NECTIN4 (nectin-4, PVRL4) is a single-pass type I transmembrane glycoprotein of the immunoglobulin superfamily with three extracellular Ig-like domains (V, C, C) and a cytoplasmic tail that binds afadin. It localizes to cadherin-based adherens junctions at the plasma membrane, where its N-terminal IgV domain mediates homophilic trans-interaction and heterophilic adhesion with nectin-1, contributing to epithelial cell-cell adhesion. It is expressed mainly in placenta and skin and is re-expressed in many carcinomas; its ectodomain can be shed by ADAM17. Loss-of-function mutations cause ectodermal dysplasia-syndactyly syndrome. Nectin-4 is the epithelial receptor for measles virus, a reported ligand for the inhibitory NK-cell receptor TIGIT, and the target of the antibody-drug conjugate enfortumab vedotin.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:21982860 A secreted protein microarray platform for extracellular pro... | MODIFY | Summary: Nectin-4 binds nectin-1 in a secreted-protein microarray screen. Reason: The nectin-1/nectin-4 trans-heterophilic interaction is an adhesive interaction; cell adhesion molecule binding is the informative term. Proposed replacements: cell adhesion molecule binding Supporting Evidence: PMID:22902367 heterophilic adhesion has been observed between nectin-1 and nectin-3; nectin-1 and nectin-4; and between nectin-2 and nectin-3 |
| GO:0005515 protein binding | IPI PMID:21982860 A secreted protein microarray platform for extracellular pro... | MODIFY | Summary: Nectin-4 binds TIGIT in a secreted-protein microarray screen. Reason: Interaction with the inhibitory receptor TIGIT is better captured as signaling receptor binding. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:32503945 We show that the TIGIT-Nectin4 interaction inhibits natural killer cell activity, a critical part of the innate immune response. |
| GO:0005515 protein binding | IPI PMID:22048310 Adherens junction protein nectin-4 is the epithelial recepto... | MODIFY | Summary: Nectin-4 binds measles virus hemagglutinin with high affinity. Reason: Nectin-4 is the epithelial receptor for measles virus; virus receptor activity is the informative term. Proposed replacements: virus receptor activity Supporting Evidence: PMID:22048310 This adherens junction protein of the immunoglobulin superfamily interacts with the viral attachment protein with high affinity through its membrane-distal domain. file:human/NECTIN4/NECTIN4-uniprot.txt (Microbial infection) Acts as a receptor for measles virus. |
| GO:0005515 protein binding | IPI PMID:22902367 Nectin ectodomain structures reveal a canonical adhesive int... | MODIFY | Summary: SPR and structures show nectin-1/nectin-4 heterophilic binding. Reason: Adhesive heterophilic binding; cell adhesion molecule binding is informative. Proposed replacements: cell adhesion molecule binding Supporting Evidence: PMID:22902367 heterophilic adhesion has been observed between nectin-1 and nectin-3; nectin-1 and nectin-4; and between nectin-2 and nectin-3 |
| GO:0005515 protein binding | IPI PMID:23202587 Structure of measles virus hemagglutinin bound to its epithe... | MODIFY | Summary: Crystal structure of nectin-4 IgV domain bound to measles virus H. Reason: Receptor-virus attachment; virus receptor activity. Proposed replacements: virus receptor activity Supporting Evidence: PMID:23202587 nectin-4 binds the MV-H Ξ²4-Ξ²5 groove exclusively via its N-terminal IgV domain |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Binary interactome screen hit with ZNF582. Reason: Bare protein binding with a nuclear zinc-finger protein from a high-throughput screen; uninformative and of uncertain physiological relevance for a cell-surface adhesion molecule. Supporting Evidence: file:human/NECTIN4/NECTIN4-uniprot.txt Q96NY8; Q96NG8: ZNF582; NbExp=2; IntAct=EBI-4314784, EBI-21898620; |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary interactome screen hit with DEFB121. Reason: Bare protein binding from a high-throughput Y2H screen; uninformative. Supporting Evidence: file:human/NECTIN4/NECTIN4-uniprot.txt Q96NY8; Q5J5C9: DEFB121; NbExp=3; IntAct=EBI-4314784, EBI-10244198; |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Interactome screen hit with ZNF582. Reason: Bare protein binding; uninformative. Supporting Evidence: file:human/NECTIN4/NECTIN4-uniprot.txt Q96NY8; Q96NG8: ZNF582; NbExp=2; IntAct=EBI-4314784, EBI-21898620; |
| GO:0005576 extracellular region | EXP PMID:15784625 Nectin-4, a new serological breast cancer marker, is a subst... | KEEP AS NON CORE | Summary: Soluble nectin-4 ectodomain shed by ADAM17/TACE is found in patient sera and culture supernatants. Reason: The extracellular pool is a shed ectodomain; the functional form is the transmembrane adhesion molecule at adherens junctions. Supporting Evidence: PMID:15784625 The soluble Nectin-4 form (43 kDa) is formed by the entire Nectin-4 ectodomain. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt Secreted location (processed form) mapped to extracellular region. Reason: Shed ectodomain pool, secondary. Supporting Evidence: PMID:15784625 The soluble Nectin-4 form (43 kDa) is formed by the entire Nectin-4 ectodomain. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane inherited at the nectin family node. Reason: Single-pass type I transmembrane adhesion molecule at the cell surface. Supporting Evidence: PMID:22048310 This adherens junction protein of the immunoglobulin superfamily interacts with the viral attachment protein with high affinity through its membrane-distal domain. file:human/NECTIN4/NECTIN4-uniprot.txt Cell junction, adherens junction {ECO:0000269|PubMed:11544254}. Note=Colocalizes with AFDN at cadherin-based adherens junctions (PubMed:11544254). |
| GO:0005886 plasma membrane | IC PMID:32503945 Nectin4 is a novel TIGIT ligand which combines checkpoint in... | ACCEPT | Summary: Curator inference of plasma membrane localization from cell-surface TIGIT-Ig staining. Reason: Nectin-4-overexpressing cells are stained by TIGIT-Ig, showing surface exposure of the ectodomain. Supporting Evidence: PMID:32503945 (E) FACS staining of Raji cells overexpressing Nectin4 with TIGIT-Ig. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence plasma membrane. Reason: Consistent with other evidence. Supporting Evidence: file:human/NECTIN4/NECTIN4-uniprot.txt Cell junction, adherens junction {ECO:0000269|PubMed:11544254}. Note=Colocalizes with AFDN at cadherin-based adherens junctions (PubMed:11544254). |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt Cell membrane mapping. Reason: Correct. Supporting Evidence: file:human/NECTIN4/NECTIN4-uniprot.txt Cell junction, adherens junction {ECO:0000269|PubMed:11544254}. Note=Colocalizes with AFDN at cadherin-based adherens junctions (PubMed:11544254). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-419003 | ACCEPT | Summary: Reactome nectin adhesion reactions at the plasma membrane. Reason: Correct. Supporting Evidence: Reactome:R-HSA-419003 file:human/NECTIN4/NECTIN4-uniprot.txt Cell junction, adherens junction {ECO:0000269|PubMed:11544254}. Note=Colocalizes with AFDN at cadherin-based adherens junctions (PubMed:11544254). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-419011 | ACCEPT | Summary: Reactome nectin adhesion reactions at the plasma membrane. Reason: Correct. Supporting Evidence: Reactome:R-HSA-419011 file:human/NECTIN4/NECTIN4-uniprot.txt Cell junction, adherens junction {ECO:0000269|PubMed:11544254}. Note=Colocalizes with AFDN at cadherin-based adherens junctions (PubMed:11544254). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-420598 | ACCEPT | Summary: Reactome nectin adhesion reactions at the plasma membrane. Reason: Correct. Supporting Evidence: Reactome:R-HSA-420598 file:human/NECTIN4/NECTIN4-uniprot.txt Cell junction, adherens junction {ECO:0000269|PubMed:11544254}. Note=Colocalizes with AFDN at cadherin-based adherens junctions (PubMed:11544254). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-433711 | ACCEPT | Summary: Reactome nectin adhesion reactions at the plasma membrane. Reason: Correct. Supporting Evidence: Reactome:R-HSA-433711 file:human/NECTIN4/NECTIN4-uniprot.txt Cell junction, adherens junction {ECO:0000269|PubMed:11544254}. Note=Colocalizes with AFDN at cadherin-based adherens junctions (PubMed:11544254). |
| GO:0005912 adherens junction | IBA GO_REF:0000033 | ACCEPT | Summary: Adherens junction inherited at the nectin family node. Reason: Nectin-4 colocalizes with afadin at cadherin-based adherens junctions. Supporting Evidence: file:human/NECTIN4/NECTIN4-uniprot.txt Cell junction, adherens junction {ECO:0000269|PubMed:11544254}. Note=Colocalizes with AFDN at cadherin-based adherens junctions (PubMed:11544254). PMID:22048310 This adherens junction protein of the immunoglobulin superfamily interacts with the viral attachment protein with high affinity through its membrane-distal domain. |
| GO:0005912 adherens junction | IDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by... | ACCEPT | Summary: NECTIN4 identified among E-cadherin-proximal proteins at adherens junctions by proximity biotinylation. Reason: Consistent with afadin-linked localization to cadherin-based adherens junctions; curator judgement from the full dataset retained. Supporting Evidence: PMID:25468996 We used proximity biotinylation and quantitative proteomics to identify 561 proteins in the vicinity of the cytoplasmic tail of E-cadherin. file:human/NECTIN4/NECTIN4-uniprot.txt Cell junction, adherens junction {ECO:0000269|PubMed:11544254}. Note=Colocalizes with AFDN at cadherin-based adherens junctions (PubMed:11544254). |
| GO:0005912 adherens junction | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt adherens junction mapping. Reason: Correct. Supporting Evidence: file:human/NECTIN4/NECTIN4-uniprot.txt Cell junction, adherens junction {ECO:0000269|PubMed:11544254}. Note=Colocalizes with AFDN at cadherin-based adherens junctions (PubMed:11544254). |
| GO:0007155 cell adhesion | IEA GO_REF:0000002 | MODIFY | Summary: InterPro family mapping to cell adhesion. Reason: Correct but general; nectin-4 mediates both homophilic and heterophilic (with nectin-1) cell-cell adhesion, terms already carried. Proposed replacements: homophilic cell-cell adhesion heterophilic cell-cell adhesion Supporting Evidence: file:human/NECTIN4/NECTIN4-uniprot.txt Seems to be involved in cell adhesion through trans-homophilic and -heterophilic interactions, the latter including specifically interactions with NECTIN1. |
| GO:0007156 homophilic cell-cell adhesion | IBA GO_REF:0000033 | ACCEPT | Summary: Homophilic cell-cell adhesion inherited at nectin node. Reason: Nectin-4 forms homophilic trans dimers via its IgV domain. Supporting Evidence: PMID:22902367 polar residues (Ser130 and Gln64) stabilizing the nectin-4 homodimer file:human/NECTIN4/NECTIN4-uniprot.txt Seems to be involved in cell adhesion through trans-homophilic and -heterophilic interactions, the latter including specifically interactions with NECTIN1. |
| GO:0007157 heterophilic cell-cell adhesion | IBA GO_REF:0000033 | ACCEPT | Summary: Heterophilic cell-cell adhesion inherited at nectin node. Reason: Nectin-4 binds nectin-1 in trans. Supporting Evidence: PMID:22902367 heterophilic adhesion has been observed between nectin-1 and nectin-3; nectin-1 and nectin-4; and between nectin-2 and nectin-3 file:human/NECTIN4/NECTIN4-uniprot.txt Seems to be involved in cell adhesion through trans-homophilic and -heterophilic interactions, the latter including specifically interactions with NECTIN1. |
| GO:0007165 signal transduction | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Signal transduction inferred from receptor ligand activity. Reason: Follows logically from the TIGIT ligand activity; nectin-4 acts as a ligand initiating TIGIT signaling in NK cells, which is peripheral to its adhesive function. Supporting Evidence: PMID:32503945 We show that the TIGIT-Nectin4 interaction inhibits natural killer cell activity, a critical part of the innate immune response. |
| GO:0042802 identical protein binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA prediction of identical protein binding. Reason: Nectin-4 self-associates (homophilic trans dimer); the more informative description is homophilic cell adhesion. Supporting Evidence: PMID:22902367 polar residues (Ser130 and Gln64) stabilizing the nectin-4 homodimer |
| GO:0042802 identical protein binding | IPI PMID:22902367 Nectin ectodomain structures reveal a canonical adhesive int... | KEEP AS NON CORE | Summary: Nectin-4 homodimer in crystal structures and SPR. Reason: Self-association is real and underlies homophilic adhesion; retained as a supporting binding activity. Supporting Evidence: PMID:22902367 polar residues (Ser130 and Gln64) stabilizing the nectin-4 homodimer |
| GO:0045953 negative regulation of natural killer cell mediated cytotoxicity | IDA PMID:32503945 Nectin4 is a novel TIGIT ligand which combines checkpoint in... | KEEP AS NON CORE | Summary: Nectin-4 on tumour cells inhibits NK cell killing via TIGIT. Reason: Immune checkpoint ligand role shown with blocking antibodies; peripheral to the adhesion function. Supporting Evidence: PMID:32503945 We show that the TIGIT-Nectin4 interaction inhibits natural killer cell activity, a critical part of the innate immune response. |
| GO:0046718 symbiont entry into host cell | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro nectin-family mapping to symbiont entry into host cell. Reason: Nectin-4 is an entry receptor for measles virus in airway epithelia (although it does not mediate alpha-herpesvirus entry); host-side role in viral entry, non-core. Supporting Evidence: PMID:22048310 This adherens junction protein of the immunoglobulin superfamily interacts with the viral attachment protein with high affinity through its membrane-distal domain. file:human/NECTIN4/NECTIN4-uniprot.txt (Microbial infection) Acts as a receptor for measles virus. |
| GO:0048018 receptor ligand activity | IDA PMID:32503945 Nectin4 is a novel TIGIT ligand which combines checkpoint in... | KEEP AS NON CORE | Summary: Nectin-4 acts as a ligand for TIGIT on NK cells. Reason: Supported by Ig-fusion binding and functional assays in the cited study; independent confirmation is limited, and this is peripheral to adhesion. Supporting Evidence: PMID:32503945 We show that the TIGIT-Nectin4 interaction inhibits natural killer cell activity, a critical part of the innate immune response. PMID:32503945 (E) FACS staining of Raji cells overexpressing Nectin4 with TIGIT-Ig. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: Detected in exosomes from prostatic secretions. Reason: High-throughput proteomic detection of a minor vesicular pool. Supporting Evidence: |
| GO:0098631 cell adhesion mediator activity | IBA GO_REF:0000033 | ACCEPT | Summary: Cell adhesion mediator activity inherited at the nectin node. Reason: Core molecular function: nectin-4 mediates adhesion via homophilic and heterophilic trans interactions. Supporting Evidence: PMID:22902367 Nectins are immunoglobulin superfamily glycoproteins that mediate intercellular adhesion in many vertebrate tissues. PMID:22902367 heterophilic adhesion has been observed between nectin-1 and nectin-3; nectin-1 and nectin-4; and between nectin-2 and nectin-3 file:human/NECTIN4/NECTIN4-uniprot.txt Seems to be involved in cell adhesion through trans-homophilic and -heterophilic interactions, the latter including specifically interactions with NECTIN1. |
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Download this section (compressed HTML)Q: Is the NECTIN4-TIGIT interaction reproducible with physiological expression levels, and does it act in vivo in NK-cell control of tumours?
Q: Which adhesion partners and afadin-dependent signals underlie the ectodermal dysplasia-syndactyly phenotype of NECTIN4 loss?
Experiment: Surface plasmon resonance of purified NECTIN4 and TIGIT ectodomains alongside PVR controls, plus TIGIT reporter assays with NECTIN4-knockout tumour cells.
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