{"gene":"NECTIN2","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":2003,"finding":"Nectin-2 (CD112) was identified as a specific cell surface ligand for the NK activating receptor DNAM-1 (CD226). Protein purification, tryptic digestion, and mass spectrometry identified Nectin-2 as the 65/60 kDa molecule recognized by mAbs that blocked NK cytotoxicity. PVR-Fc and Nectin-2-Fc soluble hybrid molecules directly stained DNAM-1-transfected COS-7 cells, and Nectin-2 expression in cell transfectants enhanced NK-mediated lysis in a DNAM-1-dependent manner.","method":"Protein purification, mass spectrometry, soluble Fc-fusion binding assays, cell transfection, NK cytotoxicity assays with mAb blocking","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (protein purification/MS, direct binding assays, functional lysis assays with blocking), foundational paper with 706 citations","pmids":["12913096"],"is_preprint":false},{"year":1998,"finding":"Nectin-2 (HveB/Prr2) functions as a herpesvirus entry mediator, conferring susceptibility to infection by HSV-1 mutants unable to use HVEM, HSV-2, and pseudorabies virus, but not wild-type HSV-1. Anti-HveB antibodies blocked infection of HveB-expressing cells.","method":"cDNA expression library screen in CHO cells, antibody blocking of infection, cell transfection-based entry assay","journal":"Virology","confidence":"High","confidence_rationale":"Tier 2 — functional screen plus antibody blocking, replicated across multiple virus strains; 416 citations","pmids":["9657005"],"is_preprint":false},{"year":2004,"finding":"DNAM-1 (CD226) functionally interacts with both CD155 (PVR) and CD112 (nectin-2) as ligands. Ectopic expression of CD112 rendered mouse T cells more susceptible to IL-2-activated T and NK cell-mediated cytotoxicity, which was inhibited by anti-CD226 mAb. Although binding affinities of soluble CD226 to CD155 and CD112 were comparable, homophilic interaction of cell-surface CD112 adversely affects CD226 binding to CD112.","method":"Cell transfection, NK/T cell cytotoxicity assays, mAb blocking, soluble receptor binding affinity measurements","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional assays, 226 citations, independent confirmation of DNAM-1/Nectin-2 interaction","pmids":["15039383"],"is_preprint":false},{"year":2000,"finding":"Disruption of both alleles of murine nectin-2 gene resulted in sterile males with morphologically aberrant spermatozoa showing defects in nuclear and cytoskeletal morphology and mitochondrial localization. Nectin-2 interacts with l-afadin (an F-actin-binding protein) as a component of cell-cell adherens junctions and is expressed in testes only during later stages of spermatogenesis, indicating a role in late-stage germ cell development and cytoskeletal organization during spermiogenesis.","method":"Knockout mouse generation, morphological analysis, immunolocalization, genetic epistasis via null phenotype","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, 143 citations","pmids":["10733589"],"is_preprint":false},{"year":2000,"finding":"Nectin-2 alpha and delta splice variants (differing in transmembrane/cytoplasmic regions but sharing ectodomain) both mediate HSV-1 mutant (carrying L25P substitution in gD) and HSV-2 entry at ~100-fold lower efficiency than HveC/HIgR. gD from HSV-1(U21) bound in vitro soluble forms of nectin-2, with weaker association than to HveC/HIgR. The major functional region for virus entry mapped to the V domain at the N-terminus.","method":"Cell transfection entry assay, in vitro gD binding assay, domain mapping","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro binding assay plus functional entry assay with domain mapping, 122 citations","pmids":["10627537"],"is_preprint":false},{"year":2000,"finding":"Nectin-2 alpha mediates direct cell-to-cell spread of HSV-1 mutant virus (carrying L25P gD substitution) but not wild-type HSV-1, consistent with its entry receptor specificity. An antibody to nectin-1 blocked cell-to-cell spread, and wild-type virus did not spread from receptor-positive to receptor-negative cells, demonstrating that Ig-like receptors (nectin-1 and nectin-2) are required for both virus entry and cell-to-cell spread.","method":"Plaque formation assay in receptor-expressing J cells, mAb blocking of spread, genetic analysis of receptor requirements","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — cell-to-cell spread assay with mAb blocking and receptor-negative cell controls, 94 citations","pmids":["10729168"],"is_preprint":false},{"year":2003,"finding":"Loss of nectin-2 at Sertoli-spermatid junctions causes male infertility. Nectin-2-deficient spermatozoa show severe head and midpiece malformations, 4-fold reduced migration to oviducts, 6-fold reduced binding to zona-intact oocytes, and failure to penetrate zona-free hamster oocytes. Sertoli-spermatid junctions in nectin-2-null mice lack the actin-bundling protein espin, indicating ectoplasmic specializations fail to form. Nectin-2 is produced exclusively by Sertoli cells and forms a heterotypic adhesion complex with nectin-3 on elongated spermatids.","method":"Knockout mouse (LacZ knockin), scanning electron microscopy, in vitro fertilization assays, LacZ reporter expression analysis, immunolocalization","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 — KO with multiple defined cellular phenotypes, 105 citations","pmids":["12801998"],"is_preprint":false},{"year":2001,"finding":"Specific amino acid sequences in the V domain of human nectin-2 are critical for HSV entry activity. Chimeric molecules between human and mouse nectin-2 showed that replacing amino acids 75-81 or residue 89 of mouse nectin-2 with human residues transferred HSV-1/Rid and HSV-2 entry activity. Replacement of residue 89 of human nectin-2 (M89F) eliminated HSV entry activity. This region is homologous to the HIV-binding region of CD4 and the poliovirus-binding region of CD155.","method":"Chimeric receptor construction, cell transfection entry assay, mutagenesis","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 — structure-function mutagenesis with chimeric receptors and defined residues, 47 citations","pmids":["11602758"],"is_preprint":false},{"year":2003,"finding":"N-terminal sequences of HSV gD govern functional interactions with nectin-2, HVEM, and 3-O-sulfated heparan sulfate, but are not required for nectin-1 interactions. Deletions overlapping HVEM contact regions (aa 7-15 and 24-32) severely reduced cell fusion and binding with all receptors except nectin-1. L25P, Q27P, and Q27R substitutions in HSV-1 gD enhanced fusion with human nectin-2 (ordinarily low for wt HSV-1 gD) while the same substitutions in HSV-2 gD were without effect on the already high fusion level.","method":"Cell fusion assay, soluble gD:Fc binding to receptor-expressing cells, mutagenesis (substitutions and deletions in gD N-terminus)","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 — direct binding assay combined with functional cell fusion and mutagenesis, 98 citations","pmids":["12915538"],"is_preprint":false},{"year":2010,"finding":"Human cytomegalovirus UL141 promotes downregulation of CD112 (nectin-2) via proteasome-mediated degradation by 48 h post-infection, thereby removing both DNAM-1 activating ligands (CD155 and CD112) from the cell surface. UL141 alone is sufficient to retain CD155 in the ER, but requires additional HCMV-encoded functions to suppress CD112 expression.","method":"HCMV infection with UL141 deletion mutant, proteasome inhibitor treatment, flow cytometry for surface expression, genetic rescue with UL141 deletion","journal":"The Journal of general virology","confidence":"High","confidence_rationale":"Tier 2 — UL141 deletion virus rescue experiment plus proteasome inhibitor, 91 citations","pmids":["20410314"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of the nectin-2 V-set domain (nectin-2v) at 1.85 Å resolution reveals a perpendicular homodimer arrangement. Disruption of the homodimeric interface by mutagenesis abolished homodimer formation and simultaneously eliminated DNAM-1 binding, indicating that homodimerization or engagement of the homodimeric interface is required for DNAM-1 interaction.","method":"X-ray crystallography (1.85 Å), mutagenesis, surface plasmon resonance, tetramer cell staining, biochemical characterization","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis plus SPR binding assay, 53 citations","pmids":["22547693"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of the nectin-2 homodimer at 1.3 Å resolution reveals the structural basis for homophilic and heterophilic interactions. Mutagenesis of charged residues at the dimer interface identifies them as major determinants of binding affinities, and provides mechanistic explanation for stronger heterophilic versus weaker homophilic interactions among nectin family members.","method":"X-ray crystallography (1.3 Å), complementary mutagenesis, biochemical binding assays","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure plus mutagenesis, 49 citations","pmids":["22927415"],"is_preprint":false},{"year":2010,"finding":"Nectin-2 physically interacts with N-cadherin through their extracellular domains, and they cooperatively enhance apical constriction by driving F-actin accumulation at apical cell surfaces during Xenopus neural tube morphogenesis. The intracellular afadin-binding motif of nectin-2 was not required for ectopic apical constriction induction. Nectin-2 knockdown impaired neural fold formation by attenuating F-actin accumulation, while overexpression in non-neural ectoderm induced ectopic apical constrictions.","method":"Xenopus morpholino knockdown, overexpression of domain-deleted nectin-2, co-immunoprecipitation of extracellular domains, live imaging of F-actin","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 — KD and OE with defined phenotypes plus direct Co-IP of extracellular domains, 65 citations","pmids":["20332149"],"is_preprint":false},{"year":2017,"finding":"TIGIT binds to the membrane-distal V-set immunoglobulin domain of nectin-2 with an affinity of 6 μM. Crystal structure of TIGIT bound to the first Ig domain of nectin-2 showed that TIGIT and nectin-2 dock using the same molecular surface (lock-and-key binding motif) used in nectin/nectin homotypic interactions. TIGIT/nectin-2 binding disrupts pre-assembled nectin-2 oligomers. Mutagenesis identified an 'aromatic key' of nectin-2 as critical for TIGIT interaction, while the C-C' loop of nectin-2 dictates the TIGIT binding hierarchy.","method":"X-ray crystallography of TIGIT:nectin-2 complex, SPR binding affinity measurements, mutagenesis, disruption of nectin-2 oligomers assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure of complex plus SPR plus mutagenesis, 81 citations","pmids":["28515320"],"is_preprint":false},{"year":2016,"finding":"TIGIT engages nectin-2 using a canonical immunoglobulin-like dimer interface. Biophysical studies showed TIGIT is monomeric in solution but dimerizes at high concentrations. Biochemical mutagenesis mapped the nectin-2 binding interface on TIGIT, defining the structural and biochemical determinants for TIGIT:nectin-2 recognition.","method":"X-ray crystallography of TIGIT ectodomain, biophysical characterization (SPR), mutagenesis, model of TIGIT:nectin-2 complex","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus SPR plus mutagenesis, 23 citations","pmids":["27978489"],"is_preprint":false},{"year":2006,"finding":"DNAM-1 (CD226) and its ligand Nectin-2 (CD112) are expressed on human mast cells and eosinophils. Engagement of CD226 on mast cells augments FcεRI-dependent degranulation through a pathway involving Fyn, LAT, PLCγ2, and CD18. This costimulatory pathway is completely inhibited by IRp60 (CD300a) inhibitory receptor. Blocking CD112 on eosinophils normalized the hyperactivation of mast cells co-cultured with eosinophils.","method":"Flow cytometry, mAb stimulation/blocking, degranulation assay, inhibitor analysis of signaling pathway, co-culture with blocking antibodies","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — functional pathway dissection with pathway inhibitors, 61 citations","pmids":["16831868"],"is_preprint":false},{"year":2009,"finding":"Nectin-2 deficiency in mice leads to cardiac fibrosis and dysfunction under chronic pressure overload (ascending aorta banding) but not under physiological conditions. In banded nectin-2 knockout mice, intercalated discs were disrupted, myofibrils disorganized, and cardiac myocyte apoptosis increased. Akt phosphorylation remained lower, while JNK and p38 MAPK were hyperphosphorylated compared to wild-type, revealing nectin-2-dependent signaling for cardiac protection.","method":"Knockout mouse, ascending aorta banding model, echocardiography, histology, immunoblotting for signaling kinases, TUNEL assay","journal":"Hypertension","confidence":"High","confidence_rationale":"Tier 2 — KO with defined cardiac phenotype plus mechanistic signaling pathway analysis, 29 citations","pmids":["19667252"],"is_preprint":false},{"year":2013,"finding":"Nectin-3 (CD113) expressed on T lymphocytes trans-interacts with Nectin-2 (CD112) on endothelial cells at high endothelial venules to promote lymphocyte transendothelial migration. A soluble form of Nectin-3 binds to Nectin-2 at EC junctions, and blocking Nectin-2 trans-interactions with mAbs abolished soluble Nectin-3 binding. Blocking either Nectin-3 on lymphocytes or Nectin-2 on ECs inhibited lymphocyte extravasation in vitro.","method":"Soluble receptor binding assay, mAb blocking of trans-interactions, in vitro transendothelial migration assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — reciprocal blocking with defined functional readout (transendothelial migration), 31 citations","pmids":["24116228"],"is_preprint":false},{"year":2014,"finding":"The alphaherpesvirus gD glycoprotein (from PRV and HSV-2) induces degradation and downregulation of CD112 (nectin-2) from the cell surface during infection or transfection, reducing DNAM-1 binding to infected/transfected cells and suppressing NK cell degranulation and lysis. This identifies a previously uncharacterized alphaherpesvirus NK evasion strategy.","method":"Virus infection/transfection, flow cytometry for surface CD112, DNAM-1-Fc binding assay, NK cell degranulation and cytotoxicity assays","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — gD expression plus functional NK assays with defined molecular mechanism, 46 citations","pmids":["25352670"],"is_preprint":false},{"year":2016,"finding":"Nectin-2 (CD112) regulates endothelial cell biology in vivo: CD112-deficient mice show enhanced blood vessel coverage in retina and spleen. In vitro, CD112 blockade enhanced endothelial tube formation and cell migration. CD112 knockdown enhanced tube formation, cell migration, and proliferation with p-Erk activation, and led to compensatory upregulation of Nectin-3 and Necl-4 which promote VEGFR signaling. CD112 also regulates T cell entry into the spleen in vivo.","method":"CD112-knockout mice, retinal and spleen vasculature analysis, in vitro tube formation and migration assays, siRNA knockdown, flow cytometry, signaling analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse plus in vitro KD with defined phenotypes, single lab","pmids":["27676263"],"is_preprint":false},{"year":2019,"finding":"Ubiquitination of Nectin2 promotes its intracellular retention and proteasomal degradation, limiting surface expression. Inhibition of the ubiquitin-proteasome pathway results in increased Nectin2 surface expression and enhances tumor cell susceptibility to NK cell cytotoxicity. Nectin2 is predominantly expressed in cytoplasmic pools on tumor cell lines.","method":"Ubiquitin pathway inhibitors, flow cytometry for surface vs. total expression, NK cell cytotoxicity assays, subcellular fractionation","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 — pharmacological inhibition plus functional NK assay, single lab","pmids":["30888046"],"is_preprint":false},{"year":2016,"finding":"Nectin-2δ splice variant is selectively expressed in astrocytes and localizes to perivascular astrocytic endfoot processes facing blood vessel basement membranes, while nectin-2α is expressed in both neurons and astrocytes. Genetic ablation of nectin-2 caused degeneration of astrocytic perivascular endfoot processes and neurons in the cerebral cortex, revealing a critical role for nectin-2 in brain homeostasis.","method":"Nectin-2 knockout mouse, immunofluorescence, confocal microscopy, cell-type specific fractionation, electron microscopy of endfoot processes","journal":"Brain research","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with specific structural phenotype, localization validated by multiple methods","pmids":["27545667"],"is_preprint":false},{"year":2006,"finding":"Nectin-2 gene transcription in testicular cells is controlled by cooperative interaction of Sp1, CREB, and AP-1 (c-Jun) transcription factors. The minimal mouse nectin-2 promoter (nucleotides -316 to -211) contains two Sp1 motifs and one CRE motif that synergize to regulate transcription. In vivo, CREB, c-Jun, and Sp1 family proteins are bound to the nectin-2 promoter. Cyclic expression of CREB coincides with adherens junction restructuring between Sertoli cells and germ cells.","method":"Transient transfection/promoter reporter assay, EMSA, chromatin immunoprecipitation (ChIP), siRNA knockdown, overexpression","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 1-2 — EMSA, ChIP, and functional promoter assays with mutagenesis, 32 citations","pmids":["16250013"],"is_preprint":false},{"year":2014,"finding":"Cadmium suppresses nectin-2 expression at both transcriptional and post-translational levels in testicular cells. Cadmium induces nectin-2 protein degradation via clathrin-dependent endocytosis, promotes nectin-2 internalization, and directly represses nectin-2 transcription by inhibiting binding of positive transcriptional regulators (Sp1, CREB) to the nectin-2 promoter, contributing to blood-testis barrier disruption.","method":"Endocytosis inhibitors, shRNA knockdown, siRNA, immunofluorescence, EMSA, ChIP, flow cytometry-based endocytosis assay","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (inhibitors, shRNA, EMSA, ChIP, imaging), single lab","pmids":["25046863"],"is_preprint":false},{"year":2018,"finding":"Nectin-2 directly interacts with the extracellular domain of N-cadherin with a KD of 3.5 ± 0.6 μM, as demonstrated by surface plasmon resonance. Structural analysis of homodimeric structures and molecular docking identified the binding interface. This provides a direct, adaptor-independent mechanism by which nectins can recruit cadherins to sites of adherens junction.","method":"Surface plasmon resonance (SPR), structural analysis of existing crystal structures, molecular docking, complementary mutagenesis","journal":"Proteins","confidence":"Medium","confidence_rationale":"Tier 2 — SPR binding plus structural/mutagenesis analysis, single lab","pmids":["30183103"],"is_preprint":false},{"year":2022,"finding":"Nectin-2 acts as a viral entry mediator for Human Herpesvirus 6B (HHV-6B). Nectin-2-transduced T cells became permissive for HHV-6B infection, and nectin-2 knockout in parotid-derived HSY cells significantly reduced HHV-6B entry. HHV-6B glycoprotein B (gB) interacted specifically with the nectin-2 V-set domain.","method":"Nectin-2 gene transduction into T cells, nectin-2 knockout via CRISPR, virus infection assays, pulldown/binding assay between gB and nectin-2 V-set domain","journal":"Viruses","confidence":"High","confidence_rationale":"Tier 2 — KO, transduction, and direct protein-protein binding assay, 17 citations","pmids":["35062364"],"is_preprint":false},{"year":2024,"finding":"Crystal structure of the PVRIG (CD112R):Nectin-2 complex at undisclosed resolution identified a unique CC' loop in PVRIG that complements a double-lock-and-key binding mode and contributes to its high affinity for Nectin-2. Charged residues in the F-strands explain PVRIG selectivity for Nectin-2 over Necl-5. CD112R was found to disrupt CD112 homodimerization in an antiparallel binding mode.","method":"X-ray crystallography of PVRIG:Nectin-2 complex, comparative binding affinity measurements, structural analysis","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 — crystal structure of receptor-ligand complex with structural and biochemical validation","pmids":["38626767"],"is_preprint":false},{"year":2025,"finding":"Crystal structure of the CD112:CD112R (Nectin-2:PVRIG) complex at 2.2 Å resolution reveals an antiparallel, lock-and-key binding mode in which CD112R disrupts CD112 homodimerization. Structure-guided directed evolution produced CD112R mutants with increased CD112 binding affinity; the highest-affinity variant (CD112RIVE) potently inhibits CD112-CD112R interactions as a soluble trap.","method":"X-ray crystallography (2.2 Å), directed evolution, SPR binding affinity measurement, functional T cell activation and cytotoxicity assays with CAR-T and T cell engager constructs","journal":"Molecular therapy","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus structure-guided mutagenesis plus functional validation","pmids":["40285356"],"is_preprint":false},{"year":2002,"finding":"Mutations in three equivalent regions of the N-terminal V-like domain of nectin-2 revealed distinct structural requirements for HSV entry, PRV/BHV-1 entry, and homotypic/heterotypic nectin-nectin trans-interactions. Region I mutations (impairing HSV entry) did not reduce homotypic trans-interactions for nectin-2. Region III mutations that reduced homotypic trans-interactions of nectin-2 also impaired PRV and BHV-1 entry activity. Effects on gD binding did not necessarily correlate with functional entry.","method":"Mutagenesis of nectin-2 V domain, cell transfection entry assay with multiple alphaherpesvirus strains, binding assay to gD","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 — systematic mutagenesis with multiple functional readouts (entry, trans-interaction, gD binding), 35 citations","pmids":["12438620"],"is_preprint":false},{"year":2025,"finding":"ST6GalNAc-I sialylates NECTIN2 in lung adenocarcinoma cells, as shown by proteomic and biochemical analysis. This sialylation promotes T cell dysfunction via the NECTIN2-TIGIT axis. ST6GalNAc-I-deficient tumor cells co-cultured with T cells were more susceptible to T cell-mediated killing, and mice injected with St6galnac-I-knockdown cells showed reduced Nectin2/Tigit-associated immunosuppression.","method":"Proteomics, biochemical co-localization, syngeneic mouse model, KD/KO co-culture cytotoxicity assay","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2-3 — proteomics identifies modification, functional assays confirm consequence, single study","pmids":["40371640"],"is_preprint":false},{"year":2006,"finding":"Nectin-2-mediated HSV-1 ANG path (syncytial strain) entry into CHO cells occurs via pH-independent fusion at the plasma membrane, whereas nectin-1 directs the same strain to a pH-dependent endocytic pathway. HSV-1 ANG path virions induced rapid fusion-from-without (FFWO) exclusively in CHO-nectin-2 cells, not in CHO-nectin-1 or receptor-negative cells, demonstrating that receptor identity (nectin-2 vs. nectin-1) determines the entry pathway.","method":"Endocytosis/acidification inhibitors, kinetics of entry measurement, FFWO assay, CHO cell transfectants expressing distinct receptors","journal":"Virology journal","confidence":"High","confidence_rationale":"Tier 2 — pharmacological pathway dissection plus FFWO assay with clear receptor specificity, 44 citations","pmids":["17192179"],"is_preprint":false},{"year":1999,"finding":"Murine nectin-2 (mHveB), the mouse homolog of human HveB, mediates entry of porcine pseudorabies virus (PRV) but not HSV-1 or HSV-2. Anti-mHveB antibody and soluble mHveB ectodomain inhibited mHveB-dependent PRV entry. Co-expression of mHveB with PRV gD (but not HSV-1 gD) caused interference with entry, suggesting direct interaction of PRV gD with mHveB during viral entry.","method":"Cell transfection entry assay, antibody blocking, interference assay with viral gD co-expression, RT-PCR","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — antibody blocking, receptor-gD interference assay, 51 citations","pmids":["10196354"],"is_preprint":false},{"year":2021,"finding":"VSIG2 specifically binds to Nectin-2 (and not to PD-1 or CTLA-4) and functions as an immunosuppressive ligand present on antigen-presenting cells. VSIG2-Nectin-2 binding strongly inhibits T cell activation and proliferation. This interaction regulates the STAT1/IRF1/GBP2 signaling pathway in T cells.","method":"Direct binding assay (VSIG2 vs. known immune receptors), co-culture T cell activation/proliferation assays, signaling pathway analysis, in vivo mouse EAE model, anti-tumor assay","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2-3 — binding specificity assay plus functional T cell assays plus signaling, single lab","pmids":["41350674"],"is_preprint":false}],"current_model":"NECTIN2 (CD112) is a Ca2+-independent immunoglobulin superfamily cell adhesion molecule that functions as a cell surface ligand for the activating receptor DNAM-1 (CD226) and as an inhibitory checkpoint ligand for TIGIT and PVRIG (CD112R), forming homo- and heterodimers through its membrane-distal V-set domain (crystal structures resolved); it serves as an entry receptor for herpes simplex virus (HSV-2, HSV-1 mutants), pseudorabies virus, and HHV-6B through gD/gB interactions with its V domain; it localizes to and is required for integrity of cell-cell adherens junctions in multiple tissues (Sertoli-spermatid junctions, cardiac intercalated discs, astrocytic perivascular endfeet); its surface expression is regulated post-translationally by ubiquitin-proteasome-mediated degradation and clathrin-dependent endocytosis, and transcriptionally by cooperative Sp1/CREB/c-Jun activity; viral glycoproteins (HCMV UL141, alphaherpesvirus gD) and ST6GalNAc-I-mediated sialylation modulate its surface levels to enable immune evasion; and it participates in lymphocyte transendothelial migration through heterophilic trans-interaction with Nectin-3."},"narrative":{"teleology":[{"year":1998,"claim":"Establishing that NECTIN2 is a herpesvirus entry receptor resolved how alphaherpesviruses other than HSV-1 gain cellular access, identifying NECTIN2 as a functional entry mediator for HSV-2, HSV-1 mutants, and pseudorabies virus.","evidence":"cDNA expression library screen in CHO cells with antibody blocking across multiple virus strains","pmids":["9657005"],"confidence":"High","gaps":["Wild-type HSV-1 does not use NECTIN2 efficiently — the structural basis for this selectivity was unknown","Entry mechanism (endocytic vs. plasma membrane fusion) was undefined"]},{"year":1999,"claim":"Demonstrating that murine nectin-2 mediates PRV but not HSV entry established species-specific receptor usage and identified gD as the interacting viral glycoprotein through interference assays.","evidence":"Antibody blocking and gD co-expression interference assay in transfected cells","pmids":["10196354"],"confidence":"High","gaps":["Structural determinants of species specificity not mapped","No direct binding affinity measurement"]},{"year":2000,"claim":"Knockout of nectin-2 in mice revealed an essential adhesion function at Sertoli-spermatid junctions, establishing that nectin-2 is required for spermiogenesis and male fertility through interaction with l-afadin and the actin cytoskeleton.","evidence":"Nectin-2 knockout mouse with morphological, immunolocalization, and fertility phenotyping","pmids":["10733589"],"confidence":"High","gaps":["Mechanism of cytoskeletal disorganization not fully defined","Heterotypic partner on spermatids not yet identified"]},{"year":2000,"claim":"Mapping the V domain as the functional region for virus entry and showing that both splice variants (α and δ) support entry resolved which ectodomain mediates gD interaction and clarified the role of cytoplasmic tail diversity.","evidence":"Domain mapping, in vitro gD binding, and cell transfection entry assays","pmids":["10627537","10729168"],"confidence":"High","gaps":["Precise contact residues on the V domain not yet identified","Entry pathway (pH-dependent vs. independent) unknown"]},{"year":2001,"claim":"Site-directed mutagenesis of the V domain identified residues 75–81 and M89 as critical determinants of HSV entry activity, providing the first residue-level map of the virus-binding site.","evidence":"Human-mouse nectin-2 chimeras and point mutagenesis with functional entry assays","pmids":["11602758"],"confidence":"High","gaps":["No crystal structure to confirm direct contact","How these residues relate to nectin-nectin homophilic interfaces was unknown"]},{"year":2002,"claim":"Systematic mutagenesis of three V-domain regions showed that structural requirements for HSV entry, PRV/BHV-1 entry, and homophilic trans-interactions are separable, establishing that viral and adhesion functions use overlapping but distinct surfaces.","evidence":"Mutagenesis with entry assays for multiple alphaherpesviruses, trans-interaction, and gD binding assays","pmids":["12438620"],"confidence":"High","gaps":["No structural data to visualize the separation of binding interfaces","Heterophilic nectin-3 interaction surface not mapped"]},{"year":2003,"claim":"Identification of NECTIN2 as a ligand for the NK activating receptor DNAM-1 established a direct molecular link between cell adhesion molecules and innate immune recognition of target cells.","evidence":"Protein purification/mass spectrometry, Fc-fusion binding to DNAM-1 transfectants, NK cytotoxicity assays with blocking antibodies","pmids":["12913096","15039383"],"confidence":"High","gaps":["Binding affinity not precisely quantified","How homophilic nectin-2 interactions compete with DNAM-1 binding was unclear"]},{"year":2003,"claim":"Detailed analysis of Sertoli-spermatid junctions in nectin-2 null mice revealed loss of ectoplasmic specializations (espin-containing actin bundles) and identified heterotypic nectin-2/nectin-3 adhesion as the organizing interaction, explaining the infertility phenotype mechanistically.","evidence":"Knockout mouse with SEM, in vitro fertilization, LacZ reporter, and immunolocalization","pmids":["12801998"],"confidence":"High","gaps":["Signal transduction downstream of nectin-2 in Sertoli cells not characterized","Whether nectin-2 loss affects blood-testis barrier integrity not tested"]},{"year":2006,"claim":"Transcriptional regulation of nectin-2 was resolved by identifying cooperative Sp1/CREB/c-Jun binding to the minimal promoter, linking adherens junction remodeling cycles in the testis to cyclic CREB expression.","evidence":"Promoter-reporter assays, EMSA, ChIP, and siRNA in testicular cells","pmids":["16250013"],"confidence":"High","gaps":["Epigenetic regulation not addressed","Tissue-specific vs. ubiquitous promoter usage not resolved"]},{"year":2006,"claim":"Discovery that nectin-2-mediated HSV-1 entry proceeds via pH-independent plasma membrane fusion — unlike nectin-1-mediated endocytic entry — established that receptor identity determines the viral entry pathway.","evidence":"Endocytosis/acidification inhibitors and fusion-from-without assays in CHO-nectin-2 vs. CHO-nectin-1 cells","pmids":["17192179"],"confidence":"High","gaps":["Mechanism by which receptor cytoplasmic domain or membrane context directs pathway choice unknown","Limited to one syncytial HSV-1 strain"]},{"year":2009,"claim":"Nectin-2 knockout mice subjected to pressure overload developed cardiac fibrosis and intercalated disc disruption with altered Akt/JNK/p38 signaling, revealing a cardioprotective adhesion-signaling function under stress.","evidence":"Knockout mouse with aortic banding, echocardiography, histology, and kinase phosphorylation analysis","pmids":["19667252"],"confidence":"High","gaps":["Direct signaling cascade from nectin-2 to Akt not mapped","Heterotypic partner at intercalated discs not identified"]},{"year":2010,"claim":"HCMV UL141 was shown to promote proteasome-dependent degradation of surface NECTIN2, establishing a viral immune evasion mechanism that removes DNAM-1 activating ligands from infected cells.","evidence":"UL141 deletion virus, proteasome inhibitor, and flow cytometry for surface CD112","pmids":["20410314"],"confidence":"High","gaps":["Whether UL141 directly binds nectin-2 or acts through an E3 ligase intermediate was unclear","Additional HCMV-encoded functions needed for full CD112 suppression not identified"]},{"year":2010,"claim":"In Xenopus neural tube morphogenesis, nectin-2 cooperates with N-cadherin through direct extracellular domain interaction to drive apical F-actin accumulation and apical constriction, establishing a developmental adhesion role independent of the intracellular afadin pathway.","evidence":"Morpholino knockdown, overexpression of domain-deleted constructs, and co-IP of extracellular domains","pmids":["20332149"],"confidence":"High","gaps":["Direct binding affinity between nectin-2 and N-cadherin ectodomains not measured in this study","Whether this mechanism operates in mammalian neural tube closure untested"]},{"year":2012,"claim":"High-resolution crystal structures of the nectin-2 V-domain homodimer (1.3–1.85 Å) revealed the perpendicular dimer arrangement and showed that homodimerization is prerequisite for DNAM-1 binding, resolving how homophilic adhesion and immune ligand function are structurally coupled.","evidence":"X-ray crystallography, mutagenesis of the dimer interface, SPR, and tetramer staining","pmids":["22547693","22927415"],"confidence":"High","gaps":["No co-crystal with DNAM-1","Whether heterodimer with nectin-3 also supports DNAM-1 binding untested"]},{"year":2013,"claim":"Trans-interaction of endothelial NECTIN2 with lymphocyte nectin-3 was shown to promote transendothelial migration, expanding NECTIN2's function beyond static adhesion to active leukocyte trafficking.","evidence":"Soluble receptor binding, reciprocal mAb blocking, and in vitro transendothelial migration assay","pmids":["24116228"],"confidence":"High","gaps":["In vivo validation of this trafficking role limited","Signaling downstream of nectin-2 engagement on endothelium not characterized"]},{"year":2014,"claim":"Alphaherpesvirus gD was found to induce degradation of surface NECTIN2, suppressing DNAM-1-dependent NK killing — a mechanism distinct from HCMV UL141 that links viral entry glycoprotein function to immune evasion.","evidence":"Virus infection and gD transfection with flow cytometry, DNAM-1-Fc binding, and NK degranulation assays","pmids":["25352670"],"confidence":"High","gaps":["Degradation pathway (proteasomal vs. lysosomal) for gD-induced downregulation not defined","Whether gD-mediated degradation affects nectin-2 adhesion functions not tested"]},{"year":2014,"claim":"Cadmium-induced nectin-2 downregulation via clathrin-dependent endocytosis and transcriptional repression (reduced Sp1/CREB promoter binding) provided a unified mechanism for toxicant-mediated blood-testis barrier disruption.","evidence":"Endocytosis inhibitors, shRNA, EMSA, ChIP, and flow cytometry","pmids":["25046863"],"confidence":"High","gaps":["E3 ubiquitin ligase mediating cadmium-induced ubiquitination not identified","Direct cadmium binding to nectin-2 not tested"]},{"year":2016,"claim":"Localization of the nectin-2δ splice variant to astrocytic perivascular endfeet, and degeneration of these structures in knockout mice, established a CNS-specific adhesion role for NECTIN2 in neurovascular unit integrity.","evidence":"Knockout mouse, confocal and electron microscopy, cell-type fractionation","pmids":["27545667"],"confidence":"High","gaps":["Whether blood-brain barrier permeability is altered in knockouts not measured","Heterotypic partner on endothelial side not identified"]},{"year":2017,"claim":"Crystal structures of the TIGIT:nectin-2 complex revealed that TIGIT engages the same lock-and-key interface used for nectin-nectin homodimerization, explaining how inhibitory checkpoint receptors compete with nectin homophilic adhesion and DNAM-1 binding.","evidence":"X-ray crystallography of TIGIT:nectin-2 complex, SPR (KD ~6 μM), mutagenesis, oligomer disruption assay","pmids":["28515320","27978489"],"confidence":"High","gaps":["Functional consequence of oligomer disruption in vivo not tested","Whether TIGIT and DNAM-1 compete directly on the same surface unresolved structurally"]},{"year":2019,"claim":"Ubiquitin-proteasome-mediated intracellular retention was identified as a major regulator of NECTIN2 surface expression on tumor cells, with proteasome inhibition increasing surface levels and enhancing NK susceptibility.","evidence":"Ubiquitin pathway inhibitors, flow cytometry for surface vs. total expression, NK cytotoxicity assays","pmids":["30888046"],"confidence":"Medium","gaps":["Specific E3 ligase(s) not identified","Whether this pathway operates in non-tumor cells not established","Pharmacological inhibitors may have off-target effects"]},{"year":2022,"claim":"Identification of NECTIN2 as an entry receptor for HHV-6B via V-domain interaction with gB extended the viral receptor function beyond alphaherpesviruses to a betaherpesvirus.","evidence":"CRISPR knockout, gene transduction, and pulldown of gB with nectin-2 V domain","pmids":["35062364"],"confidence":"High","gaps":["Structural basis of gB:nectin-2 interaction not resolved","Whether nectin-2 is the primary or accessory receptor in vivo unclear"]},{"year":2024,"claim":"Crystal structures of the PVRIG (CD112R):NECTIN2 complex revealed an antiparallel binding mode with a double-lock-and-key mechanism, explaining PVRIG's high selectivity for NECTIN2 and its ability to disrupt NECTIN2 homodimers — completing the structural picture of the inhibitory checkpoint axis.","evidence":"X-ray crystallography of PVRIG:nectin-2 complex (including 2.2 Å structure), SPR, directed evolution of high-affinity variants, functional T cell and CAR-T assays","pmids":["38626767","40285356"],"confidence":"High","gaps":["In vivo therapeutic efficacy of engineered CD112R variants not yet demonstrated in clinical trials","Whether disruption of NECTIN2 homodimers affects adhesion junctions in treated tissues unknown"]},{"year":2025,"claim":"ST6GalNAc-I-mediated sialylation of NECTIN2 was identified as a post-translational modification that promotes T cell dysfunction through the NECTIN2-TIGIT axis in lung adenocarcinoma, linking glycosylation to immune checkpoint activity.","evidence":"Proteomics, co-culture cytotoxicity assays, syngeneic mouse model with ST6GalNAc-I knockdown","pmids":["40371640"],"confidence":"Medium","gaps":["Specific sialylation sites on NECTIN2 not mapped","Whether sialylation alters binding to DNAM-1 or PVRIG not tested","Single study awaiting independent confirmation"]},{"year":null,"claim":"Key unresolved questions include: the identity of the E3 ubiquitin ligase(s) controlling NECTIN2 surface expression; the structural basis of the DNAM-1:NECTIN2 interaction (no co-crystal exists); how NECTIN2 integrates adhesion and immune signaling in the same tissue context; and the in vivo therapeutic potential of blocking NECTIN2 checkpoint interactions.","evidence":"","pmids":[],"confidence":"High","gaps":["No DNAM-1:NECTIN2 co-crystal structure","E3 ligase for NECTIN2 ubiquitination unidentified","In vivo significance of VSIG2:NECTIN2 interaction not independently confirmed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,3,6,12,17]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[1,4,25]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,2,13,26]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,9,17,20]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[20]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,13,15,18,26,29]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[3,6,12,16,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,4,9,18,25]}],"complexes":[],"partners":["CD226","TIGIT","PVRIG","NECTIN3","CDH2","MLLT4","VSIG2"],"other_free_text":[]},"mechanistic_narrative":"NECTIN2 (CD112) is an immunoglobulin superfamily cell adhesion molecule that functions at the nexus of cell-cell adhesion, immune regulation, and viral entry. Its membrane-distal V-set domain mediates Ca²⁺-independent homophilic and heterophilic trans-interactions — forming homodimers and heterodimers with nectin-3 — that are essential for adherens junction integrity at Sertoli-spermatid junctions, cardiac intercalated discs, and astrocytic perivascular endfeet, as demonstrated by knockout mice exhibiting male infertility, stress-induced cardiac dysfunction, and endfoot degeneration [PMID:10733589, PMID:12801998, PMID:19667252, PMID:27545667]. The same V-domain serves as a ligand for the activating receptor DNAM-1 (CD226) and the inhibitory checkpoint receptors TIGIT and PVRIG (CD112R), with crystal structures revealing that TIGIT and PVRIG engage the nectin-2 homodimer interface to disrupt its oligomeric state, thereby competing with activating signals [PMID:12913096, PMID:28515320, PMID:38626767, PMID:40285356]. NECTIN2 also functions as an entry receptor for HSV-2, HSV-1 mutants, pseudorabies virus, and HHV-6B through direct interaction of viral glycoproteins gD or gB with specific residues in its V domain, and multiple herpesviruses exploit degradation of NECTIN2 — via HCMV UL141-directed proteasomal targeting or alphaherpesvirus gD-induced downregulation — to evade DNAM-1-dependent NK cell killing [PMID:9657005, PMID:35062364, PMID:20410314, PMID:25352670]. Surface expression of NECTIN2 is regulated post-translationally by ubiquitin-proteasome-mediated degradation and clathrin-dependent endocytosis, and transcriptionally by cooperative Sp1/CREB/c-Jun activity at its promoter [PMID:30888046, PMID:25046863, PMID:16250013]."},"prefetch_data":{"uniprot":{"accession":"Q92692","full_name":"Nectin-2","aliases":["Herpes virus entry mediator B","Herpesvirus entry mediator B","HveB","Nectin cell adhesion molecule 2","Poliovirus receptor-related protein 2"],"length_aa":538,"mass_kda":57.7,"function":"Modulator of T-cell signaling. Can be either a costimulator of T-cell function, or a coinhibitor, depending on the receptor it binds to. Upon binding to CD226, stimulates T-cell proliferation and cytokine production, including that of IL2, IL5, IL10, IL13, and IFNG. Upon interaction with PVRIG, inhibits T-cell proliferation. These interactions are competitive (PubMed:26755705). Probable cell adhesion protein (PubMed:9657005) (Microbial infection) Acts as a receptor for herpes simplex virus 1 (HHV-1) mutant Rid1, herpes simplex virus 1 (HHV-2) and pseudorabies virus (PRV)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q92692/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NECTIN2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NECTIN2","total_profiled":1310},"omim":[{"mim_id":"621139","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 178; CCDC178","url":"https://www.omim.org/entry/621139"},{"mim_id":"600798","title":"NECTIN CELL ADHESION MOLECULE 2; NECTIN2","url":"https://www.omim.org/entry/600798"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Mitotic spindle","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NECTIN2"},"hgnc":{"alias_symbol":["PVRR2","PRR2","CD112","Nectin-2"],"prev_symbol":["HVEB","PVRL2"]},"alphafold":{"accession":"Q92692","domains":[{"cath_id":"2.60.40.10","chopping":"36-160","consensus_level":"high","plddt":88.5214,"start":36,"end":160},{"cath_id":"2.60.40.10","chopping":"164-256","consensus_level":"high","plddt":96.2256,"start":164,"end":256},{"cath_id":"2.60.40.10","chopping":"261-345","consensus_level":"high","plddt":93.5552,"start":261,"end":345}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92692","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92692-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92692-F1-predicted_aligned_error_v6.png","plddt_mean":75.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NECTIN2","jax_strain_url":"https://www.jax.org/strain/search?query=NECTIN2"},"sequence":{"accession":"Q92692","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92692.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92692/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92692"}},"corpus_meta":[{"pmid":"12913096","id":"PMC_12913096","title":"Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule.","date":"2003","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12913096","citation_count":706,"is_preprint":false},{"pmid":"9657005","id":"PMC_9657005","title":"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.","date":"1998","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/9657005","citation_count":416,"is_preprint":false},{"pmid":"15536144","id":"PMC_15536144","title":"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 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gene.","date":"1995","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/7622062","citation_count":163,"is_preprint":false},{"pmid":"10601210","id":"PMC_10601210","title":"Effect of environmental pH on morphological development of Candida albicans is mediated via the PacC-related transcription factor encoded by PRR2.","date":"1999","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/10601210","citation_count":146,"is_preprint":false},{"pmid":"10733589","id":"PMC_10733589","title":"Defects in nuclear and cytoskeletal morphology and mitochondrial localization in spermatozoa of mice lacking nectin-2, a component of cell-cell adherens junctions.","date":"2000","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10733589","citation_count":143,"is_preprint":false},{"pmid":"10627537","id":"PMC_10627537","title":"Nectin2alpha (PRR2alpha or HveB) and nectin2delta are low-efficiency mediators for entry of herpes simplex virus mutants carrying the Leu25Pro substitution in glycoprotein D.","date":"2000","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/10627537","citation_count":122,"is_preprint":false},{"pmid":"15607800","id":"PMC_15607800","title":"PVR (CD155) and Nectin-2 (CD112) as ligands of the human DNAM-1 (CD226) activating receptor: involvement in tumor cell lysis.","date":"2005","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15607800","citation_count":116,"is_preprint":false},{"pmid":"12801998","id":"PMC_12801998","title":"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.","date":"2003","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/12801998","citation_count":105,"is_preprint":false},{"pmid":"12915538","id":"PMC_12915538","title":"Mutations in the N termini of herpes simplex virus type 1 and 2 gDs alter functional interactions with the entry/fusion receptors HVEM, nectin-2, and 3-O-sulfated heparan sulfate but not with nectin-1.","date":"2003","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/12915538","citation_count":98,"is_preprint":false},{"pmid":"10729168","id":"PMC_10729168","title":"Cell-to-cell spread of wild-type herpes simplex virus type 1, but not of syncytial strains, is mediated by the immunoglobulin-like receptors that mediate virion entry, nectin1 (PRR1/HveC/HIgR) and nectin2 (PRR2/HveB).","date":"2000","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/10729168","citation_count":94,"is_preprint":false},{"pmid":"20410314","id":"PMC_20410314","title":"Human cytomegalovirus UL141 promotes efficient downregulation of the natural killer cell activating ligand CD112.","date":"2010","source":"The Journal of general 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Protein purification, tryptic digestion, and mass spectrometry identified Nectin-2 as the 65/60 kDa molecule recognized by mAbs that blocked NK cytotoxicity. PVR-Fc and Nectin-2-Fc soluble hybrid molecules directly stained DNAM-1-transfected COS-7 cells, and Nectin-2 expression in cell transfectants enhanced NK-mediated lysis in a DNAM-1-dependent manner.\",\n      \"method\": \"Protein purification, mass spectrometry, soluble Fc-fusion binding assays, cell transfection, NK cytotoxicity assays with mAb blocking\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (protein purification/MS, direct binding assays, functional lysis assays with blocking), foundational paper with 706 citations\",\n      \"pmids\": [\"12913096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Nectin-2 (HveB/Prr2) functions as a herpesvirus entry mediator, conferring susceptibility to infection by HSV-1 mutants unable to use HVEM, HSV-2, and pseudorabies virus, but not wild-type HSV-1. Anti-HveB antibodies blocked infection of HveB-expressing cells.\",\n      \"method\": \"cDNA expression library screen in CHO cells, antibody blocking of infection, cell transfection-based entry assay\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional screen plus antibody blocking, replicated across multiple virus strains; 416 citations\",\n      \"pmids\": [\"9657005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"DNAM-1 (CD226) functionally interacts with both CD155 (PVR) and CD112 (nectin-2) as ligands. Ectopic expression of CD112 rendered mouse T cells more susceptible to IL-2-activated T and NK cell-mediated cytotoxicity, which was inhibited by anti-CD226 mAb. Although binding affinities of soluble CD226 to CD155 and CD112 were comparable, homophilic interaction of cell-surface CD112 adversely affects CD226 binding to CD112.\",\n      \"method\": \"Cell transfection, NK/T cell cytotoxicity assays, mAb blocking, soluble receptor binding affinity measurements\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays, 226 citations, independent confirmation of DNAM-1/Nectin-2 interaction\",\n      \"pmids\": [\"15039383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Disruption of both alleles of murine nectin-2 gene resulted in sterile males with morphologically aberrant spermatozoa showing defects in nuclear and cytoskeletal morphology and mitochondrial localization. Nectin-2 interacts with l-afadin (an F-actin-binding protein) as a component of cell-cell adherens junctions and is expressed in testes only during later stages of spermatogenesis, indicating a role in late-stage germ cell development and cytoskeletal organization during spermiogenesis.\",\n      \"method\": \"Knockout mouse generation, morphological analysis, immunolocalization, genetic epistasis via null phenotype\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, 143 citations\",\n      \"pmids\": [\"10733589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Nectin-2 alpha and delta splice variants (differing in transmembrane/cytoplasmic regions but sharing ectodomain) both mediate HSV-1 mutant (carrying L25P substitution in gD) and HSV-2 entry at ~100-fold lower efficiency than HveC/HIgR. gD from HSV-1(U21) bound in vitro soluble forms of nectin-2, with weaker association than to HveC/HIgR. The major functional region for virus entry mapped to the V domain at the N-terminus.\",\n      \"method\": \"Cell transfection entry assay, in vitro gD binding assay, domain mapping\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding assay plus functional entry assay with domain mapping, 122 citations\",\n      \"pmids\": [\"10627537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Nectin-2 alpha mediates direct cell-to-cell spread of HSV-1 mutant virus (carrying L25P gD substitution) but not wild-type HSV-1, consistent with its entry receptor specificity. An antibody to nectin-1 blocked cell-to-cell spread, and wild-type virus did not spread from receptor-positive to receptor-negative cells, demonstrating that Ig-like receptors (nectin-1 and nectin-2) are required for both virus entry and cell-to-cell spread.\",\n      \"method\": \"Plaque formation assay in receptor-expressing J cells, mAb blocking of spread, genetic analysis of receptor requirements\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-to-cell spread assay with mAb blocking and receptor-negative cell controls, 94 citations\",\n      \"pmids\": [\"10729168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Loss of nectin-2 at Sertoli-spermatid junctions causes male infertility. Nectin-2-deficient spermatozoa show severe head and midpiece malformations, 4-fold reduced migration to oviducts, 6-fold reduced binding to zona-intact oocytes, and failure to penetrate zona-free hamster oocytes. Sertoli-spermatid junctions in nectin-2-null mice lack the actin-bundling protein espin, indicating ectoplasmic specializations fail to form. Nectin-2 is produced exclusively by Sertoli cells and forms a heterotypic adhesion complex with nectin-3 on elongated spermatids.\",\n      \"method\": \"Knockout mouse (LacZ knockin), scanning electron microscopy, in vitro fertilization assays, LacZ reporter expression analysis, immunolocalization\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with multiple defined cellular phenotypes, 105 citations\",\n      \"pmids\": [\"12801998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Specific amino acid sequences in the V domain of human nectin-2 are critical for HSV entry activity. Chimeric molecules between human and mouse nectin-2 showed that replacing amino acids 75-81 or residue 89 of mouse nectin-2 with human residues transferred HSV-1/Rid and HSV-2 entry activity. Replacement of residue 89 of human nectin-2 (M89F) eliminated HSV entry activity. This region is homologous to the HIV-binding region of CD4 and the poliovirus-binding region of CD155.\",\n      \"method\": \"Chimeric receptor construction, cell transfection entry assay, mutagenesis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure-function mutagenesis with chimeric receptors and defined residues, 47 citations\",\n      \"pmids\": [\"11602758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"N-terminal sequences of HSV gD govern functional interactions with nectin-2, HVEM, and 3-O-sulfated heparan sulfate, but are not required for nectin-1 interactions. Deletions overlapping HVEM contact regions (aa 7-15 and 24-32) severely reduced cell fusion and binding with all receptors except nectin-1. L25P, Q27P, and Q27R substitutions in HSV-1 gD enhanced fusion with human nectin-2 (ordinarily low for wt HSV-1 gD) while the same substitutions in HSV-2 gD were without effect on the already high fusion level.\",\n      \"method\": \"Cell fusion assay, soluble gD:Fc binding to receptor-expressing cells, mutagenesis (substitutions and deletions in gD N-terminus)\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct binding assay combined with functional cell fusion and mutagenesis, 98 citations\",\n      \"pmids\": [\"12915538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human cytomegalovirus UL141 promotes downregulation of CD112 (nectin-2) via proteasome-mediated degradation by 48 h post-infection, thereby removing both DNAM-1 activating ligands (CD155 and CD112) from the cell surface. UL141 alone is sufficient to retain CD155 in the ER, but requires additional HCMV-encoded functions to suppress CD112 expression.\",\n      \"method\": \"HCMV infection with UL141 deletion mutant, proteasome inhibitor treatment, flow cytometry for surface expression, genetic rescue with UL141 deletion\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — UL141 deletion virus rescue experiment plus proteasome inhibitor, 91 citations\",\n      \"pmids\": [\"20410314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of the nectin-2 V-set domain (nectin-2v) at 1.85 Å resolution reveals a perpendicular homodimer arrangement. Disruption of the homodimeric interface by mutagenesis abolished homodimer formation and simultaneously eliminated DNAM-1 binding, indicating that homodimerization or engagement of the homodimeric interface is required for DNAM-1 interaction.\",\n      \"method\": \"X-ray crystallography (1.85 Å), mutagenesis, surface plasmon resonance, tetramer cell staining, biochemical characterization\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis plus SPR binding assay, 53 citations\",\n      \"pmids\": [\"22547693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of the nectin-2 homodimer at 1.3 Å resolution reveals the structural basis for homophilic and heterophilic interactions. Mutagenesis of charged residues at the dimer interface identifies them as major determinants of binding affinities, and provides mechanistic explanation for stronger heterophilic versus weaker homophilic interactions among nectin family members.\",\n      \"method\": \"X-ray crystallography (1.3 Å), complementary mutagenesis, biochemical binding assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure plus mutagenesis, 49 citations\",\n      \"pmids\": [\"22927415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Nectin-2 physically interacts with N-cadherin through their extracellular domains, and they cooperatively enhance apical constriction by driving F-actin accumulation at apical cell surfaces during Xenopus neural tube morphogenesis. The intracellular afadin-binding motif of nectin-2 was not required for ectopic apical constriction induction. Nectin-2 knockdown impaired neural fold formation by attenuating F-actin accumulation, while overexpression in non-neural ectoderm induced ectopic apical constrictions.\",\n      \"method\": \"Xenopus morpholino knockdown, overexpression of domain-deleted nectin-2, co-immunoprecipitation of extracellular domains, live imaging of F-actin\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KD and OE with defined phenotypes plus direct Co-IP of extracellular domains, 65 citations\",\n      \"pmids\": [\"20332149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TIGIT binds to the membrane-distal V-set immunoglobulin domain of nectin-2 with an affinity of 6 μM. Crystal structure of TIGIT bound to the first Ig domain of nectin-2 showed that TIGIT and nectin-2 dock using the same molecular surface (lock-and-key binding motif) used in nectin/nectin homotypic interactions. TIGIT/nectin-2 binding disrupts pre-assembled nectin-2 oligomers. Mutagenesis identified an 'aromatic key' of nectin-2 as critical for TIGIT interaction, while the C-C' loop of nectin-2 dictates the TIGIT binding hierarchy.\",\n      \"method\": \"X-ray crystallography of TIGIT:nectin-2 complex, SPR binding affinity measurements, mutagenesis, disruption of nectin-2 oligomers assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure of complex plus SPR plus mutagenesis, 81 citations\",\n      \"pmids\": [\"28515320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TIGIT engages nectin-2 using a canonical immunoglobulin-like dimer interface. Biophysical studies showed TIGIT is monomeric in solution but dimerizes at high concentrations. Biochemical mutagenesis mapped the nectin-2 binding interface on TIGIT, defining the structural and biochemical determinants for TIGIT:nectin-2 recognition.\",\n      \"method\": \"X-ray crystallography of TIGIT ectodomain, biophysical characterization (SPR), mutagenesis, model of TIGIT:nectin-2 complex\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus SPR plus mutagenesis, 23 citations\",\n      \"pmids\": [\"27978489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DNAM-1 (CD226) and its ligand Nectin-2 (CD112) are expressed on human mast cells and eosinophils. Engagement of CD226 on mast cells augments FcεRI-dependent degranulation through a pathway involving Fyn, LAT, PLCγ2, and CD18. This costimulatory pathway is completely inhibited by IRp60 (CD300a) inhibitory receptor. Blocking CD112 on eosinophils normalized the hyperactivation of mast cells co-cultured with eosinophils.\",\n      \"method\": \"Flow cytometry, mAb stimulation/blocking, degranulation assay, inhibitor analysis of signaling pathway, co-culture with blocking antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional pathway dissection with pathway inhibitors, 61 citations\",\n      \"pmids\": [\"16831868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Nectin-2 deficiency in mice leads to cardiac fibrosis and dysfunction under chronic pressure overload (ascending aorta banding) but not under physiological conditions. In banded nectin-2 knockout mice, intercalated discs were disrupted, myofibrils disorganized, and cardiac myocyte apoptosis increased. Akt phosphorylation remained lower, while JNK and p38 MAPK were hyperphosphorylated compared to wild-type, revealing nectin-2-dependent signaling for cardiac protection.\",\n      \"method\": \"Knockout mouse, ascending aorta banding model, echocardiography, histology, immunoblotting for signaling kinases, TUNEL assay\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined cardiac phenotype plus mechanistic signaling pathway analysis, 29 citations\",\n      \"pmids\": [\"19667252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Nectin-3 (CD113) expressed on T lymphocytes trans-interacts with Nectin-2 (CD112) on endothelial cells at high endothelial venules to promote lymphocyte transendothelial migration. A soluble form of Nectin-3 binds to Nectin-2 at EC junctions, and blocking Nectin-2 trans-interactions with mAbs abolished soluble Nectin-3 binding. Blocking either Nectin-3 on lymphocytes or Nectin-2 on ECs inhibited lymphocyte extravasation in vitro.\",\n      \"method\": \"Soluble receptor binding assay, mAb blocking of trans-interactions, in vitro transendothelial migration assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal blocking with defined functional readout (transendothelial migration), 31 citations\",\n      \"pmids\": [\"24116228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The alphaherpesvirus gD glycoprotein (from PRV and HSV-2) induces degradation and downregulation of CD112 (nectin-2) from the cell surface during infection or transfection, reducing DNAM-1 binding to infected/transfected cells and suppressing NK cell degranulation and lysis. This identifies a previously uncharacterized alphaherpesvirus NK evasion strategy.\",\n      \"method\": \"Virus infection/transfection, flow cytometry for surface CD112, DNAM-1-Fc binding assay, NK cell degranulation and cytotoxicity assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gD expression plus functional NK assays with defined molecular mechanism, 46 citations\",\n      \"pmids\": [\"25352670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Nectin-2 (CD112) regulates endothelial cell biology in vivo: CD112-deficient mice show enhanced blood vessel coverage in retina and spleen. In vitro, CD112 blockade enhanced endothelial tube formation and cell migration. CD112 knockdown enhanced tube formation, cell migration, and proliferation with p-Erk activation, and led to compensatory upregulation of Nectin-3 and Necl-4 which promote VEGFR signaling. CD112 also regulates T cell entry into the spleen in vivo.\",\n      \"method\": \"CD112-knockout mice, retinal and spleen vasculature analysis, in vitro tube formation and migration assays, siRNA knockdown, flow cytometry, signaling analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse plus in vitro KD with defined phenotypes, single lab\",\n      \"pmids\": [\"27676263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Ubiquitination of Nectin2 promotes its intracellular retention and proteasomal degradation, limiting surface expression. Inhibition of the ubiquitin-proteasome pathway results in increased Nectin2 surface expression and enhances tumor cell susceptibility to NK cell cytotoxicity. Nectin2 is predominantly expressed in cytoplasmic pools on tumor cell lines.\",\n      \"method\": \"Ubiquitin pathway inhibitors, flow cytometry for surface vs. total expression, NK cell cytotoxicity assays, subcellular fractionation\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pharmacological inhibition plus functional NK assay, single lab\",\n      \"pmids\": [\"30888046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Nectin-2δ splice variant is selectively expressed in astrocytes and localizes to perivascular astrocytic endfoot processes facing blood vessel basement membranes, while nectin-2α is expressed in both neurons and astrocytes. Genetic ablation of nectin-2 caused degeneration of astrocytic perivascular endfoot processes and neurons in the cerebral cortex, revealing a critical role for nectin-2 in brain homeostasis.\",\n      \"method\": \"Nectin-2 knockout mouse, immunofluorescence, confocal microscopy, cell-type specific fractionation, electron microscopy of endfoot processes\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with specific structural phenotype, localization validated by multiple methods\",\n      \"pmids\": [\"27545667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Nectin-2 gene transcription in testicular cells is controlled by cooperative interaction of Sp1, CREB, and AP-1 (c-Jun) transcription factors. The minimal mouse nectin-2 promoter (nucleotides -316 to -211) contains two Sp1 motifs and one CRE motif that synergize to regulate transcription. In vivo, CREB, c-Jun, and Sp1 family proteins are bound to the nectin-2 promoter. Cyclic expression of CREB coincides with adherens junction restructuring between Sertoli cells and germ cells.\",\n      \"method\": \"Transient transfection/promoter reporter assay, EMSA, chromatin immunoprecipitation (ChIP), siRNA knockdown, overexpression\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — EMSA, ChIP, and functional promoter assays with mutagenesis, 32 citations\",\n      \"pmids\": [\"16250013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cadmium suppresses nectin-2 expression at both transcriptional and post-translational levels in testicular cells. Cadmium induces nectin-2 protein degradation via clathrin-dependent endocytosis, promotes nectin-2 internalization, and directly represses nectin-2 transcription by inhibiting binding of positive transcriptional regulators (Sp1, CREB) to the nectin-2 promoter, contributing to blood-testis barrier disruption.\",\n      \"method\": \"Endocytosis inhibitors, shRNA knockdown, siRNA, immunofluorescence, EMSA, ChIP, flow cytometry-based endocytosis assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (inhibitors, shRNA, EMSA, ChIP, imaging), single lab\",\n      \"pmids\": [\"25046863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nectin-2 directly interacts with the extracellular domain of N-cadherin with a KD of 3.5 ± 0.6 μM, as demonstrated by surface plasmon resonance. Structural analysis of homodimeric structures and molecular docking identified the binding interface. This provides a direct, adaptor-independent mechanism by which nectins can recruit cadherins to sites of adherens junction.\",\n      \"method\": \"Surface plasmon resonance (SPR), structural analysis of existing crystal structures, molecular docking, complementary mutagenesis\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — SPR binding plus structural/mutagenesis analysis, single lab\",\n      \"pmids\": [\"30183103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nectin-2 acts as a viral entry mediator for Human Herpesvirus 6B (HHV-6B). Nectin-2-transduced T cells became permissive for HHV-6B infection, and nectin-2 knockout in parotid-derived HSY cells significantly reduced HHV-6B entry. HHV-6B glycoprotein B (gB) interacted specifically with the nectin-2 V-set domain.\",\n      \"method\": \"Nectin-2 gene transduction into T cells, nectin-2 knockout via CRISPR, virus infection assays, pulldown/binding assay between gB and nectin-2 V-set domain\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO, transduction, and direct protein-protein binding assay, 17 citations\",\n      \"pmids\": [\"35062364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Crystal structure of the PVRIG (CD112R):Nectin-2 complex at undisclosed resolution identified a unique CC' loop in PVRIG that complements a double-lock-and-key binding mode and contributes to its high affinity for Nectin-2. Charged residues in the F-strands explain PVRIG selectivity for Nectin-2 over Necl-5. CD112R was found to disrupt CD112 homodimerization in an antiparallel binding mode.\",\n      \"method\": \"X-ray crystallography of PVRIG:Nectin-2 complex, comparative binding affinity measurements, structural analysis\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure of receptor-ligand complex with structural and biochemical validation\",\n      \"pmids\": [\"38626767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Crystal structure of the CD112:CD112R (Nectin-2:PVRIG) complex at 2.2 Å resolution reveals an antiparallel, lock-and-key binding mode in which CD112R disrupts CD112 homodimerization. Structure-guided directed evolution produced CD112R mutants with increased CD112 binding affinity; the highest-affinity variant (CD112RIVE) potently inhibits CD112-CD112R interactions as a soluble trap.\",\n      \"method\": \"X-ray crystallography (2.2 Å), directed evolution, SPR binding affinity measurement, functional T cell activation and cytotoxicity assays with CAR-T and T cell engager constructs\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus structure-guided mutagenesis plus functional validation\",\n      \"pmids\": [\"40285356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mutations in three equivalent regions of the N-terminal V-like domain of nectin-2 revealed distinct structural requirements for HSV entry, PRV/BHV-1 entry, and homotypic/heterotypic nectin-nectin trans-interactions. Region I mutations (impairing HSV entry) did not reduce homotypic trans-interactions for nectin-2. Region III mutations that reduced homotypic trans-interactions of nectin-2 also impaired PRV and BHV-1 entry activity. Effects on gD binding did not necessarily correlate with functional entry.\",\n      \"method\": \"Mutagenesis of nectin-2 V domain, cell transfection entry assay with multiple alphaherpesvirus strains, binding assay to gD\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — systematic mutagenesis with multiple functional readouts (entry, trans-interaction, gD binding), 35 citations\",\n      \"pmids\": [\"12438620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ST6GalNAc-I sialylates NECTIN2 in lung adenocarcinoma cells, as shown by proteomic and biochemical analysis. This sialylation promotes T cell dysfunction via the NECTIN2-TIGIT axis. ST6GalNAc-I-deficient tumor cells co-cultured with T cells were more susceptible to T cell-mediated killing, and mice injected with St6galnac-I-knockdown cells showed reduced Nectin2/Tigit-associated immunosuppression.\",\n      \"method\": \"Proteomics, biochemical co-localization, syngeneic mouse model, KD/KO co-culture cytotoxicity assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — proteomics identifies modification, functional assays confirm consequence, single study\",\n      \"pmids\": [\"40371640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Nectin-2-mediated HSV-1 ANG path (syncytial strain) entry into CHO cells occurs via pH-independent fusion at the plasma membrane, whereas nectin-1 directs the same strain to a pH-dependent endocytic pathway. HSV-1 ANG path virions induced rapid fusion-from-without (FFWO) exclusively in CHO-nectin-2 cells, not in CHO-nectin-1 or receptor-negative cells, demonstrating that receptor identity (nectin-2 vs. nectin-1) determines the entry pathway.\",\n      \"method\": \"Endocytosis/acidification inhibitors, kinetics of entry measurement, FFWO assay, CHO cell transfectants expressing distinct receptors\",\n      \"journal\": \"Virology journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological pathway dissection plus FFWO assay with clear receptor specificity, 44 citations\",\n      \"pmids\": [\"17192179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Murine nectin-2 (mHveB), the mouse homolog of human HveB, mediates entry of porcine pseudorabies virus (PRV) but not HSV-1 or HSV-2. Anti-mHveB antibody and soluble mHveB ectodomain inhibited mHveB-dependent PRV entry. Co-expression of mHveB with PRV gD (but not HSV-1 gD) caused interference with entry, suggesting direct interaction of PRV gD with mHveB during viral entry.\",\n      \"method\": \"Cell transfection entry assay, antibody blocking, interference assay with viral gD co-expression, RT-PCR\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — antibody blocking, receptor-gD interference assay, 51 citations\",\n      \"pmids\": [\"10196354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VSIG2 specifically binds to Nectin-2 (and not to PD-1 or CTLA-4) and functions as an immunosuppressive ligand present on antigen-presenting cells. VSIG2-Nectin-2 binding strongly inhibits T cell activation and proliferation. This interaction regulates the STAT1/IRF1/GBP2 signaling pathway in T cells.\",\n      \"method\": \"Direct binding assay (VSIG2 vs. known immune receptors), co-culture T cell activation/proliferation assays, signaling pathway analysis, in vivo mouse EAE model, anti-tumor assay\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — binding specificity assay plus functional T cell assays plus signaling, single lab\",\n      \"pmids\": [\"41350674\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NECTIN2 (CD112) is a Ca2+-independent immunoglobulin superfamily cell adhesion molecule that functions as a cell surface ligand for the activating receptor DNAM-1 (CD226) and as an inhibitory checkpoint ligand for TIGIT and PVRIG (CD112R), forming homo- and heterodimers through its membrane-distal V-set domain (crystal structures resolved); it serves as an entry receptor for herpes simplex virus (HSV-2, HSV-1 mutants), pseudorabies virus, and HHV-6B through gD/gB interactions with its V domain; it localizes to and is required for integrity of cell-cell adherens junctions in multiple tissues (Sertoli-spermatid junctions, cardiac intercalated discs, astrocytic perivascular endfeet); its surface expression is regulated post-translationally by ubiquitin-proteasome-mediated degradation and clathrin-dependent endocytosis, and transcriptionally by cooperative Sp1/CREB/c-Jun activity; viral glycoproteins (HCMV UL141, alphaherpesvirus gD) and ST6GalNAc-I-mediated sialylation modulate its surface levels to enable immune evasion; and it participates in lymphocyte transendothelial migration through heterophilic trans-interaction with Nectin-3.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NECTIN2 (CD112) is an immunoglobulin superfamily cell adhesion molecule that functions at the nexus of cell-cell adhesion, immune regulation, and viral entry. Its membrane-distal V-set domain mediates Ca²⁺-independent homophilic and heterophilic trans-interactions — forming homodimers and heterodimers with nectin-3 — that are essential for adherens junction integrity at Sertoli-spermatid junctions, cardiac intercalated discs, and astrocytic perivascular endfeet, as demonstrated by knockout mice exhibiting male infertility, stress-induced cardiac dysfunction, and endfoot degeneration [PMID:10733589, PMID:12801998, PMID:19667252, PMID:27545667]. The same V-domain serves as a ligand for the activating receptor DNAM-1 (CD226) and the inhibitory checkpoint receptors TIGIT and PVRIG (CD112R), with crystal structures revealing that TIGIT and PVRIG engage the nectin-2 homodimer interface to disrupt its oligomeric state, thereby competing with activating signals [PMID:12913096, PMID:28515320, PMID:38626767, PMID:40285356]. NECTIN2 also functions as an entry receptor for HSV-2, HSV-1 mutants, pseudorabies virus, and HHV-6B through direct interaction of viral glycoproteins gD or gB with specific residues in its V domain, and multiple herpesviruses exploit degradation of NECTIN2 — via HCMV UL141-directed proteasomal targeting or alphaherpesvirus gD-induced downregulation — to evade DNAM-1-dependent NK cell killing [PMID:9657005, PMID:35062364, PMID:20410314, PMID:25352670]. Surface expression of NECTIN2 is regulated post-translationally by ubiquitin-proteasome-mediated degradation and clathrin-dependent endocytosis, and transcriptionally by cooperative Sp1/CREB/c-Jun activity at its promoter [PMID:30888046, PMID:25046863, PMID:16250013].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing that NECTIN2 is a herpesvirus entry receptor resolved how alphaherpesviruses other than HSV-1 gain cellular access, identifying NECTIN2 as a functional entry mediator for HSV-2, HSV-1 mutants, and pseudorabies virus.\",\n      \"evidence\": \"cDNA expression library screen in CHO cells with antibody blocking across multiple virus strains\",\n      \"pmids\": [\"9657005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Wild-type HSV-1 does not use NECTIN2 efficiently — the structural basis for this selectivity was unknown\", \"Entry mechanism (endocytic vs. plasma membrane fusion) was undefined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating that murine nectin-2 mediates PRV but not HSV entry established species-specific receptor usage and identified gD as the interacting viral glycoprotein through interference assays.\",\n      \"evidence\": \"Antibody blocking and gD co-expression interference assay in transfected cells\",\n      \"pmids\": [\"10196354\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinants of species specificity not mapped\", \"No direct binding affinity measurement\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Knockout of nectin-2 in mice revealed an essential adhesion function at Sertoli-spermatid junctions, establishing that nectin-2 is required for spermiogenesis and male fertility through interaction with l-afadin and the actin cytoskeleton.\",\n      \"evidence\": \"Nectin-2 knockout mouse with morphological, immunolocalization, and fertility phenotyping\",\n      \"pmids\": [\"10733589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of cytoskeletal disorganization not fully defined\", \"Heterotypic partner on spermatids not yet identified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mapping the V domain as the functional region for virus entry and showing that both splice variants (α and δ) support entry resolved which ectodomain mediates gD interaction and clarified the role of cytoplasmic tail diversity.\",\n      \"evidence\": \"Domain mapping, in vitro gD binding, and cell transfection entry assays\",\n      \"pmids\": [\"10627537\", \"10729168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise contact residues on the V domain not yet identified\", \"Entry pathway (pH-dependent vs. independent) unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Site-directed mutagenesis of the V domain identified residues 75–81 and M89 as critical determinants of HSV entry activity, providing the first residue-level map of the virus-binding site.\",\n      \"evidence\": \"Human-mouse nectin-2 chimeras and point mutagenesis with functional entry assays\",\n      \"pmids\": [\"11602758\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure to confirm direct contact\", \"How these residues relate to nectin-nectin homophilic interfaces was unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Systematic mutagenesis of three V-domain regions showed that structural requirements for HSV entry, PRV/BHV-1 entry, and homophilic trans-interactions are separable, establishing that viral and adhesion functions use overlapping but distinct surfaces.\",\n      \"evidence\": \"Mutagenesis with entry assays for multiple alphaherpesviruses, trans-interaction, and gD binding assays\",\n      \"pmids\": [\"12438620\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural data to visualize the separation of binding interfaces\", \"Heterophilic nectin-3 interaction surface not mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of NECTIN2 as a ligand for the NK activating receptor DNAM-1 established a direct molecular link between cell adhesion molecules and innate immune recognition of target cells.\",\n      \"evidence\": \"Protein purification/mass spectrometry, Fc-fusion binding to DNAM-1 transfectants, NK cytotoxicity assays with blocking antibodies\",\n      \"pmids\": [\"12913096\", \"15039383\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding affinity not precisely quantified\", \"How homophilic nectin-2 interactions compete with DNAM-1 binding was unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Detailed analysis of Sertoli-spermatid junctions in nectin-2 null mice revealed loss of ectoplasmic specializations (espin-containing actin bundles) and identified heterotypic nectin-2/nectin-3 adhesion as the organizing interaction, explaining the infertility phenotype mechanistically.\",\n      \"evidence\": \"Knockout mouse with SEM, in vitro fertilization, LacZ reporter, and immunolocalization\",\n      \"pmids\": [\"12801998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal transduction downstream of nectin-2 in Sertoli cells not characterized\", \"Whether nectin-2 loss affects blood-testis barrier integrity not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Transcriptional regulation of nectin-2 was resolved by identifying cooperative Sp1/CREB/c-Jun binding to the minimal promoter, linking adherens junction remodeling cycles in the testis to cyclic CREB expression.\",\n      \"evidence\": \"Promoter-reporter assays, EMSA, ChIP, and siRNA in testicular cells\",\n      \"pmids\": [\"16250013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Epigenetic regulation not addressed\", \"Tissue-specific vs. ubiquitous promoter usage not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovery that nectin-2-mediated HSV-1 entry proceeds via pH-independent plasma membrane fusion — unlike nectin-1-mediated endocytic entry — established that receptor identity determines the viral entry pathway.\",\n      \"evidence\": \"Endocytosis/acidification inhibitors and fusion-from-without assays in CHO-nectin-2 vs. CHO-nectin-1 cells\",\n      \"pmids\": [\"17192179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which receptor cytoplasmic domain or membrane context directs pathway choice unknown\", \"Limited to one syncytial HSV-1 strain\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Nectin-2 knockout mice subjected to pressure overload developed cardiac fibrosis and intercalated disc disruption with altered Akt/JNK/p38 signaling, revealing a cardioprotective adhesion-signaling function under stress.\",\n      \"evidence\": \"Knockout mouse with aortic banding, echocardiography, histology, and kinase phosphorylation analysis\",\n      \"pmids\": [\"19667252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct signaling cascade from nectin-2 to Akt not mapped\", \"Heterotypic partner at intercalated discs not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"HCMV UL141 was shown to promote proteasome-dependent degradation of surface NECTIN2, establishing a viral immune evasion mechanism that removes DNAM-1 activating ligands from infected cells.\",\n      \"evidence\": \"UL141 deletion virus, proteasome inhibitor, and flow cytometry for surface CD112\",\n      \"pmids\": [\"20410314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether UL141 directly binds nectin-2 or acts through an E3 ligase intermediate was unclear\", \"Additional HCMV-encoded functions needed for full CD112 suppression not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"In Xenopus neural tube morphogenesis, nectin-2 cooperates with N-cadherin through direct extracellular domain interaction to drive apical F-actin accumulation and apical constriction, establishing a developmental adhesion role independent of the intracellular afadin pathway.\",\n      \"evidence\": \"Morpholino knockdown, overexpression of domain-deleted constructs, and co-IP of extracellular domains\",\n      \"pmids\": [\"20332149\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding affinity between nectin-2 and N-cadherin ectodomains not measured in this study\", \"Whether this mechanism operates in mammalian neural tube closure untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"High-resolution crystal structures of the nectin-2 V-domain homodimer (1.3–1.85 Å) revealed the perpendicular dimer arrangement and showed that homodimerization is prerequisite for DNAM-1 binding, resolving how homophilic adhesion and immune ligand function are structurally coupled.\",\n      \"evidence\": \"X-ray crystallography, mutagenesis of the dimer interface, SPR, and tetramer staining\",\n      \"pmids\": [\"22547693\", \"22927415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal with DNAM-1\", \"Whether heterodimer with nectin-3 also supports DNAM-1 binding untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Trans-interaction of endothelial NECTIN2 with lymphocyte nectin-3 was shown to promote transendothelial migration, expanding NECTIN2's function beyond static adhesion to active leukocyte trafficking.\",\n      \"evidence\": \"Soluble receptor binding, reciprocal mAb blocking, and in vitro transendothelial migration assay\",\n      \"pmids\": [\"24116228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo validation of this trafficking role limited\", \"Signaling downstream of nectin-2 engagement on endothelium not characterized\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Alphaherpesvirus gD was found to induce degradation of surface NECTIN2, suppressing DNAM-1-dependent NK killing — a mechanism distinct from HCMV UL141 that links viral entry glycoprotein function to immune evasion.\",\n      \"evidence\": \"Virus infection and gD transfection with flow cytometry, DNAM-1-Fc binding, and NK degranulation assays\",\n      \"pmids\": [\"25352670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degradation pathway (proteasomal vs. lysosomal) for gD-induced downregulation not defined\", \"Whether gD-mediated degradation affects nectin-2 adhesion functions not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Cadmium-induced nectin-2 downregulation via clathrin-dependent endocytosis and transcriptional repression (reduced Sp1/CREB promoter binding) provided a unified mechanism for toxicant-mediated blood-testis barrier disruption.\",\n      \"evidence\": \"Endocytosis inhibitors, shRNA, EMSA, ChIP, and flow cytometry\",\n      \"pmids\": [\"25046863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ubiquitin ligase mediating cadmium-induced ubiquitination not identified\", \"Direct cadmium binding to nectin-2 not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Localization of the nectin-2δ splice variant to astrocytic perivascular endfeet, and degeneration of these structures in knockout mice, established a CNS-specific adhesion role for NECTIN2 in neurovascular unit integrity.\",\n      \"evidence\": \"Knockout mouse, confocal and electron microscopy, cell-type fractionation\",\n      \"pmids\": [\"27545667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether blood-brain barrier permeability is altered in knockouts not measured\", \"Heterotypic partner on endothelial side not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Crystal structures of the TIGIT:nectin-2 complex revealed that TIGIT engages the same lock-and-key interface used for nectin-nectin homodimerization, explaining how inhibitory checkpoint receptors compete with nectin homophilic adhesion and DNAM-1 binding.\",\n      \"evidence\": \"X-ray crystallography of TIGIT:nectin-2 complex, SPR (KD ~6 μM), mutagenesis, oligomer disruption assay\",\n      \"pmids\": [\"28515320\", \"27978489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of oligomer disruption in vivo not tested\", \"Whether TIGIT and DNAM-1 compete directly on the same surface unresolved structurally\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Ubiquitin-proteasome-mediated intracellular retention was identified as a major regulator of NECTIN2 surface expression on tumor cells, with proteasome inhibition increasing surface levels and enhancing NK susceptibility.\",\n      \"evidence\": \"Ubiquitin pathway inhibitors, flow cytometry for surface vs. total expression, NK cytotoxicity assays\",\n      \"pmids\": [\"30888046\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific E3 ligase(s) not identified\", \"Whether this pathway operates in non-tumor cells not established\", \"Pharmacological inhibitors may have off-target effects\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of NECTIN2 as an entry receptor for HHV-6B via V-domain interaction with gB extended the viral receptor function beyond alphaherpesviruses to a betaherpesvirus.\",\n      \"evidence\": \"CRISPR knockout, gene transduction, and pulldown of gB with nectin-2 V domain\",\n      \"pmids\": [\"35062364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of gB:nectin-2 interaction not resolved\", \"Whether nectin-2 is the primary or accessory receptor in vivo unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Crystal structures of the PVRIG (CD112R):NECTIN2 complex revealed an antiparallel binding mode with a double-lock-and-key mechanism, explaining PVRIG's high selectivity for NECTIN2 and its ability to disrupt NECTIN2 homodimers — completing the structural picture of the inhibitory checkpoint axis.\",\n      \"evidence\": \"X-ray crystallography of PVRIG:nectin-2 complex (including 2.2 Å structure), SPR, directed evolution of high-affinity variants, functional T cell and CAR-T assays\",\n      \"pmids\": [\"38626767\", \"40285356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo therapeutic efficacy of engineered CD112R variants not yet demonstrated in clinical trials\", \"Whether disruption of NECTIN2 homodimers affects adhesion junctions in treated tissues unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ST6GalNAc-I-mediated sialylation of NECTIN2 was identified as a post-translational modification that promotes T cell dysfunction through the NECTIN2-TIGIT axis in lung adenocarcinoma, linking glycosylation to immune checkpoint activity.\",\n      \"evidence\": \"Proteomics, co-culture cytotoxicity assays, syngeneic mouse model with ST6GalNAc-I knockdown\",\n      \"pmids\": [\"40371640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific sialylation sites on NECTIN2 not mapped\", \"Whether sialylation alters binding to DNAM-1 or PVRIG not tested\", \"Single study awaiting independent confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the identity of the E3 ubiquitin ligase(s) controlling NECTIN2 surface expression; the structural basis of the DNAM-1:NECTIN2 interaction (no co-crystal exists); how NECTIN2 integrates adhesion and immune signaling in the same tissue context; and the in vivo therapeutic potential of blocking NECTIN2 checkpoint interactions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No DNAM-1:NECTIN2 co-crystal structure\", \"E3 ligase for NECTIN2 ubiquitination unidentified\", \"In vivo significance of VSIG2:NECTIN2 interaction not independently confirmed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 3, 6, 12, 17]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [1, 4, 25]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 2, 13, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 9, 17, 20]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 13, 15, 18, 26, 29]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3, 6, 12, 16, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 4, 9, 18, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CD226\",\n      \"TIGIT\",\n      \"PVRIG\",\n      \"NECTIN3\",\n      \"CDH2\",\n      \"MLLT4\",\n      \"VSIG2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}