Affinage

NECTIN4

Nectin-4 · UniProt Q96NY8

Length
510 aa
Mass
55.5 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/9 claims corpus-supported (89%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NECTIN4 is a type I transmembrane immunoglobulin-superfamily cell adhesion molecule that organizes epithelial adherens junctions and, when dysregulated, drives oncogenic adhesion and survival signaling (PMID:11544254, PMID:23682311). It binds afadin through its C-terminal cytoplasmic tail and co-localizes with afadin at cadherin-based adherens junctions, mediating homophilic trans-adhesion and heterophilic trans-adhesion with nectin-1 specifically through its membrane-distal V (immunoglobulin-like) domain (PMID:11544254). Homozygous loss-of-function mutations cause ectodermal dysplasia-syndactyly syndrome, with mutant nectin-4 losing nectin-1 binding and disrupting junctional complex localization and actin organization in keratinocytes (PMID:20691405). NECTIN4-driven cell-to-cell attachment activates a matrix-independent integrin β4/SHP-2/c-Src axis that supports anchorage-independent growth and tumor formation (PMID:23682311), and the same PVRL4/α6β4/Src clustering signal sustains GPX4 expression to protect matrix-detached cells from ferroptosis (PMID:29934307). Downstream, it engages PI3K/AKT/Rac1 signaling to promote lamellipodia and invasion (PMID:19679554), WNT/β-catenin-dependent stem-cell self-renewal and EMT (PMID:28600142), and a Src-family-kinase/PI3K/Rac1 program controlling senescence-associated cell-size enlargement and survival (PMID:38062106). NECTIN4 cis-interacts with ErbB2 (HER2) via its C2 domain binding ErbB2 domain IV, enhancing ErbB2 dimerization, activation, and downstream PI3K/AKT signaling, including for trastuzumab-resistant variants (PMID:31831814). Its expression is driven transcriptionally by IRF6 in keratinocytes (PMID:25387952) and by ERRα binding the NECTIN4 promoter in cancer cells, placing it downstream of ERRα-induced PI3K/AKT activation (PMID:32030850). Independently, its V domain serves as the high-affinity epithelial entry/exit receptor for morbilliviruses—measles virus, canine distemper virus, and PPRV—through interaction with the viral attachment (H) protein (PMID:22048310, PMID:21901103, PMID:22761370, PMID:24725937, PMID:31318632), and it acts as a TIGIT ligand whose engagement inhibits NK-cell cytotoxicity (PMID:32503945, PMID:37542773). NECTIN4 expression is necessary and sufficient for sensitivity to the antibody-drug conjugate enfortumab vedotin in urothelial cancer cells (PMID:34108177).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2001 High

    Establishing NECTIN4's molecular identity answered whether it is an adhesion molecule and defined its binding partners, anchoring it within the nectin/afadin junctional system.

    Evidence Fc-fusion pulldown, reciprocal Co-IP, in vitro binding, and immunofluorescence co-localization in MDCKII and COS cells with domain-deletion constructs

    PMID:11544254

    Open questions at the time
    • Functional consequence of nectin-1 vs homophilic engagement not resolved
    • No structural model of the V-domain adhesive interface
  2. 2009 Medium

    Linking NECTIN4 expression to Rac1 activation showed it does more than adhere—it transmits signals promoting motility and invasion.

    Evidence siRNA knockdown, overexpression, invasion assays, and Rac1 activation assay in mammalian cells

    PMID:19679554

    Open questions at the time
    • Mechanism coupling adhesion to Rac1 not defined
    • Single lab, cell-line based
  3. 2010 High

    Human genetics established NECTIN4 as causative for an inherited disease and tied loss of nectin-1 binding directly to junctional and cytoskeletal disruption.

    Evidence Homozygosity mapping, candidate gene sequencing, binding assays and junctional/actin immunofluorescence in patient keratinocytes

    PMID:20691405

    Open questions at the time
    • Tissue-specific basis of ectodermal phenotype incompletely explained
    • Does not address signaling roles
  4. 2011 High

    Identification of NECTIN4 as the epithelial measles virus receptor answered how the virus exits the host and defined the V domain as the H-protein binding surface.

    Evidence Surface protein screen, siRNA knockdown, antibody block, binding assays, and basolateral infection of primary airway epithelial sheets (two concurrent papers)

    PMID:21901103 PMID:22048310

    Open questions at the time
    • Entry route into the cell not yet defined at this stage
    • Downregulation mechanism during infection unresolved
  5. 2012 Medium

    Extending receptor function to canine distemper virus showed NECTIN4 is a conserved morbillivirus epithelial receptor with implications for neurovirulence.

    Evidence Infection of nectin-4-expressing Vero cells, antibody blocking, and IHC of infected dog tissues

    PMID:22761370

    Open questions at the time
    • In vivo causality vs correlation in neurons not fully separated
    • Single lab
  6. 2013 High

    A gain-of-function screen revealed how NECTIN4-driven cell-to-cell attachment promotes transformation, defining a matrix-independent integrin β4/SHP-2/c-Src survival axis.

    Evidence Anchorage-independence screen, pathway epistasis with integrin β4/SHP-2/c-Src, and antibody-blockade xenograft

    PMID:23682311

    Open questions at the time
    • How clustering activates integrin β4 in trans not mechanistically resolved
    • Generality across tumor types untested here
  7. 2014 Medium

    Mutagenesis defined the specific V-domain residues required for morbillivirus entry, mapping the receptor-virus interface at amino-acid resolution.

    Evidence Domain-deletion and site-directed mutagenesis with virus entry and cell-to-cell spread assays for CDV

    PMID:24725937

    Open questions at the time
    • No co-crystal structure of the complex
    • Single lab
  8. 2017 Medium

    Defining the measles entry route showed NECTIN4 drives a dynamin-independent, actin/Rac1/PAK1-dependent macropinocytosis, connecting its signaling outputs to viral uptake.

    Evidence Endocytic inhibitors, siRNA of PAK1/Rac1, phalloidin staining, fluid-uptake assay, and fluorescent MeV reporters

    PMID:28250131

    Open questions at the time
    • Direct link between receptor engagement and Rac1/PAK1 activation not shown
    • Cell-line specific
  9. 2017 Medium

    Placing NECTIN4 upstream of WNT/β-catenin via PI3K/Akt connected it to cancer stem-cell self-renewal, EMT, and metastasis.

    Evidence Bidirectional knockdown/overexpression, invasion/EMT assays, in vivo models, and patient samples with pathway Western blots

    PMID:28600142

    Open questions at the time
    • Direct molecular link between NECTIN4 and PI3K not defined
    • Single lab
  10. 2018 High

    Demonstrating that NECTIN4 clustering sustains GPX4 to suppress ferroptosis revealed a context-dependent role in matrix-detached cell survival.

    Evidence PVRL4 knockdown/antibody block, α6β4 integrin KO, lipid peroxidation and ferroptosis/apoptosis assays under detachment

    PMID:29934307

    Open questions at the time
    • Molecular link from clustering to GPX4 regulation unresolved
    • Switch logic between death modes incompletely defined
  11. 2018 Medium

    Identifying ADAM-17 shedding of the NECTIN4 ectodomain and its integrin-β4-driven pro-angiogenic action established a paracrine, cleavage-generated function.

    Evidence Co-IP of soluble ectodomain with integrin-β4, pathway inhibitors, tube formation, CAM and in vivo angiogenesis assays under hypoxia

    PMID:30056265

    Open questions at the time
    • Cleavage site and physiological shedding regulation not fully defined
    • Single lab
  12. 2019 High

    Mapping the NECTIN4 C2-domain/ErbB2 domain IV cis-interaction showed it functions as a co-receptor amplifying HER2 signaling, including for trastuzumab-resistant variants.

    Evidence Reciprocal Co-IP with domain-deletion mapping in breast cancer lines, BrdU DNA synthesis, and pathway Western blots

    PMID:31831814

    Open questions at the time
    • Structural basis of cis-dimer enhancement not resolved
    • In vivo relevance to HER2 therapy resistance untested here
  13. 2019 Medium

    Pharmacological epistasis placed NECTIN4-driven proliferation, migration and EMT in papillary thyroid cancer squarely on the PI3K/AKT axis.

    Evidence siRNA knockdown with SC79 rescue and LY294002 phenocopy plus EMT/pathway Western blots

    PMID:31114323

    Open questions at the time
    • Upstream link from NECTIN4 to PI3K not defined
    • Single tumor type, single lab
  14. 2019 Medium

    Showing PPRV H-protein binding to NECTIN4 triggers an AKT-mTOR-inactivating autophagic wave extended its morbillivirus-receptor role to early infection control.

    Evidence Co-IP of viral H with NECTIN4, siRNA knockdown, LC3-II quantification, phospho-AKT/mTOR blots, and mTOR inhibition

    PMID:31318632

    Open questions at the time
    • Mechanism coupling receptor engagement to AKT-mTOR not defined
    • Single lab
  15. 2020 Medium

    Identifying NECTIN4 as a TIGIT ligand that inhibits NK cytotoxicity defined an immune-evasion function distinct from other TIGIT ligands.

    Evidence Fc-fusion staining, TIGIT binding assays, NK killing assays, and in vivo tumor models with blocking antibody

    PMID:32503945

    Open questions at the time
    • Affinity and structural interface defined only later
    • Single lab
  16. 2020 High

    ChIP and reporter assays established ERRα as a direct transcriptional driver of NECTIN4, placing NECTIN4 downstream of ERRα-induced PI3K/AKT signaling.

    Evidence ChIP, dual-luciferase reporter, siRNA epistasis, pathway Western blots, and xenograft in gallbladder cancer

    PMID:32030850

    Open questions at the time
    • Other transcriptional regulators across tissues not addressed
    • Direct NECTIN4-to-PI3K coupling not shown
  17. 2020 Medium

    Loss-of-function and peptide competition implicated NECTIN4 homophilic adhesion in compact ovarian cancer spheroid formation.

    Evidence siRNA knockdown, real-time spheroid imaging, and concentration-dependent N4-derived peptide inhibition with scrambled control

    PMID:32629816

    Open questions at the time
    • Signaling consequences of spheroid compaction not addressed
    • Single lab
  18. 2020 Low

    A domain-dissection study proposed cleaved NECTIN4 fragments have separable nuclear (DNA repair, via IMPORTIN-α2) and cytoplasmic (angiogenesis) functions.

    Evidence Domain-specific constructs, Co-IP with IMPORTIN-α2, fractionation/IF, comet/γ-H2AX, tube formation, and CAM assays

    PMID:32603697

    Open questions at the time
    • Non-canonical nuclear localization requires independent validation
    • Physiological generation of these fragments not established
    • Single lab
  19. 2021 Medium

    Establishing that NECTIN4 expression is necessary and sufficient for enfortumab vedotin sensitivity provided the mechanistic rationale for the ADC in urothelial cancer.

    Evidence Stable overexpression and knockdown in bladder cancer lines with drug-sensitivity and clonogenic assays

    PMID:34108177

    Open questions at the time
    • Quantitative expression threshold for response not defined
    • Resistance mechanisms beyond expression loss untested
  20. 2021 Medium

    Knockdown in cutaneous SCC linked NECTIN4 to ERK signaling and cyclin D1-dependent proliferation alongside its adhesion role.

    Evidence siRNA knockdown, attachment/migration assays, ERK and cyclin D1 Western blots, proliferation assay in A431 cells

    PMID:33808400

    Open questions at the time
    • Direct coupling of NECTIN4 to ERK not shown
    • Single cell line
  21. 2021 Low

    NECTIN4 was associated with hypoxia-driven lymphangiogenesis and lymphatic metastasis via CXCR4/CXCL12-LYVE-1 modulation in breast cancer.

    Evidence siRNA knockdown of Nectin-4 and VEGF-C, LYVE-1 density, tube formation, migration, and pathway Western blots

    PMID:33945869

    Open questions at the time
    • Pathway ordering not directly validated
    • Single lab, limited mechanistic depth
  22. 2023 Medium

    Biophysical mapping quantified the TIGIT-nectin-4 interaction and located its interface, refining the immune-checkpoint ligand model.

    Evidence Surface plasmon resonance and structure-guided mutagenesis of TIGIT

    PMID:37542773

    Open questions at the time
    • No full co-crystal structure
    • Weaker affinity than TIGIT-nectin-2; functional significance of the differential not resolved
  23. 2023 Medium

    Linking NECTIN4 to Src-family-kinase/PI3K/Rac1-mediated senescence-associated cell-size enlargement and survival expanded its signaling role beyond proliferation and adhesion.

    Evidence Bidirectional overexpression/knockdown in a DNA-damage senescence model, single-cell live imaging, and Src/PI3K/Rac1 inhibitors

    PMID:38062106

    Open questions at the time
    • Mechanism linking cell size to survival not fully resolved
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NECTIN4 adhesion and clustering are physically coupled to its diverse intracellular signaling outputs (integrin β4/Src, PI3K/AKT, Rac1, WNT) and a unifying structural basis for its adhesive, viral-receptor, and HER2 co-receptor interfaces remain undefined.
  • No structural model integrating the V/C2 domain functions
  • Direct biochemical link from receptor engagement to PI3K/Rac1 not established
  • In vivo relevance of cleaved fragment functions unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 3 GO:0098631 cell adhesion mediator activity 3 GO:0048018 receptor ligand activity 2 GO:0060089 molecular transducer activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005886 plasma membrane 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1500931 Cell-Cell communication 2 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 1 R-HSA-5357801 Programmed Cell Death 1
Partners
ADAM17AFDNERBB2ITGB4KPNA2PVRL1TIGIT
Complex memberships
nectin-afadin adherens junction complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Nectin-4 was identified as a new member of the nectin family that binds afadin via its C-terminal cytoplasmic sequence and co-localizes with afadin at cadherin-based adherens junctions in MDCKII epithelial cells. Nectin-4 trans-interacts heterophilically with nectin-1 (but not nectin-2, nectin-3, or PVR/CD155) through its V (membrane-distal immunoglobulin-like) domain, and also exhibits homophilic binding. Soluble chimeric Fc-fusion pulldown assays, reciprocal co-immunoprecipitation in COS cells, in vitro protein-protein interaction assays, co-localization by immunofluorescence microscopy, domain-deletion constructs The Journal of Biological Chemistry High 11544254
2009 Exogenous expression of Nectin-4 in mammalian cells increased lamellipodia formation and invasive ability through activation of the small GTPase Rac1. siRNA knockdown, exogenous overexpression, cell invasion assays, Rac1 activation assay Cancer Research Medium 19679554
2010 Homozygous loss-of-function mutations in PVRL4/nectin-4 cause ectodermal dysplasia-syndactyly syndrome (EDSS). In patient keratinocytes, mutated nectin-4 lost its ability to bind nectin-1, and adherens junction complexes (nectin-afadin and cadherin-catenin) showed altered membrane localization accompanied by actin cytoskeleton reorganization in hair follicle structures. Homozygosity mapping, candidate gene sequencing, co-immunoprecipitation/binding assay in patient keratinocytes, immunofluorescence of adherens junction components, actin cytoskeleton staining American Journal of Human Genetics High 20691405
2011 Nectin-4 (PVRL4), an adherens junction protein of the immunoglobulin superfamily, functions as the epithelial exit receptor for measles virus. Its membrane-distal (V) domain interacts with the viral attachment (H) protein with high affinity. Nectin-4 supports MV entry and non-cytopathic lateral spread in well-differentiated primary human airway epithelial sheets infected basolaterally; MV infection downregulates nectin-4 surface expression. Functional surface protein screen, siRNA knockdown, antibody blocking, flow cytometry, confocal microscopy, surface biotinylation, virus binding assay in primary airway epithelial cells and cancer cell lines Nature / PLoS Pathogens High 21901103 22048310
2012 Wild-type canine distemper virus (CDV) uses nectin-4 as an epithelial cell receptor; infection is blocked by anti-nectin-4 antibody, and CDV antigen co-localises with nectin-4-positive neurons and epithelial cells in vivo, implicating nectin-4 in CDV neurovirulence. Infection of Vero cells expressing dog nectin-4, antibody blocking assay, immunohistochemistry of infected dog tissues Journal of Virology Medium 22761370
2013 PVRL4/Nectin-4 promotes anchorage-independent growth by driving cell-to-cell attachment and activating a matrix-independent integrin β4/SHP-2/c-Src signaling axis, which is required for breast cancer cell transformation. Blocking PVRL4-driven cell-to-cell attachment with monoclonal antibodies inhibited orthotopic tumor growth in vivo. Gain-of-function screen for anchorage independence, epistasis with integrin β4/SHP-2/c-Src pathway components (knockdown/inhibition), in vivo xenograft with anti-PVRL4 antibody treatment eLife High 23682311
2014 The V domain of PVRL4/nectin-4 is critical for canine distemper virus (CDV) entry and cell-to-cell spread. Four specific amino acid residues in the V domain of dog PVRL4 and two in the CDV hemagglutinin were essential for receptor-mediated virus entry. Domain-deletion and site-directed mutagenesis constructs, virus entry and cell-to-cell spread assays Virology Medium 24725937
2015 PVRL4 (nectin-4) transcriptional expression is not directly regulated by p63 (unlike nectin-1), but is controlled by the transcription factor IRF6: IRF6 depletion in keratinocytes reduced Pvrl4 expression, and Pvrl4 was downregulated in AEC syndrome keratinocytes in parallel with decreased IRF6. p63 knockout mouse skin analysis, siRNA depletion of p63 and IRF6 in primary keratinocytes, chromatin immunoprecipitation (p63 binds Pvrl1 but not Pvrl4), RT-qPCR in patient-derived AEC keratinocytes and conditional mouse model Experimental Dermatology Medium 25387952
2017 Measles virus enters PVRL4-positive breast cancer and colon cancer cells via a PVRL4-mediated macropinocytosis pathway that is dynamin-independent but requires actin polymerization, Rac1, and PAK1 (in MCF7 cells); MV entry induced membrane ruffles and elevated fluid uptake. Pharmacological inhibitors of endocytic pathways (EIPA, dynasore, actin inhibitors), siRNA knockdown of PAK1 and Rac1, phalloidin staining, fluid-phase uptake assay, recombinant fluorescent MeV reporters Journal of Virology Medium 28250131
2017 Nectin-4 is a marker for breast cancer stem cells and activates WNT/β-catenin signaling via the PI3K/Akt axis to support BCSC self-renewal. Nectin-4 depletion inhibited EMT, metastasis, invasion, and the WNT/β-catenin pathway; overexpression in null cells induced WNT/β-catenin signaling via PI3K/Akt. siRNA knockdown, stable overexpression in nectin-4-null cells, in vitro invasion/EMT assays, in vivo mouse models, ex vivo patient samples, Western blot for pathway components The International Journal of Biochemistry & Cell Biology Medium 28600142
2018 PVRL4/Nectin-4 mediates spontaneous cell clustering of matrix-detached epithelial and carcinoma cells. This clustering activates a PVRL4/α6β4 integrin/Src signaling axis that sustains GPX4 expression and protects against lipid peroxidation/ferroptosis. In the absence of α6β4, PVRL4-mediated clustering paradoxically increased lipid peroxidation and triggered ferroptosis; inhibiting clustering shifted cell death from ferroptosis to apoptosis. Antibody blocking and siRNA knockdown of PVRL4, α6β4 integrin knockout/knockdown, lipid peroxidation assays, GPX4 expression analysis, ferroptosis/apoptosis assays under matrix-detached conditions The Journal of Biological Chemistry High 29934307
2018 Following hypoxia-induced ADAM-17 upregulation in metastatic breast cancer stem cells, ADAM-17 sheds the ecto-domain of nectin-4. The soluble nectin-4 ecto-domain physically interacts with integrin-β4 on endothelial cells and promotes angiogenesis via the Src/PI3K/AKT/iNOS pathway (not via Phospho-ERK or NF-κB). Co-immunoprecipitation of soluble nectin-4 ecto-domain with integrin-β4, pathway inhibitor experiments (Src, PI3K, AKT, iNOS, ERK, NF-κB), in vitro tube formation, in ovo CAM assay, in vivo angiogenesis model, siRNA knockdown of nectin-4 and ADAM-17 The International Journal of Biochemistry & Cell Biology Medium 30056265
2019 Nectin-4 physically cis-interacts with ErbB2 (HER2) through its third immunoglobulin-like (C2) domain binding to domain IV of ErbB2, enhancing ErbB2 dimerization and activation and downstream PI3K/AKT signaling for DNA synthesis. Nectin-4 also cis-interacts with trastuzumab-resistant ErbB2 splice variants (p95-ErbB2 and ErbB2ΔEx16) and enhances their activation, additionally activating JAK-STAT3 signaling for the p95-ErbB2 variant. Co-immunoprecipitation in breast cancer cell lines (T47D, SUM190-PT), domain-deletion constructs mapping the interaction surfaces, DNA synthesis assay (BrdU), Western blot for pathway activation Scientific Reports High 31831814
2019 NECTIN4 promotes papillary thyroid cancer cell proliferation, migration, invasion, and EMT via the PI3K/AKT pathway; AKT phosphorylation activator SC79 reversed si-NECTIN4 knockdown effects, and AKT inhibitor LY294002 phenocopied siRNA knockdown. siRNA knockdown, colony formation assay, proliferation assay, migration/invasion assay, Western blot for EMT markers and PI3K/AKT pathway, SC79 rescue and LY294002 pharmacological inhibitor Cancer Management and Research Medium 31114323
2019 PPRV (peste des petits ruminants virus) induces an early wave of autophagy upon infection via binding of viral H protein to NECTIN4 receptor, inactivating the AKT-mTOR pathway. This NECTIN4-mediated AKT-mTOR-dependent autophagic wave is a critical early step for control of infection. Co-immunoprecipitation of viral H protein with NECTIN4, siRNA knockdown of NECTIN4, autophagosome/LC3-II quantification, phospho-AKT/mTOR Western blot, pharmacological mTOR inhibition Autophagy Medium 31318632
2020 Nectin-4 is a novel ligand of the immune checkpoint receptor TIGIT; the TIGIT-Nectin-4 interaction inhibits natural killer cell cytotoxicity. Unlike other known TIGIT ligands that also bind additional receptors, Nectin-4 interacts only with TIGIT. Blocking Nectin-4 with antibodies enhanced tumor cell killing in vitro and in vivo. NK cell staining with Fc-fusion proteins of tumor markers, TIGIT receptor-ligand binding assays, NK cell killing assays (in vitro), in vivo tumor models with blocking antibody Journal for Immunotherapy of Cancer Medium 32503945
2020 Nectin-4 knockdown cells did not form tightly compacted ovarian cancer spheroids, while control cells formed compact spheroids within 24 h. Synthetic peptides derived from nectin-4 (N4-P10) disrupted spheroid formation in a concentration-dependent manner without cytotoxicity, implicating nectin-4-mediated homophilic adhesion in spheroid compaction. siRNA knockdown of nectin-4, real-time digital photography of spheroid formation, peptide inhibition assays (concentration-response), scrambled peptide control International Journal of Molecular Sciences Medium 32629816
2020 ERRα (estrogen-related receptor-α) directly binds the NECTIN4 promoter and enhances its transcription, as shown by chromatin immunoprecipitation and dual-luciferase reporter assays. ERRα-induced Nectin-4 upregulation activates the PI3K/AKT pathway, and Nectin-4 depletion blocks ERRα-induced PI3K/AKT activation and gallbladder cancer cell proliferation/invasion. ChIP assay, dual-luciferase reporter assay, siRNA knockdown of ERRα and Nectin-4, Western blot for PI3K/AKT pathway, proliferation and invasion assays, in vivo xenograft Cancer Science High 32030850
2021 NECTIN4 expression is both necessary and sufficient for sensitivity to the ADC enfortumab vedotin (EV) in luminal and basal subtypes of urothelial bladder cancer cells; stable knockdown of NECTIN4 conferred EV resistance, and overexpression of NECTIN4 in low-expressing cells conferred EV sensitivity. Stable overexpression and knockdown of NECTIN4 in bladder cancer cell lines, EV drug sensitivity assays (cell proliferation and clonogenic assays) Clinical Cancer Research Medium 34108177
2021 NECTIN4 knockdown in A431 cutaneous SCC cells prevented cell-cell attachment, increased cell migration, downregulated ERK signaling, decreased cyclin D1 expression, and inhibited cell proliferation, demonstrating roles for NECTIN4 in cell-cell interactions, migration, and proliferation in SCC. siRNA knockdown, cell-cell attachment assay, migration assay, Western blot for ERK signaling and cyclin D1, proliferation assay Biomedicines Medium 33808400
2021 Nectin-4 promotes lymphangiogenesis and lymphatic metastasis in breast cancer by stimulating CXCR4 and CXCL12 expression under hypoxia in lymph-node-derived primary cells and modulating the CXCR4/CXCL12-LYVE-1 axis; depletion of Nectin-4 or VEGF-C attenuated LYVE-1 expression, tube formation, and migration. siRNA knockdown of Nectin-4 and VEGF-C, LYVE-1 lymphatic vessel density quantification, tube formation assay, migration assay, Western blot for CXCR4/CXCL12 and lymphangiogenic markers Vascular Pharmacology Low 33945869
2023 TIGIT recognizes the membrane-distal ectodomain of nectin-4; the TIGIT-nectin-4 interaction is weaker than the characterized TIGIT-nectin-2 interaction. Structure-guided mutagenesis mapped the nectin-4 binding interface on TIGIT. Surface plasmon resonance (biophysical binding assay), structure-guided mutagenesis of TIGIT Biochemical and Biophysical Research Communications Medium 37542773
2023 Nectin-4 regulates senescence-associated cell size enlargement: overexpression of Nectin-4 induced enlarged cell morphology resembling senescent cells, and knockdown of Nectin-4 suppressed the cell size increase during DNA damage-induced senescence without altering senescence induction per se. Nectin-4-dependent cell size increase is mediated by the Src family kinase/PI3K/Rac1 pathway. Nectin-4 knockdown in senescent cells induced apoptosis, with cell size positively correlated with survival. Overexpression and siRNA knockdown, DNA damage-induced senescence model, single-cell tracking (live imaging), pathway inhibitors (Src/PI3K/Rac1), cell size quantification Scientific Reports Medium 38062106
2020 The endo-domain of NECTIN-4 (lacking the extracellular region) translocates to the nucleus by physically interacting with IMPORTIN-α2, where it activates DNA repair and enhances cell growth. The ecto-domain (lacking the signal peptide and cytoplasmic region) localizes to the cytoplasm and specifically activates angiogenesis. Domain-specific overexpression constructs, co-immunoprecipitation (NECTIN-4 endo-domain with IMPORTIN-α2), subcellular fractionation/immunofluorescence, comet and γ-H2AX assays for DNA repair, in vitro tube formation, in ovo CAM assay European Journal of Pharmacology Low 32603697

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer research 561 27013195
2011 Adherens junction protein nectin-4 is the epithelial receptor for measles virus. Nature 479 22048310
2011 Tumor cell marker PVRL4 (nectin 4) is an epithelial cell receptor for measles virus. PLoS pathogens 410 21901103
2020 EV-101: A Phase I Study of Single-Agent Enfortumab Vedotin in Patients With Nectin-4-Positive Solid Tumors, Including Metastatic Urothelial Carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 288 32031899
2001 Nectin4/PRR4, a new afadin-associated member of the nectin family that trans-interacts with nectin1/PRR1 through V domain interaction. The Journal of biological chemistry 275 11544254
2009 Identification of nectin-4 oncoprotein as a diagnostic and therapeutic target for lung cancer. Cancer research 226 19679554
2023 Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance. Clinical cancer research : an official journal of the American Association for Cancer Research 184 36534531
2010 Nectin 4 overexpression in ovarian cancer tissues and serum: potential role as a serum biomarker. American journal of clinical pathology 163 20959669
2007 Nectin-4 is a new histological and serological tumor associated marker for breast cancer. BMC cancer 150 17474988
2021 Heterogeneity in NECTIN4 Expression Across Molecular Subtypes of Urothelial Cancer Mediates Sensitivity to Enfortumab Vedotin. Clinical cancer research : an official journal of the American Association for Cancer Research 144 34108177
2021 Expression of Nectin-4 in Bladder Urothelial Carcinoma, in Morphologic Variants, and Nonurothelial Histotypes. Applied immunohistochemistry & molecular morphology : AIMM 137 33901032
2022 Management of Dermatologic Events Associated With the Nectin-4-directed Antibody-Drug Conjugate Enfortumab Vedotin. The oncologist 115 35274723
2024 NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 107 38657187
2020 Nectin4 is a novel TIGIT ligand which combines checkpoint inhibition and tumor specificity. Journal for immunotherapy of cancer 107 32503945
2012 Nectin4 is an epithelial cell receptor for canine distemper virus and involved in neurovirulence. Journal of virology 106 22761370
2013 A role for PVRL4-driven cell-cell interactions in tumorigenesis. eLife 105 23682311
2012 Nectin 4 is the epithelial cell receptor for measles virus. Trends in microbiology 100 22721863
2010 Mutations in PVRL4, encoding cell adhesion molecule nectin-4, cause ectodermal dysplasia-syndactyly syndrome. American journal of human genetics 97 20691405
2017 Nectin-4 is a breast cancer stem cell marker that induces WNT/β-catenin signaling via Pi3k/Akt axis. The international journal of biochemistry & cell biology 83 28600142
2023 First-in-Human Study of the Radioligand 68Ga-N188 Targeting Nectin-4 for PET/CT Imaging of Advanced Urothelial Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 82 37093191
2020 Expression of Nectin-4 and PD-L1 in Upper Tract Urothelial Carcinoma. International journal of molecular sciences 77 32751328
2021 Nectin cell adhesion molecule-4 (NECTIN-4): A potential target for cancer therapy. European journal of pharmacology 75 34547246
2022 The Anti-Nectin 4: A Promising Tumor Cells Target. A Systematic Review. Molecular cancer therapeutics 63 35131876
2021 Role of Nectin‑4 protein in cancer (Review). International journal of oncology 60 34664682
2022 Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer. Journal of nanobiotechnology 59 35614462
2022 BT8009; A Nectin-4 Targeting Bicycle Toxin Conjugate for Treatment of Solid Tumors. Molecular cancer therapeutics 59 36112771
2022 Overcoming Resistance to Anti-Nectin-4 Antibody-Drug Conjugate. Molecular cancer therapeutics 57 35534238
2018 Cell clustering mediated by the adhesion protein PVRL4 is necessary for α6β4 integrin-promoted ferroptosis resistance in matrix-detached cells. The Journal of biological chemistry 54 29934307
2017 Nectin-4 promotes gastric cancer progression via the PI3K/AKT signaling pathway. Human pathology 53 29208564
2018 The soluble nectin-4 ecto-domain promotes breast cancer induced angiogenesis via endothelial Integrin-β4. The international journal of biochemistry & cell biology 51 30056265
2014 The tumor-associated marker, PVRL4 (nectin-4), is the epithelial receptor for morbilliviruses. Viruses 51 24892636
2022 Development of Nectin4/FAP-targeted CAR-T cells secreting IL-7, CCL19, and IL-12 for malignant solid tumors. Frontiers in immunology 47 36479116
2023 Assessment of PD-L1, TROP2, and nectin-4 expression in penile squamous cell carcinoma. Human pathology 44 37977513
2019 Autophagy induction by the pathogen receptor NECTIN4 and sustained autophagy contribute to peste des petits ruminants virus infectivity. Autophagy 44 31318632
2021 Nectin-4 promotes lymphangiogenesis and lymphatic metastasis in breast cancer by regulating CXCR4-LYVE-1 axis. Vascular pharmacology 40 33945869
2024 Associations of TACSTD2/TROP2 and NECTIN-4/NECTIN-4 with molecular subtypes, PD-L1 expression, and FGFR3 mutational status in two advanced urothelial bladder cancer cohorts. Histopathology 39 38196202
2016 Expression and clinical significance of Nectin-4 in hepatocellular carcinoma. OncoTargets and therapy 37 26793002
2020 NECTIN4 Expression in Extramammary Paget's Disease: Implication of a New Therapeutic Target. International journal of molecular sciences 36 32824340
2023 Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E-based Antibody-Drug Conjugate for Treatment of Nectin-4-expressing Cancers. Molecular cancer therapeutics 35 37196158
2019 Nectin-4 cis-interacts with ErbB2 and its trastuzumab-resistant splice variants, enhancing their activation and DNA synthesis. Scientific reports 35 31831814
2015 SLAM- and nectin-4-independent noncytolytic spread of canine distemper virus in astrocytes. Journal of virology 35 25787275
2024 Therapeutic prospects of nectin-4 in cancer: applications and value. Frontiers in oncology 34 38606099
2019 NECTIN4 promotes papillary thyroid cancer cell proliferation, migration, and invasion and triggers EMT by activating AKT. Cancer management and research 34 31114323
2017 Expression of canine distemper virus receptor nectin-4 in the central nervous system of dogs. Scientific reports 34 28336928
2022 Nectin-4: a Novel Therapeutic Target for Skin Cancers. Current treatment options in oncology 33 35312963
2023 An Analysis of Nectin-4 (PVRL4) in Penile Squamous Cell Carcinoma. European urology open science 32 36660545
2021 Nectin Cell Adhesion Molecule 4 (NECTIN4) Expression in Cutaneous Squamous Cell Carcinoma: A New Therapeutic Target? Biomedicines 32 33808400
2019 NECTIN4 (PVRL4) as Putative Therapeutic Target for a Specific Subtype of High Grade Serous Ovarian Cancer-An Integrative Multi-Omics Approach. Cancers 32 31137558
2021 NECTIN4: A Novel Therapeutic Target for Melanoma. International journal of molecular sciences 31 33478111
2015 p63-dependent and independent mechanisms of nectin-1 and nectin-4 regulation in the epidermis. Experimental dermatology 31 25387952
2017 Measles Virus Enters Breast and Colon Cancer Cell Lines through a PVRL4-Mediated Macropinocytosis Pathway. Journal of virology 30 28250131
2023 Metastatic Bladder Cancer Expression and Subcellular Localization of Nectin-4 and Trop-2 in Variant Histology: A Rapid Autopsy Study. Clinical genitourinary cancer 29 37344281
2024 Translational PET Imaging of Nectin-4 Expression in Multiple Different Cancers with 68Ga-N188. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 28 38719240
2024 Nectin-4-directed antibody-drug conjugates (ADCs): Spotlight on preclinical and clinical evidence. Life sciences 28 39002610
2020 Estrogen-related receptor-α promotes gallbladder cancer development by enhancing the transcription of Nectin-4. Cancer science 28 32030850
2022 Nectin-4 is widely expressed in head and neck squamous cell carcinoma. Oncotarget 27 36268557
2014 The V domain of dog PVRL4 (nectin-4) mediates canine distemper virus entry and virus cell-to-cell spread. Virology 27 24725937
2020 Nanoformulated quinacrine regulates NECTIN-4 domain specific functions in cervical cancer stem cells. European journal of pharmacology 26 32603697
2014 Use of SLAM and PVRL4 and identification of pro-HB-EGF as cell entry receptors for wild type phocine distemper virus. PloS one 26 25171206
2023 Trop-2 and Nectin-4 immunohistochemical expression in metastatic colorectal cancer: searching for the right population for drugs' development. British journal of cancer 25 36759721
2011 Mutation in PVRL4 gene encoding nectin-4 underlies ectodermal-dysplasia-syndactyly syndrome (EDSS1). Journal of human genetics 25 21346770
2020 Inhibition of Ovarian Cancer Cell Spheroid Formation by Synthetic Peptides Derived from Nectin-4. International journal of molecular sciences 24 32629816
2025 Spatial Expression of HER2, NECTIN4, and TROP-2 in Muscle-Invasive Bladder Cancer and Metastases: Implications for Pathological and Clinical Management. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 21 40086591
2019 Serum nectin-2 and nectin-4 are diagnostic in lung cancer: which is superior? Wiener klinische Wochenschrift 21 31440821
2024 A humanized trivalent Nectin-4-targeting nanobody drug conjugate displays potent antitumor activity in gastric cancer. Journal of nanobiotechnology 20 38755613
2024 Near-infrared photoimmunotherapy targeting Nectin-4 in a preclinical model of bladder cancer. Cancer letters 19 38272345
2022 Nectin-4 promotes osteosarcoma progression and metastasis through activating PI3K/AKT/NF-κB signaling by down-regulation of miR-520c-3p. Cancer cell international 19 35953862
2025 Pilot Study of Nectin-4-Targeted PET Imaging Agent 68Ga-FZ-NR-1 in Triple-Negative Breast Cancer from Bench to First-in-Human. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 18 39947908
2025 Bulumtatug Fuvedotin (BFv, 9MW2821), a next-generation Nectin-4 targeting antibody-drug conjugate, in patients with advanced solid tumors: a first-in-human, open-label, multicenter, phase I/II study. Annals of oncology : official journal of the European Society for Medical Oncology 18 40288679
2023 Molecular and structural basis of TIGIT: Nectin-4 interaction, a recently discovered pathway crucial for cancer immunotherapy. Biochemical and biophysical research communications 18 37542773
2023 An iodine‑labelled Antibody-drug conjugate PET probe for noninvasive monitoring of Nectin-4 expression in urothelial carcinoma. International journal of pharmaceutics 18 38160990
2023 Scratching the Surface: NECTIN-4 as a Surrogate for Enfortumab Vedotin Resistance. Clinical cancer research : an official journal of the American Association for Cancer Research 17 36749325
2022 Nectin-4 and DNA mismatch repair proteins expression in upper urinary tract urothelial carcinoma (UTUC) as a model for tumor targeting approaches: an ImGO pilot study. BMC cancer 17 35164713
2018 Potential role for nectin-4 in the pathogenesis of pre-eclampsia: a molecular genetic study. BMC medical genetics 17 30217189
2024 Biomarkers of Response to Anti-NECTIN4 Antibody-Drug Conjugate Enfortumab Vedotin in Urothelial Cancer. European urology focus 16 38631991
2023 Immunohistochemical Analysis of HER2, EGFR, and Nectin-4 Expression in Upper Urinary Tract Urothelial Carcinoma. Anticancer research 16 36585180
2025 Nectin-4 expression patterns and therapeutics in oncology. Cancer letters 15 40209851
2014 A novel homozygous nonsense mutation in the PVRL4 gene and expansion of clinical spectrum of EDSS1. Annals of human genetics 15 25529316
2022 TROP-2, Nectin-4, GPNMB, and B7-H3 Are Potentially Therapeutic Targets for Anaplastic Thyroid Carcinoma. Cancers 14 35158847
2022 Heterogenous NECTIN4 expression in urothelial high-risk non-muscle-invasive bladder cancer. Virchows Archiv : an international journal of pathology 14 35484425
2022 Discovery and Optimization of a Synthetic Class of Nectin-4-Targeted CD137 Agonists for Immuno-oncology. Journal of medicinal chemistry 14 35819182
2024 TROP-2, NECTIN-4 and predictive biomarkers in sarcomatoid and rhabdoid bladder urothelial carcinoma. Pathologica 13 38482675
2024 Nectin-4 Positivity in Genitourinary Malignancies: A Systematic Review. JCO precision oncology 13 39626158
2022 Nectin-4 as Blood-Based Biomarker Enables Detection of Early Ovarian Cancer Stages. Cancers 13 36497350
2019 Nectin-4 and p63 immunohistochemical expression in canine prostate tumourigenesis. Veterinary and comparative oncology 13 30767361
2024 Development and validation of bioanalytical assays for the quantification of 9MW2821, a nectin-4-targeting antibody-drug conjugate. Journal of pharmaceutical and biomedical analysis 12 38908237
2024 Targeted therapeutic strategies for Nectin-4 in breast cancer: Recent advances and future prospects. Breast (Edinburgh, Scotland) 12 39577073
2023 Nectin-4 has emerged as a compelling target for breast cancer. European journal of pharmacology 12 38059449
2021 Expressions of PD-L1 and Nectin-4 in urothelial cancer patients treated with pembrolizumab. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 12 34687441
2023 Nectin-4: a Tumor Cell Target and Status of Inhibitor Development. Current oncology reports 11 36696077
2023 Nectin-4 is frequently expressed in primary salivary gland cancer and corresponding lymph node metastases and represents an important treatment-related biomarker. Clinical & experimental metastasis 11 37480387
2023 Nectin-4 regulates cellular senescence-associated enlargement of cell size. Scientific reports 11 38062106
2025 Evaluation of Nectin-4 and Trop-2: Implications for Patient Outcomes and Therapy in Penile Cancer. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 10 40252843
2022 Nectin4 antagonises type I interferon production by targeting TRAF3 for autophagic degradation and disrupting TRAF3-TBK1 complex formation. International journal of biological macromolecules 10 35878672
2025 Spatial distribution and subtype-specific expression patterns of Nectin-4 in muscle-invasive bladder cancer. BJU international 9 39801278
2025 A novel and promising therapeutic approach for treating pancreatic cancer: Nectin‑4‑targeted antibody‑drug conjugates alone or combined with autophagy inhibitors. International journal of molecular medicine 9 40017149
2025 Nectin-4-Targeting Radiotracers: Novel Theranostic Agents for Precision Oncology in Cancer. Molecular diagnosis & therapy 9 40474033
2020 Genetic variants in NECTIN4 encoding an adhesion molecule are associated with continued opioid use. PloS one 9 32555608
2013 Ablation of nectin4 binding compromises CD46 usage by a hybrid vesicular stomatitis virus/measles virus. Journal of virology 9 24335299
2022 NECTIN4 expression in sebaceous and sweat gland carcinoma. European journal of dermatology : EJD 8 35866909

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