout BMDCs, co-immunoprecipitation (NRP1-TLR4), ERK/NF-κB phosphorylation assays, flow cytometry for surface markers, cytokine ELISAs","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO combined with Co-IP and multiple signaling readouts, single lab","pmids":["27815442"],"is_preprint":false},{"year":2020,"finding":"Conditional deletion of Nrp1 in epidermal keratinocytes inhibits psoriasis mediated by Vegfa overexpression or c-Jun/JunB deletion, demonstrating an epidermal cell-autonomous function of Vegfa/Nrp1/Flt1. Anti-Nrp1 antibody treatment reverses the psoriasis phenotype. Fosl1 was identified as a key downstream transcription factor in the Vegfa/Nrp1 regulatory network.","method":"Conditional keratinocyte-specific Nrp1 knockout mice, psoriasis mouse models, anti-Nrp1 antibody treatment, transcriptional and chromatin profiling (ATAC-seq/RNA-seq)","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific in vivo knockout with pharmacological validation and genomic mechanism studies","pmids":["31934626"],"is_preprint":false},{"year":2023,"finding":"NRP1 interacts with EGFR via its b1/b2 domain (extracellular interaction), leading to EGFR phosphorylation and activation of the AKT signaling pathway to promote prostate cancer cell proliferation and migration. HIF1α binds the NRP1 promoter and regulates its transcriptional activation.","method":"Co-immunoprecipitation (NRP1-EGFR), domain deletion constructs, AKT/EGFR phosphorylation western blot, ChIP assay (HIF1α-NRP1 promoter), siRNA knockdown, NRP1 inhibitor (EG01377) treatment, xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping and downstream signaling assays plus in vivo validation, single lab","pmids":["36841806"],"is_preprint":false},{"year":2023,"finding":"USP9X is a deubiquitinating enzyme that stabilizes NRP1 protein. USP9X-mediated NRP1 deubiquitination enhances hepatic stellate cell (HSC) activation, promoting TGF-β1, VEGFA, and PDGF-BB-mediated liver fibrosis.","method":"Co-immunoprecipitation, GST pull-down, in vitro and in vivo ubiquitination assays, USP9X knockdown/overexpression, mouse CCl4 liver fibrosis model, immunohistochemistry","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pull-down and ubiquitination assays with in vivo validation, single lab","pmids":["36653359"],"is_preprint":false},{"year":2024,"finding":"NRP1 forms stable complexes with endoglin (ENG) and VEGFR2 at the endothelial cell surface; VEGF-A enhances these interactions. ENG augments NRP1/VEGFR2 interactions, suggesting tripartite complex formation bridged by ENG. Optimal VEGF-A-mediated VEGFR2 and Erk1/2 phosphorylation and sprouting require both ENG and NRP1.","method":"FRAP-based IgG-mediated immobilization co-mobility assay, overexpression/knockdown of ENG and NRP1 in murine embryonic endothelial cells (MEEC+/+ and MEEC-/-), VEGFR2/Erk1/2 phosphorylation assays, sprouting assays, MEK1/2 inhibitor","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative FRAP-based interaction assay combined with genetic cell models and functional sprouting assays, single lab","pmids":["38242992"],"is_preprint":false},{"year":2018,"finding":"NRP1 and VEGFR2 undergo homo- and hetero-interactions in the plasma membrane. NRP1 self-associates (homo-interactions) and interacts with VEGFR2 in the absence of ligand; these interactions are modulated by VEGFA.","method":"Quantitative FRET in plasma membrane, VEGFA ligand addition/removal experiments","journal":"Biochimica et biophysica acta. Biomembranes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative FRET methodology in living cells, single lab","pmids":["29630862"],"is_preprint":false},{"year":2019,"finding":"Sema3a-Nrp1 signaling confers fast-twitch myofiber specificity to Twist2+ muscle progenitors. Sema3a is expressed by slow/intermediate myofibers (type I/IIa) but not IIb fibers, acting as a chemorepellent that restricts Tw2+/Nrp1+ progenitors to fuse with type IIb fibers.","method":"RNA sequencing, immunofluorescence, stripe migration assays, chimeric cell-cell fusion assays, Sema3a transgenic mouse model","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro migration assays, chimeric fusion assays, and in vivo transgenic model together establishing the Sema3a-Nrp1 mechanism","pmids":["31474563"],"is_preprint":false},{"year":2021,"finding":"MAOA activates SEMA3C in a Twist1-dependent transcriptional manner; SEMA3C then stimulates cMET via autocrine/paracrine interaction with co-activated PlexinA2 and NRP1, facilitating prostate cancer perineural invasion.","method":"In vitro PNI assays, orthotopic xenograft model, MAOA inhibitor treatment, SEMA3C/NRP1/PlexinA2 knockdown, cMET phosphorylation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional in vitro and in vivo assays with pathway inhibition, single lab","pmids":["33420365"],"is_preprint":false},{"year":2015,"finding":"Wedelolactone promotes formation of a Sema3A-PlexinA1-NRP1 complex on BMSCs, activating β-catenin nuclear accumulation and osteoblastogenesis. In osteoclastic cells, it induces PlexinA1-NRP1 complex formation while sequestering PlexinA1-DAP12 complex and suppressing PLCγ2 phosphorylation, inhibiting osteoclastogenesis.","method":"Co-immunoprecipitation (Sema3A-NRP1-PlexinA1), co-immunoprecipitation (PlexinA1-DAP12), β-catenin nuclear localization immunofluorescence, PLCγ2 phosphorylation western blot, ALP/TRAP activity assays, Sema3A antibody blocking","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IPs with ligand blocking and multiple signaling readouts, single lab","pmids":["27803667"],"is_preprint":false},{"year":2015,"finding":"NRP1 co-localizes with DDR2 at the plasma membrane of differentiating osteoblasts, prolongs DDR2 protein half-life (stabilizes DDR2), and enhances DDR2-induced ERK1/2 and Runx2 phosphorylation to stimulate osteoblast differentiation. NRP1 does not alter DDR2 mRNA transcription.","method":"Co-localization immunofluorescence, co-immunoprecipitation (NRP1-DDR2), half-life determination assay, ERK1/2/Runx2 phosphorylation western blot, ALP activity and OCN secretion assays, NRP1 overexpression/siRNA knockdown","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and half-life assay combined with multiple osteogenic readouts, single lab","pmids":["25924845"],"is_preprint":false},{"year":2024,"finding":"NRP1 functions as an entry receptor for mammalian orthoreovirus (reovirus), binding with nanomolar affinity through multivalent interactions involving outer-capsid protein σ3 and capsid turret protein λ2 engaging multiple NRP1 extracellular domains. NRP1 contributes to reovirus dissemination and neurovirulence in mice.","method":"Receptor identification assays, nanomolar affinity binding measurements, gene-segment exchange capsid mutants, NRP1-binding-deficient capsid mutants, in vivo mouse dissemination and neurovirulence assays","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — affinity measurements, capsid mutant mapping, and in vivo neurovirulence validation with multiple orthogonal methods","pmids":["38729153"],"is_preprint":false},{"year":2023,"finding":"NRP1 binds YAP (co-immunoprecipitation), and mechanical compression disrupts this binding, releasing YAP to translocate to the nucleus. NRP1 knockdown promotes LATS1 expression and reduces YAP, inhibiting endothelial cell proliferation. NRP1 thus transduces mechanical stress inhibition via the LATS1/YAP axis in hypertrophic scars.","method":"Co-immunoprecipitation (NRP1-YAP), NRP1 knockdown, LATS1/pYAP western blot, mechanical compression culture model, rat tail-scar model, bioinformatics screening","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional knockdown and in vivo model, single lab","pmids":["37704618"],"is_preprint":false},{"year":2018,"finding":"RNA-binding protein Lin28B directly binds the NRP-1 3'UTR (confirmed by RIP), increasing NRP-1 mRNA stability and expression, which in turn activates Wnt/β-catenin signaling to promote gastric cancer cell stemness.","method":"RNA immunoprecipitation (RIP), luciferase reporter assay, mRNA stability assay, Lin28B overexpression/knockdown, Wnt/β-catenin signaling western blot, spheroid formation assays","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and reporter assay with functional stemness readouts, single lab","pmids":["29787985"],"is_preprint":false},{"year":2021,"finding":"NRP1 promotes IL-17A production by intestinal ILC3s in an NF-κB signaling-dependent and cell-intrinsic manner. Genetic NRP1 deficiency reduces ILC3 frequency in the gut and impairs IL-17A production, altering microbiota composition and improving DSS-induced colitis outcomes.","method":"NRP1 conditional knockout mice, ILC3 frequency/IL-17A production assays, NF-κB signaling analysis, DSS colitis model, pharmacological NRP1 inhibition (EG00229)","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with pharmacological validation and defined immune signaling pathway, single lab","pmids":["39741194"],"is_preprint":false},{"year":2021,"finding":"Myeloma-secreted galectin-1 potently interacts with CD304 (NRP1) on monocytic MDSCs, expanding the M-MDSC population and increasing CD304 expression. Blockade of CD304 reduces MDSC migration and reverses MDSC-mediated suppression of melphalan cytotoxicity.","method":"High-throughput flow cytometry screening, galectin-1 in vitro treatment of MDSCs, CD304/NRP1 blockade assays, co-culture with myeloma cell lines (high/low galectin-1), cytotoxicity assays","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional binding assay and blockade experiments with clinical relevance, single lab","pmids":["33771821"],"is_preprint":false},{"year":2024,"finding":"VEGFR1, VEGFR2, and NRP1 show distinct trafficking dynamics in HUVECs: VEGFR1 has faster internalization and recycling rates than VEGFR2, whereas NRP1 is predominantly retained at the cell surface (high surface fraction). These differences in subcellular localization influence VEGF ligand sensing and receptor complex composition.","method":"Quantitative trafficking experiments (receptor internalization and recycling rates measured simultaneously for all three receptors on HUVECs), computational modeling","journal":"PLoS computational biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative experimental trafficking data combined with computational modeling, single lab","pmids":["38324585"],"is_preprint":false},{"year":2024,"finding":"Dnmt3a1 regulates hippocampus-dependent memory via Nrp1 as a downstream target. Dnmt3a1 activity is required for Nrp1 expression in hippocampal neurons, and Nrp1 is required for long-term spatial and contextual memory. NRP1 overexpression does not rescue memory impairments from Dnmt3a2 reduction, indicating isoform-specific regulation.","method":"Dnmt3a1-specific knockout mice, RNA sequencing, Nrp1 knockdown and overexpression in hippocampus, behavioral memory tests (spatial object recognition, contextual fear memory), rescue experiments","journal":"Neuropsychopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with RNA-seq identification of target and in vivo rescue behavioral assays, single lab","pmids":["38499720"],"is_preprint":false},{"year":2024,"finding":"YAP/TEAD4 binding to the NRP1 promoter is induced by ionizing radiation in NSCLC cells, transcriptionally upregulating NRP1 expression and conferring radioresistance. NRP1 is identified as a direct transcriptional target of the YAP/TEAD4 complex.","method":"ChIP assay (TEAD4-NRP1 promoter), YAP dephosphorylation analysis, YAP/TEAD4 inhibition, NRP1 expression rescue experiments, radiation-resistant A549/H1299 cell models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-validated transcriptional regulation with functional rescue experiments, single lab","pmids":["39187525"],"is_preprint":false},{"year":2018,"finding":"CMTM6 physically interacts with NRP1 (co-immunoprecipitation) in oral squamous cell carcinoma cells. NRP1 is required for CMTM6-driven tumorigenesis: NRP1 silencing abrogates CMTM6-induced oncogenic effects, and NRP1 depletion destabilizes CMTM6 protein, suggesting NRP1 protects CMTM6 from degradation.","method":"Co-immunoprecipitation (CMTM6-NRP1), gain/loss-of-function experiments, CMTM6 protein stability assay in NRP1-silenced cells","journal":"American journal of cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP in one cell line, no mechanistic follow-up of interaction mode","pmids":["32642284"],"is_preprint":false},{"year":2019,"finding":"NRP1 knockdown in neuroblastoma SK-N-AS cells increases β1 integrin expression and promotes migration and invasion, indicating NRP1 exerts tumor-suppressive effects in neuroblastoma via regulation of β1 integrin levels.","method":"NRP1 siRNA knockdown, wound-healing assay, Matrigel invasion assay, β1 integrin western blot, β1 integrin siRNA knockdown","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown approach with phenotypic and protein-level readouts, no direct interaction demonstrated, single lab","pmids":["29750423"],"is_preprint":false},{"year":2020,"finding":"NRP1 contributes to cancer stem cell stemness and radioresistance in breast cancer through downregulation of Bcl-2 via the m6A methyltransferase WTAP in an m6A-dependent manner.","method":"NRP1 siRNA/plasmid transfection, WTAP m6A methylation assay, Bcl-2 western blot, γH2AX immunofluorescence, flow cytometry apoptosis, shRNA-NRP1 xenograft model with radiotherapy","journal":"Apoptosis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic linkage between NRP1 and WTAP/m6A suggested but pathway not directly validated at the molecular interaction level, single lab","pmids":["36333630"],"is_preprint":false}],"current_model":"NRP1 is a multifunctional transmembrane co-receptor that binds VEGF-A (via its b1 domain residues Y297/D320) and class-3 semaphorins (SEMA3A, SEMA3C) to form signaling complexes with VEGFR2, plexins, and other receptors; in endothelium it promotes tip-cell identity, enhances VEGFR2 signaling and internalization in cis while suppressing it in trans, mediates vascular permeability through an ABL-SFK kinase cascade requiring its cytoplasmic domain, regulates sprouting angiogenesis by suppressing ALK1/ALK5-Smad2/3 activity downstream of Notch, and is proteolytically cleaved by ADAM9/10 to generate inhibitory C-terminal fragments; in neurons NRP1 acts as a co-receptor for Reelin (with VLDLR) to control cortical dendritic development and mediates SEMA3A-dependent axon guidance and sympathetic nervous system development; additional mechanistic roles include modulating immune cell function (dendritic cell maturation via TLR4 interaction, ILC3 IL-17A production via NF-κB, MDSC activity via galectin-1), being stabilized by the deubiquitinase USP9X, and acting as an entry receptor for mammalian orthoreovirus."},"narrative":{"mechanistic_narrative":"NRP1 is a multifunctional transmembrane co-receptor that integrates VEGF and class-3 semaphorin cues to control endothelial behavior during angiogenesis and to guide neuronal and other developmental processes [PMID:21653826, PMID:17428830]. Its b1 domain residues Y297 and D320 mediate high-affinity VEGF binding and assembly of the NRP1-VEGFR2 complex, driving FAK phosphorylation and endothelial migration; binding-deficient mutants act dominant-negatively by heterodimerizing with wild-type NRP1 and NRP2 [PMID:21653826]. NRP1 self-associates and partners with VEGFR2 even before ligand engagement, and these interactions are reorganized by VEGF-A, with endoglin further bridging a tripartite NRP1/VEGFR2/ENG complex required for optimal VEGFR2 and Erk1/2 phosphorylation and sprouting [PMID:38242992, PMID:29630862]. NRP1 functions cell-autonomously in endothelial tip cells to promote angiogenesis [PMID:23315162], and acts as the pivot of endothelial heterogeneity in the Dll4/Notch loop by limiting Smad2/3 activation through ALK1/ALK5 to suppress the stalk-cell phenotype [PMID:26081042]. The spatial geometry of NRP1 presentation tunes signaling output: in cis VEGF drives rapid VEGFR2/NRP1 co-internalization, whereas NRP1 in trans arrests VEGFR2 endocytosis and reshapes downstream PLCγ/ERK kinetics [PMID:24656741]. VEGF165-induced vascular permeability requires the NRP1 cytoplasmic domain, which activates an ABL→SRC-family kinase cascade within the receptor complex [PMID:28289053]. NRP1 output is further controlled by ADAM9/10-mediated cleavage that generates inhibitory C-terminal fragments [PMID:29880492]. Beyond vasculature, SEMA3A signaling through NRP1 directs sympathetic neuron positioning and axon guidance [PMID:22790009] and confers fast-twitch myofiber specificity to muscle progenitors [PMID:31474563], and NRP1 serves as a co-receptor with VLDLR for Reelin to control cortical dendritic development [PMID:33009002]. NRP1 also acts as an entry receptor for mammalian orthoreovirus through multivalent capsid engagement of its extracellular domains, contributing to viral dissemination and neurovirulence [PMID:38729153]. A disease-linked gain-of-function interaction occurs in Charcot-Marie-Tooth type 2N, where CMT2N-causing AlaRS mutations loosen the aminoacylation domain and create an aberrant interaction with the NRP1 b1b2 domains not seen with wild-type AlaRS [PMID:33753480].","teleology":[{"year":2007,"claim":"Resolved whether SEMA3A and VEGF compete at NRP1 to coordinate neurovascular patterning, establishing that VEGF164—not SEMA3A—drives NRP1-dependent angiogenesis while SEMA3A patterns axons independently.","evidence":"Sema3a and Vegf isoform mouse knockouts with genetic interaction analysis of vessel and axon patterning","pmids":["17428830"],"confidence":"High","gaps":["Does not define how distinct ligands engage the same receptor without competition","Mechanism of NRP1 ligand selectivity not resolved"]},{"year":2011,"claim":"Mapped the molecular determinants of VEGF binding to NRP1, showing b1-domain residues Y297/D320 are essential for VEGFR2 complex formation and downstream FAK signaling, and that non-binding mutants act dominant-negatively.","evidence":"Site-directed mutagenesis, VEGF binding/Co-IP/phosphorylation and migration assays in HUVECs","pmids":["21653826"],"confidence":"High","gaps":["Does not establish in vivo requirement of these residues","Stoichiometry of the NRP1-VEGFR2 complex unresolved"]},{"year":2011,"claim":"Extended NRP1 function beyond endothelium by showing an autocrine VEGF/NRP1 loop sustains cancer stem-cell self-renewal and tumor initiation in skin.","evidence":"Conditional Nrp1 knockout in tumor epithelium with CSC self-renewal assays and VEGF gain/loss","pmids":["22012397"],"confidence":"High","gaps":["Cytoplasmic effectors in epithelial cells not defined here","Relationship to VEGFR2 in epithelium unclear"]},{"year":2012,"claim":"Defined cell-autonomous SEMA3A/NRP1 roles in sympathetic nervous system development, linking NRP1 loss to cardiac innervation defects and bradycardia.","evidence":"Lineage-specific conditional Nrp1 knockouts and Sema3a/NRP compound mutants with cardiac phenotyping","pmids":["22790009"],"confidence":"High","gaps":["Downstream plexin partners not dissected","Cytoplasmic signaling for neuronal positioning unresolved"]},{"year":2014,"claim":"Established NRP1 as a cell-autonomous tip-cell determinant in brain angiogenesis and showed the spatial context (cis vs trans) of NRP1 dictates VEGFR2 trafficking and signaling output.","evidence":"Endothelial conditional knockout with mosaic analysis; co-culture cis/trans systems with internalization and phosphorylation time courses and tumor models","pmids":["23315162","24656741"],"confidence":"High","gaps":["Molecular basis of trans-mediated endocytic arrest not fully defined","How cis/trans balance is set in vivo unclear"]},{"year":2014,"claim":"Broadened the active NRP1 ligand repertoire in the nervous system by showing VEGF189, in addition to VEGF165, binds NRP1 and supports neuronal migration, survival, and axon guidance.","evidence":"In situ ligand binding, VEGF isoform knock-in mice, in vitro neuronal assays","pmids":["25519242"],"confidence":"Medium","gaps":["Receptor complex composition for VEGF189 not defined","Single-lab functional characterization"]},{"year":2015,"claim":"Positioned NRP1 as the pivot of endothelial tip/stalk heterogeneity by showing it suppresses stalk-cell behavior via ALK1/ALK5-Smad2/3 inhibition downstream of Notch.","evidence":"Genetic epistasis in zebrafish and mouse, endothelial Nrp1 knockout, Smad2/3 phosphorylation and ALK inhibitor experiments","pmids":["26081042"],"confidence":"High","gaps":["Direct biochemical link between NRP1 and ALK receptors not shown","How Notch transcriptionally controls NRP1 not resolved"]},{"year":2015,"claim":"Identified cytoplasmic-domain-dependent GIPC1-Syx-RhoA signaling as an NRP1 output controlling cancer proliferation through p27 degradation.","evidence":"Co-IP, RhoA activity assays, NRP1 cytoplasmic deletion mutants, RhoA/ROCK inhibition in cancer cells","pmids":["26209534"],"confidence":"Medium","gaps":["Single-lab pathway without in vivo validation here","Receptor partner upstream of GIPC1-Syx in this context not defined"]},{"year":2015,"claim":"Revealed NRP1 stabilizes and amplifies non-VEGF receptors, prolonging DDR2 half-life and enhancing ERK1/2/Runx2 signaling to drive osteoblast differentiation.","evidence":"Co-localization, Co-IP, protein half-life and osteogenic differentiation assays","pmids":["25924845"],"confidence":"Medium","gaps":["Mechanism of DDR2 stabilization unknown","Single-lab finding without in vivo confirmation"]},{"year":2016,"claim":"Demonstrated an immunoregulatory role in which VEGF-dependent NRP1 directly engages TLR4 to suppress dendritic cell maturation via ERK/NF-κB inhibition.","evidence":"Conditional NRP1-knockout BMDCs, NRP1-TLR4 Co-IP, signaling and surface-marker readouts","pmids":["27815442"],"confidence":"Medium","gaps":["Structural basis of NRP1-TLR4 interaction unknown","Single-lab Co-IP without reciprocal structural validation"]},{"year":2017,"claim":"Defined the cytoplasmic-domain mechanism for VEGF165-induced vascular permeability, establishing an NRP1-cytoplasmic-domain→ABL→SRC-family-kinase cascade independent of GIPC1.","evidence":"NRP1 cytoplasmic-domain knock-in mice, Miles assay, ABL/SFK kinase assays, choroidal neovascularization model","pmids":["28289053"],"confidence":"High","gaps":["How ABL is recruited to the cytoplasmic domain not defined","Direct NCD-ABL binding interface unresolved"]},{"year":2018,"claim":"Identified a negative-feedback mechanism whereby VEGF drives ADAM9/10 cleavage of NRP1, producing inhibitory C-terminal fragments that suppress VEGFR2 signaling and angiogenesis.","evidence":"ADAM9/10 knockdown, ADAM10 inhibitor, C-terminal fragment overexpression, sprouting and angiogenesis assays","pmids":["29880492"],"confidence":"High","gaps":["In vivo physiological relevance of cleavage not established","Cleavage site and regulation incompletely defined"]},{"year":2018,"claim":"Characterized NRP1/VEGFR2 plasma-membrane organization, showing pre-ligand homo- and hetero-interactions modulated by VEGFA.","evidence":"Quantitative FRET in plasma membrane with VEGFA addition/removal","pmids":["29630862"],"confidence":"Medium","gaps":["Functional consequence of pre-ligand assembly not measured","Single biophysical method"]},{"year":2018,"claim":"Extended NRP1 cytoplasmic GIPC1 signaling to integrin- and YAP-dependent cancer stem-cell programs, linking NRP1/GIPC1/integrin-FAK/Src to YAP1/ΔNp63α and RhoA-p38 outputs.","evidence":"Co-IP of NRP1-GIPC1-integrin complexes, kinase assays, rescue experiments, xenograft models","pmids":["29755126","30456845"],"confidence":"Medium","gaps":["Same-lab findings without independent replication","Direct NRP1-integrin contact interface not mapped"]},{"year":2020,"claim":"Established NRP1 as a Reelin co-receptor that complexes with VLDLR to augment Reelin signaling and control cortical dendritic development.","evidence":"NRP1-VLDLR Co-IP, in utero electroporation knockdown, Dab1 and dendritic morphology assays, Reelin CTR mutant binding","pmids":["33009002"],"confidence":"High","gaps":["Structural basis of Reelin CTR-NRP1 binding not solved","Single-lab characterization"]},{"year":2020,"claim":"Defined an epidermal cell-autonomous VEGFA/NRP1/FLT1 axis driving psoriasis, with Fosl1 as a downstream effector and therapeutic responsiveness to anti-NRP1 antibody.","evidence":"Keratinocyte-specific Nrp1 knockout, psoriasis models, anti-Nrp1 antibody, ATAC-seq/RNA-seq","pmids":["31934626"],"confidence":"High","gaps":["Cytoplasmic signaling linking NRP1 to Fosl1 not dissected","Receptor partner in keratinocytes (FLT1 vs VEGFR2) roles incomplete"]},{"year":2021,"claim":"Connected NRP1 to a Mendelian disease by showing CMT2N-causing AlaRS mutations structurally loosen the aminoacylation domain to enable an aberrant gain-of-function interaction with the NRP1 b1b2 domains.","evidence":"X-ray crystallography, SAXS, HDX, switchSENSE, Co-IP in patient samples","pmids":["33753480"],"confidence":"High","gaps":["Downstream cellular consequence of aberrant binding on NRP1 signaling not defined","Causal link to neuropathy phenotype mechanistically incomplete"]},{"year":2021,"claim":"Established SEMA3A/NRP1 as a chemorepellent system specifying fast-twitch myofiber identity by restricting Tw2+/Nrp1+ progenitor fusion.","evidence":"RNA-seq, stripe migration and chimeric fusion assays, Sema3a transgenic mice","pmids":["31474563"],"confidence":"High","gaps":["Plexin co-receptor identity in muscle not defined","Downstream cytoskeletal signaling not resolved"]},{"year":2021,"claim":"Implicated NRP1 in immune and tumor microenvironment functions, promoting ILC3 IL-17A via NF-κB and serving as a galectin-1 binding partner expanding MDSCs.","evidence":"NRP1 conditional knockout and pharmacological inhibition (ILC3/colitis); flow-cytometry galectin-1 binding and blockade assays (MDSC)","pmids":["39741194","33771821"],"confidence":"Medium","gaps":["Direct NRP1 ligand driving ILC3 NF-κB not identified","Single-lab characterizations in each immune context"]},{"year":2023,"claim":"Expanded the NRP1 receptor-partner network in cancer to EGFR, with extracellular b1/b2 engagement driving AKT activation, and identified transcriptional control of NRP1 by HIF1α.","evidence":"NRP1-EGFR Co-IP, domain deletions, phosphorylation assays, ChIP of HIF1α on the NRP1 promoter, xenograft","pmids":["36841806"],"confidence":"Medium","gaps":["Direct vs indirect NRP1-EGFR contact not fully resolved","Single-lab finding"]},{"year":2023,"claim":"Identified post-translational and mechanotransductive control of NRP1, with USP9X deubiquitinating and stabilizing NRP1 in fibrosis, and NRP1 binding YAP to relay mechanical stress via the LATS1/YAP axis.","evidence":"Co-IP/ubiquitination assays and CCl4 fibrosis model (USP9X); NRP1-YAP Co-IP, compression model and rat scar model (mechanotransduction)","pmids":["36653359","37704618"],"confidence":"Medium","gaps":["USP9X ubiquitin-site specificity on NRP1 not mapped","Single-lab Co-IPs without reciprocal structural validation"]},{"year":2024,"claim":"Refined the endothelial VEGF receptor module by showing endoglin bridges a tripartite NRP1/VEGFR2/ENG complex needed for optimal signaling, and quantified distinct receptor trafficking with NRP1 predominantly surface-retained.","evidence":"FRAP co-mobility assays and ENG/NRP1 gain/loss with sprouting (ENG); quantitative trafficking measurements with computational modeling (HUVEC)","pmids":["38242992","38324585"],"confidence":"Medium","gaps":["Structural arrangement of the tripartite complex unknown","Single-lab quantitative datasets"]},{"year":2024,"claim":"Established NRP1 as an entry receptor for mammalian orthoreovirus through multivalent capsid engagement of its extracellular domains, contributing to dissemination and neurovirulence.","evidence":"Affinity binding measurements, capsid mutant mapping, in vivo dissemination and neurovirulence assays","pmids":["38729153"],"confidence":"High","gaps":["Whether viral entry co-opts native NRP1 signaling unknown","Post-binding internalization route not defined"]},{"year":2024,"claim":"Linked NRP1 to neuronal gene-regulatory control of memory, identifying it as a Dnmt3a1-dependent transcriptional target required for long-term spatial and contextual memory.","evidence":"Dnmt3a1 knockout mice, RNA-seq, hippocampal Nrp1 knockdown/overexpression, behavioral and rescue assays","pmids":["38499720"],"confidence":"Medium","gaps":["NRP1 ligand/partner mediating memory function not identified","Mechanism downstream of NRP1 in neurons unresolved"]},{"year":null,"claim":"How NRP1's single short cytoplasmic domain selectively assembles distinct signaling complexes (VEGFR2, plexins, VLDLR, TLR4, EGFR, integrins, endoglin) to produce context-specific outputs remains 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mutations at these sites abolish high-affinity VEGF binding, disrupt NRP1-VEGFR2 (KDR) complex formation, reduce FAK Tyr407 phosphorylation, and impair endothelial cell migration and angiogenesis. NRP1 non-binding mutants can act dominantly negative by heterodimerizing with wild-type NRP1 and NRP2.\",\n      \"method\": \"Site-directed mutagenesis, VEGF binding assays, co-immunoprecipitation, phosphorylation assays, migration assays, coculture angiogenesis model, overexpression in HUVECs\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro mutagenesis with multiple orthogonal functional readouts (binding, Co-IP, phosphorylation, migration, angiogenesis) in a single rigorous study\",\n      \"pmids\": [\"21653826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NRP1 promotes brain angiogenesis cell-autonomously in endothelium and specifically in tip cells. Endothelial NRP1-expressing cells preferentially attain the tip cell position over NRP1-negative cells in chimeric vessel sprouts. Neural progenitor- and macrophage-derived NRP1 are dispensable for this process.\",\n      \"method\": \"Conditional endothelial-specific Nrp1 knockout, genetic mosaic analysis in chimeric mice, in vivo brain vessel imaging\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional knockouts with mosaic genetic analysis, replicated across multiple lineage-specific models\",\n      \"pmids\": [\"23315162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NRP1 suppresses the stalk-cell phenotype during sprouting angiogenesis by limiting Smad2/3 activation through ALK1 and ALK5 (TGF-β/BMP receptors). Notch signaling downregulates NRP1, thereby relieving ALK1/ALK5 inhibition and driving stalk-cell behavior. NRP1 levels act as the pivot for endothelial cell heterogeneity in the Dll4/Notch lateral feedback loop.\",\n      \"method\": \"Genetic epistasis in zebrafish and mouse, endothelial-specific NRP1 knockout, Smad2/3 phosphorylation assays, ALK inhibitor experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis in two model organisms plus biochemical phosphorylation readouts, multiple orthogonal approaches\",\n      \"pmids\": [\"26081042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NRP1 presented in trans (on a different cell than VEGFR2) arrests VEGFR2 endocytosis, prolonging phosphorylation of PLCγ and ERK2 while reducing ERK1 phosphorylation, and suppresses tumor initiation and vascularization. In cis, VEGF induces rapid VEGFR2/NRP1 complex formation and co-internalization. The trans effect requires high-affinity VEGF binding and the NRP1 C-terminal domain.\",\n      \"method\": \"Co-culture cis/trans cell systems, VEGFR2 internalization assays, phosphorylation time courses, NRP1 domain-deletion constructs, mouse fibrosarcoma/melanoma tumor models\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstituted cis vs trans systems with domain mutants, multiple signaling readouts, and in vivo tumor validation\",\n      \"pmids\": [\"24656741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"VEGF165-induced vascular permeability requires both VEGFR2 and NRP1, specifically the VEGF164-binding site of NRP1 and the NRP1 cytoplasmic domain (NCD). The NCD promotes ABL kinase activation within the receptor complex, which in turn activates VEGFR2-recruited SRC family kinases (SFKs). GIPC1, a known NCD interactor, is not required for this permeability response.\",\n      \"method\": \"In vivo vascular leakage assays (Miles assay), NRP1 cytoplasmic domain knock-in mice, ABL and SFK kinase assays, tissue culture signaling experiments, choroidal neovascularization mouse model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo knock-in mouse model combined with in vitro kinase hierarchy dissection and domain-specific mutants\",\n      \"pmids\": [\"28289053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SEMA3A is required for axon patterning of limb nerves but not for angiogenesis; VEGF164 (not SEMA3A) controls NRP1-dependent angiogenesis in vivo. There is no genetic interaction between SEMA3A and VEGF164 during vasculogenesis, angiogenesis, or limb axon patterning, arguing against ligand competition at NRP1 controlling neurovascular congruence.\",\n      \"method\": \"Mouse knockouts of Sema3a and Vegf isoforms, genetic interaction analysis, in vivo axon and vessel patterning assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple mouse knockout models with epistasis analysis across both vascular and neural compartments\",\n      \"pmids\": [\"17428830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NRP1 (via an autocrine VEGF loop) promotes cancer stem cell (CSC) stemness and symmetric division in skin papillomas. Conditional deletion of Nrp1 in tumor epithelial cells blocks VEGF's ability to promote cancer stemness and renewal. NRP1 deletion in normal epidermis also prevents skin tumor initiation.\",\n      \"method\": \"Conditional Nrp1 knockout in tumor epithelial cells (mouse model), CSC functional assays (symmetric division, self-renewal), VEGFR2 blockade, VEGF overexpression/deletion\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional in vivo knockout with multiple functional CSC readouts and corroborating VEGF gain/loss experiments\",\n      \"pmids\": [\"22012397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"VEGF upregulates NRP1 proteolytic cleavage via ADAM9 and ADAM10 metalloproteinases, generating C-terminal NRP1 fragments (lacking ligand-binding A and B regions) that inhibit VEGF-induced VEGFR2 phosphorylation, endothelial cell motility, and angiogenesis.\",\n      \"method\": \"siRNA knockdown of ADAM9/10, pharmacological ADAM10 inhibitor, adenoviral overexpression of NRP1 C-terminal constructs, VEGFR2 phosphorylation assays, aortic ring sprouting assay, coculture angiogenesis model\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal approaches (genetic KD, pharmacological inhibition, domain overexpression) with functional readouts in single lab\",\n      \"pmids\": [\"29880492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"VEGF-A/NRP1 signaling induces formation of a GIPC1-Syx complex that activates RhoA, leading to degradation of the CDK inhibitor p27 and cancer cell proliferation. The NRP1 cytoplasmic domain is required for this effect. RhoA/ROCK inhibition blocks VEGF-A-induced proliferation.\",\n      \"method\": \"Co-immunoprecipitation (GIPC1-NRP1, GIPC1-Syx), RhoA activity assays, shRNA knockdown, NRP1 cytoplasmic deletion mutants, C3 exoenzyme/Y27632 inhibition, p27 western blot, proliferation assays\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with multiple knockdowns and rescue experiments, single lab\",\n      \"pmids\": [\"26209534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NRP-1 forms a complex with GIPC1 and α6/β4-integrin to activate FAK/Src signaling, which stabilizes a YAP1/ΔNp63α complex to enhance epidermal cancer stem cell survival, invasion, and angiogenesis. Loss of NRP-1 reduces tumor vascularization and tumor growth.\",\n      \"method\": \"Co-immunoprecipitation (NRP1-GIPC1-integrin), FAK/Src kinase assays, YAP1/ΔNp63α western blot, NRP-1 knockout xenograft model, constitutively active YAP1/ΔNp63α rescue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and rescue experiments with in vivo validation, single lab\",\n      \"pmids\": [\"29755126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NRP-1/GIPC1/Syx complex activates RhoA-dependent p38 MAPK signaling to enhance epidermal cancer stem cell spheroid formation, invasion, migration, and angiogenic potential. Pharmacological inhibition of VEGF-A/NRP-1 interaction or RhoA reduces p38 activity and tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, RhoA/p38 kinase assays, NRP1 knockout cells, constitutively active RhoA/p38 rescue, tumor growth assays\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IPs and rescue assays, same lab as PMID:29755126\",\n      \"pmids\": [\"30456845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SEMA3A signaling through NRP1 has multiple cell-autonomous roles in sympathetic nervous system development, including neuronal cell body positioning, aggregation, and axon guidance during sympathetic chain assembly and heart/aorta innervation. Loss of NRP1 in the sympathetic lineage causes sinus bradycardia, similar to Sema3a-null mice.\",\n      \"method\": \"Lineage-specific conditional Nrp1 knockout (sympathetic vs. vascular), Sema3a and NRP1/NRP2 compound mutant mice, cardiac function assessment\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional knockouts with genetic epistasis and functional cardiac phenotype\",\n      \"pmids\": [\"22790009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"VEGF189 can bind NRP1 and promote NRP1-dependent neuronal migration, survival, and axon guidance responses, demonstrating that VEGF189 (in addition to VEGF165) is a biologically active NRP1 ligand in the nervous system.\",\n      \"method\": \"In situ ligand-binding assays, NRP1 mutant mice, in vitro neuronal migration and survival assays, VEGF isoform knock-in mouse models\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding assays combined with genetic mouse models and in vitro functional assays, single lab\",\n      \"pmids\": [\"25519242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Reelin's C-terminal region (CTR) binds NRP1, which forms a complex with VLDLR (a canonical Reelin receptor) in superficial neocortical layers. NRP1 acts as a co-receptor for VLDLR, augments Reelin signaling (reducing Dab1 accumulation), and is required for normal dendritic development in superficial-layer neurons. Proteolytic removal of the 6 C-terminal Reelin residues abolishes NRP1 binding.\",\n      \"method\": \"Co-immunoprecipitation (NRP1-VLDLR), in utero electroporation NRP1 knockdown, Dab1 accumulation assays, dendritic morphology analysis, binding studies with Reelin CTR mutants\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — Co-IP complex formation plus in vivo knockdown with defined neuronal phenotype and biochemical Reelin signaling readout, single lab with multiple methods\",\n      \"pmids\": [\"33009002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CMT2N-causing mutations in the aminoacylation domain of AlaRS (including R329H) cause structural loosening of the domain and enable aberrant interaction with the b1b2 domains of NRP1. Wild-type AlaRS does not interact with NRP1. The aberrant AlaRS-NRP1 interaction is confirmed in patient samples.\",\n      \"method\": \"X-ray crystallography, SAXS, hydrogen-deuterium exchange, switchSENSE hydrodynamic measurements, protease digestion, co-immunoprecipitation in patient samples, in vitro binding assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus multiple orthogonal biophysical methods, patient sample validation\",\n      \"pmids\": [\"33753480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In endothelium, VEGF requires NRP-1 to inhibit LPS-dependent dendritic cell maturation. NRP-1-deficient BMDCs are completely insensitive to VEGF-mediated suppression of LPS-induced maturation. Mechanistically, NRP-1 directly interacts with TLR4 in the presence of VEGF and suppresses downstream ERK and NF-κB signaling, resulting in inhibition of MHC II, CD40, CD86 expression, and proinflammatory cytokine production.\",\n      \"method\": \"Conditional NRP-1 knockout BMDCs, co-immunoprecipitation (NRP1-TLR4), ERK/NF-κB phosphorylation assays, flow cytometry for surface markers, cytokine ELISAs\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO combined with Co-IP and multiple signaling readouts, single lab\",\n      \"pmids\": [\"27815442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional deletion of Nrp1 in epidermal keratinocytes inhibits psoriasis mediated by Vegfa overexpression or c-Jun/JunB deletion, demonstrating an epidermal cell-autonomous function of Vegfa/Nrp1/Flt1. Anti-Nrp1 antibody treatment reverses the psoriasis phenotype. Fosl1 was identified as a key downstream transcription factor in the Vegfa/Nrp1 regulatory network.\",\n      \"method\": \"Conditional keratinocyte-specific Nrp1 knockout mice, psoriasis mouse models, anti-Nrp1 antibody treatment, transcriptional and chromatin profiling (ATAC-seq/RNA-seq)\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific in vivo knockout with pharmacological validation and genomic mechanism studies\",\n      \"pmids\": [\"31934626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NRP1 interacts with EGFR via its b1/b2 domain (extracellular interaction), leading to EGFR phosphorylation and activation of the AKT signaling pathway to promote prostate cancer cell proliferation and migration. HIF1α binds the NRP1 promoter and regulates its transcriptional activation.\",\n      \"method\": \"Co-immunoprecipitation (NRP1-EGFR), domain deletion constructs, AKT/EGFR phosphorylation western blot, ChIP assay (HIF1α-NRP1 promoter), siRNA knockdown, NRP1 inhibitor (EG01377) treatment, xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping and downstream signaling assays plus in vivo validation, single lab\",\n      \"pmids\": [\"36841806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP9X is a deubiquitinating enzyme that stabilizes NRP1 protein. USP9X-mediated NRP1 deubiquitination enhances hepatic stellate cell (HSC) activation, promoting TGF-β1, VEGFA, and PDGF-BB-mediated liver fibrosis.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, in vitro and in vivo ubiquitination assays, USP9X knockdown/overexpression, mouse CCl4 liver fibrosis model, immunohistochemistry\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pull-down and ubiquitination assays with in vivo validation, single lab\",\n      \"pmids\": [\"36653359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NRP1 forms stable complexes with endoglin (ENG) and VEGFR2 at the endothelial cell surface; VEGF-A enhances these interactions. ENG augments NRP1/VEGFR2 interactions, suggesting tripartite complex formation bridged by ENG. Optimal VEGF-A-mediated VEGFR2 and Erk1/2 phosphorylation and sprouting require both ENG and NRP1.\",\n      \"method\": \"FRAP-based IgG-mediated immobilization co-mobility assay, overexpression/knockdown of ENG and NRP1 in murine embryonic endothelial cells (MEEC+/+ and MEEC-/-), VEGFR2/Erk1/2 phosphorylation assays, sprouting assays, MEK1/2 inhibitor\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative FRAP-based interaction assay combined with genetic cell models and functional sprouting assays, single lab\",\n      \"pmids\": [\"38242992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NRP1 and VEGFR2 undergo homo- and hetero-interactions in the plasma membrane. NRP1 self-associates (homo-interactions) and interacts with VEGFR2 in the absence of ligand; these interactions are modulated by VEGFA.\",\n      \"method\": \"Quantitative FRET in plasma membrane, VEGFA ligand addition/removal experiments\",\n      \"journal\": \"Biochimica et biophysica acta. Biomembranes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative FRET methodology in living cells, single lab\",\n      \"pmids\": [\"29630862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sema3a-Nrp1 signaling confers fast-twitch myofiber specificity to Twist2+ muscle progenitors. Sema3a is expressed by slow/intermediate myofibers (type I/IIa) but not IIb fibers, acting as a chemorepellent that restricts Tw2+/Nrp1+ progenitors to fuse with type IIb fibers.\",\n      \"method\": \"RNA sequencing, immunofluorescence, stripe migration assays, chimeric cell-cell fusion assays, Sema3a transgenic mouse model\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro migration assays, chimeric fusion assays, and in vivo transgenic model together establishing the Sema3a-Nrp1 mechanism\",\n      \"pmids\": [\"31474563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAOA activates SEMA3C in a Twist1-dependent transcriptional manner; SEMA3C then stimulates cMET via autocrine/paracrine interaction with co-activated PlexinA2 and NRP1, facilitating prostate cancer perineural invasion.\",\n      \"method\": \"In vitro PNI assays, orthotopic xenograft model, MAOA inhibitor treatment, SEMA3C/NRP1/PlexinA2 knockdown, cMET phosphorylation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional in vitro and in vivo assays with pathway inhibition, single lab\",\n      \"pmids\": [\"33420365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Wedelolactone promotes formation of a Sema3A-PlexinA1-NRP1 complex on BMSCs, activating β-catenin nuclear accumulation and osteoblastogenesis. In osteoclastic cells, it induces PlexinA1-NRP1 complex formation while sequestering PlexinA1-DAP12 complex and suppressing PLCγ2 phosphorylation, inhibiting osteoclastogenesis.\",\n      \"method\": \"Co-immunoprecipitation (Sema3A-NRP1-PlexinA1), co-immunoprecipitation (PlexinA1-DAP12), β-catenin nuclear localization immunofluorescence, PLCγ2 phosphorylation western blot, ALP/TRAP activity assays, Sema3A antibody blocking\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IPs with ligand blocking and multiple signaling readouts, single lab\",\n      \"pmids\": [\"27803667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NRP1 co-localizes with DDR2 at the plasma membrane of differentiating osteoblasts, prolongs DDR2 protein half-life (stabilizes DDR2), and enhances DDR2-induced ERK1/2 and Runx2 phosphorylation to stimulate osteoblast differentiation. NRP1 does not alter DDR2 mRNA transcription.\",\n      \"method\": \"Co-localization immunofluorescence, co-immunoprecipitation (NRP1-DDR2), half-life determination assay, ERK1/2/Runx2 phosphorylation western blot, ALP activity and OCN secretion assays, NRP1 overexpression/siRNA knockdown\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and half-life assay combined with multiple osteogenic readouts, single lab\",\n      \"pmids\": [\"25924845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NRP1 functions as an entry receptor for mammalian orthoreovirus (reovirus), binding with nanomolar affinity through multivalent interactions involving outer-capsid protein σ3 and capsid turret protein λ2 engaging multiple NRP1 extracellular domains. NRP1 contributes to reovirus dissemination and neurovirulence in mice.\",\n      \"method\": \"Receptor identification assays, nanomolar affinity binding measurements, gene-segment exchange capsid mutants, NRP1-binding-deficient capsid mutants, in vivo mouse dissemination and neurovirulence assays\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — affinity measurements, capsid mutant mapping, and in vivo neurovirulence validation with multiple orthogonal methods\",\n      \"pmids\": [\"38729153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NRP1 binds YAP (co-immunoprecipitation), and mechanical compression disrupts this binding, releasing YAP to translocate to the nucleus. NRP1 knockdown promotes LATS1 expression and reduces YAP, inhibiting endothelial cell proliferation. NRP1 thus transduces mechanical stress inhibition via the LATS1/YAP axis in hypertrophic scars.\",\n      \"method\": \"Co-immunoprecipitation (NRP1-YAP), NRP1 knockdown, LATS1/pYAP western blot, mechanical compression culture model, rat tail-scar model, bioinformatics screening\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional knockdown and in vivo model, single lab\",\n      \"pmids\": [\"37704618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RNA-binding protein Lin28B directly binds the NRP-1 3'UTR (confirmed by RIP), increasing NRP-1 mRNA stability and expression, which in turn activates Wnt/β-catenin signaling to promote gastric cancer cell stemness.\",\n      \"method\": \"RNA immunoprecipitation (RIP), luciferase reporter assay, mRNA stability assay, Lin28B overexpression/knockdown, Wnt/β-catenin signaling western blot, spheroid formation assays\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and reporter assay with functional stemness readouts, single lab\",\n      \"pmids\": [\"29787985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NRP1 promotes IL-17A production by intestinal ILC3s in an NF-κB signaling-dependent and cell-intrinsic manner. Genetic NRP1 deficiency reduces ILC3 frequency in the gut and impairs IL-17A production, altering microbiota composition and improving DSS-induced colitis outcomes.\",\n      \"method\": \"NRP1 conditional knockout mice, ILC3 frequency/IL-17A production assays, NF-κB signaling analysis, DSS colitis model, pharmacological NRP1 inhibition (EG00229)\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with pharmacological validation and defined immune signaling pathway, single lab\",\n      \"pmids\": [\"39741194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Myeloma-secreted galectin-1 potently interacts with CD304 (NRP1) on monocytic MDSCs, expanding the M-MDSC population and increasing CD304 expression. Blockade of CD304 reduces MDSC migration and reverses MDSC-mediated suppression of melphalan cytotoxicity.\",\n      \"method\": \"High-throughput flow cytometry screening, galectin-1 in vitro treatment of MDSCs, CD304/NRP1 blockade assays, co-culture with myeloma cell lines (high/low galectin-1), cytotoxicity assays\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional binding assay and blockade experiments with clinical relevance, single lab\",\n      \"pmids\": [\"33771821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VEGFR1, VEGFR2, and NRP1 show distinct trafficking dynamics in HUVECs: VEGFR1 has faster internalization and recycling rates than VEGFR2, whereas NRP1 is predominantly retained at the cell surface (high surface fraction). These differences in subcellular localization influence VEGF ligand sensing and receptor complex composition.\",\n      \"method\": \"Quantitative trafficking experiments (receptor internalization and recycling rates measured simultaneously for all three receptors on HUVECs), computational modeling\",\n      \"journal\": \"PLoS computational biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative experimental trafficking data combined with computational modeling, single lab\",\n      \"pmids\": [\"38324585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Dnmt3a1 regulates hippocampus-dependent memory via Nrp1 as a downstream target. Dnmt3a1 activity is required for Nrp1 expression in hippocampal neurons, and Nrp1 is required for long-term spatial and contextual memory. NRP1 overexpression does not rescue memory impairments from Dnmt3a2 reduction, indicating isoform-specific regulation.\",\n      \"method\": \"Dnmt3a1-specific knockout mice, RNA sequencing, Nrp1 knockdown and overexpression in hippocampus, behavioral memory tests (spatial object recognition, contextual fear memory), rescue experiments\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with RNA-seq identification of target and in vivo rescue behavioral assays, single lab\",\n      \"pmids\": [\"38499720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YAP/TEAD4 binding to the NRP1 promoter is induced by ionizing radiation in NSCLC cells, transcriptionally upregulating NRP1 expression and conferring radioresistance. NRP1 is identified as a direct transcriptional target of the YAP/TEAD4 complex.\",\n      \"method\": \"ChIP assay (TEAD4-NRP1 promoter), YAP dephosphorylation analysis, YAP/TEAD4 inhibition, NRP1 expression rescue experiments, radiation-resistant A549/H1299 cell models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-validated transcriptional regulation with functional rescue experiments, single lab\",\n      \"pmids\": [\"39187525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CMTM6 physically interacts with NRP1 (co-immunoprecipitation) in oral squamous cell carcinoma cells. NRP1 is required for CMTM6-driven tumorigenesis: NRP1 silencing abrogates CMTM6-induced oncogenic effects, and NRP1 depletion destabilizes CMTM6 protein, suggesting NRP1 protects CMTM6 from degradation.\",\n      \"method\": \"Co-immunoprecipitation (CMTM6-NRP1), gain/loss-of-function experiments, CMTM6 protein stability assay in NRP1-silenced cells\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP in one cell line, no mechanistic follow-up of interaction mode\",\n      \"pmids\": [\"32642284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NRP1 knockdown in neuroblastoma SK-N-AS cells increases β1 integrin expression and promotes migration and invasion, indicating NRP1 exerts tumor-suppressive effects in neuroblastoma via regulation of β1 integrin levels.\",\n      \"method\": \"NRP1 siRNA knockdown, wound-healing assay, Matrigel invasion assay, β1 integrin western blot, β1 integrin siRNA knockdown\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown approach with phenotypic and protein-level readouts, no direct interaction demonstrated, single lab\",\n      \"pmids\": [\"29750423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NRP1 contributes to cancer stem cell stemness and radioresistance in breast cancer through downregulation of Bcl-2 via the m6A methyltransferase WTAP in an m6A-dependent manner.\",\n      \"method\": \"NRP1 siRNA/plasmid transfection, WTAP m6A methylation assay, Bcl-2 western blot, γH2AX immunofluorescence, flow cytometry apoptosis, shRNA-NRP1 xenograft model with radiotherapy\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic linkage between NRP1 and WTAP/m6A suggested but pathway not directly validated at the molecular interaction level, single lab\",\n      \"pmids\": [\"36333630\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NRP1 is a multifunctional transmembrane co-receptor that binds VEGF-A (via its b1 domain residues Y297/D320) and class-3 semaphorins (SEMA3A, SEMA3C) to form signaling complexes with VEGFR2, plexins, and other receptors; in endothelium it promotes tip-cell identity, enhances VEGFR2 signaling and internalization in cis while suppressing it in trans, mediates vascular permeability through an ABL-SFK kinase cascade requiring its cytoplasmic domain, regulates sprouting angiogenesis by suppressing ALK1/ALK5-Smad2/3 activity downstream of Notch, and is proteolytically cleaved by ADAM9/10 to generate inhibitory C-terminal fragments; in neurons NRP1 acts as a co-receptor for Reelin (with VLDLR) to control cortical dendritic development and mediates SEMA3A-dependent axon guidance and sympathetic nervous system development; additional mechanistic roles include modulating immune cell function (dendritic cell maturation via TLR4 interaction, ILC3 IL-17A production via NF-κB, MDSC activity via galectin-1), being stabilized by the deubiquitinase USP9X, and acting as an entry receptor for mammalian orthoreovirus.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NRP1 is a multifunctional transmembrane co-receptor that integrates VEGF and class-3 semaphorin cues to control endothelial behavior during angiogenesis and to guide neuronal and other developmental processes [#0, #5]. Its b1 domain residues Y297 and D320 mediate high-affinity VEGF binding and assembly of the NRP1-VEGFR2 complex, driving FAK phosphorylation and endothelial migration; binding-deficient mutants act dominant-negatively by heterodimerizing with wild-type NRP1 and NRP2 [#0]. NRP1 self-associates and partners with VEGFR2 even before ligand engagement, and these interactions are reorganized by VEGF-A, with endoglin further bridging a tripartite NRP1/VEGFR2/ENG complex required for optimal VEGFR2 and Erk1/2 phosphorylation and sprouting [#19, #20]. NRP1 functions cell-autonomously in endothelial tip cells to promote angiogenesis [#1], and acts as the pivot of endothelial heterogeneity in the Dll4/Notch loop by limiting Smad2/3 activation through ALK1/ALK5 to suppress the stalk-cell phenotype [#2]. The spatial geometry of NRP1 presentation tunes signaling output: in cis VEGF drives rapid VEGFR2/NRP1 co-internalization, whereas NRP1 in trans arrests VEGFR2 endocytosis and reshapes downstream PLC\\u03b3/ERK kinetics [#3]. VEGF165-induced vascular permeability requires the NRP1 cytoplasmic domain, which activates an ABL\\u2192SRC-family kinase cascade within the receptor complex [#4]. NRP1 output is further controlled by ADAM9/10-mediated cleavage that generates inhibitory C-terminal fragments [#7]. Beyond vasculature, SEMA3A signaling through NRP1 directs sympathetic neuron positioning and axon guidance [#11] and confers fast-twitch myofiber specificity to muscle progenitors [#21], and NRP1 serves as a co-receptor with VLDLR for Reelin to control cortical dendritic development [#13]. NRP1 also acts as an entry receptor for mammalian orthoreovirus through multivalent capsid engagement of its extracellular domains, contributing to viral dissemination and neurovirulence [#25]. A disease-linked gain-of-function interaction occurs in Charcot-Marie-Tooth type 2N, where CMT2N-causing AlaRS mutations loosen the aminoacylation domain and create an aberrant interaction with the NRP1 b1b2 domains not seen with wild-type AlaRS [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved whether SEMA3A and VEGF compete at NRP1 to coordinate neurovascular patterning, establishing that VEGF164\\u2014not SEMA3A\\u2014drives NRP1-dependent angiogenesis while SEMA3A patterns axons independently.\",\n      \"evidence\": \"Sema3a and Vegf isoform mouse knockouts with genetic interaction analysis of vessel and axon patterning\",\n      \"pmids\": [\"17428830\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define how distinct ligands engage the same receptor without competition\", \"Mechanism of NRP1 ligand selectivity not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapped the molecular determinants of VEGF binding to NRP1, showing b1-domain residues Y297/D320 are essential for VEGFR2 complex formation and downstream FAK signaling, and that non-binding mutants act dominant-negatively.\",\n      \"evidence\": \"Site-directed mutagenesis, VEGF binding/Co-IP/phosphorylation and migration assays in HUVECs\",\n      \"pmids\": [\"21653826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish in vivo requirement of these residues\", \"Stoichiometry of the NRP1-VEGFR2 complex unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended NRP1 function beyond endothelium by showing an autocrine VEGF/NRP1 loop sustains cancer stem-cell self-renewal and tumor initiation in skin.\",\n      \"evidence\": \"Conditional Nrp1 knockout in tumor epithelium with CSC self-renewal assays and VEGF gain/loss\",\n      \"pmids\": [\"22012397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoplasmic effectors in epithelial cells not defined here\", \"Relationship to VEGFR2 in epithelium unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined cell-autonomous SEMA3A/NRP1 roles in sympathetic nervous system development, linking NRP1 loss to cardiac innervation defects and bradycardia.\",\n      \"evidence\": \"Lineage-specific conditional Nrp1 knockouts and Sema3a/NRP compound mutants with cardiac phenotyping\",\n      \"pmids\": [\"22790009\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream plexin partners not dissected\", \"Cytoplasmic signaling for neuronal positioning unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established NRP1 as a cell-autonomous tip-cell determinant in brain angiogenesis and showed the spatial context (cis vs trans) of NRP1 dictates VEGFR2 trafficking and signaling output.\",\n      \"evidence\": \"Endothelial conditional knockout with mosaic analysis; co-culture cis/trans systems with internalization and phosphorylation time courses and tumor models\",\n      \"pmids\": [\"23315162\", \"24656741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of trans-mediated endocytic arrest not fully defined\", \"How cis/trans balance is set in vivo unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Broadened the active NRP1 ligand repertoire in the nervous system by showing VEGF189, in addition to VEGF165, binds NRP1 and supports neuronal migration, survival, and axon guidance.\",\n      \"evidence\": \"In situ ligand binding, VEGF isoform knock-in mice, in vitro neuronal assays\",\n      \"pmids\": [\"25519242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor complex composition for VEGF189 not defined\", \"Single-lab functional characterization\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Positioned NRP1 as the pivot of endothelial tip/stalk heterogeneity by showing it suppresses stalk-cell behavior via ALK1/ALK5-Smad2/3 inhibition downstream of Notch.\",\n      \"evidence\": \"Genetic epistasis in zebrafish and mouse, endothelial Nrp1 knockout, Smad2/3 phosphorylation and ALK inhibitor experiments\",\n      \"pmids\": [\"26081042\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between NRP1 and ALK receptors not shown\", \"How Notch transcriptionally controls NRP1 not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified cytoplasmic-domain-dependent GIPC1-Syx-RhoA signaling as an NRP1 output controlling cancer proliferation through p27 degradation.\",\n      \"evidence\": \"Co-IP, RhoA activity assays, NRP1 cytoplasmic deletion mutants, RhoA/ROCK inhibition in cancer cells\",\n      \"pmids\": [\"26209534\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab pathway without in vivo validation here\", \"Receptor partner upstream of GIPC1-Syx in this context not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed NRP1 stabilizes and amplifies non-VEGF receptors, prolonging DDR2 half-life and enhancing ERK1/2/Runx2 signaling to drive osteoblast differentiation.\",\n      \"evidence\": \"Co-localization, Co-IP, protein half-life and osteogenic differentiation assays\",\n      \"pmids\": [\"25924845\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of DDR2 stabilization unknown\", \"Single-lab finding without in vivo confirmation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated an immunoregulatory role in which VEGF-dependent NRP1 directly engages TLR4 to suppress dendritic cell maturation via ERK/NF-\\u03baB inhibition.\",\n      \"evidence\": \"Conditional NRP1-knockout BMDCs, NRP1-TLR4 Co-IP, signaling and surface-marker readouts\",\n      \"pmids\": [\"27815442\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of NRP1-TLR4 interaction unknown\", \"Single-lab Co-IP without reciprocal structural validation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the cytoplasmic-domain mechanism for VEGF165-induced vascular permeability, establishing an NRP1-cytoplasmic-domain\\u2192ABL\\u2192SRC-family-kinase cascade independent of GIPC1.\",\n      \"evidence\": \"NRP1 cytoplasmic-domain knock-in mice, Miles assay, ABL/SFK kinase assays, choroidal neovascularization model\",\n      \"pmids\": [\"28289053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ABL is recruited to the cytoplasmic domain not defined\", \"Direct NCD-ABL binding interface unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a negative-feedback mechanism whereby VEGF drives ADAM9/10 cleavage of NRP1, producing inhibitory C-terminal fragments that suppress VEGFR2 signaling and angiogenesis.\",\n      \"evidence\": \"ADAM9/10 knockdown, ADAM10 inhibitor, C-terminal fragment overexpression, sprouting and angiogenesis assays\",\n      \"pmids\": [\"29880492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological relevance of cleavage not established\", \"Cleavage site and regulation incompletely defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Characterized NRP1/VEGFR2 plasma-membrane organization, showing pre-ligand homo- and hetero-interactions modulated by VEGFA.\",\n      \"evidence\": \"Quantitative FRET in plasma membrane with VEGFA addition/removal\",\n      \"pmids\": [\"29630862\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of pre-ligand assembly not measured\", \"Single biophysical method\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended NRP1 cytoplasmic GIPC1 signaling to integrin- and YAP-dependent cancer stem-cell programs, linking NRP1/GIPC1/integrin-FAK/Src to YAP1/\\u0394Np63\\u03b1 and RhoA-p38 outputs.\",\n      \"evidence\": \"Co-IP of NRP1-GIPC1-integrin complexes, kinase assays, rescue experiments, xenograft models\",\n      \"pmids\": [\"29755126\", \"30456845\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Same-lab findings without independent replication\", \"Direct NRP1-integrin contact interface not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established NRP1 as a Reelin co-receptor that complexes with VLDLR to augment Reelin signaling and control cortical dendritic development.\",\n      \"evidence\": \"NRP1-VLDLR Co-IP, in utero electroporation knockdown, Dab1 and dendritic morphology assays, Reelin CTR mutant binding\",\n      \"pmids\": [\"33009002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Reelin CTR-NRP1 binding not solved\", \"Single-lab characterization\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined an epidermal cell-autonomous VEGFA/NRP1/FLT1 axis driving psoriasis, with Fosl1 as a downstream effector and therapeutic responsiveness to anti-NRP1 antibody.\",\n      \"evidence\": \"Keratinocyte-specific Nrp1 knockout, psoriasis models, anti-Nrp1 antibody, ATAC-seq/RNA-seq\",\n      \"pmids\": [\"31934626\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoplasmic signaling linking NRP1 to Fosl1 not dissected\", \"Receptor partner in keratinocytes (FLT1 vs VEGFR2) roles incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected NRP1 to a Mendelian disease by showing CMT2N-causing AlaRS mutations structurally loosen the aminoacylation domain to enable an aberrant gain-of-function interaction with the NRP1 b1b2 domains.\",\n      \"evidence\": \"X-ray crystallography, SAXS, HDX, switchSENSE, Co-IP in patient samples\",\n      \"pmids\": [\"33753480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream cellular consequence of aberrant binding on NRP1 signaling not defined\", \"Causal link to neuropathy phenotype mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established SEMA3A/NRP1 as a chemorepellent system specifying fast-twitch myofiber identity by restricting Tw2+/Nrp1+ progenitor fusion.\",\n      \"evidence\": \"RNA-seq, stripe migration and chimeric fusion assays, Sema3a transgenic mice\",\n      \"pmids\": [\"31474563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Plexin co-receptor identity in muscle not defined\", \"Downstream cytoskeletal signaling not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Implicated NRP1 in immune and tumor microenvironment functions, promoting ILC3 IL-17A via NF-\\u03baB and serving as a galectin-1 binding partner expanding MDSCs.\",\n      \"evidence\": \"NRP1 conditional knockout and pharmacological inhibition (ILC3/colitis); flow-cytometry galectin-1 binding and blockade assays (MDSC)\",\n      \"pmids\": [\"39741194\", \"33771821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NRP1 ligand driving ILC3 NF-\\u03baB not identified\", \"Single-lab characterizations in each immune context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded the NRP1 receptor-partner network in cancer to EGFR, with extracellular b1/b2 engagement driving AKT activation, and identified transcriptional control of NRP1 by HIF1\\u03b1.\",\n      \"evidence\": \"NRP1-EGFR Co-IP, domain deletions, phosphorylation assays, ChIP of HIF1\\u03b1 on the NRP1 promoter, xenograft\",\n      \"pmids\": [\"36841806\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect NRP1-EGFR contact not fully resolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified post-translational and mechanotransductive control of NRP1, with USP9X deubiquitinating and stabilizing NRP1 in fibrosis, and NRP1 binding YAP to relay mechanical stress via the LATS1/YAP axis.\",\n      \"evidence\": \"Co-IP/ubiquitination assays and CCl4 fibrosis model (USP9X); NRP1-YAP Co-IP, compression model and rat scar model (mechanotransduction)\",\n      \"pmids\": [\"36653359\", \"37704618\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"USP9X ubiquitin-site specificity on NRP1 not mapped\", \"Single-lab Co-IPs without reciprocal structural validation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined the endothelial VEGF receptor module by showing endoglin bridges a tripartite NRP1/VEGFR2/ENG complex needed for optimal signaling, and quantified distinct receptor trafficking with NRP1 predominantly surface-retained.\",\n      \"evidence\": \"FRAP co-mobility assays and ENG/NRP1 gain/loss with sprouting (ENG); quantitative trafficking measurements with computational modeling (HUVEC)\",\n      \"pmids\": [\"38242992\", \"38324585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural arrangement of the tripartite complex unknown\", \"Single-lab quantitative datasets\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established NRP1 as an entry receptor for mammalian orthoreovirus through multivalent capsid engagement of its extracellular domains, contributing to dissemination and neurovirulence.\",\n      \"evidence\": \"Affinity binding measurements, capsid mutant mapping, in vivo dissemination and neurovirulence assays\",\n      \"pmids\": [\"38729153\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether viral entry co-opts native NRP1 signaling unknown\", \"Post-binding internalization route not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked NRP1 to neuronal gene-regulatory control of memory, identifying it as a Dnmt3a1-dependent transcriptional target required for long-term spatial and contextual memory.\",\n      \"evidence\": \"Dnmt3a1 knockout mice, RNA-seq, hippocampal Nrp1 knockdown/overexpression, behavioral and rescue assays\",\n      \"pmids\": [\"38499720\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NRP1 ligand/partner mediating memory function not identified\", \"Mechanism downstream of NRP1 in neurons unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NRP1's single short cytoplasmic domain selectively assembles distinct signaling complexes (VEGFR2, plexins, VLDLR, TLR4, EGFR, integrins, endoglin) to produce context-specific outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model of multi-partner complex assembly\", \"Rules governing cis vs trans and ligand-specific complex choice undefined\", \"Integration of co-receptor signaling across tissues not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 4, 19]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [25]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 4, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 19, 20, 24, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 4, 19]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2, 11, 13, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 28, 29]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [14, 16, 25]}\n    ],\n    \"complexes\": [\n      \"NRP1-VEGFR2 complex\",\n      \"NRP1/VEGFR2/endoglin complex\",\n      \"NRP1-VLDLR Reelin co-receptor complex\",\n      \"SEMA3A-PlexinA1-NRP1 complex\"\n    ],\n    \"partners\": [\n      \"VEGFR2\",\n      \"ENG\",\n      \"VLDLR\",\n      \"TLR4\",\n      \"EGFR\",\n      \"GIPC1\",\n      \"USP9X\",\n      \"NRP2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":10,"faith_total":10,"faith_pct":100.0}}