Affinage

Showing NECTIN1 — PVRL1 is a alias.

NECTIN1

Nectin-1 · UniProt Q15223

Length
517 aa
Mass
57.2 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1998 High

    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

    PMID:9861033

    Open questions at the time
    • Structural basis of the V-domain/gD contact not resolved
    • Did not address adhesion function of the same domain
  2. 2002 High

    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

    PMID:11483743 PMID:12011057 PMID:12072525 PMID:12359441

    Open questions at the time
    • Atomic detail awaited crystallographic confirmation
    • Functional consequence of gD-induced adhesion loss not yet measured
  3. 2001 High

    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

    PMID:11544254 PMID:12011057

    Open questions at the time
    • Downstream signaling from heterophilic engagement not addressed
    • In vivo relevance of affinity differences untested at this stage
  4. 2000 High

    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

    PMID:10729168

    Open questions at the time
    • Mechanism by which junctional receptor is repurposed for spread unresolved
    • Did not address syncytial fusion
  5. 2004 High

    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

    PMID:12072519 PMID:15507614

    Open questions at the time
    • Endogenous signals controlling localization not defined
    • Generality across natural tissues untested
  6. 2010 High

    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

    PMID:18076965 PMID:20089288

    Open questions at the time
    • Ubiquitin ligase mediating degradation not yet identified at this stage
    • Functional benefit to the virus inferred but not directly tested
  7. 2011 High

    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

    PMID:21325282 PMID:21980294 PMID:22146396

    Open questions at the time
    • Dynamics of dimer-to-gD switching not captured
    • Conformational changes in gD inferred from static structures
  8. 2017 High

    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

    PMID:28381567

    Open questions at the time
    • Direct ubiquitination of nectin-1 not demonstrated
    • Role of CIN85 not fully resolved
  9. 2009 High

    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

    PMID:19805039

    Open questions at the time
    • Receptor usage in peripheral entry not addressed
    • Neuron-subtype specificity not resolved
  10. 2021 High

    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

    PMID:34468169

    Open questions at the time
    • VZV glycoprotein engaging nectin-1 not defined
    • Structural basis of VZV recognition unknown
  11. 2007 High

    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

    PMID:17472964

    Open questions at the time
    • Direct link between nectin-1 ligation and Rap1 activation not biochemically traced
    • Receptor partner driving the signal not identified
  12. 2010 High

    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

    PMID:18703497 PMID:21038445

    Open questions at the time
    • Molecular link between nectin engagement and desmosome assembly unresolved
    • Signaling intermediates not identified
  13. 2012 High

    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

    PMID:22955284

    Open questions at the time
    • Stoichiometry and cis/trans context of nectin-1/FGFR complex in vivo not defined
    • Relationship to adhesion-mediated signaling unclear
  14. 2011 High

    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

    PMID:18181141 PMID:20501653 PMID:22118475

    Open questions at the time
    • Fate and signaling of the shed ectodomain unresolved
    • Causal link from spine changes to behavior not established here
  15. 2022 Medium

    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

    PMID:23418609 PMID:35379771

    Open questions at the time
    • Synaptic partner mediating the memory effect not identified
    • Single-lab findings for each circuit
  16. 2019 Medium

    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

    PMID:30759143

    Open questions at the time
    • Physiological context of nectin-1/CD96 signaling unknown
    • Single-lab functional evidence
  17. 2020 High

    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

    PMID:32554531

    Open questions at the time
    • Molecular basis of the dominant-interfering mutant not dissected
    • Downstream signaling in palatal fusion unresolved
  18. 2022 High

    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

    PMID:36229674

    Open questions at the time
    • Mechanistic link between IGF1 signaling and nectin-1-dependent junctions unresolved
    • Adhesion partner mediating tumor suppression not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 4 GO:0098631 cell adhesion mediator activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 3 R-HSA-162582 Signal Transduction 2
Partners
ADAM10AFADINCBLCD96E-CADHERINFGFRNECTIN-3NECTIN-4
Complex memberships
adherens junctionnectin-afadin complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 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. Monoclonal antibody epitope mapping, soluble V-domain competition assay, engineered deletion constructs expressing V domain alone, in vitro pulldown/binding assay Proceedings of the National Academy of Sciences of the United States of America High 9861033
2001 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). Soluble Fc-fusion binding to transfected cells, co-immunoprecipitation, in vitro Fc-fusion binding assay, inhibition by anti-V-domain mAbs and HSV gD The Journal of biological chemistry High 11544254
2002 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. SPR/affinity measurements, competition binding with soluble Fc-fusions and mAbs, chimeric nectin1/PVR receptors with substituted beta-strands The Journal of biological chemistry High 12011057
2001 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. Nectin-1/PVR chimeric receptor constructs tested for HSV entry activity and gD binding in cell-based assays Journal of virology High 11483743
2002 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. Site-directed mutagenesis of nectin-1 residues 77 and 85, HSV entry assays, soluble gD binding assays Journal of virology High 12072525
2002 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. Transfer of nectin-1 residue segments to nectin-2 by mutagenesis, HSV entry assays Virology High 12359441
2000 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. Cell-to-cell spread assays in J cells expressing nectin-1 isoforms, mAb blocking, receptor-positive to receptor-negative cell contact assays Journal of virology High 10729168
2002 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. Confocal microscopy of nectin-1 localization, calcium depletion, soluble gD binding assay, HSV/PRV infection quantification Journal of virology High 12072519
2003 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. Fluorescence/confocal microscopy of nectin-1-GFP fusions during HSV infection, co-localization studies, afadin interaction experiments Journal of virology High 12885915
2011 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. X-ray crystallography, site-directed mutagenesis (F129A), HSV entry assay PLoS pathogens High 21980294
2011 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. X-ray crystallography of gD/nectin-1 complex, structural analysis of dimerization interface Nature communications High 22146396
2011 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. X-ray crystallography, site-directed mutagenesis of dimerization interface, cell surface adhesion assays The Journal of biological chemistry High 21325282
2010 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. Primary cortical neuron stimulation with NMDA/AMPA/mGluR agonists, Ca2+ chelation, calmodulin inhibitor, ADAM10 knockout/knockdown, Western blotting for cleavage products The Journal of biological chemistry High 20501653
2008 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. 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 Virology High 18076965
2010 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. Flow cytometry of surface nectin-1, virion entry kinetics, cytoplasmic tail deletion constructs Virology High 20089288
2017 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). Co-immunoprecipitation, siRNA knockdown of Cbl/CIN85, flow cytometry for surface nectin-1, infection assays with ΔICP0 virus Journal of virology High 28381567
2004 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. Chimeric receptor constructs (nectin1-EGFR1, GPI-nectin1), endosome acidification inhibitors (bafilomycin, NH4Cl, wortmannin), EGFR1 inhibitor (AG1478), entry assays in J cells Journal of virology High 15507614
2011 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. Co-expression of nectin-1 and αVβ3-integrin, lipid raft fractionation, entry assays with raft/endosome inhibitors, Na+/H+ exchanger inhibitor (EIPA) Journal of virology Medium 22171266
2012 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. 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 The Journal of biological chemistry High 22955284
2008 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. Immunofluorescence and confocal microscopy of cultured hippocampal neurons, actin depolymerizing agents (cytochalasin D), co-localization with N-cadherin The Journal of comparative neurology Medium 18181141
2011 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. Alanine scanning mutagenesis of nectin-1 ectodomain cleavage sites, expression of cleavage-resistant mutants in hippocampal neurons, spine density quantification Journal of neurochemistry Medium 22118475
2007 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. Nectin-1-null mouse model, western blotting for loricrin/SPRR/repetin, primary keratinocyte culture, ERK inhibitor (PD98059), Ca2+ stimulation assay The Journal of biological chemistry High 17472964
2008 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. Nectin-1-null mouse model, immunohistochemistry, electron microscopy of desmosome morphology, enamel composition analysis Human molecular genetics High 18703497
2010 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. Single and compound nectin-1/nectin-3 null mouse models, immunohistochemistry, electron microscopy Developmental dynamics High 21038445
2009 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. Single and double KO mouse models (nectin-1 KO, HVEM KO), intracranial HSV inoculation, immunohistochemistry for viral antigens Proceedings of the National Academy of Sciences of the United States of America High 19805039
2015 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. p63-null mouse model, ChIP, siRNA knockdown of p63, RT-qPCR Experimental dermatology High 25387952
2004 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. Dual pipette force-separation assay for cell doublets expressing nectin-1, nectin-3, E-cadherin in L cells The Journal of biological chemistry Medium 15550395
2013 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. Synaptoneurosmal fractionation and Western blot, intra-hippocampal antibody infusion, contextual vs. auditory fear conditioning behavioral assays in rats PloS one Medium 23418609
2019 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. In vitro direct binding assay (SPR), cell surface expression of nectin-1-GFP in K562 cells, NK cytotoxicity assay, HSV infection assay PloS one Medium 30759143
2022 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. Genetic NECTIN1 inactivation in zebrafish and human melanoma xenograft models, in vitro migration assays, analysis of human biopsy specimens with dual staining Nature genetics High 36229674
2022 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. siRNA knockdown of nectin-1 and NMHC-IIB in TG neuron cultures, in vivo corneal nerve antibody blocking, qPCR, immunofluorescence Frontiers in microbiology Medium 35295302
2021 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. siRNA knockdown, soluble nectin-1 addition assay, ectopic expression in resistant cell line, iPSC-derived human neuronal model Journal of virology High 34468169
2008 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. Western blot for nectin-1 levels and half-life in infected cells, lactacystin/MG132 pharmacological inhibition, cell-free CPAF cleavage assay with recombinant protein Microbes and infection High 18983929
2016 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. Fluorescence microscopy of nectin-1-GFP redistribution upon gD-coated surface or gD-expressing cell contact, afadin-binding mutants, filopodia surfing assay Virology Medium 27723487
2013 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. Binding competition assays (ELISA/FACS), gD mutants with engineered disulfide bonds, functional entry/fusion assays Virology Medium 24314649
2020 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. In utero lentiviral gene delivery, conditional Afdn deletion, Nectin1/Nectin4 single and double loss-of-function in mice, palate phenotype scoring Development (Cambridge, England) High 32554531
2014 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. 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 of virology High 25231300
2022 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. Neonatal stress model, conditional nectin-1 inactivation in MEC (Cre-lox), memory behavioral assays, synaptic fractionation and protein quantification Translational psychiatry Medium 35379771

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Nectin4/PRR4, a new afadin-associated member of the nectin family that trans-interacts with nectin1/PRR1 through V domain interaction. The Journal of biological chemistry 275 11544254
2011 Structure of herpes simplex virus glycoprotein D bound to the human receptor nectin-1. PLoS pathogens 150 21980294
2004 Comparative usage of herpesvirus entry mediator A and nectin-1 by laboratory strains and clinical isolates of herpes simplex virus. Virology 118 15110526
2002 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. The Journal of biological chemistry 118 12011057
2010 miR-661 expression in SNAI1-induced epithelial to mesenchymal transition contributes to breast cancer cell invasion by targeting Nectin-1 and StarD10 messengers. Oncogene 107 20543867
1998 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. Proceedings of the National Academy of Sciences of the United States of America 106 9861033
2003 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. Journal of virology 98 12915538
2000 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). Journal of virology 94 10729168
2011 Binding of herpes simplex virus glycoprotein D to nectin-1 exploits host cell adhesion. Nature communications 92 22146396
2002 Disruption of adherens junctions liberates nectin-1 to serve as receptor for herpes simplex virus and pseudorabies virus entry. Journal of virology 92 12072519
1973 Characteristics and purification of PRR1, an RNA phage specific for the broad host range Pseudomonas R1822 drug resistance plasmid. Journal of virology 90 4128383
2007 The murine pan T cell marker CD96 is an adhesion receptor for CD155 and nectin-1. Biochemical and biophysical research communications 79 17971293
2009 Infection of neurons and encephalitis after intracranial inoculation of herpes simplex virus requires the entry receptor nectin-1. Proceedings of the National Academy of Sciences of the United States of America 76 19805039
2004 Entry of herpes simplex virus mediated by chimeric forms of nectin1 retargeted to endosomes or to lipid rafts occurs through acidic endosomes. Journal of virology 76 15507614
2005 Potential nectin-1 binding site on herpes simplex virus glycoprotein d. Journal of virology 75 15613355
2017 Structural basis of nectin-1 recognition by pseudorabies virus glycoprotein D. PLoS pathogens 71 28542478
2004 In vivo role of nectin-1 in entry of herpes simplex virus type 1 (HSV-1) and HSV-2 through the vaginal mucosa. Journal of virology 68 14963155
2018 Enhanced Sensitivity of Patient-Derived Pediatric High-Grade Brain Tumor Xenografts to Oncolytic HSV-1 Virotherapy Correlates with Nectin-1 Expression. Scientific reports 67 30224769
2008 HVEM and nectin-1 are the major mediators of herpes simplex virus 1 (HSV-1) entry into human conjunctival epithelium. Investigative ophthalmology & visual science 67 18502984
2003 Cellular localization of nectin-1 and glycoprotein D during herpes simplex virus infection. Journal of virology 64 12885915
1999 A fission yeast gene (prr1(+)) that encodes a response regulator implicated in oxidative stress response. Journal of biochemistry 61 10348908
2008 The cell adhesion molecule nectin-1 is critical for normal enamel formation in mice. Human molecular genetics 55 18703497
2008 The herpes simplex virus receptor nectin-1 is down-regulated after trans-interaction with glycoprotein D. Virology 54 18076965
2004 Separation force measurements reveal different types of modulation of E-cadherin-based adhesion by nectin-1 and -3. The Journal of biological chemistry 54 15550395
2007 Nectin-1 expression by squamous cell carcinoma is a predictor of herpes oncolytic sensitivity. Molecular therapy : the journal of the American Society of Gene Therapy 53 17164781
2001 Transcription from the gene encoding the herpesvirus entry receptor nectin-1 (HveC) in nervous tissue of adult mouse. Virology 53 11531408
2008 Role for nectin-1 in herpes simplex virus 1 entry and spread in human retinal pigment epithelial cells. The FEBS journal 51 18803666
2011 Herpesvirus entry mediator and nectin-1 mediate herpes simplex virus 1 infection of the murine cornea. Journal of virology 49 21795335
2012 The transcription factors Pap1 and Prr1 collaborate to activate antioxidant, but not drug tolerance, genes in response to H2O2. Nucleic acids research 48 22344694
2011 αVβ3-integrin relocalizes nectin1 and routes herpes simplex virus to lipid rafts. Journal of virology 47 22171266
2010 Activity-dependent alpha-cleavage of nectin-1 is mediated by a disintegrin and metalloprotease 10 (ADAM10). The Journal of biological chemistry 47 20501653
2014 Entry mechanisms of herpes simplex virus 1 into murine epidermis: involvement of nectin-1 and herpesvirus entry mediator as cellular receptors. Journal of virology 46 25320325
2011 Crystal Structure of the cis-Dimer of Nectin-1: implications for the architecture of cell-cell junctions. The Journal of biological chemistry 46 21325282
2005 Enhanced nectin-1 expression and herpes oncolytic sensitivity in highly migratory and invasive carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 46 16000587
2001 HveC (nectin-1) is expressed at high levels in sensory neurons, but not in motor neurons, of the rat peripheral nervous system. Journal of neurovirology 45 11582520
2002 Amino acid substitutions in the V domain of nectin-1 (HveC) that impair entry activity for herpes simplex virus types 1 and 2 but not for Pseudorabies virus or bovine herpesvirus 1. Journal of virology 41 12072525
2014 Crystal structure of herpes simplex virus 2 gD bound to nectin-1 reveals a conserved mode of receptor recognition. Journal of virology 39 25231300
2007 Nectin-1 is a marker of thyroid cancer sensitivity to herpes oncolytic therapy. The Journal of clinical endocrinology and metabolism 39 17327376
2003 The domains of glycoprotein D required to block apoptosis induced by herpes simplex virus 1 are largely distinct from those involved in cell-cell fusion and binding to nectin1. Journal of virology 39 12610150
2001 Novel, soluble isoform of the herpes simplex virus (HSV) receptor nectin1 (or PRR1-HIgR-HveC) modulates positively and negatively susceptibility to HSV infection. Journal of virology 39 11356977
2004 Herpes simplex virus entry receptor nectin-1 is widely expressed in the murine eye. Current eye research 38 15590476
2002 Role of fission yeast Tup1-like repressors and Prr1 transcription factor in response to salt stress. Molecular biology of the cell 38 12221110
2015 Role of Nectin-1 and Herpesvirus Entry Mediator as Cellular Receptors for Herpes Simplex Virus 1 on Primary Murine Dermal Fibroblasts. Journal of virology 37 26136572
2010 Cooperation of nectin-1 and nectin-3 is required for normal ameloblast function and crown shape development in mouse teeth. Developmental dynamics : an official publication of the American Association of Anatomists 36 21038445
2013 Induction of conformational changes at the N-terminus of herpes simplex virus glycoprotein D upon binding to HVEM and nectin-1. Virology 35 24314649
2002 Mutations in the N-terminal domains of nectin-1 and nectin-2 reveal differences in requirements for entry of various alphaherpesviruses and for nectin-nectin interactions. Journal of virology 35 12438620
2000 The Prr1 response regulator is essential for transcription of ste11+ and for sexual development in fission yeast. Molecular & general genetics : MGG 35 11129048
2019 Interaction between nectin-1 and the human natural killer cell receptor CD96. PloS one 32 30759143
2009 Generation of herpesvirus entry mediator (HVEM)-restricted herpes simplex virus type 1 mutant viruses: resistance of HVEM-expressing cells and identification of mutations that rescue nectin-1 recognition. Journal of virology 32 19129446
2015 p63-dependent and independent mechanisms of nectin-1 and nectin-4 regulation in the epidermis. Experimental dermatology 31 25387952
2008 Temporal and spatial localization of nectin-1 and l-afadin during synaptogenesis in hippocampal neurons. The Journal of comparative neurology 31 18181141
2001 Chimeric nectin1-poliovirus receptor molecules identify a nectin1 region functional in herpes simplex virus entry. Journal of virology 31 11483743
2010 Glycoprotein D actively induces rapid internalization of two nectin-1 isoforms during herpes simplex virus entry. Virology 29 20089288
2006 Complete genome sequence of the broad host range single-stranded RNA phage PRR1 places it in the Levivirus genus with characteristics shared with Alloleviviruses. Journal of virology 29 16940544
2012 Herpes B virus utilizes human nectin-1 but not HVEM or PILRα for cell-cell fusion and virus entry. Journal of virology 28 22345445
2012 Nectin-1 binds and signals through the fibroblast growth factor receptor. The Journal of biological chemistry 28 22955284
2009 Role of nectin-1, HVEM, and PILR-alpha in HSV-2 entry into human retinal pigment epithelial cells. Investigative ophthalmology & visual science 27 19234349
2007 Up-regulation of loricrin expression by cell adhesion molecule nectin-1 through Rap1-ERK signaling in keratinocytes. The Journal of biological chemistry 27 17472964
2007 Global transcriptional responses of Pseudomonas aeruginosa to phage PRR1 infection. Journal of virology 26 18077716
2006 Expression of entry receptor nectin-1 of herpes simplex virus 1 and/or herpes simplex virus 2 in normal and neoplastic human nervous system tissues. Acta virologica 23 16599187
2017 Cbl E3 Ligase Mediates the Removal of Nectin-1 from the Surface of Herpes Simplex Virus 1-Infected Cells. Journal of virology 22 28381567
2011 Ectodomain shedding of nectin-1 regulates the maintenance of dendritic spine density. Journal of neurochemistry 22 22118475
2006 Expression of nectin-1 in normal and herpes simplex virus type 1-infected murine brain. Applied immunohistochemistry & molecular morphology : AIMM 22 16932027
2003 Characterization of the Prr1 response regulator with special reference to sexual development in Schizosaccharomyces pombe. Bioscience, biotechnology, and biochemistry 21 12723602
2012 Chronological lifespan extension by Ecl1 family proteins depends on Prr1 response regulator in fission yeast. Genes to cells : devoted to molecular & cellular mechanisms 20 22212525
2008 The host adherens junction molecule nectin-1 is downregulated in Chlamydia trachomatis-infected genital epithelial cells. Microbiology (Reading, England) 19 18451037
2008 The capsid of the small RNA phage PRR1 is stabilized by metal ions. Journal of molecular biology 19 18786545
2014 Different roles of the three loops forming the adhesive interface of nectin-4 in measles virus binding and cell entry, nectin-4 homodimerization, and heterodimerization with nectin-1. Journal of virology 18 25275122
2008 The host adherens junction molecule nectin-1 is degraded by chlamydial protease-like activity factor (CPAF) in Chlamydia trachomatis-infected genital epithelial cells. Microbes and infection 18 18983929
2004 The herpes simplex virus JMP mutant enters receptor-negative J cells through a novel pathway independent of the known receptors nectin1, HveA, and nectin2. Journal of virology 18 15078954
2020 Crystal structure of bovine herpesvirus 1 glycoprotein D bound to nectin-1 reveals the basis for its low-affinity binding to the receptor. Science advances 17 32426511
2020 Disruption of the nectin-afadin complex recapitulates features of the human cleft lip/palate syndrome CLPED1. Development (Cambridge, England) 17 32554531
2013 A key role for nectin-1 in the ventral hippocampus in contextual fear memory. PloS one 17 23418609
2006 Nectin-1 expression in the normal and neoplastic human uterine cervix. Archives of pathology & laboratory medicine 17 16879022
2004 Effects of linker-insertion mutations in herpes simplex virus 1 gD on glycoprotein-induced fusion with cells expressing HVEM or nectin-1. Virology 17 14972557
2001 Comparison of murine and human nectin1 binding to herpes simplex virus glycoprotein D (gD) reveals a weak interaction of murine nectin1 to gD and a gD-dependent pathway of entry. Virology 17 11289808
2014 Epithelial-mesenchymal transition enhances response to oncolytic herpesviral therapy through nectin-1. Human gene therapy 16 24568312
2008 Nectin-1 (HveC) is expressed at high levels in neural subtypes that regulate radial migration of cortical and cerebellar neurons of the developing human and murine brain. Journal of neurovirology 16 18444088
2002 Substitution in the murine nectin1 receptor of a single conserved amino acid at a position distal from the herpes simplex virus gD binding site confers high-affinity binding to gD. Journal of virology 16 11991974
2022 Nectin-1 and Non-muscle Myosin Heavy Chain-IIB: Major Mediators of Herpes Simplex Virus-1 Entry Into Corneal Nerves. Frontiers in microbiology 15 35295302
2022 Loss of NECTIN1 triggers melanoma dissemination upon local IGF1 depletion. Nature genetics 15 36229674
2021 Nectin-1 Is an Entry Mediator for Varicella-Zoster Virus Infection of Human Neurons. Journal of virology 15 34468169
2006 Expression of nectin-1, nectin-3, N-cadherin, and NCAM in spinal motoneurons after sciatic nerve transection. Experimental neurology 15 16777094
2023 Cell entry of Bovine herpesvirus-1 through clathrin- and caveolin-mediated endocytosis requires activation of PI3K-Akt-NF-κB and Ras-p38 MAPK pathways as well as the interaction of BoHV-1 gD with cellular receptor nectin-1. Veterinary microbiology 14 36774841
2021 Nectin-1 Expression Correlates with the Susceptibility of Malignant Melanoma to Oncolytic Herpes Simplex Virus In Vitro and In Vivo. Cancers 14 34205379
2019 Nectin-1 Expression in Colorectal Cancer: Is There a Group of Patients with High Risk for Early Disease Recurrence? Oncology 14 30917374
2012 Eutopic endometrium and peritoneal, ovarian and colorectal endometriotic tissues express a different profile of nectin-1, -3, -4 and nectin-like molecule 2. Human reproduction (Oxford, England) 14 22926846
2006 Spatiotemporal changes of the herpes simplex virus entry receptor nectin-1 in murine brain during postnatal development. Journal of neurovirology 13 16877297
2022 Targeting NECTIN-1 Based on CRISPR/Cas9 System Attenuated the Herpes Simplex Virus Infection in Human Corneal Epithelial Cells In Vitro. Translational vision science & technology 12 35119473
2022 Disrupted presynaptic nectin1-based neuronal adhesion in the entorhinal-hippocampal circuit contributes to early-life stress-induced memory deficits. Translational psychiatry 12 35379771
2013 PRR1 coat protein binding to its RNA translational operator. Acta crystallographica. Section D, Biological crystallography 12 23519411
2007 Calcium depletion enhances nectin-1 expression and herpes oncolytic therapy of squamous cell carcinoma. Cancer gene therapy 12 17525764
2006 The first immunoglobulin-like domain of porcine nectin-1 is sufficient to confer resistance to pseudorabies virus infection in transgenic mice. Archives of virology 12 16583156
2006 The requirements for herpes simplex virus type 1 cell-cell spread via nectin-1 parallel those for virus entry. Virus research 12 16823958
2024 Nectin1 is a pivotal host factor involved in attachment and entry of red-spotted grouper nervous necrosis virus in the early stages of the viral life cycle. Journal of virology 11 39194240
2021 A monoclonal antibody neutralizes pesudorabies virus by blocking gD binding to the receptor nectin-1. International journal of biological macromolecules 11 34339791
2016 Herpes simplex virus glycoprotein D relocates nectin-1 from intercellular contacts. Virology 11 27723487
2003 Optical biosensor analysis in studying herpes simplex virus glycoprotein D binding to target nectin1 receptor. Journal of pharmaceutical and biomedical analysis 11 12899960
2002 Critical residues in the CC' ridge of the human nectin1 receptor V domain enable herpes simplex virus entry into the cell and act synergistically with the downstream region. Virology 11 12359441
2018 Chronic Stress Reduces Nectin-1 mRNA Levels and Disrupts Dendritic Spine Plasticity in the Adult Mouse Perirhinal Cortex. Frontiers in cellular neuroscience 10 29593501

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