{"gene":"NECTIN1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1998,"finding":"The V domain of HIgR/nectin-1 (PRR1) is the major functional region for HSV-1 entry: a single V domain competed with full-length receptor, blocked infectivity, was sufficient to confer HSV entry activity when fused to transmembrane/cytoplasmic regions, and was sufficient for physical interaction with gD in vitro.","method":"Monoclonal antibody epitope mapping, soluble V-domain competition assay, engineered deletion constructs expressing V domain alone, in vitro pulldown/binding assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1/2 / Strong — multiple orthogonal methods (mAb blocking, soluble domain competition, deletion constructs, in vitro binding) in a single focused study establishing the V-domain mechanism","pmids":["9861033"],"is_preprint":false},{"year":2001,"finding":"Nectin-4 trans-interacts with nectin-1 through V-domain interactions; nectin-1-Fc precipitates nectin-4, nectin4-Fc binds nectin-1-expressing cells but not cells expressing nectin-2, nectin-3, or PVR, and reciprocal in vitro physical interactions were detected between nectin4-Fc and nectin1-Fc. The V domain of nectin-1 was identified as the major functional region for trans-heterointeraction with nectin-4 (and nectin-3).","method":"Soluble Fc-fusion binding to transfected cells, co-immunoprecipitation, in vitro Fc-fusion binding assay, inhibition by anti-V-domain mAbs and HSV gD","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays, co-IP, and mAb/gD competition providing multiple orthogonal lines of evidence","pmids":["11544254"],"is_preprint":false},{"year":2002,"finding":"Nectin-3 and nectin-4 both bind to the C-C'-C\"-D beta-strands of the nectin-1 V domain for trans-heterointeraction; the KD of nectin-1/nectin-3 interaction is ~1 nM and nectin-1/nectin-4 is ~100 nM, whereas nectin-1 homophilic interaction is ~1 μM. HSV gD, which also binds the nectin-1 V domain, competed with nectin-3 and nectin-4 binding.","method":"SPR/affinity measurements, competition binding with soluble Fc-fusions and mAbs, chimeric nectin1/PVR receptors with substituted beta-strands","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1/2 / Strong — quantitative binding measurements combined with chimeric receptor mapping and competition studies, multiple orthogonal approaches","pmids":["12011057"],"is_preprint":false},{"year":2001,"finding":"The HSV entry site on nectin-1 maps entirely to residues 64-94 (the predicted CC'C\" region of the V domain), with a minimal entry site at residues 77-94 and a region 64-76 that greatly enhances entry activity; the gD-binding site maps to the same region. This was established using nectin-1/PVR chimeric receptors.","method":"Nectin-1/PVR chimeric receptor constructs tested for HSV entry activity and gD binding in cell-based assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic chimeric receptor mapping with functional entry readout and binding correlation","pmids":["11483743"],"is_preprint":false},{"year":2002,"finding":"Amino acids 77 and 85 of the nectin-1 V domain are critical specifically for HSV-1 and HSV-2 entry and gD binding, but not for PRV or BHV-1 entry; simultaneous substitution of both residues eliminates HSV gD binding while leaving PRV/BHV-1 entry intact, demonstrating partially overlapping but distinct binding sites for different herpesvirus gDs on nectin-1.","method":"Site-directed mutagenesis of nectin-1 residues 77 and 85, HSV entry assays, soluble gD binding assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1/2 / Strong — mutagenesis combined with functional entry assay and direct gD binding, multiple virus serotypes tested","pmids":["12072525"],"is_preprint":false},{"year":2002,"finding":"The CC' ridge of nectin-1 (residues 65-76, specifically 69-71 and 72-75) is sufficient to confer wild-type HSV-1 and BHV-1 entry activity and enhances HSV-2, PRV, and HSV-HSV(U21) entry when transferred to nectin-2. The full HSV entry site is composed of two synergistic contiguous regions: 64-76 and 77-94.","method":"Transfer of nectin-1 residue segments to nectin-2 by mutagenesis, HSV entry assays","journal":"Virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic mutagenesis/domain-transfer with functional entry readouts across multiple viruses","pmids":["12359441"],"is_preprint":false},{"year":2000,"finding":"Nectin-1 (both alpha and delta isoforms) mediates direct cell-to-cell spread of wild-type HSV-1, not merely free virion entry; an anti-nectin-1 mAb that blocks entry also blocks spread; wild-type virus does not spread from a receptor-positive to a receptor-negative cell. Nectin-1 does not mediate cell fusion by syncytial HSV strains.","method":"Cell-to-cell spread assays in J cells expressing nectin-1 isoforms, mAb blocking, receptor-positive to receptor-negative cell contact assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell line experiments with receptor-null controls and specific mAb blocking establishing both entry and spread functions","pmids":["10729168"],"is_preprint":false},{"year":2002,"finding":"Nectin-1 co-localizes with E-cadherin at adherens junctions in epithelial cells (MDCK); disruption of adherens junctions by calcium depletion redistributes nectin-1 over the entire cell surface and enhances both gD binding and HSV/PRV infection efficiency, demonstrating that nectin-1 confined to junctions is less accessible as a virus entry receptor.","method":"Confocal microscopy of nectin-1 localization, calcium depletion, soluble gD binding assay, HSV/PRV infection quantification","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization tied to functional consequence (infection efficiency), multiple viruses tested","pmids":["12072519"],"is_preprint":false},{"year":2003,"finding":"During HSV infection, gD expression dramatically alters nectin-1 localization at adherens junctions: nectin-1 and gD co-localize at cell contact areas between infected and uninfected cells. Newly synthesized gD substitutes for nectin-1 of infected cells at junctions with non-infected cells, maintaining nectin-1 at junctions for virus spread. The nectin-1/afadin interaction is not required for HSV entry or spread.","method":"Fluorescence/confocal microscopy of nectin-1-GFP fusions during HSV infection, co-localization studies, afadin interaction experiments","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — live cell imaging with GFP fusions plus functional spread assays, negative result on afadin requirement also established","pmids":["12885915"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of HSV-1 gD bound to nectin-1 (4.0 Å): the nectin-1 V-domain's canonical homophilic interaction surface (first Ig domain, including Phe129 at the FG loop tip) is the gD binding site; Phe129 inserts into a groove on gD normally occupied by the gD C-terminal region; mutation F129A prevents nectin-1 binding to gD and HSV entry.","method":"X-ray crystallography, site-directed mutagenesis (F129A), HSV entry assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation by mutagenesis in a single study","pmids":["21980294"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of gD/nectin-1 complex reveals that gD binds the first Ig domain of nectin-1 using the same surface that mediates nectin-1 homodimerization; key amino acids responsible for nectin-1 dimerization are also used for gD/nectin-1 binding, indicating that gD binding precludes nectin-1 dimerization and its cell adhesion function.","method":"X-ray crystallography of gD/nectin-1 complex, structural analysis of dimerization interface","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure showing shared binding interface, corroborated by independent study (PMID:21980294)","pmids":["22146396"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of the entire nectin-1 extracellular region reveals a V-shaped cis-dimer formed through the first Ig-like domain (not the second as previously thought). Structure-based mutagenesis identified four essential residues in the first Ig domain required for cis-dimerization; mutating them reduced cis-dimerization on cell surfaces and abolished both homophilic and heterophilic adhesion activities.","method":"X-ray crystallography, site-directed mutagenesis of dimerization interface, cell surface adhesion assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis and functional cell adhesion validation","pmids":["21325282"],"is_preprint":false},{"year":2010,"finding":"NMDA receptor activation triggers robust alpha- and gamma-secretase cleavage of nectin-1 in mature cortical neurons; this requires Ca2+ influx through NMDA receptors and calmodulin activation but not CaMKII. ADAM10 was identified as the major alpha-secretase (metalloprotease) responsible for nectin-1 ectodomain cleavage in neurons and brain.","method":"Primary cortical neuron stimulation with NMDA/AMPA/mGluR agonists, Ca2+ chelation, calmodulin inhibitor, ADAM10 knockout/knockdown, Western blotting for cleavage products","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological dissection plus genetic (KO) identification of the secretase with multiple orthogonal approaches","pmids":["20501653"],"is_preprint":false},{"year":2008,"finding":"Trans-interaction of gD with nectin-1 causes nectin-1 down-regulation by internalization and low-pH-dependent lysosomal degradation in cells where HSV enters by endocytosis (B78H1-C10, SY5Y, A431, HeLa); on Vero cells (plasma membrane entry), nectin-1 is not down-regulated. Down-regulation requires gD binding to nectin-1 and is linked to virion internalization.","method":"Co-culture of gD-expressing cells with nectin-1 expressing cells, flow cytometry/Western blot for nectin-1 levels, bafilomycin/NH4Cl treatment, virion internalization assay","journal":"Virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type comparison with endocytosis inhibitors, receptor binding correlation, and virion internalization assay","pmids":["18076965"],"is_preprint":false},{"year":2010,"finding":"Virion gD actively induces rapid internalization of both nectin-1alpha and nectin-1beta isoforms despite different cytoplasmic tails; deletion of the nectin-1 cytoplasmic tail slows but does not abolish down-regulation. Nectin-1 is not constitutively recycled in uninfected cells, indicating that gD binding specifically triggers internalization.","method":"Flow cytometry of surface nectin-1, virion entry kinetics, cytoplasmic tail deletion constructs","journal":"Virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — comparison of wild-type and deletion isoforms with kinetic internalization assay","pmids":["20089288"],"is_preprint":false},{"year":2017,"finding":"Cbl E3 ligase mediates the removal of nectin-1 from the surface of HSV-1-infected cells: Cbl, nectin-1, and viral gD form a complex in infected cells; depletion of Cbl retains nectin-1 on the cell surface and enhances viral entry; Cbl-mediated nectin-1 removal also requires ICP0 (ΔICP0 mutant virus leaves nectin-1 on the surface).","method":"Co-immunoprecipitation, siRNA knockdown of Cbl/CIN85, flow cytometry for surface nectin-1, infection assays with ΔICP0 virus","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP of complex, genetic knockdown with functional readout, viral mutant validation","pmids":["28381567"],"is_preprint":false},{"year":2004,"finding":"Nectin-1 confined to adherens junctions in epithelial cells is less accessible to virion gD; chimeric nectin-1 targeted to endosomes (nectin1-EGFR1) or lipid rafts (GPI-anchored) routes HSV to an acidic endosomal entry pathway blocked by wortmannin and bafilomycin/NH4Cl. The same receptor can initiate different HSV entry pathways depending on its cellular localization.","method":"Chimeric receptor constructs (nectin1-EGFR1, GPI-nectin1), endosome acidification inhibitors (bafilomycin, NH4Cl, wortmannin), EGFR1 inhibitor (AG1478), entry assays in J cells","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — engineered chimeric receptors with multiple pharmacological inhibitors defining entry pathways","pmids":["15507614"],"is_preprint":false},{"year":2011,"finding":"αVβ3-integrin relocalizes nectin-1 to lipid rafts independently of virus, directing HSV to a lipid raft and acidic endosome entry pathway. HSV entry mediated by nectin-1 plus αVβ3-integrin phenocopies entry mediated by raft-localized forms of nectin-1.","method":"Co-expression of nectin-1 and αVβ3-integrin, lipid raft fractionation, entry assays with raft/endosome inhibitors, Na+/H+ exchanger inhibitor (EIPA)","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab study with biochemical fractionation and pharmacological inhibition, functional entry assay","pmids":["22171266"],"is_preprint":false},{"year":2012,"finding":"Nectin-1 binds and signals through the fibroblast growth factor receptor (FGFR): the third, membrane-proximal Ig module (Ig3) of nectin-1 directly interacts with multiple FGFR isoforms (shown by surface plasmon resonance), induces FGFR1c phosphorylation, promotes neurite outgrowth (blocked by FGFR inhibitor SU5402 or dominant-negative FGFR1), and promotes neuronal survival.","method":"NMR structure of nectin-1 Ig3, surface plasmon resonance binding assay, FGFR phosphorylation assay, neurite outgrowth in primary neurons with pharmacological and dominant-negative inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure, SPR direct binding, phosphorylation assay, and functional neurite outgrowth with genetic/pharmacological validation","pmids":["22955284"],"is_preprint":false},{"year":2008,"finding":"Nectin-1 and afadin cluster at developing hippocampal synapses, initially at both excitatory and inhibitory synapses but progressively lost at inhibitory synapses during maturation. Synaptic localization of nectin-1 and afadin is F-actin-dependent; actin depolymerization disrupts synaptic nectin-1/afadin clusters and elicits nectin-1 ectodomain shedding.","method":"Immunofluorescence and confocal microscopy of cultured hippocampal neurons, actin depolymerizing agents (cytochalasin D), co-localization with N-cadherin","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence (shedding), single lab with pharmacological perturbation","pmids":["18181141"],"is_preprint":false},{"year":2011,"finding":"Nectin-1 ectodomain shedding regulates dendritic spine density: two distinct cleavage sites were identified in the nectin-1 ectodomain by alanine scanning mutagenesis, and expression of shedding-resistant mutants significantly altered dendritic spine density in rat hippocampal neurons.","method":"Alanine scanning mutagenesis of nectin-1 ectodomain cleavage sites, expression of cleavage-resistant mutants in hippocampal neurons, spine density quantification","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with defined functional readout (spine density), single lab","pmids":["22118475"],"is_preprint":false},{"year":2007,"finding":"Nectin-1 regulates loricrin expression in epidermal keratinocytes through Ca2+-induced activation of Rap1-ERK signaling: nectin-1-null mice show markedly reduced loricrin and impaired cornified envelope integrity; Ca2+-induced ERK activation through Rap1 and loricrin expression were reduced in nectin-1-null primary keratinocytes; ERK inhibition in wild-type keratinocytes reduced loricrin levels.","method":"Nectin-1-null mouse model, western blotting for loricrin/SPRR/repetin, primary keratinocyte culture, ERK inhibitor (PD98059), Ca2+ stimulation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout model with pathway-level mechanistic dissection (Rap1-ERK) using pharmacological and genetic approaches","pmids":["17472964"],"is_preprint":false},{"year":2008,"finding":"Absence of nectin-1 in mice causes defective enamel formation: nectin-1-null mice exhibit hypomineralized incisors with separation at the stratum intermedium (SI)-ameloblast interface; nectin-1 is normally localized at this interface; desmosomes at the interface are smaller and less numerous in nectin-1-null mice, indicating nectin-1 participates in desmosome assembly between SI and ameloblasts.","method":"Nectin-1-null mouse model, immunohistochemistry, electron microscopy of desmosome morphology, enamel composition analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout model with ultrastructural (EM) and immunohistochemical evidence linking nectin-1 to desmosome regulation","pmids":["18703497"],"is_preprint":false},{"year":2010,"finding":"Heterophilic interaction between nectin-1 (expressed in ameloblasts) and nectin-3 (expressed in stratum intermedium cells) is required for normal enamel formation and recruits desmosomal junctions at the SI-ameloblast interface; nectin-1;nectin-3 compound mutant mice show severely reduced SI-ameloblast desmosomes and defective enamel.","method":"Single and compound nectin-1/nectin-3 null mouse models, immunohistochemistry, electron microscopy","journal":"Developmental dynamics","confidence":"High","confidence_rationale":"Tier 2 / Strong — compound knockout with ultrastructural characterization, corroborates nectin-1/desmosome findings from PMID:18703497","pmids":["21038445"],"is_preprint":false},{"year":2009,"finding":"Nectin-1 is required for HSV infection of neurons in the CNS and development of encephalitis: nectin-1 KO mice showed no signs of encephalitis and no HSV antigens in brain parenchyma after intracranial inoculation, while HVEM KO mice were indistinguishable from wild-type. HVEM KO/nectin-1 KO double-KO abolished all infection including ventricle-lining cells.","method":"Single and double KO mouse models (nectin-1 KO, HVEM KO), intracranial HSV inoculation, immunohistochemistry for viral antigens","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic ablation with multiple KO combinations establishing receptor hierarchy in CNS infection","pmids":["19805039"],"is_preprint":false},{"year":2015,"finding":"Nectin-1 transcription is directly regulated by the transcription factor p63: p63-null mouse skin shows strongly reduced Pvrl1/nectin-1 expression; chromatin immunoprecipitation (ChIP) shows p63 binds two conserved intronic Pvrl1 enhancer regions; siRNA depletion of p63 downregulates nectin-1 in keratinocytes.","method":"p63-null mouse model, ChIP, siRNA knockdown of p63, RT-qPCR","journal":"Experimental dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic (KO, siRNA) and ChIP evidence demonstrating direct transcriptional regulation","pmids":["25387952"],"is_preprint":false},{"year":2004,"finding":"Nectin-1 forms heterodimers with nectin-3 that adhere more strongly than homodimers; nectin-3 that cannot trans-interact with nectin-1 inhibits E-cadherin-mediated adhesion; trans-interaction of nectin-1 with high-level nectin-3 does not have an agonistic effect on E-cadherin adhesion, whereas trans-interaction of nectin-3 with low-level endogenous nectin-1 has a significant agonistic effect on cadherin-based adhesion.","method":"Dual pipette force-separation assay for cell doublets expressing nectin-1, nectin-3, E-cadherin in L cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct force measurement with defined cell lines, single lab with multiple cell combinations","pmids":["15550395"],"is_preprint":false},{"year":2013,"finding":"Nectin-1 in the ventral hippocampus plays a key role in contextual fear memory consolidation: nectin-1 protein was transiently upregulated in synapse-enriched ventral (but not dorsal) hippocampal fractions ~2 h after contextual fear conditioning; infusion of anti-nectin-1 antibody (R165) into the ventral hippocampus immediately after training impaired contextual fear memory without affecting acoustic memory or anxiety.","method":"Synaptoneurosmal fractionation and Western blot, intra-hippocampal antibody infusion, contextual vs. auditory fear conditioning behavioral assays in rats","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization to synaptoneurosomal fraction with functional manipulation and behavioral readout, single lab","pmids":["23418609"],"is_preprint":false},{"year":2019,"finding":"Human nectin-1 directly interacts with the NK cell receptor CD96; the binding site is on the nectin-1 V-domain at the canonical nectin adhesive interface; the affinity of nectin-1 for CD96 is lower than for nectin-3 or nectin-1 itself but comparable to that for HSV gD. Overexpression of nectin-1 in K562 cells increased susceptibility to NK-92 cell cytotoxicity.","method":"In vitro direct binding assay (SPR), cell surface expression of nectin-1-GFP in K562 cells, NK cytotoxicity assay, HSV infection assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SPR direct binding with defined affinity, functional NK cytotoxicity assay, single lab","pmids":["30759143"],"is_preprint":false},{"year":2022,"finding":"NECTIN1 loss stimulates melanoma cell migration and spreading specifically in response to decreased IGF1 signaling; in human melanoma specimens, adherens junctions were present only in areas with low IGF1 levels and absent in NECTIN1-deficient tumors, establishing NECTIN1 as a determinant of melanoma dissemination gated on IGF1 microenvironmental signals.","method":"Genetic NECTIN1 inactivation in zebrafish and human melanoma xenograft models, in vitro migration assays, analysis of human biopsy specimens with dual staining","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model (zebrafish and xenograft) plus human specimen analysis with multiple orthogonal approaches","pmids":["36229674"],"is_preprint":false},{"year":2022,"finding":"Nectin-1 and NMHC-IIB are the major mediators of HSV-1 entry into corneal nerves: both are expressed in corneal nerves and TG neurons; siRNA knockdown of nectin-1 or NMHC-IIB each reduced HSV-1 entry and replication; HSV-1 exposure upregulated NMHC-IIB and this upregulation was inhibited when nectin-1 (gD receptor) was knocked down, establishing that nectin-1 engagement drives NMHC-IIB upregulation and facilitates gB-dependent entry.","method":"siRNA knockdown of nectin-1 and NMHC-IIB in TG neuron cultures, in vivo corneal nerve antibody blocking, qPCR, immunofluorescence","journal":"Frontiers in microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA and antibody blocking in both in vitro neurons and in vivo corneal model, single lab","pmids":["35295302"],"is_preprint":false},{"year":2021,"finding":"Nectin-1 is an entry mediator for varicella-zoster virus (VZV) in human neurons: knockdown of endogenous nectin-1 or addition of soluble nectin-1 (during but not after infection) markedly decreased VZV infectivity; ectopic expression of human nectin-1 in a VZV-resistant cell line conferred susceptibility.","method":"siRNA knockdown, soluble nectin-1 addition assay, ectopic expression in resistant cell line, iPSC-derived human neuronal model","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — three orthogonal approaches (knockdown, soluble receptor competition, ectopic expression) in a human neuronal model","pmids":["34468169"],"is_preprint":false},{"year":2008,"finding":"Nectin-1 is degraded by the Chlamydia trachomatis-secreted protease CPAF: nectin-1 half-life is greatly reduced in infected cells; cell-free assays show recombinant GST-CPAF degrades nectin-1; this degradation is blocked by lactacystin (CPAF inhibitor) but not by the proteasome inhibitor MG132; nectin-1 downregulation is post-transcriptional.","method":"Western blot for nectin-1 levels and half-life in infected cells, lactacystin/MG132 pharmacological inhibition, cell-free CPAF cleavage assay with recombinant protein","journal":"Microbes and infection","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted cell-free cleavage assay with recombinant CPAF plus in-cell pharmacological validation","pmids":["18983929"],"is_preprint":false},{"year":2016,"finding":"HSV gD disrupts intercellular homophilic trans-interaction of nectin-1 and induces rapid redistribution of nectin-1 from cell junctions; this does not require nectin-1/afadin interaction. Interaction with afadin is also dispensable for virion surfing along nectin-1-rich filopodia.","method":"Fluorescence microscopy of nectin-1-GFP redistribution upon gD-coated surface or gD-expressing cell contact, afadin-binding mutants, filopodia surfing assay","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging with afadin-binding mutants and gD-coated surface assay, single lab","pmids":["27723487"],"is_preprint":false},{"year":2013,"finding":"HVEM and nectin-1 elicit non-reciprocal competition for binding to gD: nectin-1 induces a new N-terminal conformation of gD distinct from the HVEM-induced N-terminal hairpin. HVEM function is affected by mutations that impair hairpin formation. Nectin-1 binding actively modifies the gD N-terminal conformation.","method":"Binding competition assays (ELISA/FACS), gD mutants with engineered disulfide bonds, functional entry/fusion assays","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with competition binding, single lab","pmids":["24314649"],"is_preprint":false},{"year":2020,"finding":"Disruption of the nectin-afadin complex in palatal epithelium causes cleft palate: lentiviral-mediated conditional loss of afadin (nectin's obligate binding partner) in palatal epithelium induces high-penetrance cleft palate; loss of Nectin1 or Nectin4 alone causes mild palate closure defects, but combined loss causes severe cleft palate similar to afadin loss. A human disease NECTIN1 mutant causes cleft palate at higher penetrance than complete loss, suggesting dominant-interfering mechanism.","method":"In utero lentiviral gene delivery, conditional Afdn deletion, Nectin1/Nectin4 single and double loss-of-function in mice, palate phenotype scoring","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis with multiple allele combinations and human disease mutant validation","pmids":["32554531"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of HSV-2 gD bound to nectin-1 reveals a conserved binding mode identical to HSV-1 gD: nectin-1 I80 is an important gD-interacting residue; nectin-1 mutations similarly affect binding of both HSV-1 and HSV-2 gDs; cross-inhibition by soluble HSV-1/HSV-2 gDs in cell-based fusion assay confirmed the shared recognition mode.","method":"X-ray crystallography of free and nectin-1-bound HSV-2 gD, SPR mutagenesis of nectin-1 interface residues, cell-based fusion assay with soluble gD inhibition","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with SPR mutagenesis and functional fusion assay validation","pmids":["25231300"],"is_preprint":false},{"year":2022,"finding":"Disrupted presynaptic nectin-1 in the medial entorhinal cortex (MEC)-CA1 pathway contributes to early-life stress-induced memory deficits: neonatal stress reduced nectin-1 in MEC; conditional inactivation of nectin-1 in MEC excitatory neurons reproduced stress-induced spatial memory deficits and CA1 neuronal plasticity deficits in mice.","method":"Neonatal stress model, conditional nectin-1 inactivation in MEC (Cre-lox), memory behavioral assays, synaptic fractionation and protein quantification","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional genetic inactivation in a defined circuit with behavioral and structural readouts, single lab","pmids":["35379771"],"is_preprint":false}],"current_model":"NECTIN1/nectin-1 is a Ca2+-independent immunoglobulin-superfamily cell adhesion molecule that forms cis-dimers through its first Ig-like (V) domain and mediates homophilic and heterophilic (with nectin-3, nectin-4, CD96, FGFR) trans-interactions at adherens junctions; as the principal entry receptor for HSV-1/2, VZV, and other alphaherpesviruses, its V-domain (residues 64-94, especially the CC′ ridge and key residues including F129) is bound by viral glycoprotein D at the same surface used for nectin-nectin adhesion, triggering gD conformational changes, displacement of nectin-1 from junctions, and Cbl E3-ligase/ICP0-dependent internalization and degradation of the receptor to facilitate viral spread; in neurons, nectin-1 undergoes activity-dependent ADAM10-mediated alpha-cleavage regulated by NMDA-receptor Ca2+/calmodulin signaling, and its ectodomain shedding controls dendritic spine density; in keratinocytes it signals through Rap1-ERK to drive loricrin expression; and its interaction with afadin is required for palate morphogenesis, enamel formation (through nectin-1/nectin-3 heterophilic desmosome recruitment), and melanoma cell spreading in an IGF1-sensitive manner."},"narrative":{"mechanistic_narrative":"NECTIN1 (nectin-1) is a Ca2+-independent immunoglobulin-superfamily cell adhesion molecule that builds and maintains adherens junctions through self-association and heterophilic engagement of partner nectins, and is exploited as the principal entry receptor for human alphaherpesviruses [PMID:21325282, PMID:19805039]. Its extracellular region forms a V-shaped cis-dimer through the first Ig-like (V) domain, and four residues in this domain are required for cis-dimerization and for both homophilic and heterophilic adhesion [PMID:21325282]. The same V-domain surface mediates high-affinity trans-heterointeractions with nectin-3 (~1 nM) and nectin-4 (~100 nM) at the C-C'-C\"-D beta-strands, far exceeding the homophilic affinity [PMID:12011057], and these interactions drive tissue morphogenesis: nectin-1/nectin-3 heterophilic engagement recruits desmosomes at the ameloblast-stratum intermedium interface to enable enamel formation [PMID:18703497, PMID:21038445], the nectin-afadin complex is required for palate closure [PMID:32554531], and in keratinocytes nectin-1 drives loricrin expression and cornified-envelope integrity via Ca2+-induced Rap1-ERK signaling [PMID:17472964]. Crystallographic studies show that HSV glycoprotein D binds the V-domain at the very surface used for nectin homodimerization, with Phe129 inserting into a gD groove, so that gD binding precludes nectin-1 dimerization and adhesion; F129A abolishes both gD binding and viral entry [PMID:21980294, PMID:22146396]. Beyond serving as a docking site, gD engagement actively disrupts nectin-1 trans-interactions and redistributes the receptor from junctions [PMID:27723487], and triggers receptor down-regulation through internalization and lysosomal degradation, executed in infected cells by a Cbl E3-ligase/ICP0-dependent pathway [PMID:18076965, PMID:28381567]. In the nervous system, nectin-1 is required for HSV CNS infection and for VZV entry into human neurons [PMID:19805039, PMID:34468169], signals through FGFR via its membrane-proximal Ig3 module to promote neurite outgrowth and survival [PMID:22955284], and undergoes NMDA-receptor/Ca2+/calmodulin-driven ADAM10 alpha-cleavage whose ectodomain shedding controls dendritic spine density [PMID:20501653, PMID:22118475]. Nectin-1 also binds the NK receptor CD96 at its adhesive interface [PMID:30759143] and acts as a determinant of melanoma dissemination gated on IGF1 signaling [PMID:36229674].","teleology":[{"year":1998,"claim":"Establishing which part of nectin-1 supports HSV entry localized both the viral receptor function and the gD-binding activity to a single domain, defining the molecular target for entry.","evidence":"mAb epitope mapping, soluble V-domain competition, deletion constructs, and in vitro gD binding","pmids":["9861033"],"confidence":"High","gaps":["Structural basis of the V-domain/gD contact not resolved","Did not address adhesion function of the same domain"]},{"year":2002,"claim":"Fine-mapping defined the precise residues and beta-strand segments of the V domain used for HSV entry and showed they overlap the heterophilic nectin-binding surface, revealing competition between adhesion and viral hijacking.","evidence":"Nectin-1/PVR chimeric receptors, residue 77/85 mutagenesis, CC' ridge transfer, and SPR/competition binding with gD and nectin-3/4","pmids":["11483743","12072525","12359441","12011057"],"confidence":"High","gaps":["Atomic detail awaited crystallographic confirmation","Functional consequence of gD-induced adhesion loss not yet measured"]},{"year":2001,"claim":"Defining nectin-1's heterophilic partners and their relative affinities established its physiological adhesion repertoire and the affinity hierarchy that the virus must overcome.","evidence":"Fc-fusion binding to transfected cells, co-IP, and quantitative SPR with chimeric receptors","pmids":["11544254","12011057"],"confidence":"High","gaps":["Downstream signaling from heterophilic engagement not addressed","In vivo relevance of affinity differences untested at this stage"]},{"year":2000,"claim":"Showing nectin-1 mediates direct cell-to-cell viral spread, not just free-virion entry, expanded its role from a docking molecule to a determinant of viral propagation through tissue.","evidence":"Cell-to-cell spread assays in nectin-1-expressing J cells with mAb blocking and receptor-null contact controls","pmids":["10729168"],"confidence":"High","gaps":["Mechanism by which junctional receptor is repurposed for spread unresolved","Did not address syncytial fusion"]},{"year":2004,"claim":"Linking nectin-1 subcellular localization to entry pathway showed that the same receptor routes HSV through plasma-membrane or acidic-endosome entry depending on where it sits, explaining cell-type-dependent entry routes.","evidence":"Confocal localization, calcium depletion, chimeric receptors targeting endosomes/lipid rafts, and endosome-acidification inhibitors","pmids":["12072519","15507614"],"confidence":"High","gaps":["Endogenous signals controlling localization not defined","Generality across natural tissues untested"]},{"year":2010,"claim":"Identifying gD-induced internalization and lysosomal degradation of nectin-1 revealed an active receptor-removal mechanism distinct from passive sequestration, with isoform-independence implicating an extracellular trigger.","evidence":"Co-culture down-regulation assays, flow cytometry, endocytosis inhibitors, and cytoplasmic-tail deletion constructs","pmids":["18076965","20089288"],"confidence":"High","gaps":["Ubiquitin ligase mediating degradation not yet identified at this stage","Functional benefit to the virus inferred but not directly tested"]},{"year":2011,"claim":"Crystal structures of the nectin-1 ectodomain and the gD/nectin-1 complex established that gD occupies the homodimerization surface, providing a unified structural basis for receptor usage and adhesion blockade.","evidence":"X-ray crystallography of free and gD-bound nectin-1 with structure-based mutagenesis (F129A, dimer-interface residues) and entry/adhesion assays","pmids":["21325282","21980294","22146396"],"confidence":"High","gaps":["Dynamics of dimer-to-gD switching not captured","Conformational changes in gD inferred from static structures"]},{"year":2017,"claim":"Identifying Cbl and ICP0 as the effectors of nectin-1 removal closed the loop on the degradation mechanism, defining the host-viral machinery that strips the receptor to favor spread.","evidence":"Co-IP of Cbl/nectin-1/gD complex, siRNA depletion with surface-receptor and entry readouts, and ΔICP0 viral mutant","pmids":["28381567"],"confidence":"High","gaps":["Direct ubiquitination of nectin-1 not demonstrated","Role of CIN85 not fully resolved"]},{"year":2009,"claim":"In vivo receptor-knockout hierarchy established nectin-1 as the essential receptor for HSV neuronal infection and encephalitis, distinguishing it from HVEM in the CNS.","evidence":"Single and double nectin-1/HVEM knockout mice with intracranial HSV inoculation and viral antigen immunohistochemistry","pmids":["19805039"],"confidence":"High","gaps":["Receptor usage in peripheral entry not addressed","Neuron-subtype specificity not resolved"]},{"year":2021,"claim":"Extending receptor function to VZV in human neurons broadened nectin-1's role across alphaherpesviruses and into authentic human neuronal models.","evidence":"siRNA knockdown, soluble nectin-1 competition, and ectopic expression in a resistant line using iPSC-derived neurons","pmids":["34468169"],"confidence":"High","gaps":["VZV glycoprotein engaging nectin-1 not defined","Structural basis of VZV recognition unknown"]},{"year":2007,"claim":"Knockout phenotyping in skin revealed nectin-1 as an upstream regulator of terminal keratinocyte differentiation through Rap1-ERK-driven loricrin expression, moving beyond pure adhesion into signaling.","evidence":"Nectin-1-null mice, primary keratinocyte Ca2+ stimulation, ERK inhibition, and loricrin/cornified-envelope analysis","pmids":["17472964"],"confidence":"High","gaps":["Direct link between nectin-1 ligation and Rap1 activation not biochemically traced","Receptor partner driving the signal not identified"]},{"year":2010,"claim":"Mouse genetics defined nectin-1 (and its heterophilic partner nectin-3) as organizers of desmosome recruitment at the ameloblast interface required for enamel mineralization, connecting heterophilic adhesion to tissue architecture.","evidence":"Single and compound nectin-1/nectin-3 null mice with immunohistochemistry and electron microscopy of desmosomes","pmids":["18703497","21038445"],"confidence":"High","gaps":["Molecular link between nectin engagement and desmosome assembly unresolved","Signaling intermediates not identified"]},{"year":2012,"claim":"Discovery that the membrane-proximal Ig3 module binds and activates FGFR added a receptor-tyrosine-kinase signaling output to nectin-1, mechanistically grounding its neurotrophic effects.","evidence":"NMR structure of Ig3, SPR binding to FGFR isoforms, FGFR phosphorylation, and neurite outgrowth/survival assays with inhibitors and dominant-negative FGFR","pmids":["22955284"],"confidence":"High","gaps":["Stoichiometry and cis/trans context of nectin-1/FGFR complex in vivo not defined","Relationship to adhesion-mediated signaling unclear"]},{"year":2011,"claim":"Linking NMDA-receptor-driven ADAM10 cleavage and ectodomain shedding to dendritic spine density established nectin-1 processing as an activity-dependent regulator of synaptic structure.","evidence":"Cortical/hippocampal neuron stimulation, Ca2+/calmodulin pharmacology, ADAM10 knockout/knockdown, cleavage-site alanine scanning, and spine-density quantification","pmids":["20501653","22118475","18181141"],"confidence":"High","gaps":["Fate and signaling of the shed ectodomain unresolved","Causal link from spine changes to behavior not established here"]},{"year":2022,"claim":"Circuit-level genetic manipulations tied presynaptic nectin-1 in defined hippocampal/entorhinal pathways to fear and spatial memory consolidation, advancing its synaptic adhesion role into cognition.","evidence":"Synaptoneurosomal fractionation, intra-hippocampal antibody infusion, conditional MEC nectin-1 inactivation, and behavioral memory assays","pmids":["23418609","35379771"],"confidence":"Medium","gaps":["Synaptic partner mediating the memory effect not identified","Single-lab findings for each circuit"]},{"year":2019,"claim":"Identifying CD96 as a nectin-1 binding partner at the adhesive interface and showing modulation of NK cytotoxicity extended nectin-1's interaction network into immune recognition.","evidence":"SPR direct binding, K562 nectin-1 overexpression, and NK-92 cytotoxicity assay","pmids":["30759143"],"confidence":"Medium","gaps":["Physiological context of nectin-1/CD96 signaling unknown","Single-lab functional evidence"]},{"year":2020,"claim":"Genetic epistasis in palatal epithelium placed nectin-1 and nectin-4 downstream of the nectin-afadin adhesion complex in palate morphogenesis and revealed a human disease mutation acting by dominant interference.","evidence":"In utero lentiviral conditional Afdn deletion, Nectin1/Nectin4 single and double loss-of-function in mice, and human NECTIN1 mutant analysis","pmids":["32554531"],"confidence":"High","gaps":["Molecular basis of the dominant-interfering mutant not dissected","Downstream signaling in palatal fusion unresolved"]},{"year":2022,"claim":"Demonstrating that NECTIN1 loss promotes melanoma migration specifically under low IGF1 signaling defined a microenvironment-gated tumor-suppressive adhesion function.","evidence":"NECTIN1 inactivation in zebrafish and human xenograft models, migration assays, and dual-stained human biopsy analysis","pmids":["36229674"],"confidence":"High","gaps":["Mechanistic link between IGF1 signaling and nectin-1-dependent junctions unresolved","Adhesion partner mediating tumor suppression not identified"]},{"year":null,"claim":"How nectin-1 integrates its adhesion, FGFR-coupled signaling, ectodomain shedding, and immune (CD96) functions into a unified context-dependent signaling logic across epithelia, neurons, and tumors remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No single framework reconciling adhesion vs. signaling outputs","Cis/trans determinants selecting between partners not defined","Endogenous ligand controlling localization-dependent function unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2,11,26]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,9,24,31]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[18,21]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,8,14]}],"pathway":[{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[24,29,35]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[21,22,23,35]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[18,21]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[12,18,27,37]}],"complexes":["nectin-afadin complex","adherens junction"],"partners":["NECTIN-3","NECTIN-4","AFADIN","FGFR","CD96","CBL","E-CADHERIN","ADAM10"],"other_free_text":[]}},"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":"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":275,"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":"12011057","id":"PMC_12011057","title":"Prominent role of the Ig-like V domain in trans-interactions of nectins. Nectin3 and nectin 4 bind to the predicted C-C'-C\"-D beta-strands of the nectin1 V domain.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12011057","citation_count":118,"is_preprint":false},{"pmid":"15110526","id":"PMC_15110526","title":"Comparative usage of herpesvirus entry mediator A and nectin-1 by laboratory strains and clinical isolates of herpes simplex virus.","date":"2004","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/15110526","citation_count":118,"is_preprint":false},{"pmid":"20543867","id":"PMC_20543867","title":"miR-661 expression in SNAI1-induced epithelial to mesenchymal transition contributes to breast cancer cell invasion by targeting Nectin-1 and StarD10 messengers.","date":"2010","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/20543867","citation_count":107,"is_preprint":false},{"pmid":"9861033","id":"PMC_9861033","title":"The V domain of herpesvirus Ig-like receptor (HIgR) contains a major functional region in herpes simplex virus-1 entry into cells and interacts physically with the viral glycoprotein D.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9861033","citation_count":106,"is_preprint":false},{"pmid":"12915538","id":"PMC_12915538","title":"Mutations in the N termini of herpes simplex virus type 1 and 2 gDs alter functional interactions with the entry/fusion receptors HVEM, nectin-2, and 3-O-sulfated heparan sulfate but not with nectin-1.","date":"2003","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/12915538","citation_count":98,"is_preprint":false},{"pmid":"10729168","id":"PMC_10729168","title":"Cell-to-cell spread of wild-type herpes simplex virus type 1, but not of syncytial strains, is mediated by the immunoglobulin-like receptors that mediate virion entry, nectin1 (PRR1/HveC/HIgR) and nectin2 (PRR2/HveB).","date":"2000","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/10729168","citation_count":94,"is_preprint":false},{"pmid":"22146396","id":"PMC_22146396","title":"Binding of herpes simplex virus glycoprotein D to nectin-1 exploits host cell adhesion.","date":"2011","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/22146396","citation_count":92,"is_preprint":false},{"pmid":"12072519","id":"PMC_12072519","title":"Disruption of adherens junctions liberates nectin-1 to serve as receptor for herpes simplex virus and pseudorabies virus entry.","date":"2002","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/12072519","citation_count":92,"is_preprint":false},{"pmid":"4128383","id":"PMC_4128383","title":"Characteristics and purification of PRR1, an RNA phage specific for the broad host range Pseudomonas R1822 drug resistance plasmid.","date":"1973","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/4128383","citation_count":90,"is_preprint":false},{"pmid":"17971293","id":"PMC_17971293","title":"The murine pan T cell marker CD96 is an adhesion receptor for CD155 and nectin-1.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17971293","citation_count":79,"is_preprint":false},{"pmid":"15507614","id":"PMC_15507614","title":"Entry of herpes simplex virus mediated by chimeric forms of nectin1 retargeted to endosomes or to lipid rafts occurs through acidic endosomes.","date":"2004","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/15507614","citation_count":76,"is_preprint":false},{"pmid":"19805039","id":"PMC_19805039","title":"Infection of neurons and encephalitis after intracranial inoculation of herpes simplex virus requires the entry receptor nectin-1.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19805039","citation_count":76,"is_preprint":false},{"pmid":"15613355","id":"PMC_15613355","title":"Potential nectin-1 binding site on herpes simplex virus glycoprotein d.","date":"2005","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/15613355","citation_count":75,"is_preprint":false},{"pmid":"28542478","id":"PMC_28542478","title":"Structural basis of nectin-1 recognition by pseudorabies virus glycoprotein D.","date":"2017","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/28542478","citation_count":71,"is_preprint":false},{"pmid":"14963155","id":"PMC_14963155","title":"In vivo role of nectin-1 in entry of herpes simplex virus type 1 (HSV-1) and HSV-2 through the vaginal mucosa.","date":"2004","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/14963155","citation_count":68,"is_preprint":false},{"pmid":"18502984","id":"PMC_18502984","title":"HVEM and nectin-1 are the major mediators of herpes simplex virus 1 (HSV-1) entry into human conjunctival epithelium.","date":"2008","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/18502984","citation_count":67,"is_preprint":false},{"pmid":"30224769","id":"PMC_30224769","title":"Enhanced Sensitivity of Patient-Derived Pediatric High-Grade Brain Tumor Xenografts to Oncolytic HSV-1 Virotherapy Correlates with Nectin-1 Expression.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30224769","citation_count":67,"is_preprint":false},{"pmid":"12885915","id":"PMC_12885915","title":"Cellular localization of nectin-1 and glycoprotein D during herpes simplex virus infection.","date":"2003","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/12885915","citation_count":64,"is_preprint":false},{"pmid":"10348908","id":"PMC_10348908","title":"A fission yeast gene (prr1(+)) that encodes a response regulator implicated in oxidative stress response.","date":"1999","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10348908","citation_count":61,"is_preprint":false},{"pmid":"18703497","id":"PMC_18703497","title":"The cell adhesion molecule nectin-1 is critical for normal enamel formation in mice.","date":"2008","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18703497","citation_count":55,"is_preprint":false},{"pmid":"18076965","id":"PMC_18076965","title":"The herpes simplex virus receptor nectin-1 is down-regulated after trans-interaction with glycoprotein D.","date":"2008","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/18076965","citation_count":54,"is_preprint":false},{"pmid":"15550395","id":"PMC_15550395","title":"Separation force measurements reveal different types of modulation of E-cadherin-based adhesion by nectin-1 and -3.","date":"2004","source":"The Journal of biological 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epitope mapping, soluble V-domain competition assay, engineered deletion constructs expressing V domain alone, in vitro pulldown/binding assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 / Strong — multiple orthogonal methods (mAb blocking, soluble domain competition, deletion constructs, in vitro binding) in a single focused study establishing the V-domain mechanism\",\n      \"pmids\": [\"9861033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Nectin-4 trans-interacts with nectin-1 through V-domain interactions; nectin-1-Fc precipitates nectin-4, nectin4-Fc binds nectin-1-expressing cells but not cells expressing nectin-2, nectin-3, or PVR, and reciprocal in vitro physical interactions were detected between nectin4-Fc and nectin1-Fc. The V domain of nectin-1 was identified as the major functional region for trans-heterointeraction with nectin-4 (and nectin-3).\",\n      \"method\": \"Soluble Fc-fusion binding to transfected cells, co-immunoprecipitation, in vitro Fc-fusion binding assay, inhibition by anti-V-domain mAbs and HSV gD\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays, co-IP, and mAb/gD competition providing multiple orthogonal lines of evidence\",\n      \"pmids\": [\"11544254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Nectin-3 and nectin-4 both bind to the C-C'-C\\\"-D beta-strands of the nectin-1 V domain for trans-heterointeraction; the KD of nectin-1/nectin-3 interaction is ~1 nM and nectin-1/nectin-4 is ~100 nM, whereas nectin-1 homophilic interaction is ~1 μM. HSV gD, which also binds the nectin-1 V domain, competed with nectin-3 and nectin-4 binding.\",\n      \"method\": \"SPR/affinity measurements, competition binding with soluble Fc-fusions and mAbs, chimeric nectin1/PVR receptors with substituted beta-strands\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 / Strong — quantitative binding measurements combined with chimeric receptor mapping and competition studies, multiple orthogonal approaches\",\n      \"pmids\": [\"12011057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The HSV entry site on nectin-1 maps entirely to residues 64-94 (the predicted CC'C\\\" region of the V domain), with a minimal entry site at residues 77-94 and a region 64-76 that greatly enhances entry activity; the gD-binding site maps to the same region. This was established using nectin-1/PVR chimeric receptors.\",\n      \"method\": \"Nectin-1/PVR chimeric receptor constructs tested for HSV entry activity and gD binding in cell-based assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic chimeric receptor mapping with functional entry readout and binding correlation\",\n      \"pmids\": [\"11483743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Amino acids 77 and 85 of the nectin-1 V domain are critical specifically for HSV-1 and HSV-2 entry and gD binding, but not for PRV or BHV-1 entry; simultaneous substitution of both residues eliminates HSV gD binding while leaving PRV/BHV-1 entry intact, demonstrating partially overlapping but distinct binding sites for different herpesvirus gDs on nectin-1.\",\n      \"method\": \"Site-directed mutagenesis of nectin-1 residues 77 and 85, HSV entry assays, soluble gD binding assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 / Strong — mutagenesis combined with functional entry assay and direct gD binding, multiple virus serotypes tested\",\n      \"pmids\": [\"12072525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The CC' ridge of nectin-1 (residues 65-76, specifically 69-71 and 72-75) is sufficient to confer wild-type HSV-1 and BHV-1 entry activity and enhances HSV-2, PRV, and HSV-HSV(U21) entry when transferred to nectin-2. The full HSV entry site is composed of two synergistic contiguous regions: 64-76 and 77-94.\",\n      \"method\": \"Transfer of nectin-1 residue segments to nectin-2 by mutagenesis, HSV entry assays\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic mutagenesis/domain-transfer with functional entry readouts across multiple viruses\",\n      \"pmids\": [\"12359441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Nectin-1 (both alpha and delta isoforms) mediates direct cell-to-cell spread of wild-type HSV-1, not merely free virion entry; an anti-nectin-1 mAb that blocks entry also blocks spread; wild-type virus does not spread from a receptor-positive to a receptor-negative cell. Nectin-1 does not mediate cell fusion by syncytial HSV strains.\",\n      \"method\": \"Cell-to-cell spread assays in J cells expressing nectin-1 isoforms, mAb blocking, receptor-positive to receptor-negative cell contact assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell line experiments with receptor-null controls and specific mAb blocking establishing both entry and spread functions\",\n      \"pmids\": [\"10729168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Nectin-1 co-localizes with E-cadherin at adherens junctions in epithelial cells (MDCK); disruption of adherens junctions by calcium depletion redistributes nectin-1 over the entire cell surface and enhances both gD binding and HSV/PRV infection efficiency, demonstrating that nectin-1 confined to junctions is less accessible as a virus entry receptor.\",\n      \"method\": \"Confocal microscopy of nectin-1 localization, calcium depletion, soluble gD binding assay, HSV/PRV infection quantification\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization tied to functional consequence (infection efficiency), multiple viruses tested\",\n      \"pmids\": [\"12072519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"During HSV infection, gD expression dramatically alters nectin-1 localization at adherens junctions: nectin-1 and gD co-localize at cell contact areas between infected and uninfected cells. Newly synthesized gD substitutes for nectin-1 of infected cells at junctions with non-infected cells, maintaining nectin-1 at junctions for virus spread. The nectin-1/afadin interaction is not required for HSV entry or spread.\",\n      \"method\": \"Fluorescence/confocal microscopy of nectin-1-GFP fusions during HSV infection, co-localization studies, afadin interaction experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live cell imaging with GFP fusions plus functional spread assays, negative result on afadin requirement also established\",\n      \"pmids\": [\"12885915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of HSV-1 gD bound to nectin-1 (4.0 Å): the nectin-1 V-domain's canonical homophilic interaction surface (first Ig domain, including Phe129 at the FG loop tip) is the gD binding site; Phe129 inserts into a groove on gD normally occupied by the gD C-terminal region; mutation F129A prevents nectin-1 binding to gD and HSV entry.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis (F129A), HSV entry assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation by mutagenesis in a single study\",\n      \"pmids\": [\"21980294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of gD/nectin-1 complex reveals that gD binds the first Ig domain of nectin-1 using the same surface that mediates nectin-1 homodimerization; key amino acids responsible for nectin-1 dimerization are also used for gD/nectin-1 binding, indicating that gD binding precludes nectin-1 dimerization and its cell adhesion function.\",\n      \"method\": \"X-ray crystallography of gD/nectin-1 complex, structural analysis of dimerization interface\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure showing shared binding interface, corroborated by independent study (PMID:21980294)\",\n      \"pmids\": [\"22146396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of the entire nectin-1 extracellular region reveals a V-shaped cis-dimer formed through the first Ig-like domain (not the second as previously thought). Structure-based mutagenesis identified four essential residues in the first Ig domain required for cis-dimerization; mutating them reduced cis-dimerization on cell surfaces and abolished both homophilic and heterophilic adhesion activities.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis of dimerization interface, cell surface adhesion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis and functional cell adhesion validation\",\n      \"pmids\": [\"21325282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NMDA receptor activation triggers robust alpha- and gamma-secretase cleavage of nectin-1 in mature cortical neurons; this requires Ca2+ influx through NMDA receptors and calmodulin activation but not CaMKII. ADAM10 was identified as the major alpha-secretase (metalloprotease) responsible for nectin-1 ectodomain cleavage in neurons and brain.\",\n      \"method\": \"Primary cortical neuron stimulation with NMDA/AMPA/mGluR agonists, Ca2+ chelation, calmodulin inhibitor, ADAM10 knockout/knockdown, Western blotting for cleavage products\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological dissection plus genetic (KO) identification of the secretase with multiple orthogonal approaches\",\n      \"pmids\": [\"20501653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Trans-interaction of gD with nectin-1 causes nectin-1 down-regulation by internalization and low-pH-dependent lysosomal degradation in cells where HSV enters by endocytosis (B78H1-C10, SY5Y, A431, HeLa); on Vero cells (plasma membrane entry), nectin-1 is not down-regulated. Down-regulation requires gD binding to nectin-1 and is linked to virion internalization.\",\n      \"method\": \"Co-culture of gD-expressing cells with nectin-1 expressing cells, flow cytometry/Western blot for nectin-1 levels, bafilomycin/NH4Cl treatment, virion internalization assay\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type comparison with endocytosis inhibitors, receptor binding correlation, and virion internalization assay\",\n      \"pmids\": [\"18076965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Virion gD actively induces rapid internalization of both nectin-1alpha and nectin-1beta isoforms despite different cytoplasmic tails; deletion of the nectin-1 cytoplasmic tail slows but does not abolish down-regulation. Nectin-1 is not constitutively recycled in uninfected cells, indicating that gD binding specifically triggers internalization.\",\n      \"method\": \"Flow cytometry of surface nectin-1, virion entry kinetics, cytoplasmic tail deletion constructs\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comparison of wild-type and deletion isoforms with kinetic internalization assay\",\n      \"pmids\": [\"20089288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cbl E3 ligase mediates the removal of nectin-1 from the surface of HSV-1-infected cells: Cbl, nectin-1, and viral gD form a complex in infected cells; depletion of Cbl retains nectin-1 on the cell surface and enhances viral entry; Cbl-mediated nectin-1 removal also requires ICP0 (ΔICP0 mutant virus leaves nectin-1 on the surface).\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of Cbl/CIN85, flow cytometry for surface nectin-1, infection assays with ΔICP0 virus\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP of complex, genetic knockdown with functional readout, viral mutant validation\",\n      \"pmids\": [\"28381567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Nectin-1 confined to adherens junctions in epithelial cells is less accessible to virion gD; chimeric nectin-1 targeted to endosomes (nectin1-EGFR1) or lipid rafts (GPI-anchored) routes HSV to an acidic endosomal entry pathway blocked by wortmannin and bafilomycin/NH4Cl. The same receptor can initiate different HSV entry pathways depending on its cellular localization.\",\n      \"method\": \"Chimeric receptor constructs (nectin1-EGFR1, GPI-nectin1), endosome acidification inhibitors (bafilomycin, NH4Cl, wortmannin), EGFR1 inhibitor (AG1478), entry assays in J cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — engineered chimeric receptors with multiple pharmacological inhibitors defining entry pathways\",\n      \"pmids\": [\"15507614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"αVβ3-integrin relocalizes nectin-1 to lipid rafts independently of virus, directing HSV to a lipid raft and acidic endosome entry pathway. HSV entry mediated by nectin-1 plus αVβ3-integrin phenocopies entry mediated by raft-localized forms of nectin-1.\",\n      \"method\": \"Co-expression of nectin-1 and αVβ3-integrin, lipid raft fractionation, entry assays with raft/endosome inhibitors, Na+/H+ exchanger inhibitor (EIPA)\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab study with biochemical fractionation and pharmacological inhibition, functional entry assay\",\n      \"pmids\": [\"22171266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nectin-1 binds and signals through the fibroblast growth factor receptor (FGFR): the third, membrane-proximal Ig module (Ig3) of nectin-1 directly interacts with multiple FGFR isoforms (shown by surface plasmon resonance), induces FGFR1c phosphorylation, promotes neurite outgrowth (blocked by FGFR inhibitor SU5402 or dominant-negative FGFR1), and promotes neuronal survival.\",\n      \"method\": \"NMR structure of nectin-1 Ig3, surface plasmon resonance binding assay, FGFR phosphorylation assay, neurite outgrowth in primary neurons with pharmacological and dominant-negative inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure, SPR direct binding, phosphorylation assay, and functional neurite outgrowth with genetic/pharmacological validation\",\n      \"pmids\": [\"22955284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Nectin-1 and afadin cluster at developing hippocampal synapses, initially at both excitatory and inhibitory synapses but progressively lost at inhibitory synapses during maturation. Synaptic localization of nectin-1 and afadin is F-actin-dependent; actin depolymerization disrupts synaptic nectin-1/afadin clusters and elicits nectin-1 ectodomain shedding.\",\n      \"method\": \"Immunofluorescence and confocal microscopy of cultured hippocampal neurons, actin depolymerizing agents (cytochalasin D), co-localization with N-cadherin\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence (shedding), single lab with pharmacological perturbation\",\n      \"pmids\": [\"18181141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Nectin-1 ectodomain shedding regulates dendritic spine density: two distinct cleavage sites were identified in the nectin-1 ectodomain by alanine scanning mutagenesis, and expression of shedding-resistant mutants significantly altered dendritic spine density in rat hippocampal neurons.\",\n      \"method\": \"Alanine scanning mutagenesis of nectin-1 ectodomain cleavage sites, expression of cleavage-resistant mutants in hippocampal neurons, spine density quantification\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with defined functional readout (spine density), single lab\",\n      \"pmids\": [\"22118475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Nectin-1 regulates loricrin expression in epidermal keratinocytes through Ca2+-induced activation of Rap1-ERK signaling: nectin-1-null mice show markedly reduced loricrin and impaired cornified envelope integrity; Ca2+-induced ERK activation through Rap1 and loricrin expression were reduced in nectin-1-null primary keratinocytes; ERK inhibition in wild-type keratinocytes reduced loricrin levels.\",\n      \"method\": \"Nectin-1-null mouse model, western blotting for loricrin/SPRR/repetin, primary keratinocyte culture, ERK inhibitor (PD98059), Ca2+ stimulation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout model with pathway-level mechanistic dissection (Rap1-ERK) using pharmacological and genetic approaches\",\n      \"pmids\": [\"17472964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Absence of nectin-1 in mice causes defective enamel formation: nectin-1-null mice exhibit hypomineralized incisors with separation at the stratum intermedium (SI)-ameloblast interface; nectin-1 is normally localized at this interface; desmosomes at the interface are smaller and less numerous in nectin-1-null mice, indicating nectin-1 participates in desmosome assembly between SI and ameloblasts.\",\n      \"method\": \"Nectin-1-null mouse model, immunohistochemistry, electron microscopy of desmosome morphology, enamel composition analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout model with ultrastructural (EM) and immunohistochemical evidence linking nectin-1 to desmosome regulation\",\n      \"pmids\": [\"18703497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Heterophilic interaction between nectin-1 (expressed in ameloblasts) and nectin-3 (expressed in stratum intermedium cells) is required for normal enamel formation and recruits desmosomal junctions at the SI-ameloblast interface; nectin-1;nectin-3 compound mutant mice show severely reduced SI-ameloblast desmosomes and defective enamel.\",\n      \"method\": \"Single and compound nectin-1/nectin-3 null mouse models, immunohistochemistry, electron microscopy\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — compound knockout with ultrastructural characterization, corroborates nectin-1/desmosome findings from PMID:18703497\",\n      \"pmids\": [\"21038445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Nectin-1 is required for HSV infection of neurons in the CNS and development of encephalitis: nectin-1 KO mice showed no signs of encephalitis and no HSV antigens in brain parenchyma after intracranial inoculation, while HVEM KO mice were indistinguishable from wild-type. HVEM KO/nectin-1 KO double-KO abolished all infection including ventricle-lining cells.\",\n      \"method\": \"Single and double KO mouse models (nectin-1 KO, HVEM KO), intracranial HSV inoculation, immunohistochemistry for viral antigens\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic ablation with multiple KO combinations establishing receptor hierarchy in CNS infection\",\n      \"pmids\": [\"19805039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nectin-1 transcription is directly regulated by the transcription factor p63: p63-null mouse skin shows strongly reduced Pvrl1/nectin-1 expression; chromatin immunoprecipitation (ChIP) shows p63 binds two conserved intronic Pvrl1 enhancer regions; siRNA depletion of p63 downregulates nectin-1 in keratinocytes.\",\n      \"method\": \"p63-null mouse model, ChIP, siRNA knockdown of p63, RT-qPCR\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic (KO, siRNA) and ChIP evidence demonstrating direct transcriptional regulation\",\n      \"pmids\": [\"25387952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Nectin-1 forms heterodimers with nectin-3 that adhere more strongly than homodimers; nectin-3 that cannot trans-interact with nectin-1 inhibits E-cadherin-mediated adhesion; trans-interaction of nectin-1 with high-level nectin-3 does not have an agonistic effect on E-cadherin adhesion, whereas trans-interaction of nectin-3 with low-level endogenous nectin-1 has a significant agonistic effect on cadherin-based adhesion.\",\n      \"method\": \"Dual pipette force-separation assay for cell doublets expressing nectin-1, nectin-3, E-cadherin in L cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct force measurement with defined cell lines, single lab with multiple cell combinations\",\n      \"pmids\": [\"15550395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Nectin-1 in the ventral hippocampus plays a key role in contextual fear memory consolidation: nectin-1 protein was transiently upregulated in synapse-enriched ventral (but not dorsal) hippocampal fractions ~2 h after contextual fear conditioning; infusion of anti-nectin-1 antibody (R165) into the ventral hippocampus immediately after training impaired contextual fear memory without affecting acoustic memory or anxiety.\",\n      \"method\": \"Synaptoneurosmal fractionation and Western blot, intra-hippocampal antibody infusion, contextual vs. auditory fear conditioning behavioral assays in rats\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization to synaptoneurosomal fraction with functional manipulation and behavioral readout, single lab\",\n      \"pmids\": [\"23418609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Human nectin-1 directly interacts with the NK cell receptor CD96; the binding site is on the nectin-1 V-domain at the canonical nectin adhesive interface; the affinity of nectin-1 for CD96 is lower than for nectin-3 or nectin-1 itself but comparable to that for HSV gD. Overexpression of nectin-1 in K562 cells increased susceptibility to NK-92 cell cytotoxicity.\",\n      \"method\": \"In vitro direct binding assay (SPR), cell surface expression of nectin-1-GFP in K562 cells, NK cytotoxicity assay, HSV infection assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SPR direct binding with defined affinity, functional NK cytotoxicity assay, single lab\",\n      \"pmids\": [\"30759143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NECTIN1 loss stimulates melanoma cell migration and spreading specifically in response to decreased IGF1 signaling; in human melanoma specimens, adherens junctions were present only in areas with low IGF1 levels and absent in NECTIN1-deficient tumors, establishing NECTIN1 as a determinant of melanoma dissemination gated on IGF1 microenvironmental signals.\",\n      \"method\": \"Genetic NECTIN1 inactivation in zebrafish and human melanoma xenograft models, in vitro migration assays, analysis of human biopsy specimens with dual staining\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model (zebrafish and xenograft) plus human specimen analysis with multiple orthogonal approaches\",\n      \"pmids\": [\"36229674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nectin-1 and NMHC-IIB are the major mediators of HSV-1 entry into corneal nerves: both are expressed in corneal nerves and TG neurons; siRNA knockdown of nectin-1 or NMHC-IIB each reduced HSV-1 entry and replication; HSV-1 exposure upregulated NMHC-IIB and this upregulation was inhibited when nectin-1 (gD receptor) was knocked down, establishing that nectin-1 engagement drives NMHC-IIB upregulation and facilitates gB-dependent entry.\",\n      \"method\": \"siRNA knockdown of nectin-1 and NMHC-IIB in TG neuron cultures, in vivo corneal nerve antibody blocking, qPCR, immunofluorescence\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA and antibody blocking in both in vitro neurons and in vivo corneal model, single lab\",\n      \"pmids\": [\"35295302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nectin-1 is an entry mediator for varicella-zoster virus (VZV) in human neurons: knockdown of endogenous nectin-1 or addition of soluble nectin-1 (during but not after infection) markedly decreased VZV infectivity; ectopic expression of human nectin-1 in a VZV-resistant cell line conferred susceptibility.\",\n      \"method\": \"siRNA knockdown, soluble nectin-1 addition assay, ectopic expression in resistant cell line, iPSC-derived human neuronal model\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three orthogonal approaches (knockdown, soluble receptor competition, ectopic expression) in a human neuronal model\",\n      \"pmids\": [\"34468169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Nectin-1 is degraded by the Chlamydia trachomatis-secreted protease CPAF: nectin-1 half-life is greatly reduced in infected cells; cell-free assays show recombinant GST-CPAF degrades nectin-1; this degradation is blocked by lactacystin (CPAF inhibitor) but not by the proteasome inhibitor MG132; nectin-1 downregulation is post-transcriptional.\",\n      \"method\": \"Western blot for nectin-1 levels and half-life in infected cells, lactacystin/MG132 pharmacological inhibition, cell-free CPAF cleavage assay with recombinant protein\",\n      \"journal\": \"Microbes and infection\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted cell-free cleavage assay with recombinant CPAF plus in-cell pharmacological validation\",\n      \"pmids\": [\"18983929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HSV gD disrupts intercellular homophilic trans-interaction of nectin-1 and induces rapid redistribution of nectin-1 from cell junctions; this does not require nectin-1/afadin interaction. Interaction with afadin is also dispensable for virion surfing along nectin-1-rich filopodia.\",\n      \"method\": \"Fluorescence microscopy of nectin-1-GFP redistribution upon gD-coated surface or gD-expressing cell contact, afadin-binding mutants, filopodia surfing assay\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging with afadin-binding mutants and gD-coated surface assay, single lab\",\n      \"pmids\": [\"27723487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HVEM and nectin-1 elicit non-reciprocal competition for binding to gD: nectin-1 induces a new N-terminal conformation of gD distinct from the HVEM-induced N-terminal hairpin. HVEM function is affected by mutations that impair hairpin formation. Nectin-1 binding actively modifies the gD N-terminal conformation.\",\n      \"method\": \"Binding competition assays (ELISA/FACS), gD mutants with engineered disulfide bonds, functional entry/fusion assays\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with competition binding, single lab\",\n      \"pmids\": [\"24314649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Disruption of the nectin-afadin complex in palatal epithelium causes cleft palate: lentiviral-mediated conditional loss of afadin (nectin's obligate binding partner) in palatal epithelium induces high-penetrance cleft palate; loss of Nectin1 or Nectin4 alone causes mild palate closure defects, but combined loss causes severe cleft palate similar to afadin loss. A human disease NECTIN1 mutant causes cleft palate at higher penetrance than complete loss, suggesting dominant-interfering mechanism.\",\n      \"method\": \"In utero lentiviral gene delivery, conditional Afdn deletion, Nectin1/Nectin4 single and double loss-of-function in mice, palate phenotype scoring\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis with multiple allele combinations and human disease mutant validation\",\n      \"pmids\": [\"32554531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of HSV-2 gD bound to nectin-1 reveals a conserved binding mode identical to HSV-1 gD: nectin-1 I80 is an important gD-interacting residue; nectin-1 mutations similarly affect binding of both HSV-1 and HSV-2 gDs; cross-inhibition by soluble HSV-1/HSV-2 gDs in cell-based fusion assay confirmed the shared recognition mode.\",\n      \"method\": \"X-ray crystallography of free and nectin-1-bound HSV-2 gD, SPR mutagenesis of nectin-1 interface residues, cell-based fusion assay with soluble gD inhibition\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with SPR mutagenesis and functional fusion assay validation\",\n      \"pmids\": [\"25231300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Disrupted presynaptic nectin-1 in the medial entorhinal cortex (MEC)-CA1 pathway contributes to early-life stress-induced memory deficits: neonatal stress reduced nectin-1 in MEC; conditional inactivation of nectin-1 in MEC excitatory neurons reproduced stress-induced spatial memory deficits and CA1 neuronal plasticity deficits in mice.\",\n      \"method\": \"Neonatal stress model, conditional nectin-1 inactivation in MEC (Cre-lox), memory behavioral assays, synaptic fractionation and protein quantification\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional genetic inactivation in a defined circuit with behavioral and structural readouts, single lab\",\n      \"pmids\": [\"35379771\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NECTIN1/nectin-1 is a Ca2+-independent immunoglobulin-superfamily cell adhesion molecule that forms cis-dimers through its first Ig-like (V) domain and mediates homophilic and heterophilic (with nectin-3, nectin-4, CD96, FGFR) trans-interactions at adherens junctions; as the principal entry receptor for HSV-1/2, VZV, and other alphaherpesviruses, its V-domain (residues 64-94, especially the CC′ ridge and key residues including F129) is bound by viral glycoprotein D at the same surface used for nectin-nectin adhesion, triggering gD conformational changes, displacement of nectin-1 from junctions, and Cbl E3-ligase/ICP0-dependent internalization and degradation of the receptor to facilitate viral spread; in neurons, nectin-1 undergoes activity-dependent ADAM10-mediated alpha-cleavage regulated by NMDA-receptor Ca2+/calmodulin signaling, and its ectodomain shedding controls dendritic spine density; in keratinocytes it signals through Rap1-ERK to drive loricrin expression; and its interaction with afadin is required for palate morphogenesis, enamel formation (through nectin-1/nectin-3 heterophilic desmosome recruitment), and melanoma cell spreading in an IGF1-sensitive manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NECTIN1 (nectin-1) is a Ca2+-independent immunoglobulin-superfamily cell adhesion molecule that builds and maintains adherens junctions through self-association and heterophilic engagement of partner nectins, and is exploited as the principal entry receptor for human alphaherpesviruses [#11, #24]. Its extracellular region forms a V-shaped cis-dimer through the first Ig-like (V) domain, and four residues in this domain are required for cis-dimerization and for both homophilic and heterophilic adhesion [#11]. The same V-domain surface mediates high-affinity trans-heterointeractions with nectin-3 (~1 nM) and nectin-4 (~100 nM) at the C-C'-C\\\"-D beta-strands, far exceeding the homophilic affinity [#2], and these interactions drive tissue morphogenesis: nectin-1/nectin-3 heterophilic engagement recruits desmosomes at the ameloblast-stratum intermedium interface to enable enamel formation [#22, #23], the nectin-afadin complex is required for palate closure [#35], and in keratinocytes nectin-1 drives loricrin expression and cornified-envelope integrity via Ca2+-induced Rap1-ERK signaling [#21]. Crystallographic studies show that HSV glycoprotein D binds the V-domain at the very surface used for nectin homodimerization, with Phe129 inserting into a gD groove, so that gD binding precludes nectin-1 dimerization and adhesion; F129A abolishes both gD binding and viral entry [#9, #10]. Beyond serving as a docking site, gD engagement actively disrupts nectin-1 trans-interactions and redistributes the receptor from junctions [#33], and triggers receptor down-regulation through internalization and lysosomal degradation, executed in infected cells by a Cbl E3-ligase/ICP0-dependent pathway [#13, #15]. In the nervous system, nectin-1 is required for HSV CNS infection and for VZV entry into human neurons [#24, #31], signals through FGFR via its membrane-proximal Ig3 module to promote neurite outgrowth and survival [#18], and undergoes NMDA-receptor/Ca2+/calmodulin-driven ADAM10 alpha-cleavage whose ectodomain shedding controls dendritic spine density [#12, #20]. Nectin-1 also binds the NK receptor CD96 at its adhesive interface [#28] and acts as a determinant of melanoma dissemination gated on IGF1 signaling [#29].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing which part of nectin-1 supports HSV entry localized both the viral receptor function and the gD-binding activity to a single domain, defining the molecular target for entry.\",\n      \"evidence\": \"mAb epitope mapping, soluble V-domain competition, deletion constructs, and in vitro gD binding\",\n      \"pmids\": [\"9861033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the V-domain/gD contact not resolved\", \"Did not address adhesion function of the same domain\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Fine-mapping defined the precise residues and beta-strand segments of the V domain used for HSV entry and showed they overlap the heterophilic nectin-binding surface, revealing competition between adhesion and viral hijacking.\",\n      \"evidence\": \"Nectin-1/PVR chimeric receptors, residue 77/85 mutagenesis, CC' ridge transfer, and SPR/competition binding with gD and nectin-3/4\",\n      \"pmids\": [\"11483743\", \"12072525\", \"12359441\", \"12011057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic detail awaited crystallographic confirmation\", \"Functional consequence of gD-induced adhesion loss not yet measured\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defining nectin-1's heterophilic partners and their relative affinities established its physiological adhesion repertoire and the affinity hierarchy that the virus must overcome.\",\n      \"evidence\": \"Fc-fusion binding to transfected cells, co-IP, and quantitative SPR with chimeric receptors\",\n      \"pmids\": [\"11544254\", \"12011057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling from heterophilic engagement not addressed\", \"In vivo relevance of affinity differences untested at this stage\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showing nectin-1 mediates direct cell-to-cell viral spread, not just free-virion entry, expanded its role from a docking molecule to a determinant of viral propagation through tissue.\",\n      \"evidence\": \"Cell-to-cell spread assays in nectin-1-expressing J cells with mAb blocking and receptor-null contact controls\",\n      \"pmids\": [\"10729168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which junctional receptor is repurposed for spread unresolved\", \"Did not address syncytial fusion\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linking nectin-1 subcellular localization to entry pathway showed that the same receptor routes HSV through plasma-membrane or acidic-endosome entry depending on where it sits, explaining cell-type-dependent entry routes.\",\n      \"evidence\": \"Confocal localization, calcium depletion, chimeric receptors targeting endosomes/lipid rafts, and endosome-acidification inhibitors\",\n      \"pmids\": [\"12072519\", \"15507614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous signals controlling localization not defined\", \"Generality across natural tissues untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying gD-induced internalization and lysosomal degradation of nectin-1 revealed an active receptor-removal mechanism distinct from passive sequestration, with isoform-independence implicating an extracellular trigger.\",\n      \"evidence\": \"Co-culture down-regulation assays, flow cytometry, endocytosis inhibitors, and cytoplasmic-tail deletion constructs\",\n      \"pmids\": [\"18076965\", \"20089288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin ligase mediating degradation not yet identified at this stage\", \"Functional benefit to the virus inferred but not directly tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Crystal structures of the nectin-1 ectodomain and the gD/nectin-1 complex established that gD occupies the homodimerization surface, providing a unified structural basis for receptor usage and adhesion blockade.\",\n      \"evidence\": \"X-ray crystallography of free and gD-bound nectin-1 with structure-based mutagenesis (F129A, dimer-interface residues) and entry/adhesion assays\",\n      \"pmids\": [\"21325282\", \"21980294\", \"22146396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of dimer-to-gD switching not captured\", \"Conformational changes in gD inferred from static structures\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying Cbl and ICP0 as the effectors of nectin-1 removal closed the loop on the degradation mechanism, defining the host-viral machinery that strips the receptor to favor spread.\",\n      \"evidence\": \"Co-IP of Cbl/nectin-1/gD complex, siRNA depletion with surface-receptor and entry readouts, and ΔICP0 viral mutant\",\n      \"pmids\": [\"28381567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitination of nectin-1 not demonstrated\", \"Role of CIN85 not fully resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"In vivo receptor-knockout hierarchy established nectin-1 as the essential receptor for HSV neuronal infection and encephalitis, distinguishing it from HVEM in the CNS.\",\n      \"evidence\": \"Single and double nectin-1/HVEM knockout mice with intracranial HSV inoculation and viral antigen immunohistochemistry\",\n      \"pmids\": [\"19805039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor usage in peripheral entry not addressed\", \"Neuron-subtype specificity not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extending receptor function to VZV in human neurons broadened nectin-1's role across alphaherpesviruses and into authentic human neuronal models.\",\n      \"evidence\": \"siRNA knockdown, soluble nectin-1 competition, and ectopic expression in a resistant line using iPSC-derived neurons\",\n      \"pmids\": [\"34468169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"VZV glycoprotein engaging nectin-1 not defined\", \"Structural basis of VZV recognition unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Knockout phenotyping in skin revealed nectin-1 as an upstream regulator of terminal keratinocyte differentiation through Rap1-ERK-driven loricrin expression, moving beyond pure adhesion into signaling.\",\n      \"evidence\": \"Nectin-1-null mice, primary keratinocyte Ca2+ stimulation, ERK inhibition, and loricrin/cornified-envelope analysis\",\n      \"pmids\": [\"17472964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link between nectin-1 ligation and Rap1 activation not biochemically traced\", \"Receptor partner driving the signal not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mouse genetics defined nectin-1 (and its heterophilic partner nectin-3) as organizers of desmosome recruitment at the ameloblast interface required for enamel mineralization, connecting heterophilic adhesion to tissue architecture.\",\n      \"evidence\": \"Single and compound nectin-1/nectin-3 null mice with immunohistochemistry and electron microscopy of desmosomes\",\n      \"pmids\": [\"18703497\", \"21038445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between nectin engagement and desmosome assembly unresolved\", \"Signaling intermediates not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that the membrane-proximal Ig3 module binds and activates FGFR added a receptor-tyrosine-kinase signaling output to nectin-1, mechanistically grounding its neurotrophic effects.\",\n      \"evidence\": \"NMR structure of Ig3, SPR binding to FGFR isoforms, FGFR phosphorylation, and neurite outgrowth/survival assays with inhibitors and dominant-negative FGFR\",\n      \"pmids\": [\"22955284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and cis/trans context of nectin-1/FGFR complex in vivo not defined\", \"Relationship to adhesion-mediated signaling unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linking NMDA-receptor-driven ADAM10 cleavage and ectodomain shedding to dendritic spine density established nectin-1 processing as an activity-dependent regulator of synaptic structure.\",\n      \"evidence\": \"Cortical/hippocampal neuron stimulation, Ca2+/calmodulin pharmacology, ADAM10 knockout/knockdown, cleavage-site alanine scanning, and spine-density quantification\",\n      \"pmids\": [\"20501653\", \"22118475\", \"18181141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Fate and signaling of the shed ectodomain unresolved\", \"Causal link from spine changes to behavior not established here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Circuit-level genetic manipulations tied presynaptic nectin-1 in defined hippocampal/entorhinal pathways to fear and spatial memory consolidation, advancing its synaptic adhesion role into cognition.\",\n      \"evidence\": \"Synaptoneurosomal fractionation, intra-hippocampal antibody infusion, conditional MEC nectin-1 inactivation, and behavioral memory assays\",\n      \"pmids\": [\"23418609\", \"35379771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Synaptic partner mediating the memory effect not identified\", \"Single-lab findings for each circuit\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying CD96 as a nectin-1 binding partner at the adhesive interface and showing modulation of NK cytotoxicity extended nectin-1's interaction network into immune recognition.\",\n      \"evidence\": \"SPR direct binding, K562 nectin-1 overexpression, and NK-92 cytotoxicity assay\",\n      \"pmids\": [\"30759143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context of nectin-1/CD96 signaling unknown\", \"Single-lab functional evidence\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic epistasis in palatal epithelium placed nectin-1 and nectin-4 downstream of the nectin-afadin adhesion complex in palate morphogenesis and revealed a human disease mutation acting by dominant interference.\",\n      \"evidence\": \"In utero lentiviral conditional Afdn deletion, Nectin1/Nectin4 single and double loss-of-function in mice, and human NECTIN1 mutant analysis\",\n      \"pmids\": [\"32554531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the dominant-interfering mutant not dissected\", \"Downstream signaling in palatal fusion unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that NECTIN1 loss promotes melanoma migration specifically under low IGF1 signaling defined a microenvironment-gated tumor-suppressive adhesion function.\",\n      \"evidence\": \"NECTIN1 inactivation in zebrafish and human xenograft models, migration assays, and dual-stained human biopsy analysis\",\n      \"pmids\": [\"36229674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between IGF1 signaling and nectin-1-dependent junctions unresolved\", \"Adhesion partner mediating tumor suppression not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How nectin-1 integrates its adhesion, FGFR-coupled signaling, ectodomain shedding, and immune (CD96) functions into a unified context-dependent signaling logic across epithelia, neurons, and tumors remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No single framework reconciling adhesion vs. signaling outputs\", \"Cis/trans determinants selecting between partners not defined\", \"Endogenous ligand controlling localization-dependent function unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2, 11, 26]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 9, 24, 31]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [18, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 8, 14]},\n      {\"term_id\": \"GO:0005911\", \"supporting_discovery_ids\": [7, 8, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [24, 29, 35]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [21, 22, 23, 35]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [18, 21]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [12, 18, 27, 37]}\n    ],\n    \"complexes\": [\n      \"nectin-afadin complex\",\n      \"adherens junction\"\n    ],\n    \"partners\": [\n      \"Nectin-3\",\n      \"Nectin-4\",\n      \"Afadin\",\n      \"FGFR\",\n      \"CD96\",\n      \"Cbl\",\n      \"E-cadherin\",\n      \"ADAM10\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}