{"gene":"NECTIN4","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":2001,"finding":"Nectin-4 was identified as a new member of the nectin family that interacts with afadin (an F-actin-associated molecule) via its carboxyl-terminal cytoplasmic sequence, co-localizes with afadin at cadherin-based adherens junctions in MDCKII epithelial cells, and trans-interacts heterophilically with nectin-1 through V domain interactions. Nectin-4-Fc binds cells expressing nectin-1 but not nectin-2, nectin-3, or PVR/CD155; reciprocal pulldown and in vitro physical interaction assays confirmed the nectin-1/nectin-4 interaction. Nectin-4 also exhibits homophilic binding.","method":"Recombinant Fc-fusion protein binding assays, co-immunoprecipitation, in vitro pulldown, co-localization by immunofluorescence in MDCKII cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (Fc-fusion binding, reciprocal Co-IP, in vitro physical interaction) in a single foundational study","pmids":["11544254"],"is_preprint":false},{"year":1999,"finding":"The nectin family member PRR/nectin is recruited to cadherin-based adherens junctions through direct interaction of its C-terminal cytoplasmic PDZ-binding motif with the PDZ domain of afadin, an actin filament-binding protein; nectin shows Ca2+-independent cell-cell adhesion activity.","method":"Co-immunoprecipitation, co-localization by immunofluorescence, cell aggregation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and functional adhesion assays, foundational study replicated across the field","pmids":["10225955"],"is_preprint":false},{"year":2002,"finding":"The V domain of nectin-1 is the major functional region mediating trans-heterointeraction with nectin-4 (and nectin-3). Affinity measurements showed the nectin-1/nectin-4 KD is ~100 nM, weaker than nectin-1/nectin-3 (KD ~1 nM) but stronger than nectin-1 homophilic (KD ~1 µM). The minimal binding region on the nectin-1 V domain was mapped to the C-C'-C\"-D β-strands using chimeric nectin-1/PVR receptors.","method":"Surface plasmon resonance / affinity measurements, competitive binding with soluble Fc-fusions, monoclonal antibody blocking, chimeric receptor domain-swap experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — quantitative binding assays plus domain-mapping with chimeric receptors, multiple orthogonal approaches","pmids":["12011057"],"is_preprint":false},{"year":2005,"finding":"Nectin-4 ectodomain shedding is mediated by the metalloprotease TACE/ADAM-17: shedding is constitutively produced, strongly enhanced by PMA, inhibited by TAPI-1 or TIMP-3, abolished in TACE-deficient fibroblasts, and modulated by TACE overexpression or siRNA silencing. The soluble form (~43 kDa) corresponds to the entire nectin-4 ectodomain.","method":"siRNA knockdown and overexpression of TACE, TACE-deficient fibroblasts, pharmacological inhibitors (TAPI-1, TIMP-3), Western blot of shed product, PMA stimulation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — genetic (KO fibroblasts, siRNA) plus pharmacological inhibition plus overexpression with defined biochemical readout","pmids":["15784625"],"is_preprint":false},{"year":2011,"finding":"Nectin-4 (PVRL4) serves as the epithelial cell receptor for measles virus. Its membrane-distal IgV domain supports virus attachment and entry; antibodies and siRNA against PVRL4 block measles virus infection. Measles virus infection downregulates PVRL4 surface expression.","method":"Expression vector transfection of non-susceptible cell lines, siRNA knockdown, antibody blocking, virus binding assay, flow cytometry, confocal microscopy, surface biotinylation","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (transfection rescue, siRNA block, antibody block, direct binding assay), independently replicated in companion Nature paper","pmids":["21901103"],"is_preprint":false},{"year":2011,"finding":"Nectin-4 is the epithelial receptor for measles virus exit from the host: it interacts with the viral attachment protein (hemagglutinin) with high affinity through its membrane-distal IgV domain, sustains MV entry and non-cytopathic lateral spread in well-differentiated primary human airway epithelial sheets infected basolaterally, and is downregulated in infected epithelial cells including macaque tracheae.","method":"Functional rescue transfection in non-permissive cells, primary airway epithelial cultures, basolateral infection assays, immunohistochemistry in macaque tissues, in vitro binding assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal experimental systems (cell lines, primary cultures, in vivo tissue), independent replication of receptor identity","pmids":["22048310"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of the membrane-distal IgV domain of human nectin-4 in complex with measles virus hemagglutinin (MV-H) revealed that nectin-4 binds exclusively via its N-terminal IgV domain to the β4-β5 groove of MV-H, with the contact interface dominated by hydrophobic interactions. The nectin-4 binding site on MV-H overlaps extensively with those of the other two MV receptors (CD46 and SLAM).","method":"X-ray crystallography (co-crystal structure of nectin-4 IgV domain with MV-H)","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with defined binding interface","pmids":["23202587"],"is_preprint":false},{"year":2012,"finding":"Crystal structures of the full ectodomains of all four nectins and Necl-5 revealed a conserved stereotyped dimeric interface (C-C'-C\"-D β-strand region of the V domain) representing the adhesive trans interaction. Quantitative binding measurements defined homophilic affinities and heterophilic specificity across the family. Targeted cross-linking confirmed the dimer interface as the adhesive trans contact.","method":"X-ray crystallography of natively glycosylated ectodomains, surface plasmon resonance, targeted cross-linking","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structures of all four nectins plus quantitative SPR and crosslinking validation","pmids":["22902367"],"is_preprint":false},{"year":2013,"finding":"The measles virus hemagglutinin β4-β5 hydrophobic groove governs functional interactions with nectin-4 and CD46 but not SLAM. A single substitution in this groove drastically reduced nectin-4 and CD46 binding while minimally altering SLAM binding. Soluble nectin-4 blocked vaccine MV entry via nectin-4 and CD46 but only partially reduced SLAM-mediated entry.","method":"Site-directed mutagenesis of MV-H, cell fusion assays, soluble nectin-4 competition, surface plasmon resonance binding kinetics, recombinant virus construction","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis with functional validation plus binding kinetics and recombinant virus assays","pmids":["23760251"],"is_preprint":false},{"year":2013,"finding":"PVRL4 promotes anchorage-independent cell proliferation by driving cell-to-cell attachment and matrix-independent integrin β4/SHP-2/c-Src signaling activation. PVRL4 was identified via a gain-of-function screen for anchorage independence; breast cancer cell transformation was shown to be dependent on PVRL4, and blocking PVRL4-mediated cell-to-cell attachment with monoclonal antibodies inhibited orthotopic tumor growth in vivo.","method":"Gain-of-function screen, co-immunoprecipitation of integrin β4/SHP-2/c-Src complex, siRNA knockdown, monoclonal antibody blocking, orthotopic xenograft mouse models","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — functional screen plus mechanistic epistasis (Co-IP of signaling complex) plus in vivo validation with antibody blockade","pmids":["23682311"],"is_preprint":false},{"year":2009,"finding":"Exogenous expression of Nectin-4 in mammalian cells increased lamellipodia formation and invasive ability through activation of the small GTPase Rac1; siRNA-mediated suppression of Nectin-4 inhibited cell growth in lung cancer cells.","method":"siRNA knockdown, exogenous overexpression, Rac1 activation assay, invasion assay, lamellipodia quantification","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 — defined signaling output (Rac1 activation) linked to Nectin-4 expression in single study","pmids":["19679554"],"is_preprint":false},{"year":2014,"finding":"Nectin-4 mutations causing EDSS1 (ectodermal dysplasia-syndactyly syndrome) perturb the Rac1 pathway: trans-interaction of nectin-1 and nectin-4 induces Rac1 activation, and mutant nectin-4 (p.Val242Met, p.Thr185Met) delays cadherin recruitment at adherens junctions and impairs nectin-1 clustering at contact sites in keratinocytes, demonstrating a role for the nectin-1/nectin-4 interaction in early adherens junction formation.","method":"Patient keratinocytes and skin biopsy, ectopic expression of mutant and WT nectin-4, cell aggregation assays, immunofluorescence for cadherin/nectin-1 clustering, Rac1 activation assay","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 — patient-derived cells with defined signaling readout (Rac1), multiple functional assays","pmids":["24577405"],"is_preprint":false},{"year":2010,"finding":"Loss-of-function mutations in PVRL4 (encoding nectin-4) cause ectodermal dysplasia-syndactyly syndrome (EDSS). Mutant nectin-4 from patients lost the capability to bind nectin-1. In patient keratinocytes, discrete hair follicle structures showed alterations in membrane localization of nectin-afadin and cadherin-catenin complexes essential for adherens junction formation, and reorganization of the actin cytoskeleton was observed.","method":"Homozygosity mapping, candidate gene sequencing, patient keratinocyte functional assays (nectin-1 binding by pull-down), immunofluorescence of adherens junction components and actin cytoskeleton in patient tissue","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — patient mutations combined with functional binding loss and cellular phenotyping of junction/actin reorganization","pmids":["20691405"],"is_preprint":false},{"year":2015,"finding":"Nectin-4 expression in stratified epithelia is regulated by IRF6: depletion of IRF6 reduces Pvrl4 expression in keratinocytes. In AEC syndrome (p63 mutation), reduced IRF6 expression correlates with decreased Pvrl4 expression. By contrast, Pvrl1 (nectin-1) is a direct p63 target gene (p63 binds to two conserved intronic Pvrl1 enhancer regions by ChIP), but Pvrl4 regulation is independent of p63 and linked to IRF6-mediated epidermal differentiation.","method":"Chromatin immunoprecipitation (ChIP), siRNA knockdown of p63 and IRF6, qRT-PCR, p63-null mouse skin, patient AEC keratinocytes, conditional AEC mouse model","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP for direct regulatory binding and multiple genetic models for Pvrl4/IRF6 link, but IRF6→PVRL4 regulation relies on correlation in patient/mouse models without direct ChIP of PVRL4 promoter","pmids":["25387952"],"is_preprint":false},{"year":2015,"finding":"Measles virus spread in human airway epithelial (HAE) cells requires the nectin-4/afadin complex: afadin knockdown limited infectious-center formation, and a nectin-4 mutant lacking the afadin-binding site in its cytoplasmic tail was less effective than WT nectin-4 at promoting MV infection. Spread occurred through intercellular membrane pores (cytoplasm flow between columnar cells on lateral surfaces) rather than visible syncytia.","method":"siRNA knockdown of afadin in primary HAE cultures, nectin-4 cytoplasmic-tail mutant expression in porcine airway epithelial primary cultures, high-resolution video microscopy, GFP cytoplasm-flow assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — direct mutagenesis of afadin-binding domain with functional readout in primary human airway cultures plus live imaging","pmids":["25926640"],"is_preprint":false},{"year":2017,"finding":"Nectin-4 ectodomain shedding in ovarian cancer is mediated by both ADAM17 and ADAM10. LPA stimulates Nectin-4 shedding; small-molecule inhibitors and siRNA knockdown of ADAM10 and ADAM17 confirmed their roles. Ascites fluid significantly increased sN4 shedding. Shed Nectin-4 is detectable at 2–20-fold higher levels in ascites than in serum.","method":"siRNA knockdown of ADAM10 and ADAM17, small-molecule inhibitor assays, LPA stimulation, ELISA quantification of shed nectin-4 in ascites and serum from matched patient samples","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic (siRNA) and pharmacological inhibition of two ADAMs with defined biochemical readout confirmed in patient specimens","pmids":["28232483"],"is_preprint":false},{"year":2018,"finding":"Matrix-detached epithelial and carcinoma cells cluster spontaneously via PVRL4 (Nectin-4), activating a PVRL4/α6β4 integrin/Src signaling axis that sustains GPX4 expression to resist ferroptosis. In the absence of α6β4, PVRL4-mediated clustering increased lipid peroxidation and triggered ferroptosis; when clustering was inhibited, single cells were more susceptible to apoptosis than ferroptosis.","method":"siRNA knockdown of PVRL4 and α6β4, antibody blocking of clustering, lipid peroxidation assays, cell viability assays, Western blot for GPX4","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — epistasis between PVRL4, α6β4, and Src with multiple mechanistic readouts (GPX4, lipid peroxidation, cell death mode)","pmids":["29934307"],"is_preprint":false},{"year":2017,"finding":"Nectin-4 promotes breast cancer stem cell (BCSC) self-renewal and metastasis by activating WNT/β-catenin signaling via the PI3K/Akt axis. Nectin-4 depletion inhibited EMT, invasion, and WNT/β-catenin pathway activity; overexpression of Nectin-4 in null cells induced WNT/β-catenin signaling via PI3K/Akt.","method":"siRNA knockdown and overexpression in breast cancer cell lines, in vitro sphere formation, invasion assay, in vivo xenograft, ex vivo and clinical sample analysis, Western blot for PI3K/Akt/β-catenin pathway components","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 3 — overexpression and knockdown with pathway readouts but no direct binding or reconstitution experiment linking Nectin-4 to WNT/β-catenin","pmids":["28600142"],"is_preprint":false},{"year":2018,"finding":"Under hypoxia, ADAM-17 expressed in metastatic breast cancer stem cells sheds the nectin-4 ecto-domain into the microenvironment, which then physically interacts with integrin-β4 on endothelial cells, promoting angiogenesis via the Src/PI3K/AKT/iNOS pathway (but not Phospho-Erk or NF-κB).","method":"Co-immunoprecipitation of shed nectin-4 ecto-domain with integrin-β4, in vitro tube formation, CAM assay, in vivo angiogenesis models, pathway inhibitors, siRNA knockdown","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP of ecto-domain/integrin-β4 plus pathway dissection but single lab, mechanistic follow-up somewhat indirect","pmids":["30056265"],"is_preprint":false},{"year":2019,"finding":"Nectin-4 cis-interacts with ErbB2 (and its trastuzumab-resistant splice variants p95-ErbB2 and ErbB2ΔEx16) through the third Ig-like domain of nectin-4 and domain IV of ErbB2, enhancing ErbB2 dimerization and activation and downstream PI3K/AKT signaling for DNA synthesis. Nectin-4 also enhanced p95-ErbB2-induced JAK-STAT3 signaling.","method":"Co-immunoprecipitation, domain-mapping using truncation/deletion constructs of nectin-4 and ErbB2, Western blot for PI3K-AKT and JAK-STAT3 phosphorylation, DNA synthesis assays in T47D and SUM190-PT breast cancer cell lines","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP with domain mapping and defined signaling readouts in two cell lines, single lab study","pmids":["31831814"],"is_preprint":false},{"year":2020,"finding":"Nectin-4 is a novel ligand of the immune checkpoint receptor TIGIT. Unlike other TIGIT ligands (which also bind additional receptors), Nectin-4 interacts exclusively with TIGIT. The TIGIT-Nectin-4 interaction inhibits NK cell cytotoxicity; blocking Nectin-4 antibodies enhanced tumor cell killing in vitro and in vivo.","method":"Fusion protein staining of NK cells, TIGIT binding assays, NK cytotoxicity killing assays, blocking antibody experiments in vitro and in syngeneic mouse models","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 — defined receptor-ligand interaction with functional NK cell readout, single lab","pmids":["32503945"],"is_preprint":false},{"year":2020,"finding":"The NECTIN4 endo-domain (lacking extracellular region) translocates to the nucleus via physical interaction with IMPORTIN-α2 and activates DNA repair, while the ecto-domain (lacking signal peptide and cytoplasmic region) is expressed in the cytoplasm and specifically activates angiogenesis. Full-length NECTIN-4 modulates both processes.","method":"Domain-specific NECTIN-4 constructs overexpressed in 5-FU-resistant cervical cancer stem cells, co-immunoprecipitation with IMPORTIN-α2, nuclear fractionation, comet assay, γ-H2AX immunofluorescence, BER pathway assays, in vitro tube formation, CAM assay","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2–3 — domain constructs with Co-IP of nuclear import factor and multiple functional readouts, single lab","pmids":["32603697"],"is_preprint":false},{"year":2023,"finding":"Nectin-4 plays a causative role in senescence-associated cell size enlargement via the Src family kinase (SFK)/PI3K/Rac1 pathway. Overexpression of Nectin-4 caused enlarged cell morphology resembling senescent cells; knockdown of Nectin-4 during DNA damage-induced senescence suppressed cell size increase without affecting senescence induction per se. Nectin-4 knockdown also induced apoptosis in senescent cells, and cell size was positively correlated with survival rate.","method":"Overexpression and knockdown of Nectin-4, pharmacological inhibition of SFK/PI3K/Rac1, single-cell tracking microscopy, flow cytometry for cell size, apoptosis assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 — gain- and loss-of-function with pathway inhibitors and defined morphological/survival readout, single lab","pmids":["38062106"],"is_preprint":false},{"year":2020,"finding":"ERRα (estrogen-related receptor-α) transcriptionally activates NECTIN-4 by directly binding to the NECTIN-4 promoter, as shown by chromatin immunoprecipitation and dual-luciferase reporter assays. ERRα-induced gallbladder cancer cell proliferation and invasion were antagonized by Nectin-4 depletion. Nectin-4 depletion inhibited ERRα-induced PI3K/AKT pathway activation.","method":"Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, siRNA knockdown, overexpression, Western blot for PI3K/AKT pathway components, in vivo xenograft","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and luciferase reporter directly demonstrate promoter binding, but downstream epistasis is single lab","pmids":["32030850"],"is_preprint":false},{"year":2005,"finding":"PICK-1 (protein interacting with C-kinase-1) directly interacts with nectins in a PDZ-domain-dependent manner and co-localizes with nectins at adherens junctions in epithelial cells, suggesting a role for PICK-1 in the regulation of nectin-based cell junctions.","method":"Co-immunoprecipitation, GST-pulldown, immunofluorescence co-localization in epithelial cells","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 3 — single pulldown/Co-IP with co-localization, no functional perturbation of nectin-4 specifically","pmids":["15811349"],"is_preprint":false}],"current_model":"NECTIN4 is a type I transmembrane immunoglobulin superfamily cell adhesion molecule that localizes to cadherin-based adherens junctions by binding afadin (via its C-terminal PDZ-binding motif) and forms Ca2+-independent trans-heterodimers with nectin-1 through V-domain interactions (with a defined β-strand binding epitope); its ectodomain is constitutively shed by TACE/ADAM-17 (and ADAM-10 in ovarian cancer) to generate a soluble form detected in patient sera; in cancer cells it drives anchorage-independent growth through a cell-cell contact–dependent integrin β4/SHP-2/c-Src signaling axis, promotes Rac1 activation and lamellipodia formation, cis-interacts with ErbB2 to enhance PI3K-AKT signaling, acts as the epithelial receptor for measles virus (and other morbilliviruses) via its IgV domain engaging the MV hemagglutinin β4-β5 hydrophobic groove, and functions as an exclusive ligand for the immune checkpoint receptor TIGIT to suppress NK cell cytotoxicity."},"narrative":{"teleology":[],"mechanism_profile":null,"mechanistic_narrative":"Parse failed — see logs"},"prefetch_data":{"uniprot":{"accession":"Q96NY8","full_name":"Nectin-4","aliases":["Ig superfamily receptor LNIR","Nectin cell adhesion molecule 4","Poliovirus receptor-related protein 4"],"length_aa":510,"mass_kda":55.5,"function":"Seems to be involved in cell adhesion through trans-homophilic and -heterophilic interactions, the latter including specifically interactions with NECTIN1. Does not act as receptor for alpha-herpesvirus entry into cells (Microbial infection) Acts as a receptor for measles virus","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q96NY8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NECTIN4","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NECTIN4","total_profiled":1310},"omim":[{"mim_id":"613573","title":"ECTODERMAL DYSPLASIA-SYNDACTYLY SYNDROME 1; EDSS1","url":"https://www.omim.org/entry/613573"},{"mim_id":"609607","title":"NECTIN CELL ADHESION MOLECULE 4; NECTIN4","url":"https://www.omim.org/entry/609607"},{"mim_id":"600644","title":"NECTIN CELL ADHESION MOLECULE 1; NECTIN1","url":"https://www.omim.org/entry/600644"},{"mim_id":"159559","title":"AFADIN; AFDN","url":"https://www.omim.org/entry/159559"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"cervix","ntpm":40.7},{"tissue":"esophagus","ntpm":96.0},{"tissue":"salivary gland","ntpm":32.2},{"tissue":"skin 1","ntpm":110.2},{"tissue":"vagina","ntpm":56.4}],"url":"https://www.proteinatlas.org/search/NECTIN4"},"hgnc":{"alias_symbol":["nectin-4","PRR4","LNIR"],"prev_symbol":["PVRL4"]},"alphafold":{"accession":"Q96NY8","domains":[{"cath_id":"2.60.40.10","chopping":"32-145","consensus_level":"high","plddt":90.6438,"start":32,"end":145},{"cath_id":"2.60.40.10","chopping":"156-243","consensus_level":"high","plddt":96.1927,"start":156,"end":243},{"cath_id":"2.60.40.10","chopping":"246-334","consensus_level":"high","plddt":93.6747,"start":246,"end":334}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96NY8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96NY8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96NY8-F1-predicted_aligned_error_v6.png","plddt_mean":79.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NECTIN4","jax_strain_url":"https://www.jax.org/strain/search?query=NECTIN4"},"sequence":{"accession":"Q96NY8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96NY8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96NY8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96NY8"}},"corpus_meta":[{"pmid":"27013195","id":"PMC_27013195","title":"Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models.","date":"2016","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/27013195","citation_count":552,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21901103","id":"PMC_21901103","title":"Tumor cell marker PVRL4 (nectin 4) is an epithelial cell receptor for measles virus.","date":"2011","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/21901103","citation_count":409,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32031899","id":"PMC_32031899","title":"EV-101: A Phase I Study of Single-Agent Enfortumab Vedotin in Patients With Nectin-4-Positive Solid Tumors, Including Metastatic Urothelial Carcinoma.","date":"2020","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32031899","citation_count":278,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11544254","id":"PMC_11544254","title":"Nectin4/PRR4, a new afadin-associated member of the nectin family that trans-interacts with nectin1/PRR1 through V domain interaction.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11544254","citation_count":272,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19679554","id":"PMC_19679554","title":"Identification of nectin-4 oncoprotein as a diagnostic and therapeutic target for lung cancer.","date":"2009","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19679554","citation_count":225,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36534531","id":"PMC_36534531","title":"Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance.","date":"2023","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/36534531","citation_count":176,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20959669","id":"PMC_20959669","title":"Nectin 4 overexpression in ovarian cancer tissues and serum: potential role as a serum biomarker.","date":"2010","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20959669","citation_count":162,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17474988","id":"PMC_17474988","title":"Nectin-4 is a new histological and serological tumor associated marker for breast cancer.","date":"2007","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/17474988","citation_count":149,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34108177","id":"PMC_34108177","title":"Heterogeneity in NECTIN4 Expression Across Molecular Subtypes of 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with afadin (an F-actin-associated molecule) via its C-terminal cytoplasmic sequence, co-localizes with afadin at cadherin-based adherens junctions, and trans-interacts heterophilically with nectin-1 through V domain interactions; nectin-4 also exhibits homophilic binding.\",\n      \"method\": \"Co-immunoprecipitation, soluble Fc-fusion protein binding assays, cell transfection, and co-localization in MDCKII epithelial cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Co-IP, Fc-fusion pulldown, cell binding assays, co-localization) in a single foundational study\",\n      \"pmids\": [\"11544254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Nectin-4 trans-hetero-interacts with nectin-1 through V-to-V domain contacts (KD ~100 nM), with C domains contributing to affinity; the binding region on nectin-1 maps to the C-C'-C\\\"-D β-strands of the V domain, shared with nectin-3.\",\n      \"method\": \"Surface plasmon resonance (binding kinetics), competition assays with soluble Fc-fusion proteins, chimeric nectin1/PVR receptor substitution experiments, monoclonal antibody blocking\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — binding kinetics, mutagenesis-equivalent chimeric constructs, multiple competition methods in one study\",\n      \"pmids\": [\"12011057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Nectin-4 is shed from the cell surface by TACE/ADAM-17, generating a soluble 43-kDa ectodomain form; shedding is constitutive, enhanced by PMA, and blocked by TAPI-1 or TIMP-3. Overexpression or siRNA silencing of TACE respectively enhanced or reduced nectin-4 shedding, and nectin-4 was not shed in TACE-deficient fibroblasts.\",\n      \"method\": \"TACE overexpression and siRNA silencing, TACE-deficient fibroblast reconstitution, metalloprotease inhibitor treatment (TAPI-1, TIMP-3), Western blot and ELISA of shed ectodomain\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic loss-of-function (TACE KO cells), siRNA, overexpression, and pharmacological inhibition converge on TACE as the sheddase\",\n      \"pmids\": [\"15784625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss-of-function mutations in PVRL4 (nectin-4) cause ectodermal dysplasia-syndactyly syndrome (EDSS); mutant nectin-4 loses the ability to bind nectin-1, and patient keratinocytes show disrupted membrane localization of nectin-afadin and cadherin-catenin complexes at adherens junctions, along with actin cytoskeleton reorganization.\",\n      \"method\": \"Homozygosity mapping, Sanger sequencing, nectin-1 binding assays in patient keratinocytes, immunofluorescence for junction complex components and actin\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human genetic loss-of-function with direct functional cellular consequences demonstrated in patient cells\",\n      \"pmids\": [\"20691405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Wild-type measles virus uses nectin-4 (PVRL4) as an epithelial cell receptor; nectin-4 supports virus attachment and entry, and measles virus infection reduces nectin-4 surface expression. Antibodies and siRNA against PVRL4 block infection.\",\n      \"method\": \"Transfection of non-susceptible cells with PVRL4 expression vector, siRNA knockdown, virus binding assay, flow cytometry, confocal microscopy, surface biotinylation\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (gain-of-function transfection, siRNA, antibody blocking, direct virus binding assay) in one study\",\n      \"pmids\": [\"21901103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The crystal structure of the N-terminal IgV domain of human nectin-4 in complex with measles virus hemagglutinin (MV-H) reveals that nectin-4 binds the MV-H β4-β5 groove exclusively via its IgV domain through predominantly hydrophobic interactions, overlapping with the binding sites of CD46 and SLAM.\",\n      \"method\": \"X-ray crystallography of MV-H/nectin-4 V-domain complex\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution crystal structure with functional validation of binding interface\",\n      \"pmids\": [\"23202587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Measles virus hemagglutinin β4-β5 hydrophobic groove governs functional interactions with nectin-4 and CD46 but not SLAM; a single substitution in the groove drastically reduces nectin-4 binding and entry while minimally affecting SLAM binding.\",\n      \"method\": \"Site-directed mutagenesis of MV hemagglutinin, cell-fusion assays, surface plasmon resonance, recombinant virus infection assays in cells expressing individual receptors\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis combined with binding kinetics and functional viral entry assays\",\n      \"pmids\": [\"23760251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PVRL4 promotes anchorage-independent proliferation by driving cell-to-cell attachment and activating a matrix-independent integrin β4/SHP-2/c-Src signaling axis; blocking PVRL4-driven cell-to-cell attachment with monoclonal antibodies inhibits orthotopic tumor growth in vivo.\",\n      \"method\": \"Gain-of-function screen, Co-immunoprecipitation of integrin β4/SHP-2/c-Src, in vitro anchorage-independence assays, in vivo orthotopic tumor models with antibody treatment\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional screen, biochemical pathway identification (Co-IP), loss-of-function in vivo with defined readout\",\n      \"pmids\": [\"23682311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The V domain of PVRL4 (nectin-4) is critical for canine distemper virus entry and cell-to-cell spread; four key amino acid residues in the nectin-4 V domain and two in CDV hemagglutinin are essential for receptor-mediated virus entry.\",\n      \"method\": \"Domain-swap constructs, site-directed mutagenesis of nectin-4 and CDV hemagglutinin, virus entry and cell-to-cell spread assays\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reciprocal mutagenesis of both receptor and viral protein with functional virus entry assays\",\n      \"pmids\": [\"24725937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PVRL4 (nectin-4) expression is regulated by the transcription factor IRF6 (and not directly by p63) in keratinocytes; IRF6 depletion reduces PVRL4 expression, linking PVRL4 to epidermal differentiation control.\",\n      \"method\": \"ChIP for p63 on Pvrl1/Pvrl4 loci, siRNA knockdown of IRF6, RT-PCR in p63-null skin, p63-AEC mutant keratinocytes\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and siRNA in multiple cellular contexts, but mechanistic link is indirect (IRF6 intermediate)\",\n      \"pmids\": [\"25387952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nectin-4 promotes anchorage-independent growth and invasiveness of cancer cells through activation of the small GTPase Rac1, increasing lamellipodia formation.\",\n      \"method\": \"Exogenous Nectin-4 overexpression in mammalian cells, Rac1 activation assay, invasion assay, siRNA knockdown\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — overexpression and siRNA with Rac1 GTPase activation assay, single lab\",\n      \"pmids\": [\"19679554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nectin-4 promotes breast cancer stem cell self-renewal by activating the WNT/β-catenin signaling pathway through the PI3K/Akt axis; Nectin-4 depletion inhibited EMT and the WNT/β-catenin pathway, while Nectin-4 overexpression in null cells induced these pathways.\",\n      \"method\": \"siRNA knockdown and stable overexpression in breast cancer cells, Western blot for β-catenin/Akt pathway, in vitro and in vivo tumor models, ex vivo patient samples\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain/loss-of-function with pathway read-outs, single lab\",\n      \"pmids\": [\"28600142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Matrix-detached cells cluster via PVRL4 (nectin-4); this clustering activates a PVRL4/α6β4 integrin/Src signaling axis that sustains GPX4 expression and protects against ferroptosis; in the absence of α6β4, PVRL4-mediated clustering paradoxically increases lipid peroxidation and triggers ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of PVRL4 and α6β4, lipid peroxidation assays, GPX4 Western blot, clustering inhibition experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, siRNA, biochemical assays) demonstrating a defined signaling axis with functional consequence\",\n      \"pmids\": [\"29934307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hypoxia-driven ADAM-17 expression in metastatic breast cancer stem cells causes shedding of the nectin-4 ectodomain, which physically interacts with integrin-β4 on endothelial cells to promote angiogenesis via the Src/PI3K/AKT/iNOS pathway.\",\n      \"method\": \"Co-immunoprecipitation of nectin-4 ectodomain with integrin-β4, HUVEC tube formation assays, in ovo CAM assay, in vivo angiogenesis models, pathway inhibitor studies\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and multiple functional assays, single lab\",\n      \"pmids\": [\"30056265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Binding of morbillivirus (PPRV) H protein to NECTIN4 induces autophagy via AKT-mTOR-dependent pathway inactivation; knockdown of NECTIN4 impairs this early autophagic wave and PPRV infection.\",\n      \"method\": \"Co-immunoprecipitation of viral H protein with NECTIN4, siRNA knockdown, Western blot for AKT/mTOR phosphorylation, autophagosome quantification, viral particle production assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus siRNA plus biochemical pathway read-outs, single study\",\n      \"pmids\": [\"31318632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nectin-4 promotes gastric cancer cell proliferation and migration through the PI3K/AKT signaling pathway; knockdown reduced and overexpression enhanced PI3K/AKT activation.\",\n      \"method\": \"siRNA knockdown and overexpression in gastric cancer cell lines, Western blot for PI3K/AKT, cell proliferation and migration assays, in vivo tumorigenicity assay\",\n      \"journal\": \"Human pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — reciprocal gain/loss-of-function with pathway read-outs, single lab\",\n      \"pmids\": [\"29208564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NECTIN4 promotes papillary thyroid cancer cell proliferation, migration, invasion, and EMT by activating the PI3K/AKT pathway; AKT phosphorylation activator SC79 reversed the effect of NECTIN4 siRNA knockdown, and AKT inhibitor LY294002 phenocopied siRNA knockdown.\",\n      \"method\": \"siRNA knockdown and overexpression, PI3K inhibitor (LY294002) and AKT activator (SC79) rescue experiments, Western blot for EMT markers, colony formation and invasion assays\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological rescue/phenocopy experiments alongside siRNA, single lab\",\n      \"pmids\": [\"31114323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nectin-4 is a novel ligand for the immune checkpoint receptor TIGIT; the TIGIT–Nectin-4 interaction inhibits NK cell cytotoxicity, and blocking antibodies against Nectin-4 enhance tumor killing in vitro and in vivo.\",\n      \"method\": \"Fusion protein binding screen of NK cell receptors, functional NK cell killing assays, in vivo tumor models with blocking antibody\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — receptor-ligand identification by fusion protein screen, confirmed with functional assays in vitro and in vivo\",\n      \"pmids\": [\"32503945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Measles virus enters PVRL4-expressing breast and colon cancer cells through a PVRL4-mediated macropinocytosis pathway dependent on dynamin-independent, actin-dependent endocytosis; in MCF7 cells specifically, entry requires Rac1 and its effector PAK1.\",\n      \"method\": \"Pharmacological inhibitors of endocytic pathways (EIPA, latrunculin), siRNA knockdown of PAK1, Rac1, phalloidin staining for actin rearrangements, fluid uptake assays, recombinant MeV reporters\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA plus pharmacological inhibitors with mechanistic pathway read-outs, single lab\",\n      \"pmids\": [\"28250131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ERRα (estrogen-related receptor-α) directly enhances Nectin-4 transcription by binding to the Nectin-4 promoter; Nectin-4 in turn activates the PI3K/AKT pathway to promote gallbladder cancer progression, and Nectin-4 depletion antagonizes ERRα-induced proliferation and invasion.\",\n      \"method\": \"ChIP and dual-luciferase reporter assays for ERRα binding to NECTIN4 promoter, ERRα overexpression/knockdown, siRNA against Nectin-4, Western blot for PI3K/AKT, in vivo xenograft models\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP and reporter assays establish direct transcriptional regulation; downstream pathway by Western blot and functional rescue\",\n      \"pmids\": [\"32030850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NECTIN-4 endo-domain (intracellular) translocates to the nucleus by physically interacting with IMPORTIN-α2 and activates DNA repair, while the ecto-domain (extracellular) specifically activates angiogenesis; NQC inhibits both processes by targeting the respective domains.\",\n      \"method\": \"Domain-specific overexpression constructs (endo- vs ecto-domain), Co-IP of NECTIN-4 endo-domain with IMPORTIN-α2, comet and γ-H2AX assays for DNA repair, in vitro tube formation, in ovo CAM angiogenesis assay\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — domain-specific constructs plus Co-IP, single lab\",\n      \"pmids\": [\"32603697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nectin-4 promotes senescence-associated cell size enlargement through a Src family kinase (SFK)/PI3K/Rac1 pathway; Nectin-4 knockdown suppresses the size increase without affecting senescence induction itself, and Nectin-4-mediated enlargement contributes to senescent cell survival.\",\n      \"method\": \"Nectin-4 overexpression and siRNA knockdown, pathway inhibitors for SFK/PI3K/Rac1, single-cell tracking for apoptosis quantification, cell size measurements during DNA damage-induced senescence\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological pathway dissection plus siRNA and overexpression with quantitative phenotypic read-outs, single lab\",\n      \"pmids\": [\"38062106\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NECTIN4 is a type I transmembrane immunoglobulin-like cell adhesion molecule that forms Ca2+-independent homophilic and heterophilic (primarily nectin-1) trans-interactions via its V domain, recruits afadin to cadherin-based adherens junctions, is proteolytically shed by TACE/ADAM-17 to release a soluble ectodomain, and activates intracellular signaling (integrin β4/SHP-2/c-Src, PI3K/AKT, SFK/PI3K/Rac1) to promote anchorage-independent survival, angiogenesis, and senescent cell enlargement; it also serves as the epithelial receptor for morbilliviruses (measles, CDV, PPRV) through its IgV domain engaging the hemagglutinin β4-β5 hydrophobic groove, and acts as a TIGIT ligand that suppresses NK cell cytotoxicity.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"Nectin-4 was identified as a new member of the nectin family that interacts with afadin (an F-actin-associated molecule) via its carboxyl-terminal cytoplasmic sequence, co-localizes with afadin at cadherin-based adherens junctions in MDCKII epithelial cells, and trans-interacts heterophilically with nectin-1 through V domain interactions. Nectin-4-Fc binds cells expressing nectin-1 but not nectin-2, nectin-3, or PVR/CD155; reciprocal pulldown and in vitro physical interaction assays confirmed the nectin-1/nectin-4 interaction. Nectin-4 also exhibits homophilic binding.\",\n      \"method\": \"Recombinant Fc-fusion protein binding assays, co-immunoprecipitation, in vitro pulldown, co-localization by immunofluorescence in MDCKII cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Fc-fusion binding, reciprocal Co-IP, in vitro physical interaction) in a single foundational study\",\n      \"pmids\": [\"11544254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The nectin family member PRR/nectin is recruited to cadherin-based adherens junctions through direct interaction of its C-terminal cytoplasmic PDZ-binding motif with the PDZ domain of afadin, an actin filament-binding protein; nectin shows Ca2+-independent cell-cell adhesion activity.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by immunofluorescence, cell aggregation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and functional adhesion assays, foundational study replicated across the field\",\n      \"pmids\": [\"10225955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The V domain of nectin-1 is the major functional region mediating trans-heterointeraction with nectin-4 (and nectin-3). Affinity measurements showed the nectin-1/nectin-4 KD is ~100 nM, weaker than nectin-1/nectin-3 (KD ~1 nM) but stronger than nectin-1 homophilic (KD ~1 µM). The minimal binding region on the nectin-1 V domain was mapped to the C-C'-C\\\"-D β-strands using chimeric nectin-1/PVR receptors.\",\n      \"method\": \"Surface plasmon resonance / affinity measurements, competitive binding with soluble Fc-fusions, monoclonal antibody blocking, chimeric receptor domain-swap experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — quantitative binding assays plus domain-mapping with chimeric receptors, multiple orthogonal approaches\",\n      \"pmids\": [\"12011057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Nectin-4 ectodomain shedding is mediated by the metalloprotease TACE/ADAM-17: shedding is constitutively produced, strongly enhanced by PMA, inhibited by TAPI-1 or TIMP-3, abolished in TACE-deficient fibroblasts, and modulated by TACE overexpression or siRNA silencing. The soluble form (~43 kDa) corresponds to the entire nectin-4 ectodomain.\",\n      \"method\": \"siRNA knockdown and overexpression of TACE, TACE-deficient fibroblasts, pharmacological inhibitors (TAPI-1, TIMP-3), Western blot of shed product, PMA stimulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic (KO fibroblasts, siRNA) plus pharmacological inhibition plus overexpression with defined biochemical readout\",\n      \"pmids\": [\"15784625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Nectin-4 (PVRL4) serves as the epithelial cell receptor for measles virus. Its membrane-distal IgV domain supports virus attachment and entry; antibodies and siRNA against PVRL4 block measles virus infection. Measles virus infection downregulates PVRL4 surface expression.\",\n      \"method\": \"Expression vector transfection of non-susceptible cell lines, siRNA knockdown, antibody blocking, virus binding assay, flow cytometry, confocal microscopy, surface biotinylation\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (transfection rescue, siRNA block, antibody block, direct binding assay), independently replicated in companion Nature paper\",\n      \"pmids\": [\"21901103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Nectin-4 is the epithelial receptor for measles virus exit from the host: it interacts with the viral attachment protein (hemagglutinin) with high affinity through its membrane-distal IgV domain, sustains MV entry and non-cytopathic lateral spread in well-differentiated primary human airway epithelial sheets infected basolaterally, and is downregulated in infected epithelial cells including macaque tracheae.\",\n      \"method\": \"Functional rescue transfection in non-permissive cells, primary airway epithelial cultures, basolateral infection assays, immunohistochemistry in macaque tissues, in vitro binding assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal experimental systems (cell lines, primary cultures, in vivo tissue), independent replication of receptor identity\",\n      \"pmids\": [\"22048310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of the membrane-distal IgV domain of human nectin-4 in complex with measles virus hemagglutinin (MV-H) revealed that nectin-4 binds exclusively via its N-terminal IgV domain to the β4-β5 groove of MV-H, with the contact interface dominated by hydrophobic interactions. The nectin-4 binding site on MV-H overlaps extensively with those of the other two MV receptors (CD46 and SLAM).\",\n      \"method\": \"X-ray crystallography (co-crystal structure of nectin-4 IgV domain with MV-H)\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with defined binding interface\",\n      \"pmids\": [\"23202587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structures of the full ectodomains of all four nectins and Necl-5 revealed a conserved stereotyped dimeric interface (C-C'-C\\\"-D β-strand region of the V domain) representing the adhesive trans interaction. Quantitative binding measurements defined homophilic affinities and heterophilic specificity across the family. Targeted cross-linking confirmed the dimer interface as the adhesive trans contact.\",\n      \"method\": \"X-ray crystallography of natively glycosylated ectodomains, surface plasmon resonance, targeted cross-linking\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures of all four nectins plus quantitative SPR and crosslinking validation\",\n      \"pmids\": [\"22902367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The measles virus hemagglutinin β4-β5 hydrophobic groove governs functional interactions with nectin-4 and CD46 but not SLAM. A single substitution in this groove drastically reduced nectin-4 and CD46 binding while minimally altering SLAM binding. Soluble nectin-4 blocked vaccine MV entry via nectin-4 and CD46 but only partially reduced SLAM-mediated entry.\",\n      \"method\": \"Site-directed mutagenesis of MV-H, cell fusion assays, soluble nectin-4 competition, surface plasmon resonance binding kinetics, recombinant virus construction\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with functional validation plus binding kinetics and recombinant virus assays\",\n      \"pmids\": [\"23760251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PVRL4 promotes anchorage-independent cell proliferation by driving cell-to-cell attachment and matrix-independent integrin β4/SHP-2/c-Src signaling activation. PVRL4 was identified via a gain-of-function screen for anchorage independence; breast cancer cell transformation was shown to be dependent on PVRL4, and blocking PVRL4-mediated cell-to-cell attachment with monoclonal antibodies inhibited orthotopic tumor growth in vivo.\",\n      \"method\": \"Gain-of-function screen, co-immunoprecipitation of integrin β4/SHP-2/c-Src complex, siRNA knockdown, monoclonal antibody blocking, orthotopic xenograft mouse models\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional screen plus mechanistic epistasis (Co-IP of signaling complex) plus in vivo validation with antibody blockade\",\n      \"pmids\": [\"23682311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Exogenous expression of Nectin-4 in mammalian cells increased lamellipodia formation and invasive ability through activation of the small GTPase Rac1; siRNA-mediated suppression of Nectin-4 inhibited cell growth in lung cancer cells.\",\n      \"method\": \"siRNA knockdown, exogenous overexpression, Rac1 activation assay, invasion assay, lamellipodia quantification\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — defined signaling output (Rac1 activation) linked to Nectin-4 expression in single study\",\n      \"pmids\": [\"19679554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Nectin-4 mutations causing EDSS1 (ectodermal dysplasia-syndactyly syndrome) perturb the Rac1 pathway: trans-interaction of nectin-1 and nectin-4 induces Rac1 activation, and mutant nectin-4 (p.Val242Met, p.Thr185Met) delays cadherin recruitment at adherens junctions and impairs nectin-1 clustering at contact sites in keratinocytes, demonstrating a role for the nectin-1/nectin-4 interaction in early adherens junction formation.\",\n      \"method\": \"Patient keratinocytes and skin biopsy, ectopic expression of mutant and WT nectin-4, cell aggregation assays, immunofluorescence for cadherin/nectin-1 clustering, Rac1 activation assay\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — patient-derived cells with defined signaling readout (Rac1), multiple functional assays\",\n      \"pmids\": [\"24577405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss-of-function mutations in PVRL4 (encoding nectin-4) cause ectodermal dysplasia-syndactyly syndrome (EDSS). Mutant nectin-4 from patients lost the capability to bind nectin-1. In patient keratinocytes, discrete hair follicle structures showed alterations in membrane localization of nectin-afadin and cadherin-catenin complexes essential for adherens junction formation, and reorganization of the actin cytoskeleton was observed.\",\n      \"method\": \"Homozygosity mapping, candidate gene sequencing, patient keratinocyte functional assays (nectin-1 binding by pull-down), immunofluorescence of adherens junction components and actin cytoskeleton in patient tissue\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — patient mutations combined with functional binding loss and cellular phenotyping of junction/actin reorganization\",\n      \"pmids\": [\"20691405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nectin-4 expression in stratified epithelia is regulated by IRF6: depletion of IRF6 reduces Pvrl4 expression in keratinocytes. In AEC syndrome (p63 mutation), reduced IRF6 expression correlates with decreased Pvrl4 expression. By contrast, Pvrl1 (nectin-1) is a direct p63 target gene (p63 binds to two conserved intronic Pvrl1 enhancer regions by ChIP), but Pvrl4 regulation is independent of p63 and linked to IRF6-mediated epidermal differentiation.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), siRNA knockdown of p63 and IRF6, qRT-PCR, p63-null mouse skin, patient AEC keratinocytes, conditional AEC mouse model\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP for direct regulatory binding and multiple genetic models for Pvrl4/IRF6 link, but IRF6→PVRL4 regulation relies on correlation in patient/mouse models without direct ChIP of PVRL4 promoter\",\n      \"pmids\": [\"25387952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Measles virus spread in human airway epithelial (HAE) cells requires the nectin-4/afadin complex: afadin knockdown limited infectious-center formation, and a nectin-4 mutant lacking the afadin-binding site in its cytoplasmic tail was less effective than WT nectin-4 at promoting MV infection. Spread occurred through intercellular membrane pores (cytoplasm flow between columnar cells on lateral surfaces) rather than visible syncytia.\",\n      \"method\": \"siRNA knockdown of afadin in primary HAE cultures, nectin-4 cytoplasmic-tail mutant expression in porcine airway epithelial primary cultures, high-resolution video microscopy, GFP cytoplasm-flow assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct mutagenesis of afadin-binding domain with functional readout in primary human airway cultures plus live imaging\",\n      \"pmids\": [\"25926640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nectin-4 ectodomain shedding in ovarian cancer is mediated by both ADAM17 and ADAM10. LPA stimulates Nectin-4 shedding; small-molecule inhibitors and siRNA knockdown of ADAM10 and ADAM17 confirmed their roles. Ascites fluid significantly increased sN4 shedding. Shed Nectin-4 is detectable at 2–20-fold higher levels in ascites than in serum.\",\n      \"method\": \"siRNA knockdown of ADAM10 and ADAM17, small-molecule inhibitor assays, LPA stimulation, ELISA quantification of shed nectin-4 in ascites and serum from matched patient samples\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic (siRNA) and pharmacological inhibition of two ADAMs with defined biochemical readout confirmed in patient specimens\",\n      \"pmids\": [\"28232483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Matrix-detached epithelial and carcinoma cells cluster spontaneously via PVRL4 (Nectin-4), activating a PVRL4/α6β4 integrin/Src signaling axis that sustains GPX4 expression to resist ferroptosis. In the absence of α6β4, PVRL4-mediated clustering increased lipid peroxidation and triggered ferroptosis; when clustering was inhibited, single cells were more susceptible to apoptosis than ferroptosis.\",\n      \"method\": \"siRNA knockdown of PVRL4 and α6β4, antibody blocking of clustering, lipid peroxidation assays, cell viability assays, Western blot for GPX4\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis between PVRL4, α6β4, and Src with multiple mechanistic readouts (GPX4, lipid peroxidation, cell death mode)\",\n      \"pmids\": [\"29934307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nectin-4 promotes breast cancer stem cell (BCSC) self-renewal and metastasis by activating WNT/β-catenin signaling via the PI3K/Akt axis. Nectin-4 depletion inhibited EMT, invasion, and WNT/β-catenin pathway activity; overexpression of Nectin-4 in null cells induced WNT/β-catenin signaling via PI3K/Akt.\",\n      \"method\": \"siRNA knockdown and overexpression in breast cancer cell lines, in vitro sphere formation, invasion assay, in vivo xenograft, ex vivo and clinical sample analysis, Western blot for PI3K/Akt/β-catenin pathway components\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — overexpression and knockdown with pathway readouts but no direct binding or reconstitution experiment linking Nectin-4 to WNT/β-catenin\",\n      \"pmids\": [\"28600142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Under hypoxia, ADAM-17 expressed in metastatic breast cancer stem cells sheds the nectin-4 ecto-domain into the microenvironment, which then physically interacts with integrin-β4 on endothelial cells, promoting angiogenesis via the Src/PI3K/AKT/iNOS pathway (but not Phospho-Erk or NF-κB).\",\n      \"method\": \"Co-immunoprecipitation of shed nectin-4 ecto-domain with integrin-β4, in vitro tube formation, CAM assay, in vivo angiogenesis models, pathway inhibitors, siRNA knockdown\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP of ecto-domain/integrin-β4 plus pathway dissection but single lab, mechanistic follow-up somewhat indirect\",\n      \"pmids\": [\"30056265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nectin-4 cis-interacts with ErbB2 (and its trastuzumab-resistant splice variants p95-ErbB2 and ErbB2ΔEx16) through the third Ig-like domain of nectin-4 and domain IV of ErbB2, enhancing ErbB2 dimerization and activation and downstream PI3K/AKT signaling for DNA synthesis. Nectin-4 also enhanced p95-ErbB2-induced JAK-STAT3 signaling.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping using truncation/deletion constructs of nectin-4 and ErbB2, Western blot for PI3K-AKT and JAK-STAT3 phosphorylation, DNA synthesis assays in T47D and SUM190-PT breast cancer cell lines\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP with domain mapping and defined signaling readouts in two cell lines, single lab study\",\n      \"pmids\": [\"31831814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nectin-4 is a novel ligand of the immune checkpoint receptor TIGIT. Unlike other TIGIT ligands (which also bind additional receptors), Nectin-4 interacts exclusively with TIGIT. The TIGIT-Nectin-4 interaction inhibits NK cell cytotoxicity; blocking Nectin-4 antibodies enhanced tumor cell killing in vitro and in vivo.\",\n      \"method\": \"Fusion protein staining of NK cells, TIGIT binding assays, NK cytotoxicity killing assays, blocking antibody experiments in vitro and in syngeneic mouse models\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — defined receptor-ligand interaction with functional NK cell readout, single lab\",\n      \"pmids\": [\"32503945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The NECTIN4 endo-domain (lacking extracellular region) translocates to the nucleus via physical interaction with IMPORTIN-α2 and activates DNA repair, while the ecto-domain (lacking signal peptide and cytoplasmic region) is expressed in the cytoplasm and specifically activates angiogenesis. Full-length NECTIN-4 modulates both processes.\",\n      \"method\": \"Domain-specific NECTIN-4 constructs overexpressed in 5-FU-resistant cervical cancer stem cells, co-immunoprecipitation with IMPORTIN-α2, nuclear fractionation, comet assay, γ-H2AX immunofluorescence, BER pathway assays, in vitro tube formation, CAM assay\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — domain constructs with Co-IP of nuclear import factor and multiple functional readouts, single lab\",\n      \"pmids\": [\"32603697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nectin-4 plays a causative role in senescence-associated cell size enlargement via the Src family kinase (SFK)/PI3K/Rac1 pathway. Overexpression of Nectin-4 caused enlarged cell morphology resembling senescent cells; knockdown of Nectin-4 during DNA damage-induced senescence suppressed cell size increase without affecting senescence induction per se. Nectin-4 knockdown also induced apoptosis in senescent cells, and cell size was positively correlated with survival rate.\",\n      \"method\": \"Overexpression and knockdown of Nectin-4, pharmacological inhibition of SFK/PI3K/Rac1, single-cell tracking microscopy, flow cytometry for cell size, apoptosis assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — gain- and loss-of-function with pathway inhibitors and defined morphological/survival readout, single lab\",\n      \"pmids\": [\"38062106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ERRα (estrogen-related receptor-α) transcriptionally activates NECTIN-4 by directly binding to the NECTIN-4 promoter, as shown by chromatin immunoprecipitation and dual-luciferase reporter assays. ERRα-induced gallbladder cancer cell proliferation and invasion were antagonized by Nectin-4 depletion. Nectin-4 depletion inhibited ERRα-induced PI3K/AKT pathway activation.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, siRNA knockdown, overexpression, Western blot for PI3K/AKT pathway components, in vivo xenograft\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and luciferase reporter directly demonstrate promoter binding, but downstream epistasis is single lab\",\n      \"pmids\": [\"32030850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PICK-1 (protein interacting with C-kinase-1) directly interacts with nectins in a PDZ-domain-dependent manner and co-localizes with nectins at adherens junctions in epithelial cells, suggesting a role for PICK-1 in the regulation of nectin-based cell junctions.\",\n      \"method\": \"Co-immunoprecipitation, GST-pulldown, immunofluorescence co-localization in epithelial cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single pulldown/Co-IP with co-localization, no functional perturbation of nectin-4 specifically\",\n      \"pmids\": [\"15811349\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NECTIN4 is a type I transmembrane immunoglobulin superfamily cell adhesion molecule that localizes to cadherin-based adherens junctions by binding afadin (via its C-terminal PDZ-binding motif) and forms Ca2+-independent trans-heterodimers with nectin-1 through V-domain interactions (with a defined β-strand binding epitope); its ectodomain is constitutively shed by TACE/ADAM-17 (and ADAM-10 in ovarian cancer) to generate a soluble form detected in patient sera; in cancer cells it drives anchorage-independent growth through a cell-cell contact–dependent integrin β4/SHP-2/c-Src signaling axis, promotes Rac1 activation and lamellipodia formation, cis-interacts with ErbB2 to enhance PI3K-AKT signaling, acts as the epithelial receptor for measles virus (and other morbilliviruses) via its IgV domain engaging the MV hemagglutinin β4-β5 hydrophobic groove, and functions as an exclusive ligand for the immune checkpoint receptor TIGIT to suppress NK cell cytotoxicity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NECTIN4 is a type I transmembrane immunoglobulin-superfamily adhesion molecule that organizes epithelial cell–cell junctions and transduces survival signals in anchorage-independent contexts. It mediates Ca²⁺-independent homophilic and heterophilic trans-interactions—principally with nectin-1 through its IgV domain (KD ~100 nM)—and recruits afadin to cadherin-based adherens junctions, thereby linking the nectin–afadin and cadherin–catenin adhesion systems [PMID:11544254, PMID:12011057]; loss-of-function mutations cause ectodermal dysplasia–syndactyly syndrome (EDSS) by disrupting these junction complexes in keratinocytes [PMID:20691405]. NECTIN4 activates integrin β4/SHP-2/c-Src and PI3K/AKT signaling axes in matrix-detached cell clusters, sustaining GPX4 expression to protect against ferroptosis and promoting anchorage-independent growth [PMID:23682311, PMID:29934307]; its TACE/ADAM-17-shed ectodomain engages integrin β4 on endothelial cells to drive angiogenesis via Src/PI3K/AKT [PMID:15784625, PMID:30056265]. The IgV domain also serves as the epithelial receptor for morbilliviruses (measles, CDV, PPRV), binding the hemagglutinin β4–β5 hydrophobic groove, and functions as a ligand for the immune checkpoint receptor TIGIT to suppress NK cell cytotoxicity [PMID:23202587, PMID:21901103, PMID:32503945].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing NECTIN4 as a new nectin-family adhesion molecule resolved how it connects to the actin cytoskeleton: it binds afadin via its cytoplasmic tail, localizes at cadherin-based adherens junctions, and engages nectin-1 in trans through V-domain interactions.\",\n      \"evidence\": \"Co-IP, Fc-fusion binding assays, and co-localization in MDCKII epithelial cells\",\n      \"pmids\": [\"11544254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and cis-clustering mode of nectin-4 at junctions unresolved\", \"No structural information on the nectin-4/afadin interface\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Quantitative binding analysis revealed that nectin-4 trans-heterodimerizes with nectin-1 at ~100 nM affinity via V-to-V domain contacts, with C domains contributing, mapping the epitope to the C-C'-C''-D β-strands shared with nectin-3.\",\n      \"evidence\": \"Surface plasmon resonance, competition assays with Fc-fusion proteins, chimeric receptor substitution, and monoclonal antibody blocking\",\n      \"pmids\": [\"12011057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of nectin-4/nectin-1 heterodimer not available\", \"Functional consequence of nectin-1 versus nectin-3 competition in tissues not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of TACE/ADAM-17 as the sheddase for nectin-4 explained how a soluble ectodomain is generated, opening a paracrine signaling dimension for the receptor.\",\n      \"evidence\": \"TACE overexpression/siRNA/KO fibroblast reconstitution with TAPI-1 and TIMP-3 inhibitor validation, ELISA and Western blot of shed ectodomain\",\n      \"pmids\": [\"15784625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage site in nectin-4 not mapped at amino acid resolution\", \"Biological function of shed ectodomain not yet defined at this point\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The demonstration that PVRL4 loss-of-function mutations cause ectodermal dysplasia–syndactyly syndrome established the gene's essential role in human epithelial morphogenesis and adherens junction integrity.\",\n      \"evidence\": \"Homozygosity mapping and Sanger sequencing in EDSS families, nectin-1 binding assays and junction immunofluorescence in patient keratinocytes\",\n      \"pmids\": [\"20691405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether residual nectin-4 expression modulates phenotype severity unknown\", \"Contribution of nectin-4/afadin versus nectin-4/nectin-1 disruption to individual disease features not dissected\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that wild-type measles virus uses nectin-4 as its epithelial receptor resolved a long-standing question about how measles exits the airway epithelium, and was subsequently extended to canine distemper virus and PPRV.\",\n      \"evidence\": \"Gain-of-function transfection of non-susceptible cells, siRNA knockdown, antibody blocking, virus binding assays, flow cytometry (measles); domain-swap mutagenesis (CDV); Co-IP with PPRV H protein (PPRV)\",\n      \"pmids\": [\"21901103\", \"24725937\", \"31318632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution of nectin-4 versus SLAM in different tissues during natural infection not fully resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The crystal structure of the nectin-4 IgV domain bound to measles hemagglutinin pinpointed the β4–β5 hydrophobic groove as the shared entry site for nectin-4 and CD46, providing atomic-level understanding of receptor usage switching.\",\n      \"evidence\": \"X-ray crystallography of MV-H/nectin-4 V-domain complex; validated by site-directed mutagenesis and SPR\",\n      \"pmids\": [\"23202587\", \"23760251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length ectodomain structure of nectin-4 not determined\", \"How MV-H conformational changes propagate to the fusion machinery upon nectin-4 binding remains unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Functional screens revealed that PVRL4 drives anchorage-independent survival by assembling cell clusters that activate an integrin β4/SHP-2/c-Src signaling axis, establishing NECTIN4 as more than an adhesion molecule—it is a signaling organizer in detached cells.\",\n      \"evidence\": \"Gain-of-function screen, Co-IP of integrin β4/SHP-2/c-Src, anchorage-independence assays, in vivo orthotopic tumor models with blocking antibody\",\n      \"pmids\": [\"23682311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PVRL4 activates integrin β4 without matrix ligand is mechanistically unclear\", \"Whether SHP-2 is recruited directly or via adaptor proteins not determined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Multiple groups convergently showed that NECTIN4 activates the PI3K/AKT pathway in diverse epithelial cancers and drives Rac1-dependent invasion and lamellipodia formation, consolidating PI3K/AKT as a central downstream effector.\",\n      \"evidence\": \"siRNA/overexpression with pathway read-outs (Western blot for p-AKT, Rac1-GTP pulldown), pharmacological rescue with AKT activator SC79 and inhibitor LY294002 across gastric, thyroid, and breast cancer models\",\n      \"pmids\": [\"19679554\", \"28600142\", \"29208564\", \"31114323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding partner linking nectin-4 cytoplasmic tail to PI3K activation not identified\", \"Relative contributions of integrin co-signaling versus autonomous nectin-4 signaling unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"PVRL4-mediated cell clustering was shown to sustain GPX4 and protect against ferroptosis via integrin α6β4/Src, while the shed ectodomain was found to act in trans on endothelial integrin β4 to promote angiogenesis—bifurcating nectin-4 function into autocrine survival and paracrine vascular signaling.\",\n      \"evidence\": \"Co-IP, siRNA against PVRL4 and α6β4, lipid peroxidation assays, GPX4 Western blot (ferroptosis); Co-IP of shed ectodomain with endothelial integrin β4, HUVEC tube formation, in ovo CAM assay (angiogenesis)\",\n      \"pmids\": [\"29934307\", \"30056265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether shed nectin-4 levels in patient sera correlate with angiogenic phenotype not tested in controlled experiments\", \"Identity of ferroptosis-relevant lipid species regulated by nectin-4/GPX4 axis not characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The identification of NECTIN4 as a functional ligand for the immune checkpoint receptor TIGIT established an immune-evasion role, where tumor-expressed nectin-4 suppresses NK cell cytotoxicity.\",\n      \"evidence\": \"Fusion protein binding screen of NK receptors, functional NK killing assays, in vivo tumor models with blocking antibody\",\n      \"pmids\": [\"32503945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NECTIN4–TIGIT interaction affects T cell exhaustion not addressed\", \"Relative contribution of nectin-4 versus PVR and nectin-2 as TIGIT ligands in tumors not quantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"NECTIN4 was found to drive senescence-associated cell enlargement through SFK/PI3K/Rac1 without affecting senescence entry, revealing a non-oncogenic role in cellular aging.\",\n      \"evidence\": \"Nectin-4 overexpression/siRNA, SFK/PI3K/Rac1 inhibitors, single-cell tracking of apoptosis and cell size during DNA damage-induced senescence\",\n      \"pmids\": [\"38062106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this pathway operates in vivo senescent tissues is untested\", \"Mechanistic link between cell size enlargement and senescent cell survival not molecularly defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how the nectin-4 cytoplasmic tail directly engages PI3K and integrin β4 at the molecular level, the structure of the nectin-4/nectin-1 heterodimer, and the in vivo hierarchy among TIGIT, PVR, and nectin-2 versus nectin-4 in tumor immune evasion.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of nectin-4/nectin-1 trans-dimer\", \"Direct adaptor linking nectin-4 cytoplasmic domain to PI3K not identified\", \"In vivo relative contribution of nectin-4 versus other TIGIT ligands in immune evasion unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 5, 17]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 11, 12, 15, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5, 8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\n      \"nectin-afadin adhesion complex\"\n    ],\n    \"partners\": [\n      \"NECTIN1\",\n      \"AFDN\",\n      \"ADAM17\",\n      \"ITGB4\",\n      \"SHP2\",\n      \"SRC\",\n      \"TIGIT\",\n      \"KPNA2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n"}