{"gene":"NRP2","run_date":"2026-06-13T19:06:35","timeline":{"discoveries":[{"year":2017,"finding":"NRP2 serves as a host cell entry receptor for Lujo virus (LUJV); LUJV glycoprotein binds the N-terminal domain of NRP2, and cells lacking NRP2 are deficient in wild-type LUJV infection. Overexpression of NRP2 or its N-terminal domain enhances VSV-LUJV infection.","method":"Genome-wide haploid genetic screen, receptor overexpression/knockout, binding assay with recombinant VSV-LUJV","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen identifying NRP2, combined with KO rescue, overexpression, and binding domain mapping in one study","pmids":["29120745"],"is_preprint":false},{"year":2012,"finding":"NRP2 acts as a receptor for class 3 semaphorins (SEMA3F) and mediates axon guidance and migration in the sympathetic nervous system. Loss of NRP2/SEMA3F signaling impairs sympathetic gangliogenesis and causes ectopic neurite extension. NRP1 and NRP2 cooperate in SNS development as demonstrated by compound mutant analysis.","method":"Genetic mouse knockout (Nrp2-/-, Sema3F-/-, compound mutants), neuroanatomical phenotyping","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple single and compound knockout mouse models with defined neuroanatomical and functional phenotypes, replicated across genotypes","pmids":["22790009"],"is_preprint":false},{"year":2020,"finding":"NRP2 promotes endothelial cell (EC) adhesion and migration over fibronectin via a Rac-1-dependent mechanism that is independent of β3 integrin (ITGB3) and VEGF stimulation. NRP2 regulates α5 integrin (ITGA5) recycling in ECs; NRP2-depleted ECs show upregulated ITGA5 expression, disrupted ITGA5 organization, and reduced total ITGA5 recycling.","method":"siRNA knockdown in ECs, adhesion/migration assays on fibronectin, flow cytometry, integrin recycling assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype and mechanistic follow-up on integrin recycling, single lab","pmids":["32528960"],"is_preprint":false},{"year":2016,"finding":"NRP2 negatively regulates WDFY1 transcription by preventing nuclear localization of the transcription factor FAC1. Maintaining WDFY1 at sub-optimal levels sustains high endocytic activity in metastatic cancer cells.","method":"NRP2 knockdown/overexpression, nuclear fractionation, transcription reporter assays, endocytic activity assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nuclear localization assay plus transcriptional reporter, single lab with two orthogonal methods","pmids":["27026195"],"is_preprint":false},{"year":2020,"finding":"NRP2 promotes angiogenesis in pancreatic neuroendocrine tumors (PNETs) via a VEGF/VEGFR2-independent pathway by activating F-actin polymerization through the SSH1/cofilin axis. Silencing SSH1 abrogated NRP2-activated HUVEC migration and F-actin polymerization.","method":"Plasmid constructs with mutant variants, Western blot, immunofluorescence, tube formation and wound-healing assays, in vivo mouse tumor model with NRP2 antibody","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection with SSH1 silencing rescue, in vitro and in vivo, single lab","pmids":["32983407"],"is_preprint":false},{"year":2013,"finding":"Nrp2 is expressed in osteoblasts and osteoclasts in bone, and Nrp2 knockout mice display trabecular bone loss accompanied by increased osteoclast numbers and decreased osteoblast counts, indicating a role for NRP2 in bone homeostasis. Nrp2 is co-expressed with plexin family coreceptors and class 3 semaphorin ligands during osteogenic differentiation.","method":"Nrp2 knockout mouse analysis, immunohistochemistry, in vitro osteogenic/osteoclast differentiation assays","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO phenotype with defined cellular mechanism, supported by in vitro differentiation data, single lab","pmids":["23598046"],"is_preprint":false},{"year":2017,"finding":"NRP2 expressed in mitral cells mediates their migration to the posteroventral olfactory bulb and axonal projection to the anterior medial amygdala in response to Semaphorin 3F. MC-specific Nrp2 knockout impairs circuit formation and abolishes odour-induced attractive social responses.","method":"MC-specific conditional Nrp2 knockout mice, in utero electroporation, behavioral assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO with defined circuit and behavioral phenotype, gain-of-function via electroporation demonstrating sufficiency","pmids":["28731029"],"is_preprint":false},{"year":2022,"finding":"NRP2 promotes endothelial cell apoptosis under low shear stress (LSS) by upregulating PARP1 protein expression, which modulates downstream apoptosis-related gene expression. Transcription factor GATA2 was identified as an upstream regulator that drives NRP2 expression. NRP2 knockdown in Apoe-/- mice markedly reduced atherosclerosis.","method":"siRNA knockdown and overexpression in HUVECs, Western blot, apoptosis assays, Apoe-/- mouse model, GATA2 transcription factor analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD/OE with defined molecular mediator (PARP1), in vivo validation, single lab","pmids":["35028975"],"is_preprint":false},{"year":2023,"finding":"GATA2 regulates NRP2 transcription by binding to the −1100 to +100 bp region of the NRP2 promoter. NRP2 forms a complex with VEGF-C under disturbed flow in endothelial cells, promoting inflammation. Quercetin inhibits the NRP2-VEGF-C complex formation.","method":"Promoter binding assay, co-immunoprecipitation for NRP2-VEGFC complex, siRNA knockdown, HUVEC disturbed flow model","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter binding and co-IP for complex formation, single lab with two orthogonal methods","pmids":["36764279"],"is_preprint":false},{"year":2021,"finding":"In gastric cancer, CAF-expressed NRP2 promotes chemoresistance by stimulating SDF-1 secretion via VEGF/NRP2 signaling in CAFs, which in turn activates the Hippo pathway (YAP/TAZ) in cancer cells. NRP2 knockdown in CAFs reduced SDF-1 secretion and restored cancer cell sensitivity to 5-FU.","method":"RNA-sequencing, CAF/cancer cell co-culture, siRNA knockdown, viability and apoptosis assays","journal":"Gastric cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD with identified downstream mediators SDF-1 and YAP/TAZ, single lab","pmids":["34826008"],"is_preprint":false},{"year":2022,"finding":"MUC16 regulates NRP2 expression via the JAK2/STAT1 signaling axis in pancreatic ductal adenocarcinoma cells. NRP2 knockdown in MUC16-overexpressed cells significantly decreased cell adhesion and migration, placing NRP2 downstream of MUC16-JAK2/STAT1 in liver metastasis.","method":"RNA-sequencing, siRNA knockdown, overexpression, cell adhesion and migration assays, in vivo mouse liver metastasis model","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by rescue experiments, in vivo validation, single lab","pmids":["35533267"],"is_preprint":false},{"year":2020,"finding":"NRP2 binds TGFβ1 and associates with TGFβ receptors, enhancing TGFβ1 signaling. TGFβ1-dependent regulation of NRP2 and GLI2 expression promotes EMT in bladder cancer. NRP2 positively regulates SPP1/Osteopontin as a downstream effector, validated in NRP2 knockout and knockdown models.","method":"NRP2 KO and knockdown models, PCR profiling array (84 EMT genes), correlation analysis in TCGA cohort and cell lines, TGFβ1 stimulation assays","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — KO/KD with downstream target validation, but no direct binding assay in this paper; co-receptor binding cited from prior work","pmids":["32038994"],"is_preprint":false},{"year":2025,"finding":"HARSWHEP (a splice variant of histidyl-tRNA synthetase) binds specifically and selectively to NRP2 via a helix-turn-helix motif. This interaction on myeloid cells inhibits proinflammatory receptor and cytokine expression and down-regulates inflammatory pathways in primary human macrophages. In animal models of ILD, HARSWHEP reduced lung inflammation and fibrosis through NRP2.","method":"Structural analysis (helix-turn-helix motif), binding assays, primary human macrophage assays, multiple animal models of lung injury/ILD","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural determination combined with binding assays and functional validation across multiple disease models with mechanistic follow-up","pmids":["40073151"],"is_preprint":false},{"year":2025,"finding":"A bispecific antibody that dimerizes NRP2 with PLXNA1 mimics SEMA3F-mediated signaling (receptor dimerization, phospho-AKT suppression, oncogene suppression, antiproliferative effects). Structural studies revealed the bsAb binds NRP2 and PLXNA1 at sites distinct from the SEMA3F-binding site but allows proper receptor complex formation and conformational flexibility for signaling.","method":"Cell-based receptor dimerization assays, phospho-AKT assay, cell proliferation assay, structural studies of antibody binding","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural studies combined with multiple orthogonal functional assays in a single rigorous study","pmids":["41391772"],"is_preprint":false},{"year":2022,"finding":"Alveolar macrophage (AM)-derived NRP2 physically binds CD11b+ Ly6Glo/+ neutrophils and promotes their phagocytosis and bacterial killing capacity, partly through increased TLR4 and TNF-α expression. Conditional deletion of NRP2 in AMs resulted in persistent bacteria, uncontrolled neutrophil influx, and decreased survival during E. coli pneumonia.","method":"Conditional AM-specific NRP2 KO mice, in vitro binding and phagocytosis assays, E. coli pneumonia model","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined cellular phenotype and in vitro binding assay, single lab","pmids":["35435271"],"is_preprint":false},{"year":2025,"finding":"CD3L1 (ITPRIPL1) signals through NRP2 as its primary receptor on macrophages, constituting the CD3L1-NRP2 axis that drives immunosuppressive M2 TAM polarization. NRP2 KO or anti-CD3L1 treatment reprogrammed TAMs toward M1 anti-tumor phenotype and suppressed tumor progression in T-cell-deficient models.","method":"Mechanistic studies in T-cell deficient osteosarcoma models, receptor identification, macrophage polarization assays, in vivo tumor models","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-ligand identification with in vivo KO phenotype, single study","pmids":["42141271"],"is_preprint":false},{"year":2025,"finding":"NRP2 functions as a co-inhibitory receptor on CD4+ T effector cells. NRP2 is co-expressed with PD-1, CTLA4, TIGIT, LAG3, and TIM3 on exhausted/late effector CD4+ T cells. Knockout of NRP2 results in hyperactive CD4+ T cell responses, accelerated allograft rejection, and enhanced delayed-type hypersensitivity. The co-inhibitory function is specific to NRP2 on T effectors, not Treg cells.","method":"Humanized SCID mice, global and CD4+ T cell-specific KO mouse models, cardiac transplantation model, delayed-type hypersensitivity model, in vitro Treg suppression assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple KO models with defined phenotype in two disease settings, cell-type-specific KO, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"NRP2 is a component of endothelial adherens junctions where it maintains VE-cadherin surface availability by promoting its interaction with p120 catenin. Endothelial-specific Nrp2 knockout mice display hyperpermeable retinal vasculature, upregulation of pro-inflammatory cytokines and adhesion molecules, increased immune cell attachment, and aortic plaque development.","method":"Endothelial-specific Nrp2 knockout mouse model, cultured immortalized mouse ECs, co-immunoprecipitation of VE-cadherin and p120 catenin, retinal vascular permeability assay, aortic plaque assessment","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo EC-specific KO with defined molecular interaction (VE-cadherin/p120 catenin) and functional vascular phenotype; preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"Guinea pig NRP2 interacts with the CMV pentamer complex (PC) in immunoprecipitation assays, functioning as an endocytic cell entry receptor. Double knockout of PDGFRA and NRP2 completely blocked GPCMV infection, while CD147/PDGFRA double KO had only limited inhibition.","method":"Immunoprecipitation, double KO cell lines, ectopic receptor re-expression, viral infection assays","journal":"The Journal of general virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and genetic KO with ectopic rescue, but in a guinea pig CMV model (ortholog context)","pmids":["41805587"],"is_preprint":false},{"year":2023,"finding":"Sema3G signals through the Nrp2/PlexinA1 receptor complex to inhibit LATS1 and activate YAP in vascular smooth muscle cells, promoting their proliferation and migration. MMP2 and MMP9 upregulation underlies enhanced migration. Verteporfin (YAP inhibitor) counteracted Sema3G-induced cyclin E and cyclin D1 expression.","method":"Nrp2/PlexinA1 inhibition, Western blot for LATS1/YAP phosphorylation, cell proliferation/migration assays, pharmacological inhibition with verteporfin","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor complex defined with inhibition rescue, multiple downstream pathway readouts, single lab","pmids":["36720439"],"is_preprint":false},{"year":2025,"finding":"NRP2 activates FAK phosphorylation through direct binding to FAK, thereby activating the focal adhesion pathway and promoting GBM cell proliferation, migration, and invasion. NRP2 knockdown inhibited GBM growth in vivo, and this inhibition was reversed by FAK agonists.","method":"NRP2 knockdown (in vitro and in vivo), FAK phosphorylation assays, direct binding assay, FAK agonist rescue experiments, animal tumor model","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay plus epistasis rescue with FAK agonist, in vivo validation, single lab","pmids":["41861662"],"is_preprint":false},{"year":2025,"finding":"NRP2 expressed on colorectal cancer-derived migrasomes is transferred to macrophages, where it binds PROX1 to drive CD5L expression and upregulate efferocytosis receptors, promoting M2-like macrophage polarization and tumor immune evasion. NRP2 knockdown in CRC cells abrogated migrasome-induced CD5L+ macrophage polarization.","method":"scRNA-seq, in vivo liver metastasis model, NRP2 KD, migrasome transfer assays, binding assay (NRP2-PROX1)","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic KD with defined receptor-binding partner interaction and functional macrophage phenotype, single lab","pmids":["41361466"],"is_preprint":false},{"year":2025,"finding":"In colorectal cancer, cancer-associated fibroblast-secreted SEMA3C binds the NRP2 receptor on liver metastasis-initiating cells, activating the MAPK pathway and promoting liver metastasis. Confirmed by in vivo and in vitro experiments.","method":"Time-resolved spatial transcriptomics, scRNA-seq, in vivo and in vitro SEMA3C-NRP2 signaling assays, MAPK pathway analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-ligand pair confirmed with in vivo and in vitro functional validation, single study","pmids":["40402249"],"is_preprint":false},{"year":2022,"finding":"NRP2 is dynamically redistributed to the basolateral membrane compartment of polarized HUVECs upon basolateral VEGF-A stimulation, co-redistributing with VEGFR2. This basolateral localization correlates with enhanced endothelial permeability.","method":"Immunocytochemistry and confocal z-section imaging, Transwell permeability assay, quantitative fluorescence intensity measurement","journal":"The journal of histochemistry and cytochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment with functional consequence (permeability), two orthogonal methods, single lab","pmids":["35876388"],"is_preprint":false},{"year":2024,"finding":"TGF-β signaling activates SMAD2, which transcriptionally upregulates NRP2 expression in ectopic endometrial stromal cells (ESCs). NRP2 depletion suppressed ESC migration, invasion, and EMT. TGF-β treatment rescued NRP2 silencing-induced suppression.","method":"ChIP assay confirming SMAD2 binding to NRP2 promoter, luciferase reporter assay, siRNA knockdown, transwell migration/invasion assays, Western blot for EMT markers","journal":"Reproductive biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase for promoter regulation, functional rescue by TGF-β, single lab","pmids":["36306654"],"is_preprint":false},{"year":2024,"finding":"FOXA1 binds to the NRP2 promoter and suppresses NRP2 transcription, exacerbating LPS-induced endothelial cell injury. Knockdown of NRP2 offset the protective effect of FOXA1 knockdown, placing NRP2 downstream of FOXA1 in the septic endothelial injury pathway.","method":"ChIP assay, dual-luciferase assay for FOXA1-NRP2 promoter binding, siRNA knockdown rescue experiments, HUVEC LPS model","journal":"Cytotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter plus epistasis rescue, single lab","pmids":["39435415"],"is_preprint":false},{"year":2022,"finding":"NRP2 promotes sorafenib resistance in clear cell renal cell carcinoma through the NRP2/NF-κB/TNFα axis. The TNF-α inhibitor adalimumab reversed NRP2-mediated sorafenib resistance.","method":"NRP2 overexpression/knockdown in ccRCC cells, NF-κB pathway analysis, pharmacological rescue with adalimumab, cell proliferation/migration/invasion assays","journal":"American journal of cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placed by knockdown and inhibitor rescue but no direct molecular binding assay","pmids":["41395296"],"is_preprint":false}],"current_model":"NRP2 is a pleiotropic transmembrane co-receptor that mediates semaphorin (SEMA3F, SEMA3C, SEMA3G) and VEGF-C/D signaling via interactions with plexin and VEGFR co-receptors, guiding axonal migration, sympathetic circuit formation, and lymphangiogenesis; it also acts as a direct entry receptor for Lujo virus and CMV pentamer complex, functions as a co-inhibitory receptor on CD4+ T effector cells, maintains endothelial adherens junctions by stabilizing VE-cadherin/p120-catenin interaction, promotes ITGA5 recycling and Rac-1-dependent EC migration, drives F-actin polymerization through the SSH1/cofilin axis, activates FAK phosphorylation in glioblastoma, regulates osteoblast/osteoclast balance in bone homeostasis, mediates immunomodulatory signaling as a receptor for the HARSWHEP splice variant in macrophages, and is transcriptionally regulated by upstream factors including GATA2, SMAD2, and FOXA1."},"narrative":{"mechanistic_narrative":"NRP2 is a pleiotropic transmembrane co-receptor that transduces class 3 semaphorin and VEGF-family cues to guide neuronal circuit formation, vascular biology, and immune regulation [PMID:22790009, PMID:28731029]. In the nervous system, NRP2 binds SEMA3F and, cooperating with NRP1, controls sympathetic gangliogenesis and neurite targeting [PMID:22790009], and in mitral cells directs migration and axonal projection that underlie odour-driven social behaviour [PMID:28731029]; semaphorin signalling is read out through NRP2/PlexinA1 receptor complexes, which can be engineered with a bispecific antibody to mimic SEMA3F-induced dimerization, suppress phospho-AKT, and restrain proliferation [PMID:41391772, PMID:36720439]. In endothelium NRP2 stabilizes adherens junctions by promoting VE-cadherin/p120-catenin interaction, and it governs cell migration and adhesion through Rac-1-dependent control of ITGA5 integrin recycling and through SSH1/cofilin-driven F-actin polymerization [PMID:32528960, PMID:32983407]. NRP2 also forms a VEGF-C complex under disturbed flow and modulates apoptosis via PARP1, linking it to endothelial inflammation and atherosclerosis [PMID:35028975, PMID:36764279]. As an immune receptor, NRP2 acts as a co-inhibitory receptor on effector CD4+ T cells, binds the HARSWHEP histidyl-tRNA synthetase splice variant and the CD3L1/ITPRIPL1 ligand on macrophages to suppress inflammation and drive immunosuppressive M2 polarization, and on alveolar macrophages physically engages neutrophils to promote bacterial clearance [PMID:40073151, PMID:42141271, PMID:35435271]. Across cancers NRP2 acts downstream of TGFβ/SMAD2 and MUC16-JAK2/STAT1 inputs to promote EMT, migration, and metastasis, and activates focal adhesion signalling via direct FAK binding [PMID:32038994, PMID:35533267, PMID:36306654, PMID:41861662]. NRP2 additionally serves as a host entry receptor for Lujo virus through its N-terminal domain and for the cytomegalovirus pentamer complex [PMID:29120745, PMID:41805587].","teleology":[{"year":2012,"claim":"Established NRP2 as a class 3 semaphorin receptor required for nervous system wiring, defining its founding role in axon guidance.","evidence":"Nrp2/Sema3F single and compound knockout mice with neuroanatomical phenotyping of the sympathetic nervous system","pmids":["22790009"],"confidence":"High","gaps":["Does not resolve the receptor complex stoichiometry with plexins in vivo","Molecular signalling output downstream of NRP2 not dissected"]},{"year":2013,"claim":"Extended NRP2 function beyond neurons to skeletal tissue, showing it balances osteoblast and osteoclast activity in bone homeostasis.","evidence":"Nrp2 knockout mouse bone analysis with in vitro osteogenic/osteoclast differentiation assays","pmids":["23598046"],"confidence":"Medium","gaps":["Ligand and plexin coreceptor driving the bone phenotype not pinpointed","Cell-autonomous versus systemic contribution unresolved"]},{"year":2016,"claim":"Identified a nuclear/transcriptional consequence of NRP2 signalling, linking it to WDFY1 repression and sustained endocytosis in metastatic cells.","evidence":"NRP2 knockdown/overexpression with nuclear fractionation and transcription reporter assays","pmids":["27026195"],"confidence":"Medium","gaps":["Mechanism connecting surface NRP2 to FAC1 nuclear exclusion unclear","Single-lab finding without orthogonal confirmation"]},{"year":2017,"claim":"Defined NRP2 as a viral entry receptor and showed its semaphorin guidance role operates at the level of specific circuit formation and behaviour.","evidence":"Genome-wide haploid screen with KO/overexpression and binding for Lujo virus; mitral-cell-specific conditional Nrp2 KO with behavioural assays for olfactory circuits","pmids":["29120745","28731029"],"confidence":"High","gaps":["Structural basis of LUJV glycoprotein-NRP2 binding not solved","Whether viral and semaphorin binding use overlapping NRP2 surfaces unknown"]},{"year":2020,"claim":"Resolved NRP2's role in endothelial migration as integrin- and VEGF-independent, acting through ITGA5 recycling, Rac-1, and the SSH1/cofilin cytoskeletal axis.","evidence":"siRNA knockdown in endothelial cells with adhesion/migration, integrin recycling assays, and SSH1 silencing rescue in tumour angiogenesis models","pmids":["32528960","32983407"],"confidence":"Medium","gaps":["Direct biochemical link between NRP2 and SSH1/Rac regulators not established","Coreceptor requirement for cytoskeletal signalling undefined"]},{"year":2022,"claim":"Positioned NRP2 within disturbed-flow endothelial pathology and innate immunity, coupling it to GATA2-driven expression, VEGF-C complex formation, and macrophage-neutrophil interactions.","evidence":"HUVEC knockdown/overexpression with PARP1 readouts and Apoe-/- atherosclerosis model; promoter binding and co-IP for GATA2 and VEGF-C; conditional AM-specific NRP2 KO in E. coli pneumonia","pmids":["35028975","36764279","35435271"],"confidence":"Medium","gaps":["Whether VEGF-C complex directly drives PARP1 induction not tested","Receptor partners mediating neutrophil binding by macrophage NRP2 unidentified"]},{"year":2024,"claim":"Mapped transcriptional control of NRP2 by SMAD2 and FOXA1, embedding it in TGFβ-driven EMT and endothelial injury responses.","evidence":"ChIP and luciferase promoter assays with siRNA rescue in endometrial stromal cells and LPS-treated HUVECs","pmids":["36306654","39435415"],"confidence":"Medium","gaps":["Opposing activation (SMAD2) versus repression (FOXA1) context-dependence not reconciled","Single-lab promoter findings"]},{"year":2025,"claim":"Defined NRP2 as a druggable immune and signalling hub: a co-inhibitory T-cell receptor, a receptor for HARSWHEP, CD3L1, and PROX1-linked macrophage programs, and a FAK-activating oncogenic node amenable to plexin-dimerizing antibodies.","evidence":"Structural and binding studies of HARSWHEP and bispecific NRP2/PLXNA1 antibody; receptor identification for CD3L1 and migrasome-transferred NRP2; CD4+ T-cell-specific KO models; direct FAK binding and agonist rescue in GBM","pmids":["40073151","41391772","42141271","41361466","40402249"],"confidence":"High","gaps":["Whether immune, viral, and semaphorin functions share one NRP2 conformation/site is unresolved","Endothelial junction and T-cell co-inhibition data remain in preprint form","Unifying structural model across diverse ligands lacking"]},{"year":null,"claim":"How a single co-receptor integrates such divergent ligands (semaphorins, VEGF-C, viral glycoproteins, HARSWHEP, CD3L1, TGFβ1) into context-specific outputs through distinct binding surfaces and coreceptor partners remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No comprehensive structural map of NRP2 ligand-binding sites","Coreceptor selection rules across tissues unknown","Causal hierarchy among NRP2's many downstream pathways undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,18]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,6,19,22]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[16,12,15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[17,23,14]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,19,22,20]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12,14,15,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,18]}],"complexes":["NRP2/PlexinA1 receptor complex","endothelial adherens junction"],"partners":["PLXNA1","VEGFC","FAK","PROX1","CD3L1","TGFB1","FAC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99435","full_name":"Protein kinase C-binding protein NELL2","aliases":["NEL-like protein 2","Nel-related protein 2"],"length_aa":816,"mass_kda":91.3,"function":"Plays multiple roles in neural tissues, regulates neuronal proliferation, survival, differentiation, polarization, as well as axon guidance and synaptic functions. Plays an important role in axon development during neuronal differentiation through the MAPK intracellular signaling pathway (By similarity). Via binding to its receptor ROBO3, plays a role in axon guidance, functioning as a repulsive axon guidance cue that contributes to commissural axon guidance to the midline (PubMed:32198364). Required for neuron survival through the modulation of MAPK signaling pathways too. Involved in the regulation of hypothalamic GNRH secretion and the control of puberty (By similarity) Epididymal-secreted protein that signals through a ROS1-pathway to regulate the epididymal initial segment (IS) maturation, sperm maturation and male fertility","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q99435/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NRP2","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NRP2","total_profiled":1310},"omim":[{"mim_id":"620997","title":"SEMAPHORIN 3G; SEMA3G","url":"https://www.omim.org/entry/620997"},{"mim_id":"618703","title":"ZINC FINGER PROTEIN 281; ZNF281","url":"https://www.omim.org/entry/618703"},{"mim_id":"618080","title":"WD REPEAT-AND FYVE DOMAIN-CONTAINING PROTEIN 1; 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Overexpression of NRP2 or its N-terminal domain enhances VSV-LUJV infection.\",\n      \"method\": \"Genome-wide haploid genetic screen, receptor overexpression/knockout, binding assay with recombinant VSV-LUJV\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen identifying NRP2, combined with KO rescue, overexpression, and binding domain mapping in one study\",\n      \"pmids\": [\"29120745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NRP2 acts as a receptor for class 3 semaphorins (SEMA3F) and mediates axon guidance and migration in the sympathetic nervous system. Loss of NRP2/SEMA3F signaling impairs sympathetic gangliogenesis and causes ectopic neurite extension. NRP1 and NRP2 cooperate in SNS development as demonstrated by compound mutant analysis.\",\n      \"method\": \"Genetic mouse knockout (Nrp2-/-, Sema3F-/-, compound mutants), neuroanatomical phenotyping\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple single and compound knockout mouse models with defined neuroanatomical and functional phenotypes, replicated across genotypes\",\n      \"pmids\": [\"22790009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NRP2 promotes endothelial cell (EC) adhesion and migration over fibronectin via a Rac-1-dependent mechanism that is independent of β3 integrin (ITGB3) and VEGF stimulation. NRP2 regulates α5 integrin (ITGA5) recycling in ECs; NRP2-depleted ECs show upregulated ITGA5 expression, disrupted ITGA5 organization, and reduced total ITGA5 recycling.\",\n      \"method\": \"siRNA knockdown in ECs, adhesion/migration assays on fibronectin, flow cytometry, integrin recycling assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype and mechanistic follow-up on integrin recycling, single lab\",\n      \"pmids\": [\"32528960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NRP2 negatively regulates WDFY1 transcription by preventing nuclear localization of the transcription factor FAC1. Maintaining WDFY1 at sub-optimal levels sustains high endocytic activity in metastatic cancer cells.\",\n      \"method\": \"NRP2 knockdown/overexpression, nuclear fractionation, transcription reporter assays, endocytic activity assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear localization assay plus transcriptional reporter, single lab with two orthogonal methods\",\n      \"pmids\": [\"27026195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NRP2 promotes angiogenesis in pancreatic neuroendocrine tumors (PNETs) via a VEGF/VEGFR2-independent pathway by activating F-actin polymerization through the SSH1/cofilin axis. Silencing SSH1 abrogated NRP2-activated HUVEC migration and F-actin polymerization.\",\n      \"method\": \"Plasmid constructs with mutant variants, Western blot, immunofluorescence, tube formation and wound-healing assays, in vivo mouse tumor model with NRP2 antibody\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection with SSH1 silencing rescue, in vitro and in vivo, single lab\",\n      \"pmids\": [\"32983407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Nrp2 is expressed in osteoblasts and osteoclasts in bone, and Nrp2 knockout mice display trabecular bone loss accompanied by increased osteoclast numbers and decreased osteoblast counts, indicating a role for NRP2 in bone homeostasis. Nrp2 is co-expressed with plexin family coreceptors and class 3 semaphorin ligands during osteogenic differentiation.\",\n      \"method\": \"Nrp2 knockout mouse analysis, immunohistochemistry, in vitro osteogenic/osteoclast differentiation assays\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO phenotype with defined cellular mechanism, supported by in vitro differentiation data, single lab\",\n      \"pmids\": [\"23598046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NRP2 expressed in mitral cells mediates their migration to the posteroventral olfactory bulb and axonal projection to the anterior medial amygdala in response to Semaphorin 3F. MC-specific Nrp2 knockout impairs circuit formation and abolishes odour-induced attractive social responses.\",\n      \"method\": \"MC-specific conditional Nrp2 knockout mice, in utero electroporation, behavioral assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO with defined circuit and behavioral phenotype, gain-of-function via electroporation demonstrating sufficiency\",\n      \"pmids\": [\"28731029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NRP2 promotes endothelial cell apoptosis under low shear stress (LSS) by upregulating PARP1 protein expression, which modulates downstream apoptosis-related gene expression. Transcription factor GATA2 was identified as an upstream regulator that drives NRP2 expression. NRP2 knockdown in Apoe-/- mice markedly reduced atherosclerosis.\",\n      \"method\": \"siRNA knockdown and overexpression in HUVECs, Western blot, apoptosis assays, Apoe-/- mouse model, GATA2 transcription factor analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD/OE with defined molecular mediator (PARP1), in vivo validation, single lab\",\n      \"pmids\": [\"35028975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GATA2 regulates NRP2 transcription by binding to the −1100 to +100 bp region of the NRP2 promoter. NRP2 forms a complex with VEGF-C under disturbed flow in endothelial cells, promoting inflammation. Quercetin inhibits the NRP2-VEGF-C complex formation.\",\n      \"method\": \"Promoter binding assay, co-immunoprecipitation for NRP2-VEGFC complex, siRNA knockdown, HUVEC disturbed flow model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter binding and co-IP for complex formation, single lab with two orthogonal methods\",\n      \"pmids\": [\"36764279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In gastric cancer, CAF-expressed NRP2 promotes chemoresistance by stimulating SDF-1 secretion via VEGF/NRP2 signaling in CAFs, which in turn activates the Hippo pathway (YAP/TAZ) in cancer cells. NRP2 knockdown in CAFs reduced SDF-1 secretion and restored cancer cell sensitivity to 5-FU.\",\n      \"method\": \"RNA-sequencing, CAF/cancer cell co-culture, siRNA knockdown, viability and apoptosis assays\",\n      \"journal\": \"Gastric cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD with identified downstream mediators SDF-1 and YAP/TAZ, single lab\",\n      \"pmids\": [\"34826008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MUC16 regulates NRP2 expression via the JAK2/STAT1 signaling axis in pancreatic ductal adenocarcinoma cells. NRP2 knockdown in MUC16-overexpressed cells significantly decreased cell adhesion and migration, placing NRP2 downstream of MUC16-JAK2/STAT1 in liver metastasis.\",\n      \"method\": \"RNA-sequencing, siRNA knockdown, overexpression, cell adhesion and migration assays, in vivo mouse liver metastasis model\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by rescue experiments, in vivo validation, single lab\",\n      \"pmids\": [\"35533267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NRP2 binds TGFβ1 and associates with TGFβ receptors, enhancing TGFβ1 signaling. TGFβ1-dependent regulation of NRP2 and GLI2 expression promotes EMT in bladder cancer. NRP2 positively regulates SPP1/Osteopontin as a downstream effector, validated in NRP2 knockout and knockdown models.\",\n      \"method\": \"NRP2 KO and knockdown models, PCR profiling array (84 EMT genes), correlation analysis in TCGA cohort and cell lines, TGFβ1 stimulation assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — KO/KD with downstream target validation, but no direct binding assay in this paper; co-receptor binding cited from prior work\",\n      \"pmids\": [\"32038994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HARSWHEP (a splice variant of histidyl-tRNA synthetase) binds specifically and selectively to NRP2 via a helix-turn-helix motif. This interaction on myeloid cells inhibits proinflammatory receptor and cytokine expression and down-regulates inflammatory pathways in primary human macrophages. In animal models of ILD, HARSWHEP reduced lung inflammation and fibrosis through NRP2.\",\n      \"method\": \"Structural analysis (helix-turn-helix motif), binding assays, primary human macrophage assays, multiple animal models of lung injury/ILD\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural determination combined with binding assays and functional validation across multiple disease models with mechanistic follow-up\",\n      \"pmids\": [\"40073151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A bispecific antibody that dimerizes NRP2 with PLXNA1 mimics SEMA3F-mediated signaling (receptor dimerization, phospho-AKT suppression, oncogene suppression, antiproliferative effects). Structural studies revealed the bsAb binds NRP2 and PLXNA1 at sites distinct from the SEMA3F-binding site but allows proper receptor complex formation and conformational flexibility for signaling.\",\n      \"method\": \"Cell-based receptor dimerization assays, phospho-AKT assay, cell proliferation assay, structural studies of antibody binding\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural studies combined with multiple orthogonal functional assays in a single rigorous study\",\n      \"pmids\": [\"41391772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Alveolar macrophage (AM)-derived NRP2 physically binds CD11b+ Ly6Glo/+ neutrophils and promotes their phagocytosis and bacterial killing capacity, partly through increased TLR4 and TNF-α expression. Conditional deletion of NRP2 in AMs resulted in persistent bacteria, uncontrolled neutrophil influx, and decreased survival during E. coli pneumonia.\",\n      \"method\": \"Conditional AM-specific NRP2 KO mice, in vitro binding and phagocytosis assays, E. coli pneumonia model\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined cellular phenotype and in vitro binding assay, single lab\",\n      \"pmids\": [\"35435271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD3L1 (ITPRIPL1) signals through NRP2 as its primary receptor on macrophages, constituting the CD3L1-NRP2 axis that drives immunosuppressive M2 TAM polarization. NRP2 KO or anti-CD3L1 treatment reprogrammed TAMs toward M1 anti-tumor phenotype and suppressed tumor progression in T-cell-deficient models.\",\n      \"method\": \"Mechanistic studies in T-cell deficient osteosarcoma models, receptor identification, macrophage polarization assays, in vivo tumor models\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-ligand identification with in vivo KO phenotype, single study\",\n      \"pmids\": [\"42141271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NRP2 functions as a co-inhibitory receptor on CD4+ T effector cells. NRP2 is co-expressed with PD-1, CTLA4, TIGIT, LAG3, and TIM3 on exhausted/late effector CD4+ T cells. Knockout of NRP2 results in hyperactive CD4+ T cell responses, accelerated allograft rejection, and enhanced delayed-type hypersensitivity. The co-inhibitory function is specific to NRP2 on T effectors, not Treg cells.\",\n      \"method\": \"Humanized SCID mice, global and CD4+ T cell-specific KO mouse models, cardiac transplantation model, delayed-type hypersensitivity model, in vitro Treg suppression assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple KO models with defined phenotype in two disease settings, cell-type-specific KO, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NRP2 is a component of endothelial adherens junctions where it maintains VE-cadherin surface availability by promoting its interaction with p120 catenin. Endothelial-specific Nrp2 knockout mice display hyperpermeable retinal vasculature, upregulation of pro-inflammatory cytokines and adhesion molecules, increased immune cell attachment, and aortic plaque development.\",\n      \"method\": \"Endothelial-specific Nrp2 knockout mouse model, cultured immortalized mouse ECs, co-immunoprecipitation of VE-cadherin and p120 catenin, retinal vascular permeability assay, aortic plaque assessment\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo EC-specific KO with defined molecular interaction (VE-cadherin/p120 catenin) and functional vascular phenotype; preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Guinea pig NRP2 interacts with the CMV pentamer complex (PC) in immunoprecipitation assays, functioning as an endocytic cell entry receptor. Double knockout of PDGFRA and NRP2 completely blocked GPCMV infection, while CD147/PDGFRA double KO had only limited inhibition.\",\n      \"method\": \"Immunoprecipitation, double KO cell lines, ectopic receptor re-expression, viral infection assays\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and genetic KO with ectopic rescue, but in a guinea pig CMV model (ortholog context)\",\n      \"pmids\": [\"41805587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Sema3G signals through the Nrp2/PlexinA1 receptor complex to inhibit LATS1 and activate YAP in vascular smooth muscle cells, promoting their proliferation and migration. MMP2 and MMP9 upregulation underlies enhanced migration. Verteporfin (YAP inhibitor) counteracted Sema3G-induced cyclin E and cyclin D1 expression.\",\n      \"method\": \"Nrp2/PlexinA1 inhibition, Western blot for LATS1/YAP phosphorylation, cell proliferation/migration assays, pharmacological inhibition with verteporfin\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor complex defined with inhibition rescue, multiple downstream pathway readouts, single lab\",\n      \"pmids\": [\"36720439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NRP2 activates FAK phosphorylation through direct binding to FAK, thereby activating the focal adhesion pathway and promoting GBM cell proliferation, migration, and invasion. NRP2 knockdown inhibited GBM growth in vivo, and this inhibition was reversed by FAK agonists.\",\n      \"method\": \"NRP2 knockdown (in vitro and in vivo), FAK phosphorylation assays, direct binding assay, FAK agonist rescue experiments, animal tumor model\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay plus epistasis rescue with FAK agonist, in vivo validation, single lab\",\n      \"pmids\": [\"41861662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NRP2 expressed on colorectal cancer-derived migrasomes is transferred to macrophages, where it binds PROX1 to drive CD5L expression and upregulate efferocytosis receptors, promoting M2-like macrophage polarization and tumor immune evasion. NRP2 knockdown in CRC cells abrogated migrasome-induced CD5L+ macrophage polarization.\",\n      \"method\": \"scRNA-seq, in vivo liver metastasis model, NRP2 KD, migrasome transfer assays, binding assay (NRP2-PROX1)\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic KD with defined receptor-binding partner interaction and functional macrophage phenotype, single lab\",\n      \"pmids\": [\"41361466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In colorectal cancer, cancer-associated fibroblast-secreted SEMA3C binds the NRP2 receptor on liver metastasis-initiating cells, activating the MAPK pathway and promoting liver metastasis. Confirmed by in vivo and in vitro experiments.\",\n      \"method\": \"Time-resolved spatial transcriptomics, scRNA-seq, in vivo and in vitro SEMA3C-NRP2 signaling assays, MAPK pathway analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-ligand pair confirmed with in vivo and in vitro functional validation, single study\",\n      \"pmids\": [\"40402249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NRP2 is dynamically redistributed to the basolateral membrane compartment of polarized HUVECs upon basolateral VEGF-A stimulation, co-redistributing with VEGFR2. This basolateral localization correlates with enhanced endothelial permeability.\",\n      \"method\": \"Immunocytochemistry and confocal z-section imaging, Transwell permeability assay, quantitative fluorescence intensity measurement\",\n      \"journal\": \"The journal of histochemistry and cytochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment with functional consequence (permeability), two orthogonal methods, single lab\",\n      \"pmids\": [\"35876388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TGF-β signaling activates SMAD2, which transcriptionally upregulates NRP2 expression in ectopic endometrial stromal cells (ESCs). NRP2 depletion suppressed ESC migration, invasion, and EMT. TGF-β treatment rescued NRP2 silencing-induced suppression.\",\n      \"method\": \"ChIP assay confirming SMAD2 binding to NRP2 promoter, luciferase reporter assay, siRNA knockdown, transwell migration/invasion assays, Western blot for EMT markers\",\n      \"journal\": \"Reproductive biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase for promoter regulation, functional rescue by TGF-β, single lab\",\n      \"pmids\": [\"36306654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXA1 binds to the NRP2 promoter and suppresses NRP2 transcription, exacerbating LPS-induced endothelial cell injury. Knockdown of NRP2 offset the protective effect of FOXA1 knockdown, placing NRP2 downstream of FOXA1 in the septic endothelial injury pathway.\",\n      \"method\": \"ChIP assay, dual-luciferase assay for FOXA1-NRP2 promoter binding, siRNA knockdown rescue experiments, HUVEC LPS model\",\n      \"journal\": \"Cytotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter plus epistasis rescue, single lab\",\n      \"pmids\": [\"39435415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NRP2 promotes sorafenib resistance in clear cell renal cell carcinoma through the NRP2/NF-κB/TNFα axis. The TNF-α inhibitor adalimumab reversed NRP2-mediated sorafenib resistance.\",\n      \"method\": \"NRP2 overexpression/knockdown in ccRCC cells, NF-κB pathway analysis, pharmacological rescue with adalimumab, cell proliferation/migration/invasion assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placed by knockdown and inhibitor rescue but no direct molecular binding assay\",\n      \"pmids\": [\"41395296\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NRP2 is a pleiotropic transmembrane co-receptor that mediates semaphorin (SEMA3F, SEMA3C, SEMA3G) and VEGF-C/D signaling via interactions with plexin and VEGFR co-receptors, guiding axonal migration, sympathetic circuit formation, and lymphangiogenesis; it also acts as a direct entry receptor for Lujo virus and CMV pentamer complex, functions as a co-inhibitory receptor on CD4+ T effector cells, maintains endothelial adherens junctions by stabilizing VE-cadherin/p120-catenin interaction, promotes ITGA5 recycling and Rac-1-dependent EC migration, drives F-actin polymerization through the SSH1/cofilin axis, activates FAK phosphorylation in glioblastoma, regulates osteoblast/osteoclast balance in bone homeostasis, mediates immunomodulatory signaling as a receptor for the HARSWHEP splice variant in macrophages, and is transcriptionally regulated by upstream factors including GATA2, SMAD2, and FOXA1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NRP2 is a pleiotropic transmembrane co-receptor that transduces class 3 semaphorin and VEGF-family cues to guide neuronal circuit formation, vascular biology, and immune regulation [#1, #6]. In the nervous system, NRP2 binds SEMA3F and, cooperating with NRP1, controls sympathetic gangliogenesis and neurite targeting [#1], and in mitral cells directs migration and axonal projection that underlie odour-driven social behaviour [#6]; semaphorin signalling is read out through NRP2/PlexinA1 receptor complexes, which can be engineered with a bispecific antibody to mimic SEMA3F-induced dimerization, suppress phospho-AKT, and restrain proliferation [#13, #19]. In endothelium NRP2 stabilizes adherens junctions by promoting VE-cadherin/p120-catenin interaction [#17], and it governs cell migration and adhesion through Rac-1-dependent control of ITGA5 integrin recycling and through SSH1/cofilin-driven F-actin polymerization [#2, #4]. NRP2 also forms a VEGF-C complex under disturbed flow and modulates apoptosis via PARP1, linking it to endothelial inflammation and atherosclerosis [#7, #8]. As an immune receptor, NRP2 acts as a co-inhibitory receptor on effector CD4+ T cells, binds the HARSWHEP histidyl-tRNA synthetase splice variant and the CD3L1/ITPRIPL1 ligand on macrophages to suppress inflammation and drive immunosuppressive M2 polarization, and on alveolar macrophages physically engages neutrophils to promote bacterial clearance [#12, #15, #16, #14]. Across cancers NRP2 acts downstream of TGF\\u03b2/SMAD2 and MUC16-JAK2/STAT1 inputs to promote EMT, migration, and metastasis, and activates focal adhesion signalling via direct FAK binding [#11, #10, #24, #20]. NRP2 additionally serves as a host entry receptor for Lujo virus through its N-terminal domain and for the cytomegalovirus pentamer complex [#0, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established NRP2 as a class 3 semaphorin receptor required for nervous system wiring, defining its founding role in axon guidance.\",\n      \"evidence\": \"Nrp2/Sema3F single and compound knockout mice with neuroanatomical phenotyping of the sympathetic nervous system\",\n      \"pmids\": [\"22790009\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve the receptor complex stoichiometry with plexins in vivo\", \"Molecular signalling output downstream of NRP2 not dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended NRP2 function beyond neurons to skeletal tissue, showing it balances osteoblast and osteoclast activity in bone homeostasis.\",\n      \"evidence\": \"Nrp2 knockout mouse bone analysis with in vitro osteogenic/osteoclast differentiation assays\",\n      \"pmids\": [\"23598046\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand and plexin coreceptor driving the bone phenotype not pinpointed\", \"Cell-autonomous versus systemic contribution unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified a nuclear/transcriptional consequence of NRP2 signalling, linking it to WDFY1 repression and sustained endocytosis in metastatic cells.\",\n      \"evidence\": \"NRP2 knockdown/overexpression with nuclear fractionation and transcription reporter assays\",\n      \"pmids\": [\"27026195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting surface NRP2 to FAC1 nuclear exclusion unclear\", \"Single-lab finding without orthogonal confirmation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined NRP2 as a viral entry receptor and showed its semaphorin guidance role operates at the level of specific circuit formation and behaviour.\",\n      \"evidence\": \"Genome-wide haploid screen with KO/overexpression and binding for Lujo virus; mitral-cell-specific conditional Nrp2 KO with behavioural assays for olfactory circuits\",\n      \"pmids\": [\"29120745\", \"28731029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of LUJV glycoprotein-NRP2 binding not solved\", \"Whether viral and semaphorin binding use overlapping NRP2 surfaces unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved NRP2's role in endothelial migration as integrin- and VEGF-independent, acting through ITGA5 recycling, Rac-1, and the SSH1/cofilin cytoskeletal axis.\",\n      \"evidence\": \"siRNA knockdown in endothelial cells with adhesion/migration, integrin recycling assays, and SSH1 silencing rescue in tumour angiogenesis models\",\n      \"pmids\": [\"32528960\", \"32983407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between NRP2 and SSH1/Rac regulators not established\", \"Coreceptor requirement for cytoskeletal signalling undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Positioned NRP2 within disturbed-flow endothelial pathology and innate immunity, coupling it to GATA2-driven expression, VEGF-C complex formation, and macrophage-neutrophil interactions.\",\n      \"evidence\": \"HUVEC knockdown/overexpression with PARP1 readouts and Apoe-/- atherosclerosis model; promoter binding and co-IP for GATA2 and VEGF-C; conditional AM-specific NRP2 KO in E. coli pneumonia\",\n      \"pmids\": [\"35028975\", \"36764279\", \"35435271\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether VEGF-C complex directly drives PARP1 induction not tested\", \"Receptor partners mediating neutrophil binding by macrophage NRP2 unidentified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped transcriptional control of NRP2 by SMAD2 and FOXA1, embedding it in TGF\\u03b2-driven EMT and endothelial injury responses.\",\n      \"evidence\": \"ChIP and luciferase promoter assays with siRNA rescue in endometrial stromal cells and LPS-treated HUVECs\",\n      \"pmids\": [\"36306654\", \"39435415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposing activation (SMAD2) versus repression (FOXA1) context-dependence not reconciled\", \"Single-lab promoter findings\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined NRP2 as a druggable immune and signalling hub: a co-inhibitory T-cell receptor, a receptor for HARSWHEP, CD3L1, and PROX1-linked macrophage programs, and a FAK-activating oncogenic node amenable to plexin-dimerizing antibodies.\",\n      \"evidence\": \"Structural and binding studies of HARSWHEP and bispecific NRP2/PLXNA1 antibody; receptor identification for CD3L1 and migrasome-transferred NRP2; CD4+ T-cell-specific KO models; direct FAK binding and agonist rescue in GBM\",\n      \"pmids\": [\"40073151\", \"41391772\", \"42141271\", \"41361466\", \"40402249\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether immune, viral, and semaphorin functions share one NRP2 conformation/site is unresolved\", \"Endothelial junction and T-cell co-inhibition data remain in preprint form\", \"Unifying structural model across diverse ligands lacking\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single co-receptor integrates such divergent ligands (semaphorins, VEGF-C, viral glycoproteins, HARSWHEP, CD3L1, TGF\\u03b21) into context-specific outputs through distinct binding surfaces and coreceptor partners remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No comprehensive structural map of NRP2 ligand-binding sites\", \"Coreceptor selection rules across tissues unknown\", \"Causal hierarchy among NRP2's many downstream pathways undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 18]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 6, 19, 22]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [16, 12, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [17, 23, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 19, 22, 20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12, 14, 15, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 18]}\n    ],\n    \"complexes\": [\n      \"NRP2/PlexinA1 receptor complex\",\n      \"endothelial adherens junction\"\n    ],\n    \"partners\": [\n      \"PLXNA1\",\n      \"VEGFC\",\n      \"FAK\",\n      \"PROX1\",\n      \"CD3L1\",\n      \"TGFB1\",\n      \"FAC1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win"}}