{"gene":"NECTIN1","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":1999,"finding":"Nectin-1 (PRR1) directly interacts with the PDZ domain of afadin via its C-terminal consensus motif (A/EXYV), and is recruited to cadherin-based cell-cell adherens junctions through this interaction; nectin-1 shows Ca2+-independent cell-cell adhesion activity.","method":"Co-immunoprecipitation, colocalization imaging, adhesion assays in EL cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding and colocalization with functional rescue; foundational paper >450 citations","pmids":["10225955"],"is_preprint":false},{"year":1998,"finding":"The V domain of nectin-1 (HIgR/PRR1) is the major functional region mediating HSV-1 entry into cells; a single V domain is sufficient for physical interaction with HSV glycoprotein D (gD) in vitro and for conferring cell susceptibility to HSV-1 entry.","method":"Deletion mutants, soluble V-domain competition assay, in vitro binding (Co-IP/pulldown), entry assay with engineered chimeric receptors","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including in vitro binding, mutagenesis, and functional entry assays","pmids":["9861033"],"is_preprint":false},{"year":2001,"finding":"Nectin-1 mediates direct cell-to-cell spread of wild-type HSV-1 through a gD-receptor interaction; a monoclonal antibody blocking nectin-1 also blocks cell-to-cell spread, and spread from receptor-positive to receptor-negative cells does not occur.","method":"Plaque assay, antibody blockade, receptor-negative J cell lines expressing nectin1","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — clean receptor KO/expression system with functional readout, replicated across multiple human cell lines","pmids":["10729168"],"is_preprint":false},{"year":2001,"finding":"Nectin-4 trans-interacts heterophilically with nectin-1 through V domain-to-V domain interactions; the V domain of nectin-1 is the major functional region involved in trans-heterointeraction with both nectin-3 and nectin-4.","method":"Soluble Fc-fusion binding to cells, co-immunoprecipitation, in vitro binding between recombinant proteins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal binding assays in same study; >272 citations","pmids":["11544254"],"is_preprint":false},{"year":2002,"finding":"Nectin-1 trans-heterophilic interactions with nectin-3 (Kd ~1 nM) and nectin-4 (Kd ~100 nM) are mediated through V-to-V domain contacts; nectin-3 and nectin-4 share a common binding region on nectin-1 mapped to the C-C'-C\"-D beta-strands of the V domain, and HSV-1 gD competes with both for binding to this region.","method":"Affinity measurements, competition binding with monoclonal antibodies and gD, chimeric nectin1/PVR receptors with strand substitutions","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including affinity measurements and chimeric receptor dissection; >118 citations","pmids":["12011057"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of HSV-1 gD bound to nectin-1 (at 4.0 Å) reveals that gD uses both its N- and C-terminal extensions to contact the first Ig domain of nectin-1 at the same surface used for nectin-1 homophilic dimerization; Phe129 at the tip of nectin-1's FG loop inserts into a groove on gD, and mutation F129A abolishes nectin-1 binding to gD and HSV entry.","method":"X-ray crystallography, site-directed mutagenesis, HSV entry assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis with functional validation","pmids":["21980294"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of the nectin-1 extracellular region reveals that it forms a V-shaped cis-dimer through the first Ig-like domain; four residues in the first Ig domain are essential for cis-dimerization, homophilic adhesion, and heterophilic adhesion activity.","method":"X-ray crystallography, site-directed mutagenesis, cell-surface cis-dimerization assay, homophilic and heterophilic adhesion assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis with functional cellular validation","pmids":["21325282"],"is_preprint":false},{"year":2011,"finding":"The gD/nectin-1 complex structure shows that gD binds nectin-1 in a mode similar to the nectin-1 homodimer interaction, using the same key residues for dimerization; gD binding to nectin-1 would preclude nectin-1 dimerization and abolish its cell adhesion function.","method":"X-ray crystallography of gD–nectin-1 complex","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — independent crystal structure of the same complex corroborating mechanism","pmids":["22146396"],"is_preprint":false},{"year":2014,"finding":"Crystal structures of HSV-2 gD unbound and bound to nectin-1 demonstrate a conserved receptor-binding mode between HSV-1 and HSV-2; nectin-1 residue I80 is important for gD interaction, confirmed by surface plasmon resonance and cell fusion assays.","method":"X-ray crystallography, surface plasmon resonance, site-directed mutagenesis, cell-based fusion assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus SPR plus mutagenesis plus functional assay","pmids":["25231300"],"is_preprint":false},{"year":2000,"finding":"Nectin-3 (PRR3) interacts with afadin through its C-terminal A/EXYV motif (PDZ-domain binding), and both proteins co-localize at intercellular junctions.","method":"In vivo co-immunoprecipitation with long and short afadin isoforms, colocalization imaging","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 — single lab Co-IP, but consistent with established nectin-1/afadin interaction mechanism","pmids":["11024295"],"is_preprint":false},{"year":2003,"finding":"During HSV infection, nectin-1 is displaced from adherens junctions in a gD-dependent manner; newly synthesized gD substitutes for nectin-1 at junctions by trans-interacting with nectin-1 on adjacent noninfected cells, redirecting nectin-1 localization and facilitating virus spread.","method":"Live-cell imaging with nectin-1-GFP fusions, immunofluorescence colocalization, HSV entry/spread assay in cells with/without afadin interaction disrupted","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment tied to functional spread outcome","pmids":["12885915"],"is_preprint":false},{"year":2009,"finding":"Nectin-1 expression is necessary for HSV infection of neurons in the CNS and for development of encephalitis after intracranial inoculation; HVEM is largely dispensable for neuronal infection by this route, while nectin-1 KO mice show no detectable virus in brain parenchyma.","method":"Genetic KO mice (nectin-1 KO, HVEM KO, double KO), intracranial inoculation, immunohistology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with specific phenotypic readout, double-KO epistasis","pmids":["19805039"],"is_preprint":false},{"year":2003,"finding":"Amino acids 77 and 85 in the V domain of nectin-1 are critical for HSV-1 and HSV-2 gD binding and entry but not for pseudorabies virus (PRV) or bovine herpesvirus 1 (BHV-1) entry, demonstrating overlapping but distinct gD binding footprints for different herpesviruses on nectin-1.","method":"Site-directed mutagenesis, soluble gD binding assay, viral entry assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis combined with binding and entry assays","pmids":["12072525"],"is_preprint":false},{"year":2001,"finding":"The HSV entry site on nectin-1 maps to residues 64–94 of the V domain (likely the C, C', C\" beta-strands and loops); the gD-binding site maps to the same region, while the epitope for the entry-blocking mAb R1.302 additionally requires residues 95–102.","method":"Chimeric nectin1/PVR receptor constructs, HSV entry functional assay, mAb epitope mapping","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 — systematic chimera mapping with functional entry readout","pmids":["11483743"],"is_preprint":false},{"year":2003,"finding":"N-terminal deletions in HSV-1 or HSV-2 gD that abolish interactions with HVEM, nectin-2, and 3-O-sulfated heparan sulfate do not impair functional interactions with nectin-1, demonstrating that gD's N-terminus is dispensable for nectin-1 binding and cell fusion.","method":"Cell fusion assay, soluble gD:Fc binding assay, site-directed mutagenesis","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 — binding and functional fusion assays with multiple gD mutants","pmids":["12915538"],"is_preprint":false},{"year":2008,"finding":"After trans-interaction with gD expressed on adjacent cells, nectin-1 is internalized and degraded via a low-pH-dependent pathway in cells where HSV enters endosomally; this down-regulation correlates with gD-mediated virion internalization.","method":"Co-culture of gD-expressing cells with nectin-1-expressing cells, receptor internalization assay, pH inhibitors (bafilomycin, NH4Cl), flow cytometry","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 — direct internalization measurement with mechanistic inhibitor dissection, single lab","pmids":["18076965"],"is_preprint":false},{"year":2004,"finding":"HSV entry mediated by nectin-1 can occur via either plasma membrane fusion or an endocytic route depending on cellular context; a chimeric nectin-1-EGFR1 receptor routes HSV through clathrin-dependent endocytosis requiring EGFR tyrosine kinase activity and acidic endosomes, while nectin-1 sorted to lipid rafts via GPI anchor also routes entry through acid endosomes.","method":"Chimeric receptor constructs, endosome acidification inhibitors, kinase inhibitors (AG1478), wortmannin, viral entry assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 — engineered chimeric receptors plus pharmacological dissection in same study","pmids":["15507614"],"is_preprint":false},{"year":2011,"finding":"αVβ3-integrin relocalizes nectin-1 to lipid rafts independently of HSV, thereby routing HSV to a lipid raft-dependent acidic endosome entry pathway; this integrin-induced relocalization is the mechanistic basis for αVβ3-integrin's control of HSV entry route.","method":"Lipid raft fractionation, co-expression of nectin-1 and αVβ3-integrin, HSV entry assay with pharmacological inhibitors","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — receptor relocalization linked to functional entry route change, single lab","pmids":["22171266"],"is_preprint":false},{"year":2010,"finding":"NMDA receptor activation (but not AMPA or mGluR) induces Ca2+/calmodulin-dependent α-secretase (ADAM10) cleavage of nectin-1 ectodomain and subsequent γ-secretase processing in primary cortical neurons; ADAM10 is identified as the major α-secretase responsible for nectin-1 ectodomain shedding.","method":"Primary cortical neuron stimulation, pharmacological receptor antagonists, ADAM10 knockdown/KO neurons, gamma-secretase inhibitors, western blot for cleavage products","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function (ADAM10 KO/KD) plus pharmacological dissection with specific readout","pmids":["20501653"],"is_preprint":false},{"year":2012,"finding":"The third membrane-proximal Ig module (Ig3) of nectin-1 directly binds fibroblast growth factor receptors (FGFRs) as measured by surface plasmon resonance; this interaction induces FGFR1c phosphorylation, neurite outgrowth in hippocampal and cerebellar neurons, and neuronal survival, all abolished by FGFR inhibitor SU5402 or dominant-negative FGFR1.","method":"NMR structure of Ig3 module, surface plasmon resonance (SPR) binding to FGFR isoforms, dominant-negative FGFR1 transfection, FGFR inhibitor, neurite outgrowth assay, cell survival assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — NMR structure plus SPR direct binding plus functional loss-of-function with multiple readouts","pmids":["22955284"],"is_preprint":false},{"year":2007,"finding":"Nectin-1 regulates loricrin expression in keratinocytes through a Ca2+-induced Rap1-ERK signaling pathway; nectin-1 knockout mice show markedly reduced loricrin in the epidermis, and inhibition of ERK reduces loricrin in wild-type keratinocytes.","method":"Nectin-1 KO mice, primary keratinocyte culture, ERK activation assay, Western blot for loricrin/repetin/SPRR","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with specific molecular and phenotypic readout plus pathway inhibition confirmation","pmids":["17472964"],"is_preprint":false},{"year":2008,"finding":"Nectin-1 and l-afadin cluster at developing hippocampal synapses in an F-actin-dependent manner, co-localizing with N-cadherin-catenin at excitatory synapses; actin depolymerization disrupts nectin-1/afadin synaptic clusters and triggers nectin-1 ectodomain shedding, suggesting a role in synaptic plasticity.","method":"Immunofluorescence in primary hippocampal neurons, actin depolymerizing agents (latrunculin, cytochalasin D), live imaging","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment tied to functional mechanism (shedding upon actin disruption), single lab","pmids":["18181141"],"is_preprint":false},{"year":2004,"finding":"Nectin-1 trans-interaction with nectin-3 modulates E-cadherin-based adhesion differently depending on which nectin is expressed at high vs. low levels; heterodimers of nectin-1/nectin-3 adhere more strongly than homodimers, and the direction of trans-interaction (nectin-1 interacting with nectin-3 or vice versa) determines whether E-cadherin adhesion is agonized or not.","method":"Dual-pipette cell separation force measurement, L cell transfection with nectin-1 or nectin-3 at varying levels, soluble nectin ectodomain competition","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative force measurement with mechanistic dissection, single lab","pmids":["15550395"],"is_preprint":false},{"year":2015,"finding":"p63 directly transcriptionally regulates Pvrl1 (nectin-1) gene expression in stratified epithelia; ChIP demonstrates p63 binding to two conserved intronic Pvrl1 enhancer regions, and p63-null skin/keratinocytes show strongly reduced nectin-1 expression.","method":"ChIP, p63 KO mouse model, siRNA knockdown, qRT-PCR and western blot","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus KO/KD with quantitative expression readout, single lab","pmids":["25387952"],"is_preprint":false},{"year":2010,"finding":"miR-661 targets the 3'-UTR of nectin-1 mRNA, destabilizing it downstream of SNAI1-induced EMT; re-expression of nectin-1 lacking the 3'-UTR counteracts SNAI1-induced invasion of breast cancer cells, establishing nectin-1 downregulation as mechanistically contributing to EMT-driven invasion.","method":"miRNA overexpression, luciferase 3'-UTR reporter assay, nectin-1 rescue construct (without 3'-UTR), invasion assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — 3'-UTR reporter plus rescue experiment with functional invasion readout, single lab","pmids":["20543867"],"is_preprint":false},{"year":2019,"finding":"Human nectin-1 directly interacts with the NK receptor CD96 via its V-domain canonical adhesive interface; the affinity of nectin-1 for CD96 is similar to its affinity for HSV gD; overexpression of nectin-1 in K562 cells increases susceptibility to NK-92 cell cytotoxicity.","method":"In vitro binding assay (SPR-equivalent), K562 cell expression of nectin-1-GFP, NK cytotoxicity assay, HSV entry assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding measurement plus functional cytotoxicity readout, single lab","pmids":["30759143"],"is_preprint":false},{"year":2007,"finding":"Murine CD96 binds nectin-1 in addition to CD155, demonstrating that nectin-1 is a ligand for the CD96 adhesion receptor; anti-CD96 and anti-CD155 antibodies block CD96/CD155 complex formation and T cell adhesion.","method":"Binding assay with monoclonal antibodies, T cell adhesion to insect cells expressing CD155, flow cytometry","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — single binding/adhesion assay, single lab, but cross-validated with multiple antibodies","pmids":["17971293"],"is_preprint":false}],"current_model":"Nectin-1 is a Ca2+-independent immunoglobulin-superfamily cell adhesion molecule that forms cis-dimers through its first Ig domain and trans-interacts homophilically and heterophilically (with nectins-3 and -4) via V-domain contacts to organize cadherin-based adherens junctions; it is recruited to junctions through its PDZ-binding C-terminal motif binding afadin, signals through FGFR and Rap1-ERK to regulate differentiation, undergoes NMDA-receptor–triggered ADAM10-mediated ectodomain shedding, serves as the principal neuronal entry receptor for HSV-1/2 (gD binding to the V-domain C-C'-C\" surface), and engages the NK cell receptor CD96 at the same canonical adhesive interface."},"narrative":{"teleology":[{"year":1998,"claim":"Identifying nectin-1's V domain as sufficient for HSV gD binding and viral entry established the minimal receptor determinant and defined the molecular basis of herpesvirus tropism.","evidence":"Deletion mutants, soluble V-domain competition, and chimeric receptor entry assays in transfected cells","pmids":["9861033"],"confidence":"High","gaps":["Structural basis of gD–V-domain interaction unknown at this stage","Relative contribution of nectin-1 vs. other HSV receptors (HVEM) in vivo not resolved"]},{"year":1999,"claim":"Demonstrating that nectin-1 binds afadin via its PDZ-binding motif and localizes to cadherin-based adherens junctions revealed its primary cell-biological function as a junctional adhesion molecule independent of its viral receptor role.","evidence":"Co-immunoprecipitation, colocalization imaging, and Ca²⁺-independent adhesion assays in EL cells","pmids":["10225955"],"confidence":"High","gaps":["How nectin-1/afadin interaction coordinates with cadherin-catenin complex assembly not defined","Signaling downstream of nectin-1 at junctions unknown"]},{"year":2001,"claim":"Mapping the gD-binding and nectin heterophilic interaction sites to the same C-C′-C″ region of the V domain established that HSV hijacks the canonical cell adhesion interface, and showing nectin-1 mediates direct cell-to-cell HSV spread linked receptor function to viral pathogenesis.","evidence":"Chimeric nectin-1/PVR constructs with functional entry readout; antibody blockade of cell-to-cell spread; Fc-fusion binding for nectin-3 and nectin-4 heterophilic interactions","pmids":["11483743","10729168","11544254"],"confidence":"High","gaps":["Atomic-resolution structure of the adhesive interface not yet available","Affinity measurements for heterophilic interactions not yet quantified"]},{"year":2002,"claim":"Quantifying binding affinities (nectin-3 Kd ~1 nM, nectin-4 Kd ~100 nM) and showing gD competition for the same V-domain surface established the thermodynamic hierarchy of nectin-1 interactions and the competitive mechanism of HSV receptor usurpation.","evidence":"Affinity measurements, competition binding with mAbs and gD, chimeric receptor strand substitutions","pmids":["12011057","12072525"],"confidence":"High","gaps":["Structural basis of competition at atomic resolution still lacking","Whether differential affinities determine tissue-specific junction composition unknown"]},{"year":2003,"claim":"Showing that gD displaces nectin-1 from adherens junctions in living infected cells and substitutes for nectin-1 in trans explained how HSV remodels cell junctions to promote spread.","evidence":"Live-cell imaging of nectin-1-GFP, immunofluorescence colocalization during HSV infection","pmids":["12885915"],"confidence":"Medium","gaps":["Kinetics of junction disassembly during infection not quantified","Whether afadin redistribution accompanies nectin-1 displacement not examined"]},{"year":2004,"claim":"Demonstrating that nectin-1 can route HSV entry through either plasma membrane fusion or endocytosis depending on membrane context (lipid rafts, chimeric receptor signaling) resolved the long-standing question of how the same receptor mediates different entry pathways.","evidence":"Chimeric nectin-1-EGFR1 receptors, GPI-anchored nectin-1, pharmacological inhibitors of endocytosis and acidification","pmids":["15507614"],"confidence":"High","gaps":["Endogenous signals that determine nectin-1 membrane microdomain sorting in vivo not identified","Whether integrin-mediated relocalization occurs in neuronal entry not tested at this point"]},{"year":2007,"claim":"Nectin-1 KO mice revealed a cell-autonomous role for nectin-1 in regulating keratinocyte terminal differentiation through Rap1-ERK–dependent loricrin expression, establishing a signaling function beyond adhesion; separately, CD96 was identified as an immune receptor ligand for nectin-1.","evidence":"Nectin-1 KO mouse epidermis analysis, ERK inhibition in primary keratinocytes; CD96 binding assay with mAb blockade","pmids":["17472964","17971293"],"confidence":"High","gaps":["How nectin-1 activates Rap1 (direct or indirect) not resolved","Functional consequence of CD96–nectin-1 interaction for NK or T cell cytotoxicity not fully tested"]},{"year":2009,"claim":"Genetic demonstration that nectin-1 is the essential HSV entry receptor in CNS neurons in vivo (HVEM dispensable) resolved the long-standing receptor-redundancy question for neuronal infection.","evidence":"Nectin-1 KO, HVEM KO, and double-KO mice with intracranial HSV inoculation and immunohistology","pmids":["19805039"],"confidence":"High","gaps":["Whether nectin-1 is equally essential for peripheral sensory neuron entry not addressed by intracranial route","Mechanism by which loss of nectin-1 blocks neuronal entry (failure of attachment vs. fusion) not distinguished"]},{"year":2010,"claim":"Identifying ADAM10 as the NMDA-receptor–activated α-secretase for nectin-1 ectodomain shedding, followed by γ-secretase processing, established a regulated proteolytic mechanism linking synaptic activity to nectin-1 turnover.","evidence":"ADAM10 KO/KD neurons, pharmacological NMDA/AMPA antagonists, γ-secretase inhibitors in primary cortical neurons","pmids":["20501653"],"confidence":"High","gaps":["Physiological consequence of nectin-1 ICD release by γ-secretase unknown","Whether ADAM10-mediated shedding affects HSV susceptibility at synapses not tested"]},{"year":2011,"claim":"Crystal structures of the nectin-1 cis-dimer and the gD–nectin-1 complex provided the atomic basis for adhesion and viral hijacking: gD occupies the same dimerization interface, competitively disrupting nectin-1 cis-dimers and trans-adhesion.","evidence":"X-ray crystallography of nectin-1 ectodomain and gD–nectin-1 complex (two independent labs), site-directed mutagenesis with entry assays","pmids":["21325282","21980294","22146396"],"confidence":"High","gaps":["Structure of nectin-1/nectin-3 heterophilic trans-complex not determined","Whether gD-induced dimer disruption is sufficient to trigger endocytosis or requires additional signaling"]},{"year":2012,"claim":"Demonstrating that nectin-1's Ig3 module directly binds and activates FGFR to promote neurite outgrowth and neuronal survival established a second signaling axis independent of afadin-mediated junction assembly.","evidence":"NMR structure of Ig3, SPR binding to FGFR isoforms, FGFR inhibitor and dominant-negative FGFR1 in hippocampal/cerebellar neurons","pmids":["22955284"],"confidence":"High","gaps":["Whether FGFR signaling through nectin-1 operates in non-neuronal tissues unknown","How Ig3-FGFR interaction is coordinated with V-domain adhesive interactions not resolved"]},{"year":2019,"claim":"Confirming that human nectin-1 binds NK receptor CD96 at its canonical V-domain adhesive interface with affinity comparable to gD established nectin-1 as an immune-modulatory ligand and extended the shared-interface paradigm to immunosurveillance.","evidence":"SPR-equivalent binding, K562 nectin-1 expression with NK-92 cytotoxicity assay","pmids":["30759143"],"confidence":"Medium","gaps":["In vivo immunological consequence of nectin-1–CD96 interaction not demonstrated","Whether CD96 engagement competes with HSV gD for the same residues not structurally resolved","Single-lab binding study awaits independent confirmation"]},{"year":null,"claim":"A full structural picture of nectin-1 heterophilic trans-complexes (nectin-1/nectin-3, nectin-1/nectin-4) and the mechanism by which nectin-1 activates Rap1 signaling remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of nectin-1/nectin-3 or nectin-1/nectin-4 trans-complex","Molecular mechanism linking nectin-1 to Rap1 activation not identified","Functional significance of γ-secretase-released nectin-1 ICD unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,3,4,6,22]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,2,25,26]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[1,2,5,8,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6,10,17,21]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[18]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[19,20]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[25,26]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,5,11]}],"complexes":["Nectin-afadin complex","Nectin-1 cis-homodimer"],"partners":["AFDN","NECTIN3","NECTIN4","CD96","FGFR1","ADAM10"],"other_free_text":[]},"mechanistic_narrative":"Nectin-1 is a Ca²⁺-independent immunoglobulin-superfamily cell adhesion molecule that organizes adherens junctions and modulates intercellular signaling through homophilic and heterophilic V-domain–mediated trans-interactions. It forms cis-dimers through its first Ig-like domain, engages nectin-3 (Kd ~1 nM) and nectin-4 heterophilically via the C-C′-C″ beta-strand surface, and is recruited to cadherin-based junctions through its C-terminal PDZ-binding motif interacting with afadin; downstream, it signals through Rap1-ERK to regulate keratinocyte differentiation and through FGFR (via its Ig3 module) to promote neurite outgrowth and neuronal survival [PMID:10225955, PMID:11544254, PMID:17472964, PMID:22955284]. The same V-domain adhesive interface serves as the principal entry receptor for HSV-1 and HSV-2 through direct binding of glycoprotein D, which competitively disrupts nectin-1 dimerization and displaces it from junctions to facilitate viral entry and cell-to-cell spread; nectin-1 is essential for HSV neuronal infection and encephalitis in vivo [PMID:9861033, PMID:21980294, PMID:19805039]. Nectin-1 additionally engages the NK cell receptor CD96 at the same canonical interface, undergoes NMDA-receptor–triggered ADAM10-mediated ectodomain shedding followed by γ-secretase processing in neurons, and its expression is transcriptionally regulated by p63 in stratified epithelia [PMID:30759143, PMID:20501653, PMID:25387952]."},"prefetch_data":{"uniprot":{"accession":"Q15223","full_name":"Nectin-1","aliases":["Herpes virus entry mediator C","Herpesvirus entry mediator C","HveC","Herpesvirus Ig-like receptor","HIgR","Nectin cell adhesion molecule 1","Poliovirus receptor-related protein 1"],"length_aa":517,"mass_kda":57.2,"function":"Cell adhesion molecule that promotes cell-cell contacts and plays important roles in the development of the nervous system (PubMed:21325282). Acts by forming homophilic or heterophilic trans-dimers (PubMed:21325282). Heterophilic interactions have been detected between NECTIN1 and NECTIN3 and between NECTIN1 and NECTIN4 (By similarity). Involved in axon guidance by promoting contacts between the commissural axons and the floor plate cells (By similarity). Involved in synaptogegesis (By similarity). Has some neurite outgrowth-promoting activity (By similarity). Promotes formation of checkerboard-like cellular pattern of hair cells and supporting cells in the auditory epithelium via heterophilic interaction with NECTIN3: NECTIN1 is present in the membrane of hair cells and associates with NECTIN3 on supporting cells, thereby mediating heterotypic adhesion between these two cell types (By similarity). Required for enamel mineralization (By similarity) (Microbial infection) Acts as a receptor for herpes simplex virus 1/HHV-1, herpes simplex virus 2/HHV-2, and pseudorabies virus/PRV (PubMed:21980294, PubMed:25231300, PubMed:28381567, PubMed:28542478, PubMed:34587223, PubMed:38857290, PubMed:39048823, PubMed:39048830, PubMed:7721102, PubMed:9616127, PubMed:9657005). Constitutes the major receptor for herpes simplex virus 1/HHV-1 entry into host cells (PubMed:34587223)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q15223/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NECTIN1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NECTIN1","total_profiled":1310},"omim":[{"mim_id":"609607","title":"NECTIN CELL ADHESION MOLECULE 4; NECTIN4","url":"https://www.omim.org/entry/609607"},{"mim_id":"603421","title":"TRANSMEMBRANE PROTEIN WITH EGF-LIKE AND 2 FOLLISTATIN-LIKE DOMAINS 1; TMEFF1","url":"https://www.omim.org/entry/603421"},{"mim_id":"600644","title":"NECTIN CELL ADHESION MOLECULE 1; NECTIN1","url":"https://www.omim.org/entry/600644"},{"mim_id":"225060","title":"CLEFT LIP/PALATE-ECTODERMAL DYSPLASIA SYNDROME; CLPED1","url":"https://www.omim.org/entry/225060"},{"mim_id":"159559","title":"AFADIN; AFDN","url":"https://www.omim.org/entry/159559"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"esophagus","ntpm":121.1},{"tissue":"skin 1","ntpm":126.9}],"url":"https://www.proteinatlas.org/search/NECTIN1"},"hgnc":{"alias_symbol":["PRR","PRR1","PVRR1","SK-12","HIgR","CLPED1","CD111","OFC7","Nectin-1"],"prev_symbol":["HVEC","ED4","PVRL1"]},"alphafold":{"accession":"Q15223","domains":[{"cath_id":"2.60.40.10","chopping":"33-144","consensus_level":"high","plddt":91.9012,"start":33,"end":144},{"cath_id":"2.60.40.10","chopping":"148-243","consensus_level":"high","plddt":95.7588,"start":148,"end":243},{"cath_id":"2.60.40.10","chopping":"247-332","consensus_level":"high","plddt":93.4437,"start":247,"end":332}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15223","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15223-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15223-F1-predicted_aligned_error_v6.png","plddt_mean":75.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NECTIN1","jax_strain_url":"https://www.jax.org/strain/search?query=NECTIN1"},"sequence":{"accession":"Q15223","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15223.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15223/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15223"}},"corpus_meta":[{"pmid":"24630626","id":"PMC_24630626","title":"Direct regulation of the NADPH oxidase RBOHD by the PRR-associated kinase BIK1 during plant immunity.","date":"2014","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/24630626","citation_count":709,"is_preprint":false},{"pmid":"10225955","id":"PMC_10225955","title":"Nectin/PRR: an immunoglobulin-like cell adhesion molecule recruited to cadherin-based adherens junctions through interaction with Afadin, a PDZ domain-containing protein.","date":"1999","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10225955","citation_count":450,"is_preprint":false},{"pmid":"11544254","id":"PMC_11544254","title":"Nectin4/PRR4, a new afadin-associated member of the nectin family that trans-interacts with nectin1/PRR1 through V domain interaction.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11544254","citation_count":272,"is_preprint":false},{"pmid":"32231277","id":"PMC_32231277","title":"Stepwise selection on homeologous PRR genes controlling flowering and maturity during soybean domestication.","date":"2020","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32231277","citation_count":269,"is_preprint":false},{"pmid":"15039383","id":"PMC_15039383","title":"Functional characterization of DNAM-1 (CD226) interaction with its ligands PVR (CD155) and nectin-2 (PRR-2/CD112).","date":"2004","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15039383","citation_count":226,"is_preprint":false},{"pmid":"21980294","id":"PMC_21980294","title":"Structure of herpes simplex virus glycoprotein D bound to the human receptor nectin-1.","date":"2011","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/21980294","citation_count":150,"is_preprint":false},{"pmid":"30968282","id":"PMC_30968282","title":"The receptor for advanced glycation end-products (RAGE) is an important pattern recognition receptor (PRR) for inflammaging.","date":"2019","source":"Biogerontology","url":"https://pubmed.ncbi.nlm.nih.gov/30968282","citation_count":133,"is_preprint":false},{"pmid":"12011057","id":"PMC_12011057","title":"Prominent role of the Ig-like V domain in trans-interactions of nectins. 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Comparative studies on a series of transgenic lines misexpressing five distinctive PRR Genes in Arabidopsis thaliana.","date":"2007","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17284849","citation_count":21,"is_preprint":false},{"pmid":"16406558","id":"PMC_16406558","title":"Chemokine production and pattern recognition receptor (PRR) expression in whole blood stimulated with pathogen-associated molecular patterns (PAMPs).","date":"2006","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/16406558","citation_count":21,"is_preprint":false},{"pmid":"22212525","id":"PMC_22212525","title":"Chronological lifespan extension by Ecl1 family proteins depends on Prr1 response regulator in fission yeast.","date":"2012","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/22212525","citation_count":20,"is_preprint":false},{"pmid":"18215268","id":"PMC_18215268","title":"MyoD- and nerve-dependent maintenance of MyoD expression in mature muscle fibres acts through the DRR/PRR element.","date":"2008","source":"BMC developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/18215268","citation_count":20,"is_preprint":false},{"pmid":"31681389","id":"PMC_31681389","title":"Positional Cloning of the Flowering Time QTL qFT12-1 Reveals the Link Between the Clock Related PRR Homolog With Photoperiodic Response in Soybeans.","date":"2019","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/31681389","citation_count":20,"is_preprint":false},{"pmid":"18786545","id":"PMC_18786545","title":"The capsid of the small RNA phage PRR1 is stabilized by metal ions.","date":"2008","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18786545","citation_count":18,"is_preprint":false},{"pmid":"28840773","id":"PMC_28840773","title":"Prorenin receptor (PRR)-mediated NADPH oxidase (Nox) signaling regulates VEGF synthesis under hyperglycemic condition in ARPE-19 cells.","date":"2017","source":"Journal of receptor and signal transduction research","url":"https://pubmed.ncbi.nlm.nih.gov/28840773","citation_count":18,"is_preprint":false},{"pmid":"26719287","id":"PMC_26719287","title":"Mosla scabra flavonoids ameliorate the influenza A virus-induced lung injury and water transport abnormality via the inhibition of PRR and AQP signaling pathways in mice.","date":"2015","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26719287","citation_count":18,"is_preprint":false},{"pmid":"26617814","id":"PMC_26617814","title":"Macrophages polarization is mediated by the combination of PRR ligands and distinct inflammatory cytokines.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26617814","citation_count":18,"is_preprint":false},{"pmid":"25275122","id":"PMC_25275122","title":"Different roles of the three loops forming the adhesive interface of nectin-4 in measles virus binding and cell entry, nectin-4 homodimerization, and heterodimerization with nectin-1.","date":"2014","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/25275122","citation_count":18,"is_preprint":false},{"pmid":"15078954","id":"PMC_15078954","title":"The herpes simplex virus JMP mutant enters receptor-negative J cells through a novel pathway independent of the known receptors nectin1, HveA, and nectin2.","date":"2004","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/15078954","citation_count":18,"is_preprint":false},{"pmid":"36361764","id":"PMC_36361764","title":"An Overview of PRR- and NLR-Mediated Immunities: Conserved Signaling Components across the Plant Kingdom That Communicate Both Pathways.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36361764","citation_count":17,"is_preprint":false},{"pmid":"34122131","id":"PMC_34122131","title":"Effects of (Pro)renin Receptor on Diabetic Cardiomyopathy Pathological Processes in Rats via the PRR-AMPK-YAP Pathway.","date":"2021","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/34122131","citation_count":17,"is_preprint":false},{"pmid":"23608644","id":"PMC_23608644","title":"PRR repeats in the intracellular domain of KISS1R are important for its export to cell membrane.","date":"2013","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/23608644","citation_count":17,"is_preprint":false},{"pmid":"16879022","id":"PMC_16879022","title":"Nectin-1 expression in the normal and neoplastic human uterine cervix.","date":"2006","source":"Archives of pathology & laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16879022","citation_count":17,"is_preprint":false},{"pmid":"33547400","id":"PMC_33547400","title":"(Pro)renin receptor involves in myocardial fibrosis and oxidative stress in diabetic cardiomyopathy via the PRR-YAP pathway.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33547400","citation_count":17,"is_preprint":false},{"pmid":"11289808","id":"PMC_11289808","title":"Comparison of murine and human nectin1 binding to herpes simplex virus glycoprotein D (gD) reveals a weak interaction of murine nectin1 to gD and a gD-dependent pathway of entry.","date":"2001","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/11289808","citation_count":17,"is_preprint":false},{"pmid":"14972557","id":"PMC_14972557","title":"Effects of linker-insertion mutations in herpes simplex virus 1 gD on glycoprotein-induced fusion with cells expressing HVEM or nectin-1.","date":"2004","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/14972557","citation_count":17,"is_preprint":false},{"pmid":"11991974","id":"PMC_11991974","title":"Substitution in the murine nectin1 receptor of a single conserved amino acid at a position distal from the herpes simplex virus gD binding site confers high-affinity binding to gD.","date":"2002","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/11991974","citation_count":16,"is_preprint":false},{"pmid":"29867919","id":"PMC_29867919","title":"Variegated Transcription of the WC1 Hybrid PRR/Co-Receptor Genes by Individual γδ T Cells and Correlation With Pathogen Responsiveness.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29867919","citation_count":16,"is_preprint":false},{"pmid":"30532257","id":"PMC_30532257","title":"Role of a fluid-phase PRR in fighting an intracellular pathogen: PTX3 in Shigella infection.","date":"2018","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/30532257","citation_count":16,"is_preprint":false},{"pmid":"36216719","id":"PMC_36216719","title":"Linking nutrient sensing, mitochondrial function, and PRR immune cell signaling in liver disease.","date":"2022","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36216719","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48502,"output_tokens":6005,"usd":0.117791},"stage2":{"model":"claude-opus-4-6","input_tokens":9673,"output_tokens":3493,"usd":0.203535},"total_usd":0.321326,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Nectin-1 (PRR1) directly interacts with the PDZ domain of afadin via its C-terminal consensus motif (A/EXYV), and is recruited to cadherin-based cell-cell adherens junctions through this interaction; nectin-1 shows Ca2+-independent cell-cell adhesion activity.\",\n      \"method\": \"Co-immunoprecipitation, colocalization imaging, adhesion assays in EL cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding and colocalization with functional rescue; foundational paper >450 citations\",\n      \"pmids\": [\"10225955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The V domain of nectin-1 (HIgR/PRR1) is the major functional region mediating HSV-1 entry into cells; a single V domain is sufficient for physical interaction with HSV glycoprotein D (gD) in vitro and for conferring cell susceptibility to HSV-1 entry.\",\n      \"method\": \"Deletion mutants, soluble V-domain competition assay, in vitro binding (Co-IP/pulldown), entry assay with engineered chimeric receptors\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including in vitro binding, mutagenesis, and functional entry assays\",\n      \"pmids\": [\"9861033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Nectin-1 mediates direct cell-to-cell spread of wild-type HSV-1 through a gD-receptor interaction; a monoclonal antibody blocking nectin-1 also blocks cell-to-cell spread, and spread from receptor-positive to receptor-negative cells does not occur.\",\n      \"method\": \"Plaque assay, antibody blockade, receptor-negative J cell lines expressing nectin1\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean receptor KO/expression system with functional readout, replicated across multiple human cell lines\",\n      \"pmids\": [\"10729168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Nectin-4 trans-interacts heterophilically with nectin-1 through V domain-to-V domain interactions; the V domain of nectin-1 is the major functional region involved in trans-heterointeraction with both nectin-3 and nectin-4.\",\n      \"method\": \"Soluble Fc-fusion binding to cells, co-immunoprecipitation, in vitro binding between recombinant proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal binding assays in same study; >272 citations\",\n      \"pmids\": [\"11544254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Nectin-1 trans-heterophilic interactions with nectin-3 (Kd ~1 nM) and nectin-4 (Kd ~100 nM) are mediated through V-to-V domain contacts; nectin-3 and nectin-4 share a common binding region on nectin-1 mapped to the C-C'-C\\\"-D beta-strands of the V domain, and HSV-1 gD competes with both for binding to this region.\",\n      \"method\": \"Affinity measurements, competition binding with monoclonal antibodies and gD, chimeric nectin1/PVR receptors with strand substitutions\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including affinity measurements and chimeric receptor dissection; >118 citations\",\n      \"pmids\": [\"12011057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of HSV-1 gD bound to nectin-1 (at 4.0 Å) reveals that gD uses both its N- and C-terminal extensions to contact the first Ig domain of nectin-1 at the same surface used for nectin-1 homophilic dimerization; Phe129 at the tip of nectin-1's FG loop inserts into a groove on gD, and mutation F129A abolishes nectin-1 binding to gD and HSV entry.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, HSV entry assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis with functional validation\",\n      \"pmids\": [\"21980294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of the nectin-1 extracellular region reveals that it forms a V-shaped cis-dimer through the first Ig-like domain; four residues in the first Ig domain are essential for cis-dimerization, homophilic adhesion, and heterophilic adhesion activity.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, cell-surface cis-dimerization assay, homophilic and heterophilic adhesion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis with functional cellular validation\",\n      \"pmids\": [\"21325282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The gD/nectin-1 complex structure shows that gD binds nectin-1 in a mode similar to the nectin-1 homodimer interaction, using the same key residues for dimerization; gD binding to nectin-1 would preclude nectin-1 dimerization and abolish its cell adhesion function.\",\n      \"method\": \"X-ray crystallography of gD–nectin-1 complex\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — independent crystal structure of the same complex corroborating mechanism\",\n      \"pmids\": [\"22146396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structures of HSV-2 gD unbound and bound to nectin-1 demonstrate a conserved receptor-binding mode between HSV-1 and HSV-2; nectin-1 residue I80 is important for gD interaction, confirmed by surface plasmon resonance and cell fusion assays.\",\n      \"method\": \"X-ray crystallography, surface plasmon resonance, site-directed mutagenesis, cell-based fusion assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus SPR plus mutagenesis plus functional assay\",\n      \"pmids\": [\"25231300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Nectin-3 (PRR3) interacts with afadin through its C-terminal A/EXYV motif (PDZ-domain binding), and both proteins co-localize at intercellular junctions.\",\n      \"method\": \"In vivo co-immunoprecipitation with long and short afadin isoforms, colocalization imaging\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab Co-IP, but consistent with established nectin-1/afadin interaction mechanism\",\n      \"pmids\": [\"11024295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"During HSV infection, nectin-1 is displaced from adherens junctions in a gD-dependent manner; newly synthesized gD substitutes for nectin-1 at junctions by trans-interacting with nectin-1 on adjacent noninfected cells, redirecting nectin-1 localization and facilitating virus spread.\",\n      \"method\": \"Live-cell imaging with nectin-1-GFP fusions, immunofluorescence colocalization, HSV entry/spread assay in cells with/without afadin interaction disrupted\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment tied to functional spread outcome\",\n      \"pmids\": [\"12885915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Nectin-1 expression is necessary for HSV infection of neurons in the CNS and for development of encephalitis after intracranial inoculation; HVEM is largely dispensable for neuronal infection by this route, while nectin-1 KO mice show no detectable virus in brain parenchyma.\",\n      \"method\": \"Genetic KO mice (nectin-1 KO, HVEM KO, double KO), intracranial inoculation, immunohistology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with specific phenotypic readout, double-KO epistasis\",\n      \"pmids\": [\"19805039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Amino acids 77 and 85 in the V domain of nectin-1 are critical for HSV-1 and HSV-2 gD binding and entry but not for pseudorabies virus (PRV) or bovine herpesvirus 1 (BHV-1) entry, demonstrating overlapping but distinct gD binding footprints for different herpesviruses on nectin-1.\",\n      \"method\": \"Site-directed mutagenesis, soluble gD binding assay, viral entry assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis combined with binding and entry assays\",\n      \"pmids\": [\"12072525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The HSV entry site on nectin-1 maps to residues 64–94 of the V domain (likely the C, C', C\\\" beta-strands and loops); the gD-binding site maps to the same region, while the epitope for the entry-blocking mAb R1.302 additionally requires residues 95–102.\",\n      \"method\": \"Chimeric nectin1/PVR receptor constructs, HSV entry functional assay, mAb epitope mapping\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — systematic chimera mapping with functional entry readout\",\n      \"pmids\": [\"11483743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"N-terminal deletions in HSV-1 or HSV-2 gD that abolish interactions with HVEM, nectin-2, and 3-O-sulfated heparan sulfate do not impair functional interactions with nectin-1, demonstrating that gD's N-terminus is dispensable for nectin-1 binding and cell fusion.\",\n      \"method\": \"Cell fusion assay, soluble gD:Fc binding assay, site-directed mutagenesis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — binding and functional fusion assays with multiple gD mutants\",\n      \"pmids\": [\"12915538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"After trans-interaction with gD expressed on adjacent cells, nectin-1 is internalized and degraded via a low-pH-dependent pathway in cells where HSV enters endosomally; this down-regulation correlates with gD-mediated virion internalization.\",\n      \"method\": \"Co-culture of gD-expressing cells with nectin-1-expressing cells, receptor internalization assay, pH inhibitors (bafilomycin, NH4Cl), flow cytometry\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct internalization measurement with mechanistic inhibitor dissection, single lab\",\n      \"pmids\": [\"18076965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HSV entry mediated by nectin-1 can occur via either plasma membrane fusion or an endocytic route depending on cellular context; a chimeric nectin-1-EGFR1 receptor routes HSV through clathrin-dependent endocytosis requiring EGFR tyrosine kinase activity and acidic endosomes, while nectin-1 sorted to lipid rafts via GPI anchor also routes entry through acid endosomes.\",\n      \"method\": \"Chimeric receptor constructs, endosome acidification inhibitors, kinase inhibitors (AG1478), wortmannin, viral entry assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — engineered chimeric receptors plus pharmacological dissection in same study\",\n      \"pmids\": [\"15507614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"αVβ3-integrin relocalizes nectin-1 to lipid rafts independently of HSV, thereby routing HSV to a lipid raft-dependent acidic endosome entry pathway; this integrin-induced relocalization is the mechanistic basis for αVβ3-integrin's control of HSV entry route.\",\n      \"method\": \"Lipid raft fractionation, co-expression of nectin-1 and αVβ3-integrin, HSV entry assay with pharmacological inhibitors\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor relocalization linked to functional entry route change, single lab\",\n      \"pmids\": [\"22171266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NMDA receptor activation (but not AMPA or mGluR) induces Ca2+/calmodulin-dependent α-secretase (ADAM10) cleavage of nectin-1 ectodomain and subsequent γ-secretase processing in primary cortical neurons; ADAM10 is identified as the major α-secretase responsible for nectin-1 ectodomain shedding.\",\n      \"method\": \"Primary cortical neuron stimulation, pharmacological receptor antagonists, ADAM10 knockdown/KO neurons, gamma-secretase inhibitors, western blot for cleavage products\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function (ADAM10 KO/KD) plus pharmacological dissection with specific readout\",\n      \"pmids\": [\"20501653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The third membrane-proximal Ig module (Ig3) of nectin-1 directly binds fibroblast growth factor receptors (FGFRs) as measured by surface plasmon resonance; this interaction induces FGFR1c phosphorylation, neurite outgrowth in hippocampal and cerebellar neurons, and neuronal survival, all abolished by FGFR inhibitor SU5402 or dominant-negative FGFR1.\",\n      \"method\": \"NMR structure of Ig3 module, surface plasmon resonance (SPR) binding to FGFR isoforms, dominant-negative FGFR1 transfection, FGFR inhibitor, neurite outgrowth assay, cell survival assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure plus SPR direct binding plus functional loss-of-function with multiple readouts\",\n      \"pmids\": [\"22955284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Nectin-1 regulates loricrin expression in keratinocytes through a Ca2+-induced Rap1-ERK signaling pathway; nectin-1 knockout mice show markedly reduced loricrin in the epidermis, and inhibition of ERK reduces loricrin in wild-type keratinocytes.\",\n      \"method\": \"Nectin-1 KO mice, primary keratinocyte culture, ERK activation assay, Western blot for loricrin/repetin/SPRR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with specific molecular and phenotypic readout plus pathway inhibition confirmation\",\n      \"pmids\": [\"17472964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Nectin-1 and l-afadin cluster at developing hippocampal synapses in an F-actin-dependent manner, co-localizing with N-cadherin-catenin at excitatory synapses; actin depolymerization disrupts nectin-1/afadin synaptic clusters and triggers nectin-1 ectodomain shedding, suggesting a role in synaptic plasticity.\",\n      \"method\": \"Immunofluorescence in primary hippocampal neurons, actin depolymerizing agents (latrunculin, cytochalasin D), live imaging\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment tied to functional mechanism (shedding upon actin disruption), single lab\",\n      \"pmids\": [\"18181141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Nectin-1 trans-interaction with nectin-3 modulates E-cadherin-based adhesion differently depending on which nectin is expressed at high vs. low levels; heterodimers of nectin-1/nectin-3 adhere more strongly than homodimers, and the direction of trans-interaction (nectin-1 interacting with nectin-3 or vice versa) determines whether E-cadherin adhesion is agonized or not.\",\n      \"method\": \"Dual-pipette cell separation force measurement, L cell transfection with nectin-1 or nectin-3 at varying levels, soluble nectin ectodomain competition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative force measurement with mechanistic dissection, single lab\",\n      \"pmids\": [\"15550395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"p63 directly transcriptionally regulates Pvrl1 (nectin-1) gene expression in stratified epithelia; ChIP demonstrates p63 binding to two conserved intronic Pvrl1 enhancer regions, and p63-null skin/keratinocytes show strongly reduced nectin-1 expression.\",\n      \"method\": \"ChIP, p63 KO mouse model, siRNA knockdown, qRT-PCR and western blot\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus KO/KD with quantitative expression readout, single lab\",\n      \"pmids\": [\"25387952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"miR-661 targets the 3'-UTR of nectin-1 mRNA, destabilizing it downstream of SNAI1-induced EMT; re-expression of nectin-1 lacking the 3'-UTR counteracts SNAI1-induced invasion of breast cancer cells, establishing nectin-1 downregulation as mechanistically contributing to EMT-driven invasion.\",\n      \"method\": \"miRNA overexpression, luciferase 3'-UTR reporter assay, nectin-1 rescue construct (without 3'-UTR), invasion assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — 3'-UTR reporter plus rescue experiment with functional invasion readout, single lab\",\n      \"pmids\": [\"20543867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Human nectin-1 directly interacts with the NK receptor CD96 via its V-domain canonical adhesive interface; the affinity of nectin-1 for CD96 is similar to its affinity for HSV gD; overexpression of nectin-1 in K562 cells increases susceptibility to NK-92 cell cytotoxicity.\",\n      \"method\": \"In vitro binding assay (SPR-equivalent), K562 cell expression of nectin-1-GFP, NK cytotoxicity assay, HSV entry assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding measurement plus functional cytotoxicity readout, single lab\",\n      \"pmids\": [\"30759143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Murine CD96 binds nectin-1 in addition to CD155, demonstrating that nectin-1 is a ligand for the CD96 adhesion receptor; anti-CD96 and anti-CD155 antibodies block CD96/CD155 complex formation and T cell adhesion.\",\n      \"method\": \"Binding assay with monoclonal antibodies, T cell adhesion to insect cells expressing CD155, flow cytometry\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single binding/adhesion assay, single lab, but cross-validated with multiple antibodies\",\n      \"pmids\": [\"17971293\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Nectin-1 is a Ca2+-independent immunoglobulin-superfamily cell adhesion molecule that forms cis-dimers through its first Ig domain and trans-interacts homophilically and heterophilically (with nectins-3 and -4) via V-domain contacts to organize cadherin-based adherens junctions; it is recruited to junctions through its PDZ-binding C-terminal motif binding afadin, signals through FGFR and Rap1-ERK to regulate differentiation, undergoes NMDA-receptor–triggered ADAM10-mediated ectodomain shedding, serves as the principal neuronal entry receptor for HSV-1/2 (gD binding to the V-domain C-C'-C\\\" surface), and engages the NK cell receptor CD96 at the same canonical adhesive interface.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Nectin-1 is a Ca²⁺-independent immunoglobulin-superfamily cell adhesion molecule that organizes adherens junctions and modulates intercellular signaling through homophilic and heterophilic V-domain–mediated trans-interactions. It forms cis-dimers through its first Ig-like domain, engages nectin-3 (Kd ~1 nM) and nectin-4 heterophilically via the C-C′-C″ beta-strand surface, and is recruited to cadherin-based junctions through its C-terminal PDZ-binding motif interacting with afadin; downstream, it signals through Rap1-ERK to regulate keratinocyte differentiation and through FGFR (via its Ig3 module) to promote neurite outgrowth and neuronal survival [PMID:10225955, PMID:11544254, PMID:17472964, PMID:22955284]. The same V-domain adhesive interface serves as the principal entry receptor for HSV-1 and HSV-2 through direct binding of glycoprotein D, which competitively disrupts nectin-1 dimerization and displaces it from junctions to facilitate viral entry and cell-to-cell spread; nectin-1 is essential for HSV neuronal infection and encephalitis in vivo [PMID:9861033, PMID:21980294, PMID:19805039]. Nectin-1 additionally engages the NK cell receptor CD96 at the same canonical interface, undergoes NMDA-receptor–triggered ADAM10-mediated ectodomain shedding followed by γ-secretase processing in neurons, and its expression is transcriptionally regulated by p63 in stratified epithelia [PMID:30759143, PMID:20501653, PMID:25387952].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identifying nectin-1's V domain as sufficient for HSV gD binding and viral entry established the minimal receptor determinant and defined the molecular basis of herpesvirus tropism.\",\n      \"evidence\": \"Deletion mutants, soluble V-domain competition, and chimeric receptor entry assays in transfected cells\",\n      \"pmids\": [\"9861033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of gD–V-domain interaction unknown at this stage\",\n        \"Relative contribution of nectin-1 vs. other HSV receptors (HVEM) in vivo not resolved\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating that nectin-1 binds afadin via its PDZ-binding motif and localizes to cadherin-based adherens junctions revealed its primary cell-biological function as a junctional adhesion molecule independent of its viral receptor role.\",\n      \"evidence\": \"Co-immunoprecipitation, colocalization imaging, and Ca²⁺-independent adhesion assays in EL cells\",\n      \"pmids\": [\"10225955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How nectin-1/afadin interaction coordinates with cadherin-catenin complex assembly not defined\",\n        \"Signaling downstream of nectin-1 at junctions unknown\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Mapping the gD-binding and nectin heterophilic interaction sites to the same C-C′-C″ region of the V domain established that HSV hijacks the canonical cell adhesion interface, and showing nectin-1 mediates direct cell-to-cell HSV spread linked receptor function to viral pathogenesis.\",\n      \"evidence\": \"Chimeric nectin-1/PVR constructs with functional entry readout; antibody blockade of cell-to-cell spread; Fc-fusion binding for nectin-3 and nectin-4 heterophilic interactions\",\n      \"pmids\": [\"11483743\", \"10729168\", \"11544254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Atomic-resolution structure of the adhesive interface not yet available\",\n        \"Affinity measurements for heterophilic interactions not yet quantified\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Quantifying binding affinities (nectin-3 Kd ~1 nM, nectin-4 Kd ~100 nM) and showing gD competition for the same V-domain surface established the thermodynamic hierarchy of nectin-1 interactions and the competitive mechanism of HSV receptor usurpation.\",\n      \"evidence\": \"Affinity measurements, competition binding with mAbs and gD, chimeric receptor strand substitutions\",\n      \"pmids\": [\"12011057\", \"12072525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of competition at atomic resolution still lacking\",\n        \"Whether differential affinities determine tissue-specific junction composition unknown\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showing that gD displaces nectin-1 from adherens junctions in living infected cells and substitutes for nectin-1 in trans explained how HSV remodels cell junctions to promote spread.\",\n      \"evidence\": \"Live-cell imaging of nectin-1-GFP, immunofluorescence colocalization during HSV infection\",\n      \"pmids\": [\"12885915\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Kinetics of junction disassembly during infection not quantified\",\n        \"Whether afadin redistribution accompanies nectin-1 displacement not examined\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that nectin-1 can route HSV entry through either plasma membrane fusion or endocytosis depending on membrane context (lipid rafts, chimeric receptor signaling) resolved the long-standing question of how the same receptor mediates different entry pathways.\",\n      \"evidence\": \"Chimeric nectin-1-EGFR1 receptors, GPI-anchored nectin-1, pharmacological inhibitors of endocytosis and acidification\",\n      \"pmids\": [\"15507614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Endogenous signals that determine nectin-1 membrane microdomain sorting in vivo not identified\",\n        \"Whether integrin-mediated relocalization occurs in neuronal entry not tested at this point\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Nectin-1 KO mice revealed a cell-autonomous role for nectin-1 in regulating keratinocyte terminal differentiation through Rap1-ERK–dependent loricrin expression, establishing a signaling function beyond adhesion; separately, CD96 was identified as an immune receptor ligand for nectin-1.\",\n      \"evidence\": \"Nectin-1 KO mouse epidermis analysis, ERK inhibition in primary keratinocytes; CD96 binding assay with mAb blockade\",\n      \"pmids\": [\"17472964\", \"17971293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How nectin-1 activates Rap1 (direct or indirect) not resolved\",\n        \"Functional consequence of CD96–nectin-1 interaction for NK or T cell cytotoxicity not fully tested\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic demonstration that nectin-1 is the essential HSV entry receptor in CNS neurons in vivo (HVEM dispensable) resolved the long-standing receptor-redundancy question for neuronal infection.\",\n      \"evidence\": \"Nectin-1 KO, HVEM KO, and double-KO mice with intracranial HSV inoculation and immunohistology\",\n      \"pmids\": [\"19805039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether nectin-1 is equally essential for peripheral sensory neuron entry not addressed by intracranial route\",\n        \"Mechanism by which loss of nectin-1 blocks neuronal entry (failure of attachment vs. fusion) not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying ADAM10 as the NMDA-receptor–activated α-secretase for nectin-1 ectodomain shedding, followed by γ-secretase processing, established a regulated proteolytic mechanism linking synaptic activity to nectin-1 turnover.\",\n      \"evidence\": \"ADAM10 KO/KD neurons, pharmacological NMDA/AMPA antagonists, γ-secretase inhibitors in primary cortical neurons\",\n      \"pmids\": [\"20501653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological consequence of nectin-1 ICD release by γ-secretase unknown\",\n        \"Whether ADAM10-mediated shedding affects HSV susceptibility at synapses not tested\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Crystal structures of the nectin-1 cis-dimer and the gD–nectin-1 complex provided the atomic basis for adhesion and viral hijacking: gD occupies the same dimerization interface, competitively disrupting nectin-1 cis-dimers and trans-adhesion.\",\n      \"evidence\": \"X-ray crystallography of nectin-1 ectodomain and gD–nectin-1 complex (two independent labs), site-directed mutagenesis with entry assays\",\n      \"pmids\": [\"21325282\", \"21980294\", \"22146396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structure of nectin-1/nectin-3 heterophilic trans-complex not determined\",\n        \"Whether gD-induced dimer disruption is sufficient to trigger endocytosis or requires additional signaling\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that nectin-1's Ig3 module directly binds and activates FGFR to promote neurite outgrowth and neuronal survival established a second signaling axis independent of afadin-mediated junction assembly.\",\n      \"evidence\": \"NMR structure of Ig3, SPR binding to FGFR isoforms, FGFR inhibitor and dominant-negative FGFR1 in hippocampal/cerebellar neurons\",\n      \"pmids\": [\"22955284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether FGFR signaling through nectin-1 operates in non-neuronal tissues unknown\",\n        \"How Ig3-FGFR interaction is coordinated with V-domain adhesive interactions not resolved\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirming that human nectin-1 binds NK receptor CD96 at its canonical V-domain adhesive interface with affinity comparable to gD established nectin-1 as an immune-modulatory ligand and extended the shared-interface paradigm to immunosurveillance.\",\n      \"evidence\": \"SPR-equivalent binding, K562 nectin-1 expression with NK-92 cytotoxicity assay\",\n      \"pmids\": [\"30759143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo immunological consequence of nectin-1–CD96 interaction not demonstrated\",\n        \"Whether CD96 engagement competes with HSV gD for the same residues not structurally resolved\",\n        \"Single-lab binding study awaits independent confirmation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A full structural picture of nectin-1 heterophilic trans-complexes (nectin-1/nectin-3, nectin-1/nectin-4) and the mechanism by which nectin-1 activates Rap1 signaling remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal structure of nectin-1/nectin-3 or nectin-1/nectin-4 trans-complex\",\n        \"Molecular mechanism linking nectin-1 to Rap1 activation not identified\",\n        \"Functional significance of γ-secretase-released nectin-1 ICD unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 3, 4, 6, 22]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 2, 25, 26]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [1, 2, 5, 8, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6, 10, 17, 21]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:1500931\", \"supporting_discovery_ids\": [0, 3, 6, 22]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [19, 20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [25, 26]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 5, 11]}\n    ],\n    \"complexes\": [\n      \"Nectin-afadin complex\",\n      \"Nectin-1 cis-homodimer\"\n    ],\n    \"partners\": [\n      \"AFDN\",\n      \"NECTIN3\",\n      \"NECTIN4\",\n      \"CD96\",\n      \"FGFR1\",\n      \"ADAM10\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}