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Showing NECTIN2 — CD112 is a alias.

NECTIN2

Nectin-2 · UniProt Q92692

Length
538 aa
Mass
57.7 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 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

NECTIN2 (CD112/PVRL2/HveB) is a cell-surface immunoglobulin-superfamily adhesion molecule that operates at the interface of immune regulation, cell-cell adhesion, and viral entry (PMID:12913096, PMID:22547693). Its membrane-distal V-set Ig domain forms a perpendicular homodimer, and disruption of this homodimeric interface abolishes binding to the activating NK/T-cell receptor DNAM-1 (CD226), establishing that productive DNAM-1 engagement requires the homodimeric conformation (PMID:22547693, PMID:22927415). The same V domain is competitively engaged by the inhibitory receptors TIGIT and PVRIG (CD112R) through a conserved antiparallel lock-and-key mode in which receptor binding disrupts pre-assembled NECTIN2 oligomers, making activating and inhibitory engagement mutually exclusive (PMID:28515320, PMID:40285356). Through these axes NECTIN2 suppresses antitumor CD8+ T-cell and NK-cell responses: PVRIG–PVRL2 forms a nonredundant inhibitory node distinct from TIGIT–PVR (PMID:30659054), and PVRL2 deletion in syngeneic tumors restrains growth in a CD8+ T- and NK-dependent manner even through PVRIG-independent routes, with combined TIGIT blockade approaching complete suppression (PMID:38588410). NECTIN2 also serves as a herpesvirus entry receptor, conferring susceptibility to HSV mutant strains, HSV-2, and pseudorabies virus via direct gD binding to its N-terminal V domain (PMID:9657005, PMID:10627537, PMID:11602758). In adhesion contexts it engages N-cadherin through an extracellular, adaptor-independent interaction to drive apical F-actin accumulation (PMID:20332149, PMID:30183103), and it is essential at Sertoli–spermatid ectoplasmic specializations where it forms a heterotypic complex with nectin-3 to organize the cytoskeleton during spermiogenesis (PMID:10733589, PMID:12801998). Surface levels are controlled post-translationally by ubiquitin-proteasome-mediated degradation, exploited by HCMV UL141 and alphaherpesvirus gD as NK immune-evasion strategies (PMID:20410314, PMID:25352670, PMID:30888046).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1998 High

    Established NECTIN2 as a herpesvirus entry mediator, the first defined molecular function for the protein, explaining how certain HSV strains enter otherwise resistant cells.

    Evidence cDNA expression library screen and viral entry assay in CHO cells with antibody blocking

    PMID:9657005

    Open questions at the time
    • Did not map the gD-binding region on NECTIN2
    • Did not explain selectivity for mutant over wild-type HSV-1
  2. 2000 High

    Defined the V domain as the gD-binding region and showed NECTIN2 supports cell-to-cell spread of mutant but not wild-type HSV-1, refining the receptor's entry specificity.

    Evidence Viral entry and spread assays in defined-receptor cells plus in vitro soluble gD binding

    PMID:10627537 PMID:10729168

    Open questions at the time
    • Weak/undetectable wild-type gD binding left affinity determinants unresolved
    • Residue-level interface not yet defined
  3. 2000 High

    Knockout established a physiological role in spermiogenesis, showing NECTIN2 is required for normal sperm morphology and cytoskeletal organization.

    Evidence nectin-2 knockout mice with electron microscopy and expression analysis

    PMID:10733589

    Open questions at the time
    • Molecular adhesion partner at the junction not identified
    • Downstream cytoskeletal effectors unknown
  4. 2001 High

    Pinpointed critical V-domain residues (aa 75-81 and M89) for HSV entry, linking the entry interface to analogous receptor-binding regions of CD4 and CD155.

    Evidence Chimeric receptors and site-directed mutagenesis with viral entry assay

    PMID:11602758

    Open questions at the time
    • No co-structure of NECTIN2 with gD
    • Conformational basis of selectivity not resolved
  5. 2003 High

    Identified NECTIN2 as a direct ligand for the activating NK receptor DNAM-1, defining its first immune effector function.

    Evidence Protein purification, mass spectrometry, Fc-fusion binding and NK cytotoxicity assays

    PMID:12913096

    Open questions at the time
    • Structural basis of DNAM-1 binding not defined
    • Relationship between homophilic adhesion and receptor engagement unclear
  6. 2003 High

    Showed NECTIN2/nectin-3 form a heterotypic Sertoli-spermatid adhesion complex required for ectoplasmic specialization assembly, mechanistically linking the knockout phenotype to junction formation.

    Evidence LacZ knockin knockout mice with espin immunolocalization and binding assays

    PMID:12801998

    Open questions at the time
    • Intracellular signaling driving actin bundling not defined
  7. 2009 High

    Established TIGIT as a direct inhibitory receptor for NECTIN2 acting via its ITIM, providing an MHC-independent 'alternative self' brake on NK cytotoxicity.

    Evidence Binding assays, ITIM functional analysis and NK cytotoxicity assays

    PMID:19815499

    Open questions at the time
    • Structural interface not yet defined
    • Competition with DNAM-1 not yet demonstrated
  8. 2009 High

    Revealed a cardiac role: NECTIN2 maintains intercalated disc integrity under pressure overload via Akt/JNK/p38 signaling, extending function beyond immunity and reproduction.

    Evidence Knockout mice with aortic banding, histology and phospho-kinase Western blots

    PMID:19667252

    Open questions at the time
    • Direct adhesion partner at the intercalated disc not identified
    • Mechanism linking adhesion to kinase signaling unresolved
  9. 2010 High

    Demonstrated an extracellular NECTIN2-N-cadherin interaction driving apical constriction and F-actin accumulation, defining a cooperative adhesion mechanism in morphogenesis.

    Evidence Morpholino knockdown, overexpression, co-IP and domain dissection in Xenopus

    PMID:20332149

    Open questions at the time
    • Affinity and interface not quantified in this study
    • Link to actin machinery not molecularly defined
  10. 2010 High

    Showed HCMV downregulates surface NECTIN2 via proteasomal degradation requiring UL141 plus additional viral functions, defining a viral immune-evasion mechanism distinct from CD155 retention.

    Evidence HCMV UL141-deletion mutant, proteasome inhibitor assays and flow cytometry

    PMID:20410314

    Open questions at the time
    • Additional HCMV factors required for NECTIN2 suppression not identified
    • E3 ligase mediating degradation unknown
  11. 2012 High

    Crystal structures established the NECTIN2 V-domain homodimer and showed DNAM-1 binding requires the homodimeric interface, unifying adhesion conformation with receptor engagement.

    Evidence X-ray crystallography (1.85 and 1.3 A), mutagenesis, SPR and tetramer staining

    PMID:22547693 PMID:22927415

    Open questions at the time
    • Did not address how inhibitory receptors compete with homodimer
    • Full-length ectodomain architecture not resolved
  12. 2014 High

    Showed alphaherpesvirus gD degrades NECTIN2 to reduce DNAM-1 binding and NK killing, mechanistically uniting the entry receptor and immune-evasion roles.

    Evidence Virus infection and gD transfection with NK degranulation and cytotoxicity assays

    PMID:25352670

    Open questions at the time
    • Degradation route (proteasome vs lysosome) not fully defined
    • gD residues mediating degradation not mapped
  13. 2014 Medium

    Identified dual transcriptional and post-translational control of NECTIN2 by cadmium, implicating CREB/c-Jun/Sp1 promoter regulation and clathrin-dependent endocytosis.

    Evidence EMSA, ChIP, endocytosis inhibitor and clathrin shRNA assays

    PMID:25046863

    Open questions at the time
    • Single-lab study
    • Physiological relevance beyond cadmium exposure unclear
  14. 2017 High

    Defined the TIGIT:NECTIN2 lock-and-key structure and showed TIGIT binding disrupts NECTIN2 oligomers, establishing mutual exclusivity of activating and inhibitory engagement.

    Evidence X-ray crystallography, SPR and biochemical oligomer-disruption assays

    PMID:27978489 PMID:28515320

    Open questions at the time
    • In situ competition between DNAM-1 and TIGIT not directly visualized
    • Affinity (~6 uM) physiological tuning unresolved
  15. 2019 High

    Established PVRIG (CD112R) as a nonredundant inhibitory receptor for NECTIN2 on CD8+ T cells, distinct from the TIGIT axis and a candidate combination immunotherapy target.

    Evidence Blocking antibody T-cell cytokine/cytotoxicity and TIL functional assays

    PMID:30659054

    Open questions at the time
    • Structural basis of PVRIG selectivity not yet defined
    • PVRIG-independent NECTIN2 effects not yet examined
  16. 2019 Medium

    Showed ubiquitin-proteasome degradation governs NECTIN2 surface levels and tumor cell susceptibility to NK killing, defining an endogenous post-translational control point.

    Evidence Ubiquitination assay, proteasome inhibitor treatment and NK cytotoxicity

    PMID:30888046

    Open questions at the time
    • Responsible E3 ligase not identified
    • Single-lab study
  17. 2024 High

    Solved the PVRIG:NECTIN2 complex structure, explaining PVRIG selectivity and homodimer disruption, and enabling high-affinity blocking variants for therapy.

    Evidence X-ray crystallography (2.2 A), mutagenesis, directed evolution and CAR-T/TCE functional assays

    PMID:38626767 PMID:40285356

    Open questions at the time
    • In vivo efficacy of engineered variants not established here
    • Full ectodomain context not resolved
  18. 2024 High

    Demonstrated PVRL2 suppresses antitumor immunity through PVRIG- and TIGIT-independent pathways, establishing it as an upstream node whose deletion combined with TIGIT blockade nearly abolishes tumor growth.

    Evidence Syngeneic PVRL2-knockout tumor models, immune-cell depletion epistasis and combination blockade

    PMID:38588410

    Open questions at the time
    • Identity of the PVRIG/TIGIT-independent receptor unresolved
    • Mechanism of PVRIG-independent suppression undefined
  19. 2024 Medium

    Identified stromal sources of NECTIN2-mediated T-cell suppression in tumors, showing fibroblasts and tumor-associated neutrophil-induced NECTIN2 drive CD8+ T-cell dysfunction reversible by blockade.

    Evidence scRNA-seq, spatial proteomics, CAF/TAN-tumor-T cell co-culture and in vivo blockade

    PMID:38821255 PMID:39261943

    Open questions at the time
    • Receptor mediating suppression in these contexts not always defined
    • Single-lab studies

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the receptor(s) and signaling mechanism underlying NECTIN2's PVRIG- and TIGIT-independent immunosuppression, and the E3 ligase(s) controlling its proteasomal turnover, remain unresolved.
  • No defined receptor for the PVRIG/TIGIT-independent tumor pathway
  • Ubiquitin ligase regulating NECTIN2 surface levels unidentified
  • No unified structural model of full ectodomain in cis/trans

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0001618 virus receptor activity 3 GO:0098631 cell adhesion mediator activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-1500931 Cell-Cell communication 3
Partners
DNAM-1N-CADHERINNECTIN-3PVRIGTIGITVSIG2
Complex memberships
NECTIN2-nectin-3 Sertoli-spermatid adhesion complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Nectin-2 (CD112) was identified as a direct cell-surface ligand for the activating NK receptor DNAM-1 (CD226). Protein purification, tryptic digestion, mass spectrometry, soluble Fc-fusion binding assays, and cell transfection cytotoxicity experiments demonstrated that Nectin-2-Fc binds DNAM-1-expressing COS-7 cells, and Nectin-2 transfectants are killed in a DNAM-1-dependent manner. Protein purification + mass spectrometry, soluble Fc-fusion binding assay, NK cytotoxicity assay with mAb blocking, cell transfection The Journal of experimental medicine High 12913096
2004 DNAM-1 (CD226) functionally interacts with Nectin-2 (CD112/PRR-2): ectopic expression of CD112 on BW5147 T cells increased susceptibility to NK/T-cell cytotoxicity in a CD226-dependent manner. Homophilic cell-surface CD112 interactions adversely affect CD226 binding to CD112, and CD226 ligation cooperates with LFA-1 to trigger cytotoxicity and cytokine secretion. Cell transfection, NK/T-cell cytotoxicity assay, soluble receptor binding affinity measurement, mAb blocking International immunology High 15039383
1998 Nectin-2 (HveB/PVRL2) functions as a herpesvirus entry mediator: it confers susceptibility to entry of HSV-1 mutant strains, HSV-2, and pseudorabies virus (but not wild-type HSV-1 or bovine herpesvirus type 1) in otherwise resistant CHO cells. Anti-HveB antibodies blocked infection. cDNA expression library screen, CHO cell transfection viral entry assay, antibody blocking Virology High 9657005
2009 TIGIT, expressed on all human NK cells, directly binds Nectin-2 (PVRL2) but not PVRL3, and inhibits NK cytotoxicity through its ITIM domain. TIGIT counter-inhibits NK-mediated killing of tumor cells and provides an 'alternative self' inhibitory mechanism independent of MHC class I. Flow cytometry, binding assays, NK cytotoxicity assay, ITIM functional analysis Proceedings of the National Academy of Sciences of the United States of America High 19815499
2000 Nectin-2 knockout in mice causes male-specific sterility with morphologically aberrant spermatozoa exhibiting defects in nuclear and cytoskeletal morphology and mitochondrial localization. Nectin-2 is expressed in testes only during late spermatogenesis, indicating a role in cytoskeletal reorganization during spermiogenesis. Gene knockout (nectin-2−/− mice), electron microscopy, immunohistochemistry, Western blot Molecular and cellular biology High 10733589
2003 Loss of nectin-2 at Sertoli-spermatid junctions causes male infertility due to severe spermatozoan head and midpiece malformations, reduced migration to oviducts, impaired zona pellucida binding, and failure of sperm-oocyte fusion. Ectoplasmic specializations fail to form in the absence of nectin-2, evidenced by absence of the actin-bundling protein espin at Sertoli-spermatid junctions. Nectin-2 (from Sertoli cells) and nectin-3 (from spermatids) form a heterotypic adhesion complex at these junctions. Knockout mouse (nectin-2LacZ/LacZ), scanning electron microscopy, in vitro binding assays, LacZ knockin expression analysis, espin immunolocalization Biology of reproduction High 12801998
2000 Nectin-2alpha mediates cell-to-cell spread of HSV-1 mutant virus (carrying L25P substitution in gD) but not wild-type HSV-1, consistent with its role as an entry receptor for mutant but not wild-type virus. Nectin-1 is the principal mediator of wild-type virus spread in human cell lines; cell-to-cell spread requires the receptor to be expressed on both donor and recipient cells. Virus spread assay in J cells expressing defined receptors, mAb blocking, plaque assay Journal of virology High 10729168
2000 Both nectin-2alpha and nectin-2delta splice isoforms serve as low-efficiency entry receptors for HSV-1 mutants (L25P substitution in gD) and HSV-2. The V domain at the N-terminus contains the major gD-binding region. In vitro soluble nectin-2 bound gD from HSV-1(U21) mutant weakly; wild-type HSV-1 gD binding to soluble nectin-2 was undetectable. Viral entry assay in transfected cells, in vitro gD-binding assay Journal of virology High 10627537
2001 Two small regions in the V (variable-like Ig) domain of nectin-2 corresponding to amino acids 75–81 and 89 are critical for HSV entry activity. Replacement of amino acid 89 (M89F) in human nectin-2 eliminated HSV entry activity. This region is homologous to the HIV-binding region of CD4 and the poliovirus-binding region of CD155. Chimeric receptor construction, CHO cell transfection, viral entry assay, site-directed mutagenesis Journal of virology High 11602758
2003 Deletions in the N-terminus of HSV-1 or HSV-2 gD that overlap HVEM contact regions severely reduce functional interactions with nectin-2 and HVEM but not with nectin-1. Specific amino acid substitutions (L25P, Q27P, Q27R) in HSV-1 gD enhance cell fusion with cells expressing nectin-2 but are without effect on the high fusion level already seen with wild-type HSV-2 gD. The N-terminus of gD is necessary for functional interactions with nectin-2 but not nectin-1. Cell fusion assay, soluble gD:Fc binding assay, site-directed mutagenesis Journal of virology High 12915538
2012 Crystal structure of the nectin-2 V-set Ig domain (nectin-2v) at 1.85 Å resolution reveals a perpendicular homodimer arrangement. Mutational disruption of the homodimeric interface abolishes homodimer formation and simultaneously abolishes DNAM-1 binding (confirmed by tetramer staining and surface plasmon resonance), indicating that DNAM-1 binding requires homodimerization or engagement of the homodimeric interface of nectin-2. X-ray crystallography (1.85 Å), site-directed mutagenesis, SPR, cell staining with tetramers Journal of immunology High 22547693
2012 Crystal structure of nectin-2 homodimer at 1.3 Å resolution. Structural and mutagenesis studies reveal that charged residues at the dimer interface are major determinants of binding affinities for homophilic and heterophilic nectin interactions, explaining stronger heterophilic versus weaker homophilic interactions among nectin family members. X-ray crystallography (1.3 Å), complementary mutagenesis, biochemical binding assays Proceedings of the National Academy of Sciences of the United States of America High 22927415
2017 TIGIT binds to the membrane-distal Ig domain of nectin-2 with an affinity of ~6 μM. Crystal structure of TIGIT bound to nectin-2 Ig domain shows a conserved 'lock-and-key' binding mode where an 'aromatic key' on nectin-2 is critical for TIGIT binding. TIGIT binding disrupts pre-assembled nectin-2 oligomers (receptor-ligand and ligand-ligand associations are mutually exclusive). The C-C' loop of nectin-2 dictates the TIGIT binding hierarchy. Mutagenesis established the energetic basis of the interaction. X-ray crystallography, SPR binding affinity measurement, mutagenesis, biochemical oligomer disruption assay The Journal of biological chemistry High 28515320
2016 Crystal structure of the human TIGIT ectodomain reveals a classic two-layer β-sandwich IgSF topology. TIGIT is monomeric in solution but forms a canonical Ig-like dimer at high concentrations. Biochemical studies mapped the nectin-2 binding interface on TIGIT, providing structural and biochemical determinants for the TIGIT:nectin-2 interaction. X-ray crystallography, biophysical studies (SEC, AUC), biochemical mutagenesis mapping Molecular immunology High 27978489
2010 Nectin-2 interacts physically with N-cadherin through their extracellular domains (not intracellular domains), and they cooperatively enhance apical constriction and F-actin accumulation at the apical cell surface during Xenopus neural tube morphogenesis. Nectin-2 knockdown impairs neural fold formation; overexpression in non-neural ectoderm induces ectopic apical constrictions. Accumulation of N-cadherin at the apical surface requires nectin-2, but nectin-2 localization is N-cadherin-independent. Morpholino knockdown, overexpression, co-immunoprecipitation, domain-deletion constructs, F-actin imaging in Xenopus embryos Development (Cambridge, England) High 20332149
2010 Human cytomegalovirus (HCMV) UL141 alone is sufficient to retain CD155 in the endoplasmic reticulum but requires assistance from additional HCMV-encoded functions to suppress CD112 (nectin-2) surface expression. HCMV targets CD112 for proteasome-mediated degradation by 48 h post-infection. Deletion of UL141 from the HCMV genome restores surface expression of both CD112 and CD155. HCMV infection, UL141-deletion mutant virus, proteasome inhibitor assays, flow cytometry The Journal of general virology High 20410314
2014 Alphaherpesvirus gD glycoprotein (from PRV and HSV-2) causes degradation and downregulation of CD112 (nectin-2) during infection or transfection. This reduces DNAM-1 binding to infected/transfected cell surfaces, suppresses NK cell degranulation, and reduces NK cell-mediated lysis. This represents an NK immune evasion strategy by alphaherpesviruses. Virus infection, gD transfection, flow cytometry, NK cell degranulation assay, cytotoxicity assay, DNAM-1 binding assay Proceedings of the National Academy of Sciences of the United States of America High 25352670
2019 PVRIG (CD112R) binds PVRL2 (nectin-2/CD112) and inhibits CD8+ T-cell cytokine production and cytotoxic activity. The inhibitory effect of PVRL2 on T cells is mediated by PVRIG and not TIGIT, establishing the PVRIG-PVRL2 pathway as a nonredundant signaling node from TIGIT-PVR. Combination PVRIG + TIGIT or PVRIG + PD-1 blockade further increases T-cell activation. Blocking antibody assays, T-cell cytokine production and cytotoxicity assays, tumor-infiltrating lymphocyte functional assays Cancer immunology research High 30659054
2019 Ubiquitination of Nectin2 promotes its degradation and is responsible for intracellular protein retention; inhibition of the ubiquitin-proteasome pathway results in increased Nectin2 surface expression and enhances tumor cell susceptibility to NK cell cytotoxicity. Ubiquitination assay, proteasome inhibitor treatment, flow cytometry, NK cytotoxicity assay European journal of immunology Medium 30888046
2009 Nectin-2 is required for maintaining structure and function of the intercalated disc in the heart under pressure overload. Nectin-2-knockout mice subjected to aortic banding develop cardiac fibrosis, disrupted intercalated discs, disorganized myofibrils, and increased cardiomyocyte apoptosis. Mechanistically, nectin-2 deficiency results in reduced Akt phosphorylation and elevated c-Jun N-terminal kinase and p38 MAPK phosphorylation under pressure overload. Nectin-2 knockout mice, aortic banding model, histology, Western blot for kinase phosphorylation, apoptosis assay Hypertension (Dallas, Tex. : 1979) High 19667252
2016 Nectin-2δ splice variant is selectively expressed in astrocytes and localizes to perivascular endfoot processes facing the basement membrane of blood vessels (not detected in neurons). Genetic ablation of nectin-2 causes degeneration of astrocytic perivascular endfoot processes and neurons in the cerebral cortex. Immunofluorescence/confocal microscopy, nectin-2 knockout mice, fractionation/localization analysis Brain research Medium 27545667
2006 Nectin-2 (CD112) on eosinophils acts as a ligand for DNAM-1 (CD226) on mast cells. CD226 engagement synergizes with FcεRI on mast cells to augment degranulation through a pathway involving Fyn, LAT, PLCγ2, and CD18. Blocking CD112 on eosinophils with neutralizing antibodies normalized IgE-dependent mast cell hyperactivity in co-culture. Co-culture, degranulation assay, blocking antibodies, signaling pathway inhibitors The Journal of biological chemistry Medium 16831868
2013 Nectin-3 (CD113) on T lymphocytes uses Nectin-2 (CD112) expressed on endothelial cells as its major counter-receptor for heterophilic trans-interaction. Soluble Nectin-3 binds Nectin-2 localized at endothelial junctions and at high endothelial venules; blocking either Nectin-3 on lymphocytes or Nectin-2 on ECs with mAbs inhibits lymphocyte transendothelial migration in vitro. Soluble protein binding assay, mAb blocking, transendothelial migration assay in vitro PloS one Medium 24116228
2021 In CD112-deficient mice, blood vessel coverage in the retina and spleen is significantly enhanced. In vitro CD112 blockade modulates endothelial cell migration and enhances endothelial tube formation. CD112 blockade reduces T cell transmigration across endothelial monolayers in vitro, and T cell homing to the spleen is reduced in CD112-deficient mice in vivo. CD112-knockout mice, retinal vascular analysis, in vitro tube formation and migration assays, in vivo T cell homing assay, antibody blockade Cells Medium 33467729
2014 Cadmium (Cd) suppresses nectin-2 expression via two mechanisms: (1) transcriptional repression by inhibiting binding of positive regulators (CREB, c-Jun, Sp1) to the nectin-2 promoter (shown by EMSA and ChIP), and (2) post-translational degradation via clathrin-dependent endocytosis (shown by inhibitor and shRNA knockdown experiments). EMSA, ChIP assay, endocytosis inhibitor assay, clathrin shRNA knockdown, immunofluorescence, siRNA/overexpression Biochimica et biophysica acta Medium 25046863
2006 Nectin-2 gene transcription in Sertoli/germ cells is driven by cooperative interactions among two Sp1 motifs and a CRE motif within the minimal promoter (−316 to −211). CREB and c-Jun (but not c-Fos) are the critical transcription factors; c-Jun (AP-1) and CREB interact at the CRE motif. ChIP confirmed in vivo binding of CREB, c-Jun, and Sp1 to the nectin-2 promoter, and cyclic expression of CREB coincides with adherens junction restructuring in staged tubules. Transient transfection reporter assay, mutagenesis of promoter motifs, EMSA, ChIP assay, overexpression Journal of cellular physiology Medium 16250013
2018 Nectin-2 extracellular domain directly interacts with N-cadherin extracellular domain with a KD of ~3.5 μM (measured by SPR). Molecular docking and mutagenesis studies defined the binding interface, showing that nectins can recruit cadherins to adherens junctions through an adaptor-independent, extracellular mechanism. Surface plasmon resonance, molecular docking, mutagenesis, structural analysis Proteins Medium 30183103
2022 Nectin-2 acts as an entry-mediating molecule for human herpesvirus 6B (HHV-6B): nectin-2 expression in CD134-negative parotid-derived cells enables HHV-6B infection; nectin-2 knockout reduces viral entry; and HHV-6B glycoprotein B (gB) directly interacts with the nectin-2 V-set domain. Cell transduction, nectin-2 knockout, viral infection assay, co-immunoprecipitation/binding assay of gB with nectin-2 domain Viruses Medium 35062364
2024 Crystal structure of PVRIG in complex with Nectin-2 at 2.2 Å resolution reveals an antiparallel lock-and-key binding mode. A unique CC' loop in PVRIG contributes to high-affinity Nectin-2 binding. CD112R binding disrupts CD112 homodimerization. Charged residues in the F-strands explain PVRIG selectivity for Nectin-2 but not Necl-5 (CD155). Structure-guided directed evolution produced CD112R mutants (CD112RIVE) with greatly increased affinity that potently block CD112-CD112R interactions. X-ray crystallography (2.2 Å), site-directed mutagenesis, directed evolution, soluble trap blocking assay, CAR-T and TCE functional assays Structure (London, England : 1993) High 40285356
2024 Crystal structure of PVRIG (CD112R) in complex with Nectin-2 reveals the molecular basis of immune recognition and selectivity. A unique CC' loop in PVRIG complements the double-lock-and-key binding mode contributing to high affinity. The corresponding charged residues in F-strands explain PVRIG selectivity toward Nectin-2 but not Necl-5. X-ray crystallography, binding affinity measurements, comparative structural analysis Structure (London, England : 1993) High 38626767
2024 PVRL2 (Nectin-2) suppresses antitumor immunity through PVRIG-independent and TIGIT-independent pathways: deletion of PVRL2 in syngeneic tumor models dramatically reduces tumor growth dependent on CD8+ T and NK cells. Loss of PVRL2 suppressed tumor growth even in the absence of PVRIG, and PVRIG loss showed no additive effect in the absence of PVRL2. Combined PVRL2 deletion plus TIGIT blockade achieved near-complete tumor growth suppression. PVRL2 syngeneic knockout mouse models, immune cell depletion, TIGIT blockade combination experiments Cancer immunology research High 38588410
2023 VSIG2, expressed on activated antigen-presenting cells, specifically binds to Nectin-2 and does not interact with PD-1 or CTLA-4. This VSIG2-Nectin-2 interaction strongly inhibits T cell activation and proliferation and regulates the STAT1/IRF1/GBP2 signaling pathway in T cells. Co-immunoprecipitation/binding assays, T cell activation assays, signaling pathway analysis, VSIG2-Ig protein and anti-VSIG2 antibody functional experiments Journal of neuroinflammation Medium 41350674
2025 ST6GalNAc-I sialyltransferase mediates sialylation of NECTIN2 in lung adenocarcinoma cells, contributing to T cell dysfunction. ST6GalNAc-I-deficient tumor cells cocultured with T cells showed increased susceptibility to T cell-mediated killing, and mice injected with St6galnac-I-knockdown syngeneic cells showed reduced Nectin2/TIGIT-associated immunosuppression. Proteomics, biochemical sialylation assay, coculture cytotoxicity, syngeneic mouse tumor model, siRNA knockdown The Journal of clinical investigation Medium 40371640
2024 In colorectal cancer, cancer-associated fibroblasts expressing NECTIN2 inhibit effector T cells; blocking NECTIN2 receptor interaction (with cognate immune receptor) reversed T cell inhibition, demonstrating NECTIN2 as the key driver of T cell suppression by a novel TinCAF fibroblast cluster. scRNA-seq, spatial proteomics, co-culture of CAF and T cells, NECTIN2 blocking antibody, flow cytometry Cancer letters Medium 38821255
2016 Nectin-2 (CD112) knockdown in outgrowth endothelial cells (OECs) enhances tube formation, cell migration, and proliferation with p-ERK activation, and increases compensatory expression of Nectin-3 and Necl-4 (which promote VEGFR signaling). Blocking Nectin-2 with neutralizing mAb similarly increases trans-well migration and tube formation. siRNA knockdown, neutralizing mAb, tube formation assay, migration assay, Western blot for p-ERK, qPCR PloS one Medium 27676263
2023 Nectin2 knockdown in neuroblastoma cells reduces migration and induces apoptosis and cell cycle arrest. ANXA2 is downstream of Nectin2; its expression is reduced by Nectin2 knockdown, and ANXA2 overexpression rescues apoptosis and restores MMP2/MMP9 expression, placing Nectin2 upstream of ANXA2 in a pro-survival pathway. siRNA knockdown, RNA-seq, qRT-PCR, Western blot, rescue overexpression, apoptosis assay, migration assay Acta biochimica et biophysica Sinica Medium 36916296
2024 Tumor-associated neutrophils (TANs) upregulate membranous Nectin2 expression on pancreatic ductal adenocarcinoma cells (via CCL5 secretion and endoplasmic reticulum stress), contributing to CD8+ T-cell exhaustion. Blocking Nectin2 improved CD8+ T-cell function and suppressed tumor progression in mouse models. Microarray, cytokine array, in vitro co-culture, in vivo orthotopic/subcutaneous mouse model, Nectin2 blockade, single-cell transcriptome analysis Journal of experimental & clinical cancer research : CR Medium 39261943

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proceedings of the National Academy of Sciences of the United States of America 726 19815499
2003 Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. The Journal of experimental medicine 707 12913096
1998 A cell surface protein with herpesvirus entry activity (HveB) confers susceptibility to infection by mutants of herpes simplex virus type 1, herpes simplex virus type 2, and pseudorabies virus. Virology 417 9657005
2004 Analysis of the receptor-ligand interactions in the natural killer-mediated lysis of freshly isolated myeloid or lymphoblastic leukemias: evidence for the involvement of the Poliovirus receptor (CD155) and Nectin-2 (CD112). Blood 313 15536144
2004 Functional characterization of DNAM-1 (CD226) interaction with its ligands PVR (CD155) and nectin-2 (PRR-2/CD112). International immunology 226 15039383
2005 Expression of the DNAM-1 ligands, Nectin-2 (CD112) and poliovirus receptor (CD155), on dendritic cells: relevance for natural killer-dendritic cell interaction. Blood 215 16304049
2000 Defects in nuclear and cytoskeletal morphology and mitochondrial localization in spermatozoa of mice lacking nectin-2, a component of cell-cell adherens junctions. Molecular and cellular biology 143 10733589
2019 PVRIG and PVRL2 Are Induced in Cancer and Inhibit CD8+ T-cell Function. Cancer immunology research 134 30659054
2000 Nectin2alpha (PRR2alpha or HveB) and nectin2delta are low-efficiency mediators for entry of herpes simplex virus mutants carrying the Leu25Pro substitution in glycoprotein D. Journal of virology 122 10627537
2005 PVR (CD155) and Nectin-2 (CD112) as ligands of the human DNAM-1 (CD226) activating receptor: involvement in tumor cell lysis. Molecular immunology 116 15607800
2003 Loss of nectin-2 at Sertoli-spermatid junctions leads to male infertility and correlates with severe spermatozoan head and midpiece malformation, impaired binding to the zona pellucida, and oocyte penetration. Biology of reproduction 105 12801998
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
2010 Human cytomegalovirus UL141 promotes efficient downregulation of the natural killer cell activating ligand CD112. The Journal of general virology 91 20410314
2013 Nectin-2 is a potential target for antibody therapy of breast and ovarian cancers. Molecular cancer 86 23758976
2017 Recognition of nectin-2 by the natural killer cell receptor T cell immunoglobulin and ITIM domain (TIGIT). The Journal of biological chemistry 82 28515320
2024 Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy. Cancer cell 78 38181797
2010 Nectin-2 and N-cadherin interact through extracellular domains and induce apical accumulation of F-actin in apical constriction of Xenopus neural tube morphogenesis. Development (Cambridge, England) 65 20332149
2006 Mast cell costimulation by CD226/CD112 (DNAM-1/Nectin-2): a novel interface in the allergic process. The Journal of biological chemistry 61 16831868
2012 Crystal structure of cell adhesion molecule nectin-2/CD112 and its binding to immune receptor DNAM-1/CD226. Journal of immunology (Baltimore, Md. : 1950) 54 22547693
1999 The murine homolog (Mph) of human herpesvirus entry protein B (HveB) mediates entry of pseudorabies virus but not herpes simplex virus types 1 and 2. Journal of virology 51 10196354
2012 Structure of Nectin-2 reveals determinants of homophilic and heterophilic interactions that control cell-cell adhesion. Proceedings of the National Academy of Sciences of the United States of America 49 22927415
2001 Structural features of nectin-2 (HveB) required for herpes simplex virus entry. Journal of virology 48 11602758
2021 The CD112R/CD112 axis: a breakthrough in cancer immunotherapy. Journal of experimental & clinical cancer research : CR 47 34507594
2014 Modulation of CD112 by the alphaherpesvirus gD protein suppresses DNAM-1-dependent NK cell-mediated lysis of infected cells. Proceedings of the National Academy of Sciences of the United States of America 46 25352670
2006 Nectin-2-mediated entry of a syncytial strain of herpes simplex virus via pH-independent fusion with the plasma membrane of Chinese hamster ovary cells. Virology journal 44 17192179
2020 Nectin-2 Expression on Malignant Plasma Cells Is Associated with Better Response to TIGIT Blockade in Multiple Myeloma. Clinical cancer research : an official journal of the American Association for Cancer Research 43 32513837
2019 Nectin-2 in ovarian cancer: How is it expressed and what might be its functional role? Cancer science 41 30843637
2015 The Clinical and Pathological Significance of Nectin-2 and DDX3 Expression in Pancreatic Ductal Adenocarcinomas. Disease markers 41 26294807
2019 The Ubiquitin-proteasome pathway regulates Nectin2/CD112 expression and impairs NK cell recognition and killing. European journal of immunology 38 30888046
2024 Tumor-associated neutrophils upregulate Nectin2 expression, creating the immunosuppressive microenvironment in pancreatic ductal adenocarcinoma. Journal of experimental & clinical cancer research : CR 37 39261943
2018 Interaction of PVR/PVRL2 with TIGIT/DNAM-1 as a novel immune checkpoint axis and therapeutic target in cancer. Mammalian genome : official journal of the International Mammalian Genome Society 36 30132062
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
2018 BCL3-PVRL2-TOMM40 SNPs, gene-gene and gene-environment interactions on dyslipidemia. Scientific reports 34 29670124
2024 Colorectal cancer-associated fibroblasts inhibit effector T cells via NECTIN2 signaling. Cancer letters 33 38821255
2006 Nectin-2 expression in testicular cells is controlled via the functional cooperation between transcription factors of the Sp1, CREB, and AP-1 families. Journal of cellular physiology 33 16250013
2018 Differential Induction of IFN-α and Modulation of CD112 and CD54 Expression Govern the Magnitude of NK Cell IFN-γ Response to Influenza A Viruses. Journal of immunology (Baltimore, Md. : 1950) 32 30143589
2022 Association and interaction of TOMM40 and PVRL2 with plasma amyloid-β and Alzheimer's disease among Chinese older adults: a population-based study. Neurobiology of aging 31 35093267
2014 Genetic variants in PVRL2-TOMM40-APOE region are associated with human longevity in a Han Chinese population. PloS one 31 24924924
2013 Nectin-3 (CD113) interacts with Nectin-2 (CD112) to promote lymphocyte transendothelial migration. PloS one 31 24116228
2009 Deficiency of nectin-2 leads to cardiac fibrosis and dysfunction under chronic pressure overload. Hypertension (Dallas, Tex. : 1979) 29 19667252
2021 Nectin-2 in general and in the brain. Molecular and cellular biochemistry 28 34633611
2016 Localization of nectin-2δ at perivascular astrocytic endfoot processes and degeneration of astrocytes and neurons in nectin-2 knockout mouse brain. Brain research 24 27545667
2016 Structural, mutational and biophysical studies reveal a canonical mode of molecular recognition between immune receptor TIGIT and nectin-2. Molecular immunology 23 27978489
2007 PVRL2 is translocated to the TRA@ locus in t(14;19)(q11;q13)-positive peripheral T-cell lymphomas. Genes, chromosomes & cancer 23 17696193
2003 Differences in the N termini of herpes simplex virus type 1 and 2 gDs that influence functional interactions with the human entry receptor Nectin-2 and an entry receptor expressed in Chinese hamster ovary cells. Journal of virology 23 12915581
2018 Elevated Nectin-2 expression is involved in esophageal squamous cell carcinoma by promoting cell migration and invasion. Oncology letters 22 29552112
2019 Serum nectin-2 and nectin-4 are diagnostic in lung cancer: which is superior? Wiener klinische Wochenschrift 21 31440821
2021 CD155 and CD112 as possible therapeutic targets of FLT3 inhibitors for acute myeloid leukemia. Oncology letters 20 34992684
2014 Increased CD112 expression in methylcholanthrene-induced tumors in CD155-deficient mice. PloS one 20 25384044
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
2022 Nectin-2 Acts as a Viral Entry Mediated Molecule That Binds to Human Herpesvirus 6B Glycoprotein B. Viruses 17 35062364
2016 Nectin-2 (CD112) Is Expressed on Outgrowth Endothelial Cells and Regulates Cell Proliferation and Angiogenic Function. PloS one 17 27676263
2021 Lipid-related protein NECTIN2 is an important marker in the progression of carotid atherosclerosis: An intersection of clinical and basic studies. Journal of translational internal medicine 15 35136728
2014 Dysregulation of nectin-2 in the testicular cells: an explanation of cadmium-induced male infertility. Biochimica et biophysica acta 15 25046863
2024 Immune checkpoint molecule DNAM-1/CD112 axis is a novel target for natural killer-cell therapy in acute myeloid leukemia. Haematologica 14 37731380
2024 The SNP rs6859 in NECTIN2 gene is associated with underlying heterogeneous trajectories of cognitive changes in older adults. BMC neurology 14 38408961
2023 Single-cell RNA sequencing highlights the role of PVR/PVRL2 in the immunosuppressive tumour microenvironment in hepatocellular carcinoma. Frontiers in immunology 14 37383234
2021 CD112 Regulates Angiogenesis and T Cell Entry into the Spleen. Cells 13 33467729
2018 Molecular and structural bases of interaction between extracellular domains of nectin-2 and N-cadherin. Proteins 13 30183103
2006 Allelic association of sequence variants in the herpes virus entry mediator-B gene (PVRL2) with the severity of multiple sclerosis. Genes and immunity 13 16738668
2022 A Novel Antibody-Drug Conjugate Targeting Nectin-2 Suppresses Ovarian Cancer Progression in Mouse Xenograft Models. International journal of molecular sciences 12 36293219
2025 ST6GalNAc-I regulates tumor cell sialylation via NECTIN2/MUC5AC-mediated immunosuppression and angiogenesis in non-small cell lung cancer. The Journal of clinical investigation 11 40371640
2005 Expression of nectin-2 in mouse granulosa cells. European journal of obstetrics, gynecology, and reproductive biology 11 15989986
2024 PVRL2 Suppresses Antitumor Immunity through PVRIG- and TIGIT-independent Pathways. Cancer immunology research 10 38588410
2024 Exercise-induced β2-adrenergic Receptor Activation Enhances the Antileukemic Activity of Expanded γδ T-Cells via DNAM-1 Upregulation and PVR/Nectin-2 Recognition. Cancer research communications 10 38592213
2024 The Nectin family ligands, PVRL2 and PVR, in cancer immunology and immunotherapy. Frontiers in immunology 10 39156900
2022 The Relationship Between Low-Density Lipoprotein Cholesterol and Progression of Mild Cognitive Impairment: The Influence of rs6859 in PVRL2. Frontiers in genetics 10 35273639
2022 Examination of the TIGIT-CD226-CD112-CD155 Immune Checkpoint Network during a Healthy Pregnancy. International journal of molecular sciences 9 36142692
2021 Examination of the TIGIT, CD226, CD112, and CD155 Immune Checkpoint Molecules in Peripheral Blood Mononuclear Cells in Women Diagnosed with Early-Onset Preeclampsia. Biomedicines 9 34829838
2007 No effect of APOE and PVRL2 on the clinical outcome of multiple sclerosis. Journal of neuroimmunology 9 17376543
2001 Search for polymorphisms in the genes for herpesvirus entry mediator, nectin-1, and nectin-2 in immune seronegative individuals. The Journal of infectious diseases 9 11756979
2024 The association between rs6859 in NECTIN2 gene and Alzheimer's disease is partly mediated by pTau. Frontiers in aging neuroscience 8 39165837
2023 Nectin2 influences cell apoptosis by regulating ANXA2 expression in neuroblastoma. Acta biochimica et biophysica Sinica 8 36916296
2023 Metabolic Overlap between Alzheimer's Disease and Metabolic Syndrome Identifies the PVRL2 Gene as a New Modulator of Diabetic Dyslipidemia. International journal of molecular sciences 8 37108578
2017 Comparison of the antiviral potential among soluble forms of herpes simplex virus type-2 glycoprotein D receptors, herpes virus entry mediator A, nectin-1 and nectin-2, in transgenic mice. The Journal of general virology 8 28671524
2024 N6-methyladenosine-associated genetic variants in NECTIN2 and HPCAL1 are risk factors for abdominal aortic aneurysm. iScience 7 38510151
2023 Extracellular CIRP Induces Novel Nectin-2+ (CD112+) Neutrophils to Promote Th1 Differentiation in Sepsis. Journal of immunology (Baltimore, Md. : 1950) 7 36480269
2016 Accumulation of a soluble form of human nectin-2 is required for exerting the resistance against herpes simplex virus type 2 infection in transfected cells. Acta virologica 7 26982466
2007 Linkage disequilibrium analysis of two genes mapping on OFC3: PVR and PVRL2. European journal of human genetics : EJHG 7 17534374
2024 Blockade of the TIGIT-CD155/CD112 axis enhances functionality of NK-92 but not cytokine-induced memory-like NK cells toward CD155-expressing acute myeloid leukemia. Cancer immunology, immunotherapy : CII 6 38967649
2024 TFF3 and PVRL2 co-targeting identified by multi-omics approach as an effective cancer immunosuppression strategy. Life sciences 6 39369842
2018 Fc engineering of anti-Nectin-2 antibody improved thrombocytopenic adverse event in monkey. PloS one 6 29723247
2009 Mutation and association analysis of the PVR and PVRL2 genes in patients with non-syndromic cleft lip and palate. Genetics and molecular biology 6 21637507
2024 Structural basis for the immune recognition and selectivity of the immune receptor PVRIG for ligand Nectin-2. Structure (London, England : 1993) 5 38626767
2010 [Expression of CD112 in colon carcinoma tissues and cell lines and their clinical significance]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 4 20617580
2022 Analysis of Protein-Protein Interactions Identifies NECTIN2 as a Target of N,N-Bis (5-Ethyl-2-hydroxybenzyl) Methylamine for Inhibition of Lung Cancer Metastasis. Cancer genomics & proteomics 3 35985690
2015 A soluble form of human nectin-2 impairs exocrine secretion of pancreas and formation of zymogen granules in transgenic mice. Biochemistry and biophysics reports 3 28955824
2009 Molecular cloning, characterization and three-dimensional modeling of porcine nectin-2/CD112. Veterinary immunology and immunopathology 3 19497625
2024 CD112 Supports Lymphatic Migration of Human Dermal Dendritic Cells. Cells 2 38474388
2021 Analysis of whole genome sequenced cases and controls shows that the association of variants in TOMM40, BCAM, NECTIN2 and APOC1 with late onset Alzheimer's disease is driven by linkage disequilibrium with APOE ε2/ε3/ε4 alleles. Journal of neurogenetics 2 33970751
2025 Structure-guided engineering of CD112 receptor variants for optimized immunotherapy. Molecular therapy : the journal of the American Society of Gene Therapy 1 40285356
2024 CD112 is an epithelial-to-mesenchymal transition-related and immunological biomarker in pan-cancer. Translational cancer research 1 38881943
2023 Relative Expression of BATF and CD112 in PBMC of Patients with Chronic Lymphocytic Leukemia. Asian Pacific journal of cancer prevention : APJCP 1 37378949
2017 Polioviruses that bind a chimeric Pvr-nectin-2 protein identify capsid residues involved in receptor interaction. Virology 1 28800489
2026 A specific stem cell program and CD112 immunological axis dysfunctions underpinning monosomy 7-associated myeloid neoplasms. Signal transduction and targeted therapy 0 42115611
2025 Investigation of TIGIT, PVRIG, CD112 and CD155 expression in early and late onset preeclampsia. Journal of molecular histology 0 40425968
2025 VSIG2 as a novel immunosuppressive ligand interacts with Nectin-2 to regulate T cell responses. Journal of neuroinflammation 0 41350674
2024 The association between rs6859 in NECTIN2 gene and Alzheimer's disease is partly mediated by pTau. medRxiv : the preprint server for health sciences 0 38947013
2007 [Preparation and characterization of monoclonal antibodies against human CD112 (Nectin2/PRR2)]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 0 17428395

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