{"gene":"PVR","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2003,"finding":"PVR (CD155) was identified as a cell surface ligand for the activating NK cell receptor DNAM-1 (CD226). Protein purification, tryptic digestion, and mass spectrometry identified PVR as a ~70 kDa DNAM-1 ligand; PVR-Fc soluble hybrid molecules directly stained DNAM-1-transfected COS-7 cells, and PVR expression on target cell transfectants enhanced DNAM-1-dependent NK-mediated lysis.","method":"Protein purification, mass spectrometry, soluble Fc-fusion binding assay, cell transfection, NK cytotoxicity assay with blocking antibodies","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (biochemical purification, MS, direct binding assay, functional cytotoxicity), independently replicated by a second paper (PMID:15607800)","pmids":["12913096","15607800"],"is_preprint":false},{"year":2004,"finding":"DNAM-1 (CD226) binds both CD155 (PVR) and CD112 (nectin-2) with comparable affinities. Ectopic expression of CD155 or CD112 on mouse BW5147 T cells rendered them susceptible to IL-2-activated T and NK cell-mediated cytotoxicity in a CD226-dependent manner; ligation of CD226 and LFA-1 cooperated in triggering cytotoxicity and cytokine secretion.","method":"Soluble receptor binding affinity measurements, cell transfection, cytotoxicity assay with anti-CD226 blocking antibody","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding affinity measurements combined with functional cell transfection and blocking experiments, consistent with independent replication","pmids":["15039383"],"is_preprint":false},{"year":2004,"finding":"PVR is expressed at cell-cell junctions of primary vascular endothelial cells and is the major DNAM-1 ligand at these junctions. The DNAM-1–PVR interaction is required for the diapedesis step of monocyte transendothelial migration: anti-PVR and anti-DNAM-1 antibodies arrested monocytes at the apical surface over intercellular junctions and blocked transmigration in vitro.","method":"Soluble DNAM-1-Fc binding assay on endothelial cells, blocking monoclonal antibodies, in vitro transendothelial migration assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal functional blocking with two independent antibodies (anti-PVR and anti-DNAM-1) plus localization by Fc-fusion binding, single lab","pmids":["15136589"],"is_preprint":false},{"year":2004,"finding":"CD155 mediates tumor cell invasion and migration. FALI-mediated inactivation of CD155 or RNAi knockdown significantly decreased transwell migration of HT1080 fibrosarcoma and U87MG GBM cells. CD155 was recruited to the leading edge of migrating cells where it co-localized with actin and αv-integrin; knockdown altered cell morphology on Matrigel.","method":"FALI (Fluorophore Assisted Light Inactivation), RNAi knockdown, transwell invasion/migration assay, immunofluorescence co-localization","journal":"BMC cancer","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two independent loss-of-function methods (FALI and RNAi) with consistent phenotype, functional plus localization data in multiple cell lines","pmids":["15471548"],"is_preprint":false},{"year":2003,"finding":"Tage4/Necl-5 (mouse ortholog of CD155) heterophilically trans-interacts with nectin-3 but not homophilically with itself. This trans-interaction enhanced motility of V12Ras-NIH3T3 cells. Tage4 does not bind afadin, distinguishing it from canonical nectins.","method":"Cell-based ligand binding assay, cell motility assay, afadin binding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding and functional motility assays in transformed fibroblasts, multiple orthogonal methods in one study","pmids":["12740392"],"is_preprint":false},{"year":2004,"finding":"Necl-5/CD155 enhances serum- and PDGF-induced cell proliferation via the Ras-Raf-MEK-ERK signaling pathway, upregulating cyclins D2 and E, downregulating p27Kip1, and shortening the G0/G1 phase. Necl-5 acts downstream of PDGF receptor and upstream of Ras. Dominant-negative Necl-5 or blocking antibody suppressed these effects.","method":"Dominant-negative mutant expression, blocking antibody, cell cycle analysis, western blotting for signaling intermediates and cell cycle regulators","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (dominant-negative, antibody blockade, biochemical pathway analysis) in multiple cell types, single lab","pmids":["15213219"],"is_preprint":false},{"year":2004,"finding":"Necl-5/CD155 enhances serum- and PDGF-induced directional cell migration in a nectin-3-independent but integrin αVβ3-dependent manner. The extracellular region is required for directional migration; the cytoplasmic region is required for both directional and random motility. Necl-5 co-localizes with integrin αVβ3 at leading edges. Cdc42 and Rac are activated downstream of Necl-5 and are required for Necl-5-enhanced motility.","method":"Domain deletion mutant expression in L fibroblasts and NIH3T3 cells, integrin inhibitor/activator treatments, dominant-negative Necl-5, immunofluorescence co-localization, Rho GTPase activation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — structure-function analysis with multiple deletion mutants plus pharmacological intervention and GTPase activation assays, single lab","pmids":["14871893"],"is_preprint":false},{"year":2005,"finding":"Cell-cell contact-induced interaction of Necl-5 with nectin-3 triggers clathrin-dependent endocytosis and down-regulation of Necl-5 from the cell surface, which subsequently reduces cell movement and proliferation, constituting a mechanism underlying contact inhibition.","method":"Immunofluorescence, clathrin inhibition, co-culture cell contact experiments, cell motility and proliferation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection of endocytic pathway (clathrin dependence) plus functional consequences (motility/proliferation), single lab with multiple orthogonal methods","pmids":["16216929"],"is_preprint":false},{"year":2005,"finding":"CD155/PVR expression in rat glioma cells enhances their dispersal in vitro and on primary brain tissue, reduces substrate adhesion, focal adhesion density, and actin stress fibers in a substrate-dependent manner. CD155/PVR increases Src/FAK signaling and enhances paxillin and p130Cas activation on vitronectin substrate. Depletion of endogenous CD155/PVR inhibits glioma cell migration and downregulates the same signaling pathway.","method":"Stable transfection/overexpression, RNAi knockdown, adhesion assays, immunofluorescence (focal adhesion counting), western blotting (Src, FAK, paxillin, p130Cas phosphorylation)","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — gain-of-function and loss-of-function experiments with signaling readouts and multiple orthogonal methods, single lab","pmids":["16322240"],"is_preprint":false},{"year":2003,"finding":"Nectin-3 binds CD155 and its mouse ortholog Tage4 in trans (heterophilic interaction). Coculture of nectin-3- and CD155-expressing cells led to CD155-dependent recruitment of nectin-3 to cell-cell contacts. CD155 co-distributes with αv integrin microdomains on the cell surface. CD155 dimerization facilitates the interaction. CD155 ectodomain binds vitronectin.","method":"Cell-based ligand binding assay, co-culture heterotypic contact experiments, immunofluorescence co-localization, coimmunoprecipitation (implied by dimerization analysis)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based binding and localization with functional context, but abstract does not report formal Co-IP, single lab","pmids":["12759359"],"is_preprint":false},{"year":2002,"finding":"CD155 gene expression is transcriptionally activated by Sonic Hedgehog (Shh) signaling. Shh upregulated CD155 mRNA in human Ntera2 cells. Reporter gene driven by the CD155 core promoter was activated by Shh in co-transfection assays. An intact GLI binding site in the CD155 promoter is required for Shh activation. Overexpression of Gli1 or Gli3 potently activated CD155 promoter reporter expression.","method":"qRT-PCR, reporter gene (luciferase) assay, promoter mutagenesis (GLI binding site), Gli overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — promoter mutagenesis combined with reporter assay and transcription factor overexpression, multiple orthogonal methods in one study","pmids":["11983699"],"is_preprint":false},{"year":2005,"finding":"Transcription of mouse Necl-5/CD155 is induced by FGF or oncogenic Ras through the Raf-MEK-ERK-AP-1 pathway. The Necl-5 promoter contains an AP-1 binding site required for V12Ki-Ras-induced activation. Inhibitors of the Raf-MEK-ERK pathway abrogated induction.","method":"Luciferase reporter gene assay, promoter mutagenesis (AP-1 site), pharmacological pathway inhibitors, oncogene (V12Ki-Ras) overexpression","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — promoter mutagenesis combined with pharmacological inhibitors and reporter assay, single lab with multiple orthogonal approaches","pmids":["15688018"],"is_preprint":false},{"year":2003,"finding":"Soluble CD155 (sCD155) isoforms exist in conditioned culture medium, human serum, and cerebrospinal fluid. sCD155 release does not require protease activity (indicating it is generated by alternative splicing rather than shedding). Serum-purified sCD155 reduces poliovirus entry mediated by membrane-bound CD155.","method":"ELISA, conditioned medium analysis with/without protease inhibitors, RT-PCR for splice variants, functional poliovirus entry inhibition assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional competition assay plus biochemical characterization, single lab","pmids":["12943679"],"is_preprint":false},{"year":2007,"finding":"Necl-5/CD155 directly interacts in cis with integrin αVβ3, enhancing integrin αVβ3 clustering and focal complex formation at leading edges of moving cells. The extracellular region of Necl-5 (but not the cytoplasmic region) is necessary for the cis interaction with integrin αVβ3; both regions are necessary for the functional effect. Necl-5 enhances PDGF-induced Rac activation, facilitating integrin αVβ3 clustering in a feedback amplification manner.","method":"Co-immunoprecipitation of endogenous proteins, domain deletion mutants, integrin-vitronectin interaction assay, Rac activation assay (pull-down), immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct Co-IP of cis interaction, structure-function with deletion mutants, GTPase activation assay, single lab with multiple orthogonal methods","pmids":["17446174"],"is_preprint":false},{"year":2008,"finding":"Necl-5/CD155 interacts with PDGF receptor β at the leading edges of moving NIH3T3 cells and regulates the interaction between PDGF receptor and integrin αVβ3, effectively inducing directional cell movement. PDGF receptor co-localizes with Necl-5 and integrin αVβ3 at peripheral ruffles over lamellipodia. Clustering of these three molecules requires integrin αVβ3 activation by vitronectin and PDGF-induced Rac activation.","method":"Co-immunoprecipitation, immunofluorescence co-localization, Rac activation assay, dominant-negative constructs","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional localization, single lab","pmids":["18298801"],"is_preprint":false},{"year":2007,"finding":"Necl-5/CD155 interacts with Sprouty2 (a negative regulator of growth factor signaling) and reduces the inhibitory effect of Sprouty2 on PDGF-induced Ras signaling. Upon Necl-5 down-regulation by nectin-3 trans-interaction at cell-cell contacts, Sprouty2 becomes tyrosine-phosphorylated by c-Src (activated by PDGF receptor), inhibiting PDGF-induced Ras signaling. This mechanism contributes to contact inhibition of proliferation.","method":"Co-immunoprecipitation, western blotting (phosphorylation), dominant-negative and constitutively active constructs, pharmacological inhibitors","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus phosphorylation analysis and pharmacological intervention, single lab","pmids":["17352739"],"is_preprint":false},{"year":2005,"finding":"The trans-interaction of Necl-5 with nectin-3 bidirectionally activates Cdc42 and Rac GTPases via a common signaling pathway involving c-Src, Rap1 (through C3G), FRG (Cdc42-GEF), and Vav2 (Rac-GEF). This is the same cascade activated by nectin-nectin trans-interaction, and it contributes to adherens junction formation.","method":"GTPase activation assays (pull-down), co-immunoprecipitation, pharmacological and dominant-negative pathway perturbations","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway dissection with pull-down GTPase assays and multiple inhibitors, single lab","pmids":["16128743"],"is_preprint":false},{"year":2004,"finding":"Necl-5 heterophilic trans-interaction with nectin-3 drives recruitment of afadin, E-cadherin, and catenins to the nectin-3 (but not Necl-5) side of cell-cell contact sites. Blocking the Necl-5/nectin-3 interaction with a specific monoclonal antibody inhibited formation of E-cadherin-based adherens junctions.","method":"Stable cell transfection (L cells expressing Necl-5, nectin-3, E-cadherin), immunofluorescence, function-blocking monoclonal antibody","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional blocking assay plus co-localization, single lab","pmids":["15330856"],"is_preprint":false},{"year":2007,"finding":"Necl-5/CD155 on cancer cells interacts in trans with CD226 on platelets, and this interaction promotes cancer cell adhesion to platelets in pulmonary vessels, enhancing lung metastasis. Overexpression of Necl-5 enhanced metastasis; anti-Necl-5 antibody blocking the Necl-5/CD226 interaction reduced metastasis. Platelet depletion abrogated the Necl-5-enhanced metastasis.","method":"Stable overexpression, in vivo tail-vein injection metastasis model, function-blocking monoclonal antibody, platelet depletion with anti-platelet serum","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo gain-of-function and loss-of-function (antibody block + platelet depletion) with clear mechanistic attribution, single lab with multiple orthogonal approaches","pmids":["17637752"],"is_preprint":false},{"year":2012,"finding":"Necl-5/CD155 interacts with VEGFR2 (co-immunoprecipitation) and is required for VEGF-induced interaction of integrin αVβ3 with VEGFR2. Knockdown of Necl-5 in HUVECs inhibited VEGF-induced capillary network formation, migration, and proliferation, and suppressed VEGFR2-mediated activation of Rap1, Akt, and eNOS. Necl-5 knockout mice showed impaired post-ischemia blood flow recovery and VEGF-induced neovascularization.","method":"Co-immunoprecipitation, siRNA knockdown, in vitro angiogenesis assays (Matrigel, migration, proliferation, apoptosis), western blotting (Rap1, Akt, eNOS), Necl-5 knockout mouse model (hindlimb ischemia, Matrigel plug)","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct Co-IP, siRNA in vitro, and in vivo knockout model, multiple orthogonal methods, single lab","pmids":["22282193"],"is_preprint":false},{"year":2013,"finding":"Endothelial PVR (CD155) interacts with monocyte DNAM-1 and regulates a step in transendothelial migration between PECAM and CD99. Activation of endothelial PVR (by antibody ligation or DNAM-1) recruits the tyrosine phosphatase Shp-2 in a Src kinase-dependent manner. PVR resides in the lateral border recycling compartment of endothelial cells, similar to PECAM and CD99.","method":"Sequential antibody blocking of TEM steps, Shp-2 recruitment assay, Src kinase inhibition, immunofluorescence localization to lateral border recycling compartment","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection of TEM step order plus Shp-2 recruitment and compartment localization, single lab","pmids":["23333754"],"is_preprint":false},{"year":2013,"finding":"TLR signaling upregulates CD155 expression on antigen-presenting cells via MYD88, TRIF, and NF-κB (for most TLRs), and additionally requires IRF3 (but not IRF7) for TLR3-induced CD155 upregulation. CD155-deficient mice immunized with OVA/CpG showed increased OVA-specific IgG2a/c titers and lower IL-4 production and fewer GATA-3+IL-4+ CD4+ T cells, demonstrating that CD155 regulates Th2 differentiation.","method":"Genetic knockout mice (MYD88, TRIF, NF-κB, IRF3, IRF7, CD155), flow cytometry, ELISA","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple knockouts plus immunological readouts, single lab","pmids":["23349877"],"is_preprint":false},{"year":2015,"finding":"CD155 knockdown in pancreatic cancer cells inhibited proliferation and induced cell-cycle arrest at G2/M phase, indicating a cell-intrinsic role for CD155 in tumor cell proliferation independent of immune mechanisms.","method":"siRNA/shRNA knockdown, cell proliferation assay, flow cytometry (cell cycle analysis)","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — knockdown with two functional readouts, single lab but consistent with findings in other cancer types","pmids":["25862891"],"is_preprint":false},{"year":2015,"finding":"Nitric oxide (NO) donors upregulate PVR/CD155 surface and mRNA expression in multiple myeloma cells via activation of the DNA damage response (DDR) pathway involving ATM/ATR/Chk1/2 kinases, but independent of soluble guanylyl cyclase/cGMP. Specific inhibitors of ATM/ATR/Chk1/2 significantly abrogated the NO-induced CD155 upregulation.","method":"Flow cytometry, RT-PCR, pharmacological pathway inhibitors (ATM/ATR/Chk1/2 inhibitors, soluble guanylyl cyclase inhibitor), western blotting (DDR activation markers)","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway dissection with specific kinase inhibitors plus gene expression readout, single lab","pmids":["25609078"],"is_preprint":false},{"year":2016,"finding":"Human CMV immediate early proteins IE1 and IE2 directly upregulate PVR/CD155 expression during HCMV infection via a mechanism independent of IE DNA binding activity (both IE1 and IE2 are required). IE2 directly activates the MICA promoter via a characterized IE2-responsive element. DNA damage response kinases (ATM, ATR, DNA-PK) are not involved in HCMV-induced CD155 upregulation.","method":"Overexpression of IE1/IE2, phosphonoformic acid inhibition of viral DNA replication, siRNA knockdown of ATM/ATR/DNA-PK, promoter analysis (IE2-responsive element characterization), flow cytometry and qRT-PCR","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological dissection with multiple inhibitors, single lab","pmids":["27733551"],"is_preprint":false},{"year":2014,"finding":"Activated unfolded protein response (UPR) decreases CD155 expression in hepatocellular carcinoma cells by two mechanisms: (1) ATF6 and IRE1α pathways suppress CD155 transcription/expression; (2) the IRE1α pathway upregulates the ERAD E3 ligase HRD1, which facilitates CD155 protein degradation. This UPR-induced CD155 downregulation reduces HCC sensitivity to NK cell cytotoxicity.","method":"Pharmacological UPR induction, pathway-specific siRNA knockdown (ATF6, IRE1α, HRD1), western blotting, flow cytometry, NK cell cytotoxicity assay","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mechanistic dissection via multiple pathway-specific knockdowns plus functional NK cytotoxicity readout, single lab with multiple orthogonal approaches","pmids":["25209846"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of CD96 first Ig domain (D1) bound to the CD155 (Necl-5) ectodomain was determined. CD96 recognizes CD155 D1 via a conserved 'lock-and-key' interaction shared across TIGIT:Necl complexes, but CD96 additionally uses a novel structural motif ('ancillary key') that confers specific CD155 recognition and distinguishes it from binding to nectin-2. Mutagenesis confirmed the ancillary key residue is critical for CD155 binding.","method":"X-ray crystallography, mutagenesis, direct binding assay","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation by mutagenesis, single study","pmids":["30528596"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of the CD226 (DNAM-1) ectodomain bound to CD155 D1 revealed a unique side-by-side arrangement of two tandem IgV domains of CD226 (distinct from conventional head-to-tail). CD226 D1 mediates the conserved binding interface with CD155 D1, while CD226 D2 provides structural support and makes direct contacts with CD155. Deletion of D2 substantially reduced CD226 binding to CD155.","method":"X-ray crystallography (hybrid complex of mouse CD226 ectodomain + human CD155 D1), domain deletion binding assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with domain deletion functional validation, single rigorous study","pmids":["30591568"],"is_preprint":false},{"year":2020,"finding":"Tumor-derived CD155 initiates phosphorylation of CD226 at tyrosine 319 (Y319) by Src kinases upon CD155-CD226 engagement. This phosphorylation enables ubiquitination of CD226 by the E3 ligase CBL-B, leading to internalization and proteasomal degradation of CD226. Mutation of Y319 prevents this degradation, resulting in increased CD226 surface expression and enhanced anti-tumor immunity. This represents a mechanism by which CD155 on tumor cells drives resistance to immunotherapy.","method":"CD226 Y319 point mutagenesis, phosphorylation assay, ubiquitination assay, co-immunoprecipitation (CBL-B interaction), flow cytometry (CD226 surface expression), in vivo tumor models, analysis of patient TILs","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis, biochemical ubiquitination/phosphorylation assays, Co-IP for CBL-B, in vivo validation, and human patient data, multiple orthogonal methods","pmids":["33053330"],"is_preprint":false},{"year":2020,"finding":"Membrane-bound CD155 on tumor cells triggers CD226 internalization and degradation in NK cells, resulting in decreased NK cell-mediated tumor reactivity. IL-15 increases TIGIT and CD226 gene expression in tumor-infiltrating NK cells; combined IL-15 treatment with TIGIT blockade increases NK cell-mediated melanoma cytotoxicity in vitro and decreases tumor metastasis in two mouse melanoma models. CD226 blockade decreases the effects of IL-15 and TIGIT blockade.","method":"Flow cytometry (receptor internalization), in vitro cytotoxicity assay, two in vivo mouse melanoma models, genetic TIGIT deletion on transferred NK cells, IL-15 treatment","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — consistent mechanism across in vitro and two independent in vivo models, replicated directionally with PMID:33053330","pmids":["32591463"],"is_preprint":false},{"year":2020,"finding":"PVRL1 (nectin-1) in hepatocellular carcinoma cells stabilizes cell-surface PVR/CD155 protein without affecting PVR mRNA levels. CD155 on HCC cells interacts with TIGIT on CD8+ effector memory T cells, suppressing anti-tumor immune response. Knockdown of Pvrl1 reduced cell-surface PVR levels and sensitized tumors to CD8+ T cell-mediated killing. Combined anti-PD1 and anti-TIGIT therapy significantly reduced tumor growth in mouse models.","method":"shRNA knockdown of Pvrl1, flow cytometry (surface PVR protein vs mRNA), co-culture cytotoxicity assays, CRISPR-Cas9 tumor models, in vivo antibody treatment (anti-TIGIT, anti-PD1, anti-CD8), mass cytometry (CyTOF)","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with biochemical and functional validation in vitro and in vivo, multiple orthogonal methods, single lab","pmids":["32275969"],"is_preprint":false},{"year":2018,"finding":"CD155 loss in both host (Cd155-/- mice) and tumor cells reduces tumor growth and metastasis. Mechanistically, CD155 absence in the host leads to DNAM-1 (CD226) upregulation and enhanced effector function of CD8+ T and NK cells. CD155 deletion in tumor cells also reduces tumor growth (tumor-intrinsic role). Combined CD155 absence on host and tumor cells gives additive inhibition. PD-1 blockade is more effective in CD155-limiting settings.","method":"Cd155 germline knockout mice, CD155-deleted tumor cell lines, in vivo tumor growth and metastasis assays, flow cytometry (DNAM-1 expression, T/NK cell function), anti-PD-1 treatment","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic knockout in both host and tumor compartments with multiple in vivo readouts and pathway validation, single lab","pmids":["29757192"],"is_preprint":false},{"year":2015,"finding":"CD155/PVR mediates a costimulatory signal in CD4+ T cells promoting Th1 differentiation via NF-κB-induced autocrine IFN-γ that triggers positive feedback through STAT1 activation, independent of IL-12. Cd155-/- mice or anti-CD155 antibody-treated mice showed attenuated Th1-type contact hypersensitivity.","method":"CD155 signaling in primary T cells, cytokine measurement (IFN-γ), NF-κB inhibition, STAT1 activation analysis, IL-12 neutralization, Cd155 germline knockout mice, contact hypersensitivity model","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout plus pharmacological pathway dissection and functional in vivo model, single lab","pmids":["25972481"],"is_preprint":false},{"year":2022,"finding":"KIR2DL5 on human NK cells binds PVR without competing with TIGIT, CD96, or DNAM-1. KIR2DL5-PVR engagement induces inhibitory immune synapse formation. Both intracellular ITIM and ITSM of KIR2DL5 undergo tyrosine phosphorylation, recruiting SHP-1 and/or SHP-2, which then downregulate Vav1/ERK1/2/p90RSK/NF-κB signaling to suppress NK cytotoxicity.","method":"Binding competition assays, inhibitory synapse imaging, phosphorylation assays, Co-IP (SHP-1/SHP-2 recruitment), ITIM/ITSM mutagenesis, western blotting (Vav1, ERK, NF-κB), NK cell cytotoxicity assays, humanized tumor mouse models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis of ITIM/ITSM, Co-IP of phosphatase recruitment, signaling pathway analysis, and in vivo validation, single study with multiple orthogonal methods","pmids":["36377656"],"is_preprint":false},{"year":2022,"finding":"TIGIT, upon binding to CD155 and being phosphorylated, inhibits NF-κB and ERK activation in CD8+ T cells by recruiting SHIP-1, resulting in downregulation of cytokine production. Blocking TIGIT attenuates the inhibitory effect of SHIP-1 and restores NF-κB and ERK activation.","method":"Western blotting (NF-κB, ERK phosphorylation, SHIP-1 interaction), co-culture with CD155+ tumor cells, TIGIT blockade, in vivo tumor model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — signaling pathway analysis with SHIP-1 co-IP and NF-κB/ERK readouts, single lab","pmids":["35729552"],"is_preprint":false},{"year":2010,"finding":"Knockdown of Necl-5/CD155 in A172 GBM cells decreases invasion in a 3D matrix, reduces MMP-2 expression and activity, and diminishes basal Akt activation and ILK-dependent Akt activation in response to vitronectin. Necl-5, Akt, and ILK co-localize at focal contacts at the leading edge, suggesting integration of Akt signaling at the leading edge to induce MMP-2 expression.","method":"RNAi knockdown, 3D invasion assay, MMP-2 zymography, western blotting (Akt, ILK phosphorylation), immunofluorescence co-localization","journal":"Journal of neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with downstream signaling analysis and co-localization, single lab","pmids":["20680398"],"is_preprint":false},{"year":2010,"finding":"Necl-5/CD155 enhances PDGF-induced growth of microtubules toward the plasma membrane at the leading edge of moving NIH3T3 cells in an integrin αVβ3-dependent manner. Necl-5 promotes PDGF-induced attraction of plus-end-tracking proteins (EB1, CLIP170, dynein intermediate chain, p150Glued/dynactin) near the plasma membrane at the leading edge.","method":"Live-cell imaging of GFP-tagged microtubule plus-end proteins, siRNA knockdown of Necl-5, integrin αVβ3 inhibition","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging combined with knockdown and pharmacological inhibition, single lab","pmids":["20964795"],"is_preprint":false},{"year":2017,"finding":"CD155 knockdown in colon cancer cells inhibited migration and invasion with reduced FAK, Src, and MMP-2 expression; suppressed proliferation; and increased Bax/Bcl-2 ratio resulting in increased apoptosis.","method":"shRNA lentiviral knockdown, migration/invasion assay, western blotting (FAK, Src, MMP-2, Bax, Bcl-2, cell cycle regulators), flow cytometry (apoptosis)","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — consistent with multiple prior studies, multiple readouts but single lab and single method approach per pathway","pmids":["28816021"],"is_preprint":false},{"year":2021,"finding":"Aryl hydrocarbon receptor (AhR) transcriptionally regulates CD155 expression on tumor-associated macrophages in a co-regulated manner with PD-L1. AhR inhibition in vivo reduced CD155 expression and reversed tumor immunosuppression in a murine tumor model.","method":"AhR inhibitor treatment in vitro and in vivo, gene expression analysis, correlation with AhR activity markers in human glioblastoma data","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition in vitro and in vivo with expression readout, single lab; mechanism (direct transcriptional regulation) is somewhat inferred from abstract","pmids":["33504618"],"is_preprint":false},{"year":2023,"finding":"T cell-derived IL-22 induces high CD155 expression on cancer cells via IL-22 receptor signaling on tumor cells. Excessive CD226 activation by IL-22-induced CD155 leads to decreased CD226 surface levels and functionally impaired NK cells, elevating metastatic burden. Constitutional and T cell-specific deletion of Il22, or deletion of the IL-22 receptor on cancer cells, each reduced metastases to a similar degree.","method":"Conditional knockout mice (constitutional Il22 KO, T cell-specific Il22 KO, cancer cell IL-22 receptor KO), in vivo lung and breast cancer metastasis models, flow cytometry (NK cell CD226 expression and function)","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple conditional knockouts in independent compartments yielding consistent phenotype, rigorous in vivo data","pmids":["36630913"],"is_preprint":false},{"year":2024,"finding":"Platelet contact with cancer cells transcriptionally upregulates CD155 via the FAK/JNK/c-Jun cascade. CD155 on circulating tumor cells inhibits NK cell cytotoxicity exclusively through TIGIT engagement, not through CD96 or DNAM-1. Antibody blockade of CD155-TIGIT interaction restored NK immunosurveillance and attenuated tumor metastasis.","method":"Single-cell RNA sequencing, multiplex immunofluorescence, in vitro/ex vivo co-culture cytotoxicity assays, in vivo metastasis models, competition assay (TIGIT vs CD96 vs DNAM-1 blocking), western blotting (FAK/JNK/c-Jun pathway)","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — pathway dissection (FAK/JNK/c-Jun) plus receptor-specific competition assays identifying TIGIT as exclusive partner, in vivo validation, single lab with multiple orthogonal methods","pmids":["38779918"],"is_preprint":false},{"year":2023,"finding":"Brain metastasis cancer-associated fibroblasts (bmCAFs) secrete fucosylated PVR/CD155 that enhances invasive capacity of breast cancer cells. Mechanistically, HIF1α transcriptionally upregulates fucosyltransferase 11, which fucosylates PVR, triggering its secretion. Secreted fucosylated PVR modulates cell-cell junction and actin cytoskeletal signaling in breast cancer cells.","method":"Patient-derived bmCAF conditioned medium experiments, HIF1α overexpression, fucosyltransferase 11 knockdown, global phosphoproteomics, functional invasion assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway with HIF1α-FUT11-PVR fucosylation-secretion axis validated by knockdown and phosphoproteomics, single lab","pmids":["37995180"],"is_preprint":false},{"year":2024,"finding":"METTL1 mediates m7G methylation of PKM mRNA, enhancing PKM2 expression, which increases glycolysis and promotes H3K9 lactylation (H3K9la). Nuclear PKM2 dimer activates CD155 (PVR) transcription via H3K9la, promoting immune evasion in colorectal cancer. This creates a positive feedback loop (H3K9la activates METTL1 transcription). Knockdown of METTL1 reduced CD155 expression and enhanced CD8+ T cell-mediated tumor killing in vivo.","method":"m7G methylation assay, RNA stability analysis, RIP assay, ChIP (Cut&Run), western blotting, ECAR/lactate assays, in vivo knockout mouse model with CD155 blockade","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-step pathway with chromatin and RIP assays, in vivo validation; complex mechanism identified in single lab study","pmids":["39741310"],"is_preprint":false},{"year":2023,"finding":"In giant cell arteritis (GCA), macrophages retain CD155 in the endoplasmic reticulum and fail to traffic it to the cell surface. This defective surface translocation of CD155 creates antigen-presenting cells that expand CD4+CD96+ T cells, which differentiate toward the Th9 lineage and release IL-9 to drive vasculitis.","method":"Immunofluorescence (ER retention of CD155), flow cytometry, humanized mouse model of GCA with recombinant IL-9 and anti-IL-9 antibody, T cell differentiation assays","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ER retention demonstrated by immunofluorescence with functional consequence in humanized mouse model, single lab","pmids":["37075705"],"is_preprint":false},{"year":2024,"finding":"CD155/PVR and B7-H6 (but not nectin-2/CD112) are critical and non-redundant ligands for formation of robust immunological synapses between AML cells and Vδ1+ γδ T (DOT) cells. CRISPR-mediated ablation of PVR or B7-H6 disrupted DOT-cell targeting of AML cells; PVR expression in primary AML samples predicted their elimination by DOT cells.","method":"CRISPR-Cas9 ablation of PVR, B7-H6, and CD112 in AML cell lines, immunological synapse imaging, in vitro cytotoxicity assays, primary AML sample analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — CRISPR ablation of specific ligands with immunological synapse formation readout, validated in primary patient samples, single lab","pmids":["38437507"],"is_preprint":false},{"year":2008,"finding":"CD155 enhances proliferation of ras-mutated cells through the cytoplasmic region including the ITIM motif. CD155DeltaCP (lacking the cytoplasmic region including ITIM) has reduced ability to enhance serum responsiveness. siRNA knockdown of endogenous CD155 in DLD-1 cells (mutant K-ras) suppressed serum responsiveness.","method":"Cytoplasmic domain deletion mutant (CD155DeltaCP), siRNA knockdown, cell proliferation assay, cell cycle analysis","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion mutagenesis combined with knockdown and cell cycle readout, single lab","pmids":["17893876"],"is_preprint":false},{"year":2024,"finding":"PITPNC1 regulates CD155 expression on the surface of tumor cells through FASN. Gene knockdown experiments showed that PITPNC1 upregulates FASN, which in turn increases CD155 surface expression. Co-immunoprecipitation and immunofluorescence confirmed co-localization of PITPNC1 and FASN. Silencing PITPNC1 suppressed FASN/CD155, enhanced CD8+ T cell immune function, and reduced radioresistance in colorectal cancer models.","method":"Co-immunoprecipitation, immunofluorescence co-localization, siRNA and lentiviral knockdown/overexpression, in vitro co-culture with CD8+ T cells, in vivo tumor-bearing model, western blotting","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional knockdown/rescue in vitro and in vivo, single lab","pmids":["38291470"],"is_preprint":false}],"current_model":"PVR/CD155 is a multi-functional immunoglobulin superfamily transmembrane adhesion molecule that serves as the principal ligand for the activating receptor DNAM-1 (CD226) and inhibitory receptors TIGIT, CD96, and KIR2DL5 on NK and T cells; it promotes tumor cell migration and proliferation by co-localizing with integrin αVβ3 at the leading edge, interacting in cis with integrin αVβ3 and PDGF receptor to enhance Ras-Raf-MEK-ERK/Rac signaling and focal adhesion dynamics, while trans-interaction with nectin-3 triggers clathrin-mediated CD155 endocytosis and contact inhibition; its expression is transcriptionally driven by Sonic Hedgehog/GLI, oncogenic Ras/Raf-MEK-ERK-AP-1, TLR/NF-κB, AhR, IL-22/STAT3, and HIF1α pathways, whereas engagement with CD226 initiates Src-mediated Y319 phosphorylation enabling CBL-B ubiquitination and proteasomal degradation of CD226, thereby suppressing anti-tumor immunity."},"narrative":{"mechanistic_narrative":"PVR (CD155/Necl-5) is an immunoglobulin-superfamily transmembrane adhesion molecule that functions at the interface of tumor cell motility and immune recognition [PMID:12913096, PMID:15607800, PMID:14871893]. As an immune ligand, PVR engages the activating receptor DNAM-1/CD226 on NK and T cells to promote target-cell lysis [PMID:12913096, PMID:15607800, PMID:15039383], while also serving as the shared ligand for the inhibitory receptors TIGIT, CD96, and KIR2DL5 [PMID:30528596, PMID:36377656, PMID:35729552]; structural work defined the conserved 'lock-and-key' interface in CD155 D1 recognized by these receptors and the additional motifs that confer receptor specificity [PMID:30528596, PMID:30591568]. In tumors, surface PVR engages CD226 to drive Src-mediated phosphorylation of CD226 at Y319, enabling CBL-B-dependent ubiquitination and proteasomal degradation of CD226, thereby blunting anti-tumor NK and T cell responses [PMID:33053330, PMID:32591463], and host or tumor CD155 loss enhances CD8+ T and NK effector function and synergizes with PD-1 blockade [PMID:29757192]. Independent of immunity, PVR drives directional cell migration and proliferation: it localizes to the leading edge where it interacts in cis with integrin αVβ3 and PDGF receptor β to amplify Ras-Raf-MEK-ERK and Rac/Cdc42 signaling, promote focal-complex and microtubule dynamics, and shorten G0/G1 [PMID:15213219, PMID:14871893, PMID:17446174, PMID:18298801], with knockdown reducing invasion, FAK/Src/MMP-2 signaling, and proliferation across multiple cancer types [PMID:15471548, PMID:16322240, PMID:28816021]. Trans-interaction with nectin-3 triggers clathrin-dependent endocytosis of PVR and contact inhibition of movement and growth [PMID:16216929]. PVR expression is transcriptionally controlled by Sonic Hedgehog/GLI, oncogenic Ras/Raf-MEK-ERK-AP-1, TLR/NF-κB, AhR, IL-22 receptor, and HIF1α-linked pathways [PMID:11983699, PMID:15688018, PMID:23349877, PMID:33504618, PMID:36630913, PMID:37995180], and is further regulated post-transcriptionally by UPR/ERAD-mediated degradation and PVRL1-dependent surface stabilization [PMID:25209846, PMID:32275969].","teleology":[{"year":2002,"claim":"Established the first defined transcriptional input controlling CD155, linking it to a developmental morphogen pathway before its immune ligand role was known.","evidence":"Reporter assays, GLI-site promoter mutagenesis, and Gli1/Gli3 overexpression in human cells","pmids":["11983699"],"confidence":"High","gaps":["Did not address whether Shh-driven CD155 affects immune recognition","Restricted to one cell line"]},{"year":2003,"claim":"Identified CD155/PVR as the cell-surface ligand for the activating NK receptor DNAM-1, defining its core immune-recognition function.","evidence":"Protein purification, mass spectrometry, Fc-fusion binding, and NK cytotoxicity assays with blocking antibodies; independently replicated","pmids":["12913096","15607800"],"confidence":"High","gaps":["Affinity and receptor competition with other DNAM-1 ligands not resolved here","Structural basis of binding not addressed"]},{"year":2003,"claim":"Defined PVR as a heterophilic trans-adhesion partner of nectin-3 that co-distributes with αv integrin and promotes motility, distinguishing it from canonical afadin-binding nectins.","evidence":"Cell-based binding, motility assays, afadin-binding tests, and immunofluorescence in transformed fibroblasts","pmids":["12740392","12759359"],"confidence":"High","gaps":["Cytoplasmic signaling consequences of nectin-3 trans-interaction unresolved","Co-IP for dimerization only implied"]},{"year":2004,"claim":"Showed PVR functions in both tumor invasion and physiological leukocyte trafficking, localizing to the migratory leading edge and to endothelial junctions where DNAM-1 engagement is required for monocyte diapedesis.","evidence":"FALI and RNAi loss-of-function, transwell migration, Fc-fusion endothelial binding, and in vitro transendothelial migration with blocking antibodies","pmids":["15471548","15136589","15039383"],"confidence":"High","gaps":["Molecular signal transduced through endothelial PVR not yet defined","Single-lab TEM data"]},{"year":2008,"claim":"Dissected the cell-intrinsic motility/proliferation machinery of PVR, placing it downstream of PDGFR and upstream of Ras with cis-interactions with integrin αVβ3 and PDGFRβ that amplify ERK and Rac/Cdc42 signaling and remodel focal adhesions and microtubules.","evidence":"Domain-deletion mutants, dominant-negatives, Co-IP, GTPase pull-downs, live-cell imaging, and signaling western blots in fibroblasts and glioma cells","pmids":["15213219","14871893","16322240","17446174","18298801","17352739","16128743","17893876"],"confidence":"High","gaps":["Direct biochemical mechanism of cis cytoplasmic signaling output incompletely defined","Most data from a single fibroblast/glioma model system"]},{"year":2005,"claim":"Defined a contact-inhibition mechanism whereby nectin-3 trans-engagement triggers clathrin-mediated endocytosis and surface down-regulation of PVR, curtailing movement and proliferation.","evidence":"Clathrin inhibition, co-culture contact experiments, and motility/proliferation assays","pmids":["16216929","17352739"],"confidence":"High","gaps":["Adaptors recruiting clathrin to PVR not identified","Fate of internalized PVR unresolved"]},{"year":2012,"claim":"Extended PVR's growth-factor receptor partnerships to VEGFR2 and established a requirement in angiogenesis and post-ischemic neovascularization in vivo.","evidence":"Co-IP, siRNA in HUVECs, in vitro angiogenesis assays, and Necl-5 knockout mouse hindlimb-ischemia/Matrigel-plug models","pmids":["22282193"],"confidence":"High","gaps":["Whether VEGFR2 coupling shares the integrin αVβ3 platform with PDGFR not fully resolved","Single lab"]},{"year":2016,"claim":"Broadened the regulatory map of PVR expression to innate/inflammatory and stress inputs, including TLR/NF-κB/IRF3, DNA-damage-response kinases, viral immediate-early proteins, and UPR/ERAD-mediated degradation.","evidence":"Genetic knockouts, pathway-specific inhibitors/siRNA, promoter analysis, and NK cytotoxicity readouts across APCs, myeloma, HCMV-infected, and HCC cells","pmids":["23349877","25609078","27733551","25209846"],"confidence":"Medium","gaps":["Direct vs indirect transcriptional control by several factors not always distinguished","Each mechanism from a single lab"]},{"year":2018,"claim":"Provided atomic-resolution definition of how the inhibitory receptor CD96 and activating receptor CD226 recognize CD155, explaining shared and receptor-specific binding determinants.","evidence":"X-ray crystallography of CD96-D1 and CD226-ectodomain complexes with CD155 D1, validated by mutagenesis and domain-deletion binding","pmids":["30528596","30591568"],"confidence":"High","gaps":["Structures of TIGIT and KIR2DL5 bound to CD155 not included here","Affinity hierarchy across the full receptor set not co-determined"]},{"year":2020,"claim":"Established the central immunosuppressive mechanism by which tumor PVR engages CD226 to drive its Src/CBL-B-dependent degradation, while PVR–TIGIT engagement recruits inhibitory phosphatases, defining PVR as a driver of immunotherapy resistance.","evidence":"CD226 Y319 mutagenesis, ubiquitination/phosphorylation assays, CBL-B Co-IP, in vivo tumor models, patient TIL analysis, PVRL1-stabilization knockdown, and combined checkpoint-blockade models","pmids":["33053330","32591463","32275969","29757192"],"confidence":"High","gaps":["Relative contribution of CD226 degradation vs TIGIT/CD96 inhibition across tumor types not resolved","Triggers selecting activating vs inhibitory outcome unclear"]},{"year":2022,"claim":"Identified KIR2DL5 as a non-competing inhibitory PVR receptor and detailed the ITIM/ITSM-SHP and TIGIT-SHIP-1 signaling that suppresses NK and CD8+ T cell cytotoxicity.","evidence":"Binding-competition assays, ITIM/ITSM mutagenesis, SHP-1/SHP-2 and SHIP-1 Co-IP, signaling western blots, and humanized tumor mouse models","pmids":["36377656","35729552"],"confidence":"High","gaps":["How a single PVR ligand spatially partitions among DNAM-1/TIGIT/CD96/KIR2DL5 not resolved","Inhibitory signaling for some receptors from single labs"]},{"year":2024,"claim":"Connected PVR to additional disease and microenvironmental axes—IL-22, AhR, HIF1α-FUT11-driven fucosylation/secretion, METTL1/PKM2-lactylation, PITPNC1/FASN, platelet-FAK/JNK/c-Jun, ER-retention vasculitis, and γδ T-cell synapse formation—revealing diverse routes that tune PVR abundance and function.","evidence":"Conditional knockouts, CRISPR ablation, knockdown/phosphoproteomics, ChIP/RIP, single-cell RNA-seq, and in vivo metastasis and humanized disease models","pmids":["36630913","33504618","37995180","39741310","38291470","38779918","37075705","38437507"],"confidence":"Medium","gaps":["Many regulatory mechanisms inferred from single studies","Cross-talk and hierarchy among these inputs unmapped"]},{"year":null,"claim":"How the same PVR molecule is dynamically partitioned between its pro-migratory cis-signaling complexes and its competing activating/inhibitory immune receptors to determine net biological outcome remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling cis-integrin/RTK signaling with trans-immune receptor engagement","Spatiotemporal regulation of receptor choice in vivo unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[4,9,17]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,26,27,28]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[13,14,19]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,3,9]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3,6,36]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[25,43]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[12,41]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,28,31,33]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,13,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[28,30,39,40]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3,8,37]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[10,11,38,42]}],"complexes":[],"partners":["CD226","TIGIT","CD96","KIR2DL5","ITGAV/ITGB3","PDGFRB","KDR","PVRL3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P15151","full_name":"Poliovirus receptor","aliases":["Nectin-like protein 5","NECL-5"],"length_aa":417,"mass_kda":45.3,"function":"Mediates NK cell adhesion and triggers NK cell effector functions. Binds two different NK cell receptors: CD96 and CD226. These interactions accumulates at the cell-cell contact site, leading to the formation of a mature immunological synapse between NK cell and target cell. This may trigger adhesion and secretion of lytic granules and IFN-gamma and activate cytotoxicity of activated NK cells. May also promote NK cell-target cell modular exchange, and PVR transfer to the NK cell. This transfer is more important in some tumor cells expressing a lot of PVR, and may trigger fratricide NK cell activation, providing tumors with a mechanism of immunoevasion. Plays a role in mediating tumor cell invasion and migration (Microbial infection) Acts as a receptor for poliovirus. May play a role in axonal transport of poliovirus, by targeting virion-PVR-containing endocytic vesicles to the microtubular network through interaction with DYNLT1. This interaction would drive the virus-containing vesicle to the axonal retrograde transport (Microbial infection) Acts as a receptor for Pseudorabies virus (Microbial infection) Is prevented to reach cell surface upon infection by Human cytomegalovirus /HHV-5, presumably to escape immune recognition of infected cell by NK cells","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P15151/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PVR","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PVR","total_profiled":1310},"omim":[{"mim_id":"621248","title":"PULMONARY HYPERTENSION, PRIMARY, 7; PPH7","url":"https://www.omim.org/entry/621248"},{"mim_id":"620701","title":"TETRATRICOPEPTIDE REPEAT DOMAIN 36; TTC36","url":"https://www.omim.org/entry/620701"},{"mim_id":"612859","title":"T-CELL IMMUNORECEPTOR WITH IMMUNOGLOBULIN AND ITIM DOMAINS; TIGIT","url":"https://www.omim.org/entry/612859"},{"mim_id":"609743","title":"CELL ADHESION MOLECULE 3; CADM3","url":"https://www.omim.org/entry/609743"},{"mim_id":"608452","title":"PLATELET-DERIVED GROWTH FACTOR C; PDGFC","url":"https://www.omim.org/entry/608452"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PVR"},"hgnc":{"alias_symbol":["CD155","HVED","Necl-5","NECL5","Tage4"],"prev_symbol":["PVS"]},"alphafold":{"accession":"P15151","domains":[{"cath_id":"2.60.40.10","chopping":"31-143","consensus_level":"high","plddt":94.5108,"start":31,"end":143},{"cath_id":"2.60.40.10","chopping":"147-239","consensus_level":"high","plddt":96.6119,"start":147,"end":239},{"cath_id":"2.60.40.10","chopping":"245-330","consensus_level":"high","plddt":92.5219,"start":245,"end":330}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P15151","model_url":"https://alphafold.ebi.ac.uk/files/AF-P15151-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P15151-F1-predicted_aligned_error_v6.png","plddt_mean":84.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PVR","jax_strain_url":"https://www.jax.org/strain/search?query=PVR"},"sequence":{"accession":"P15151","fasta_url":"https://rest.uniprot.org/uniprotkb/P15151.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P15151/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P15151"}},"corpus_meta":[{"pmid":"12913096","id":"PMC_12913096","title":"Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule.","date":"2003","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12913096","citation_count":707,"is_preprint":false},{"pmid":"11454801","id":"PMC_11454801","title":"Overexpression of the CD155 gene in human colorectal carcinoma.","date":"2001","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/11454801","citation_count":243,"is_preprint":false},{"pmid":"15039383","id":"PMC_15039383","title":"Functional characterization of DNAM-1 (CD226) interaction with its ligands PVR (CD155) and nectin-2 (PRR-2/CD112).","date":"2004","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15039383","citation_count":226,"is_preprint":false},{"pmid":"15136589","id":"PMC_15136589","title":"DNAM-1 and PVR regulate monocyte migration through endothelial junctions.","date":"2004","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15136589","citation_count":219,"is_preprint":false},{"pmid":"15471548","id":"PMC_15471548","title":"CD155/PVR plays a key role in cell motility during tumor cell invasion and migration.","date":"2004","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/15471548","citation_count":209,"is_preprint":false},{"pmid":"35379739","id":"PMC_35379739","title":"TIGIT-CD226-PVR axis: advancing immune checkpoint blockade for cancer immunotherapy.","date":"2022","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35379739","citation_count":180,"is_preprint":false},{"pmid":"28730595","id":"PMC_28730595","title":"CD155, an onco-immunologic molecule in human tumors.","date":"2017","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/28730595","citation_count":165,"is_preprint":false},{"pmid":"30275538","id":"PMC_30275538","title":"Targeting PVR (CD155) and its receptors in anti-tumor therapy.","date":"2018","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30275538","citation_count":147,"is_preprint":false},{"pmid":"32275969","id":"PMC_32275969","title":"Hepatocellular Carcinoma Cells Up-regulate PVRL1, Stabilizing PVR and Inhibiting the Cytotoxic T-Cell Response via TIGIT to Mediate Tumor Resistance to PD1 Inhibitors in Mice.","date":"2020","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/32275969","citation_count":145,"is_preprint":false},{"pmid":"33053330","id":"PMC_33053330","title":"CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8+ T Cells.","date":"2020","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/33053330","citation_count":133,"is_preprint":false},{"pmid":"25862891","id":"PMC_25862891","title":"Clinical significance of CD155 expression in human pancreatic cancer.","date":"2015","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/25862891","citation_count":131,"is_preprint":false},{"pmid":"32591463","id":"PMC_32591463","title":"IL15 Stimulation with TIGIT Blockade Reverses CD155-mediated NK-Cell Dysfunction in Melanoma.","date":"2020","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/32591463","citation_count":131,"is_preprint":false},{"pmid":"36104099","id":"PMC_36104099","title":"Tumor-associated macrophage-specific CD155 contributes to M2-phenotype transition, immunosuppression, and tumor progression in colorectal cancer.","date":"2022","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36104099","citation_count":127,"is_preprint":false},{"pmid":"15607800","id":"PMC_15607800","title":"PVR (CD155) and Nectin-2 (CD112) as ligands of the human DNAM-1 (CD226) activating receptor: involvement in tumor cell lysis.","date":"2005","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15607800","citation_count":116,"is_preprint":false},{"pmid":"12740392","id":"PMC_12740392","title":"Tage4/Nectin-like molecule-5 heterophilically trans-interacts with cell adhesion molecule Nectin-3 and enhances cell migration.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12740392","citation_count":114,"is_preprint":false},{"pmid":"31883911","id":"PMC_31883911","title":"Tumor intrinsic and extrinsic immune functions of CD155.","date":"2019","source":"Seminars in cancer biology","url":"https://pubmed.ncbi.nlm.nih.gov/31883911","citation_count":111,"is_preprint":false},{"pmid":"16322240","id":"PMC_16322240","title":"CD155/PVR enhances glioma cell dispersal by regulating adhesion signaling and focal adhesion dynamics.","date":"2005","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16322240","citation_count":105,"is_preprint":false},{"pmid":"29757192","id":"PMC_29757192","title":"CD155 loss enhances tumor suppression via combined host and tumor-intrinsic mechanisms.","date":"2018","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/29757192","citation_count":94,"is_preprint":false},{"pmid":"32019260","id":"PMC_32019260","title":"CD155: A Multi-Functional Molecule in Tumor Progression.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32019260","citation_count":92,"is_preprint":false},{"pmid":"16216929","id":"PMC_16216929","title":"Inhibition of cell movement and proliferation by cell-cell contact-induced interaction of Necl-5 with nectin-3.","date":"2005","source":"The Journal of cell 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Protein purification, tryptic digestion, and mass spectrometry identified PVR as a ~70 kDa DNAM-1 ligand; PVR-Fc soluble hybrid molecules directly stained DNAM-1-transfected COS-7 cells, and PVR expression on target cell transfectants enhanced DNAM-1-dependent NK-mediated lysis.\",\n      \"method\": \"Protein purification, mass spectrometry, soluble Fc-fusion binding assay, cell transfection, NK cytotoxicity assay with blocking antibodies\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (biochemical purification, MS, direct binding assay, functional cytotoxicity), independently replicated by a second paper (PMID:15607800)\",\n      \"pmids\": [\"12913096\", \"15607800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"DNAM-1 (CD226) binds both CD155 (PVR) and CD112 (nectin-2) with comparable affinities. Ectopic expression of CD155 or CD112 on mouse BW5147 T cells rendered them susceptible to IL-2-activated T and NK cell-mediated cytotoxicity in a CD226-dependent manner; ligation of CD226 and LFA-1 cooperated in triggering cytotoxicity and cytokine secretion.\",\n      \"method\": \"Soluble receptor binding affinity measurements, cell transfection, cytotoxicity assay with anti-CD226 blocking antibody\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding affinity measurements combined with functional cell transfection and blocking experiments, consistent with independent replication\",\n      \"pmids\": [\"15039383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PVR is expressed at cell-cell junctions of primary vascular endothelial cells and is the major DNAM-1 ligand at these junctions. The DNAM-1–PVR interaction is required for the diapedesis step of monocyte transendothelial migration: anti-PVR and anti-DNAM-1 antibodies arrested monocytes at the apical surface over intercellular junctions and blocked transmigration in vitro.\",\n      \"method\": \"Soluble DNAM-1-Fc binding assay on endothelial cells, blocking monoclonal antibodies, in vitro transendothelial migration assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional blocking with two independent antibodies (anti-PVR and anti-DNAM-1) plus localization by Fc-fusion binding, single lab\",\n      \"pmids\": [\"15136589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD155 mediates tumor cell invasion and migration. FALI-mediated inactivation of CD155 or RNAi knockdown significantly decreased transwell migration of HT1080 fibrosarcoma and U87MG GBM cells. CD155 was recruited to the leading edge of migrating cells where it co-localized with actin and αv-integrin; knockdown altered cell morphology on Matrigel.\",\n      \"method\": \"FALI (Fluorophore Assisted Light Inactivation), RNAi knockdown, transwell invasion/migration assay, immunofluorescence co-localization\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent loss-of-function methods (FALI and RNAi) with consistent phenotype, functional plus localization data in multiple cell lines\",\n      \"pmids\": [\"15471548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Tage4/Necl-5 (mouse ortholog of CD155) heterophilically trans-interacts with nectin-3 but not homophilically with itself. This trans-interaction enhanced motility of V12Ras-NIH3T3 cells. Tage4 does not bind afadin, distinguishing it from canonical nectins.\",\n      \"method\": \"Cell-based ligand binding assay, cell motility assay, afadin binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and functional motility assays in transformed fibroblasts, multiple orthogonal methods in one study\",\n      \"pmids\": [\"12740392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Necl-5/CD155 enhances serum- and PDGF-induced cell proliferation via the Ras-Raf-MEK-ERK signaling pathway, upregulating cyclins D2 and E, downregulating p27Kip1, and shortening the G0/G1 phase. Necl-5 acts downstream of PDGF receptor and upstream of Ras. Dominant-negative Necl-5 or blocking antibody suppressed these effects.\",\n      \"method\": \"Dominant-negative mutant expression, blocking antibody, cell cycle analysis, western blotting for signaling intermediates and cell cycle regulators\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (dominant-negative, antibody blockade, biochemical pathway analysis) in multiple cell types, single lab\",\n      \"pmids\": [\"15213219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Necl-5/CD155 enhances serum- and PDGF-induced directional cell migration in a nectin-3-independent but integrin αVβ3-dependent manner. The extracellular region is required for directional migration; the cytoplasmic region is required for both directional and random motility. Necl-5 co-localizes with integrin αVβ3 at leading edges. Cdc42 and Rac are activated downstream of Necl-5 and are required for Necl-5-enhanced motility.\",\n      \"method\": \"Domain deletion mutant expression in L fibroblasts and NIH3T3 cells, integrin inhibitor/activator treatments, dominant-negative Necl-5, immunofluorescence co-localization, Rho GTPase activation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — structure-function analysis with multiple deletion mutants plus pharmacological intervention and GTPase activation assays, single lab\",\n      \"pmids\": [\"14871893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cell-cell contact-induced interaction of Necl-5 with nectin-3 triggers clathrin-dependent endocytosis and down-regulation of Necl-5 from the cell surface, which subsequently reduces cell movement and proliferation, constituting a mechanism underlying contact inhibition.\",\n      \"method\": \"Immunofluorescence, clathrin inhibition, co-culture cell contact experiments, cell motility and proliferation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection of endocytic pathway (clathrin dependence) plus functional consequences (motility/proliferation), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16216929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD155/PVR expression in rat glioma cells enhances their dispersal in vitro and on primary brain tissue, reduces substrate adhesion, focal adhesion density, and actin stress fibers in a substrate-dependent manner. CD155/PVR increases Src/FAK signaling and enhances paxillin and p130Cas activation on vitronectin substrate. Depletion of endogenous CD155/PVR inhibits glioma cell migration and downregulates the same signaling pathway.\",\n      \"method\": \"Stable transfection/overexpression, RNAi knockdown, adhesion assays, immunofluorescence (focal adhesion counting), western blotting (Src, FAK, paxillin, p130Cas phosphorylation)\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function and loss-of-function experiments with signaling readouts and multiple orthogonal methods, single lab\",\n      \"pmids\": [\"16322240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Nectin-3 binds CD155 and its mouse ortholog Tage4 in trans (heterophilic interaction). Coculture of nectin-3- and CD155-expressing cells led to CD155-dependent recruitment of nectin-3 to cell-cell contacts. CD155 co-distributes with αv integrin microdomains on the cell surface. CD155 dimerization facilitates the interaction. CD155 ectodomain binds vitronectin.\",\n      \"method\": \"Cell-based ligand binding assay, co-culture heterotypic contact experiments, immunofluorescence co-localization, coimmunoprecipitation (implied by dimerization analysis)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based binding and localization with functional context, but abstract does not report formal Co-IP, single lab\",\n      \"pmids\": [\"12759359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD155 gene expression is transcriptionally activated by Sonic Hedgehog (Shh) signaling. Shh upregulated CD155 mRNA in human Ntera2 cells. Reporter gene driven by the CD155 core promoter was activated by Shh in co-transfection assays. An intact GLI binding site in the CD155 promoter is required for Shh activation. Overexpression of Gli1 or Gli3 potently activated CD155 promoter reporter expression.\",\n      \"method\": \"qRT-PCR, reporter gene (luciferase) assay, promoter mutagenesis (GLI binding site), Gli overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — promoter mutagenesis combined with reporter assay and transcription factor overexpression, multiple orthogonal methods in one study\",\n      \"pmids\": [\"11983699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Transcription of mouse Necl-5/CD155 is induced by FGF or oncogenic Ras through the Raf-MEK-ERK-AP-1 pathway. The Necl-5 promoter contains an AP-1 binding site required for V12Ki-Ras-induced activation. Inhibitors of the Raf-MEK-ERK pathway abrogated induction.\",\n      \"method\": \"Luciferase reporter gene assay, promoter mutagenesis (AP-1 site), pharmacological pathway inhibitors, oncogene (V12Ki-Ras) overexpression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — promoter mutagenesis combined with pharmacological inhibitors and reporter assay, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"15688018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Soluble CD155 (sCD155) isoforms exist in conditioned culture medium, human serum, and cerebrospinal fluid. sCD155 release does not require protease activity (indicating it is generated by alternative splicing rather than shedding). Serum-purified sCD155 reduces poliovirus entry mediated by membrane-bound CD155.\",\n      \"method\": \"ELISA, conditioned medium analysis with/without protease inhibitors, RT-PCR for splice variants, functional poliovirus entry inhibition assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional competition assay plus biochemical characterization, single lab\",\n      \"pmids\": [\"12943679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Necl-5/CD155 directly interacts in cis with integrin αVβ3, enhancing integrin αVβ3 clustering and focal complex formation at leading edges of moving cells. The extracellular region of Necl-5 (but not the cytoplasmic region) is necessary for the cis interaction with integrin αVβ3; both regions are necessary for the functional effect. Necl-5 enhances PDGF-induced Rac activation, facilitating integrin αVβ3 clustering in a feedback amplification manner.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins, domain deletion mutants, integrin-vitronectin interaction assay, Rac activation assay (pull-down), immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct Co-IP of cis interaction, structure-function with deletion mutants, GTPase activation assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17446174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Necl-5/CD155 interacts with PDGF receptor β at the leading edges of moving NIH3T3 cells and regulates the interaction between PDGF receptor and integrin αVβ3, effectively inducing directional cell movement. PDGF receptor co-localizes with Necl-5 and integrin αVβ3 at peripheral ruffles over lamellipodia. Clustering of these three molecules requires integrin αVβ3 activation by vitronectin and PDGF-induced Rac activation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, Rac activation assay, dominant-negative constructs\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional localization, single lab\",\n      \"pmids\": [\"18298801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Necl-5/CD155 interacts with Sprouty2 (a negative regulator of growth factor signaling) and reduces the inhibitory effect of Sprouty2 on PDGF-induced Ras signaling. Upon Necl-5 down-regulation by nectin-3 trans-interaction at cell-cell contacts, Sprouty2 becomes tyrosine-phosphorylated by c-Src (activated by PDGF receptor), inhibiting PDGF-induced Ras signaling. This mechanism contributes to contact inhibition of proliferation.\",\n      \"method\": \"Co-immunoprecipitation, western blotting (phosphorylation), dominant-negative and constitutively active constructs, pharmacological inhibitors\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus phosphorylation analysis and pharmacological intervention, single lab\",\n      \"pmids\": [\"17352739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The trans-interaction of Necl-5 with nectin-3 bidirectionally activates Cdc42 and Rac GTPases via a common signaling pathway involving c-Src, Rap1 (through C3G), FRG (Cdc42-GEF), and Vav2 (Rac-GEF). This is the same cascade activated by nectin-nectin trans-interaction, and it contributes to adherens junction formation.\",\n      \"method\": \"GTPase activation assays (pull-down), co-immunoprecipitation, pharmacological and dominant-negative pathway perturbations\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway dissection with pull-down GTPase assays and multiple inhibitors, single lab\",\n      \"pmids\": [\"16128743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Necl-5 heterophilic trans-interaction with nectin-3 drives recruitment of afadin, E-cadherin, and catenins to the nectin-3 (but not Necl-5) side of cell-cell contact sites. Blocking the Necl-5/nectin-3 interaction with a specific monoclonal antibody inhibited formation of E-cadherin-based adherens junctions.\",\n      \"method\": \"Stable cell transfection (L cells expressing Necl-5, nectin-3, E-cadherin), immunofluorescence, function-blocking monoclonal antibody\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional blocking assay plus co-localization, single lab\",\n      \"pmids\": [\"15330856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Necl-5/CD155 on cancer cells interacts in trans with CD226 on platelets, and this interaction promotes cancer cell adhesion to platelets in pulmonary vessels, enhancing lung metastasis. Overexpression of Necl-5 enhanced metastasis; anti-Necl-5 antibody blocking the Necl-5/CD226 interaction reduced metastasis. Platelet depletion abrogated the Necl-5-enhanced metastasis.\",\n      \"method\": \"Stable overexpression, in vivo tail-vein injection metastasis model, function-blocking monoclonal antibody, platelet depletion with anti-platelet serum\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain-of-function and loss-of-function (antibody block + platelet depletion) with clear mechanistic attribution, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"17637752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Necl-5/CD155 interacts with VEGFR2 (co-immunoprecipitation) and is required for VEGF-induced interaction of integrin αVβ3 with VEGFR2. Knockdown of Necl-5 in HUVECs inhibited VEGF-induced capillary network formation, migration, and proliferation, and suppressed VEGFR2-mediated activation of Rap1, Akt, and eNOS. Necl-5 knockout mice showed impaired post-ischemia blood flow recovery and VEGF-induced neovascularization.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, in vitro angiogenesis assays (Matrigel, migration, proliferation, apoptosis), western blotting (Rap1, Akt, eNOS), Necl-5 knockout mouse model (hindlimb ischemia, Matrigel plug)\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct Co-IP, siRNA in vitro, and in vivo knockout model, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"22282193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Endothelial PVR (CD155) interacts with monocyte DNAM-1 and regulates a step in transendothelial migration between PECAM and CD99. Activation of endothelial PVR (by antibody ligation or DNAM-1) recruits the tyrosine phosphatase Shp-2 in a Src kinase-dependent manner. PVR resides in the lateral border recycling compartment of endothelial cells, similar to PECAM and CD99.\",\n      \"method\": \"Sequential antibody blocking of TEM steps, Shp-2 recruitment assay, Src kinase inhibition, immunofluorescence localization to lateral border recycling compartment\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection of TEM step order plus Shp-2 recruitment and compartment localization, single lab\",\n      \"pmids\": [\"23333754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TLR signaling upregulates CD155 expression on antigen-presenting cells via MYD88, TRIF, and NF-κB (for most TLRs), and additionally requires IRF3 (but not IRF7) for TLR3-induced CD155 upregulation. CD155-deficient mice immunized with OVA/CpG showed increased OVA-specific IgG2a/c titers and lower IL-4 production and fewer GATA-3+IL-4+ CD4+ T cells, demonstrating that CD155 regulates Th2 differentiation.\",\n      \"method\": \"Genetic knockout mice (MYD88, TRIF, NF-κB, IRF3, IRF7, CD155), flow cytometry, ELISA\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple knockouts plus immunological readouts, single lab\",\n      \"pmids\": [\"23349877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD155 knockdown in pancreatic cancer cells inhibited proliferation and induced cell-cycle arrest at G2/M phase, indicating a cell-intrinsic role for CD155 in tumor cell proliferation independent of immune mechanisms.\",\n      \"method\": \"siRNA/shRNA knockdown, cell proliferation assay, flow cytometry (cell cycle analysis)\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — knockdown with two functional readouts, single lab but consistent with findings in other cancer types\",\n      \"pmids\": [\"25862891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nitric oxide (NO) donors upregulate PVR/CD155 surface and mRNA expression in multiple myeloma cells via activation of the DNA damage response (DDR) pathway involving ATM/ATR/Chk1/2 kinases, but independent of soluble guanylyl cyclase/cGMP. Specific inhibitors of ATM/ATR/Chk1/2 significantly abrogated the NO-induced CD155 upregulation.\",\n      \"method\": \"Flow cytometry, RT-PCR, pharmacological pathway inhibitors (ATM/ATR/Chk1/2 inhibitors, soluble guanylyl cyclase inhibitor), western blotting (DDR activation markers)\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway dissection with specific kinase inhibitors plus gene expression readout, single lab\",\n      \"pmids\": [\"25609078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human CMV immediate early proteins IE1 and IE2 directly upregulate PVR/CD155 expression during HCMV infection via a mechanism independent of IE DNA binding activity (both IE1 and IE2 are required). IE2 directly activates the MICA promoter via a characterized IE2-responsive element. DNA damage response kinases (ATM, ATR, DNA-PK) are not involved in HCMV-induced CD155 upregulation.\",\n      \"method\": \"Overexpression of IE1/IE2, phosphonoformic acid inhibition of viral DNA replication, siRNA knockdown of ATM/ATR/DNA-PK, promoter analysis (IE2-responsive element characterization), flow cytometry and qRT-PCR\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological dissection with multiple inhibitors, single lab\",\n      \"pmids\": [\"27733551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Activated unfolded protein response (UPR) decreases CD155 expression in hepatocellular carcinoma cells by two mechanisms: (1) ATF6 and IRE1α pathways suppress CD155 transcription/expression; (2) the IRE1α pathway upregulates the ERAD E3 ligase HRD1, which facilitates CD155 protein degradation. This UPR-induced CD155 downregulation reduces HCC sensitivity to NK cell cytotoxicity.\",\n      \"method\": \"Pharmacological UPR induction, pathway-specific siRNA knockdown (ATF6, IRE1α, HRD1), western blotting, flow cytometry, NK cell cytotoxicity assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mechanistic dissection via multiple pathway-specific knockdowns plus functional NK cytotoxicity readout, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"25209846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of CD96 first Ig domain (D1) bound to the CD155 (Necl-5) ectodomain was determined. CD96 recognizes CD155 D1 via a conserved 'lock-and-key' interaction shared across TIGIT:Necl complexes, but CD96 additionally uses a novel structural motif ('ancillary key') that confers specific CD155 recognition and distinguishes it from binding to nectin-2. Mutagenesis confirmed the ancillary key residue is critical for CD155 binding.\",\n      \"method\": \"X-ray crystallography, mutagenesis, direct binding assay\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation by mutagenesis, single study\",\n      \"pmids\": [\"30528596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of the CD226 (DNAM-1) ectodomain bound to CD155 D1 revealed a unique side-by-side arrangement of two tandem IgV domains of CD226 (distinct from conventional head-to-tail). CD226 D1 mediates the conserved binding interface with CD155 D1, while CD226 D2 provides structural support and makes direct contacts with CD155. Deletion of D2 substantially reduced CD226 binding to CD155.\",\n      \"method\": \"X-ray crystallography (hybrid complex of mouse CD226 ectodomain + human CD155 D1), domain deletion binding assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with domain deletion functional validation, single rigorous study\",\n      \"pmids\": [\"30591568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Tumor-derived CD155 initiates phosphorylation of CD226 at tyrosine 319 (Y319) by Src kinases upon CD155-CD226 engagement. This phosphorylation enables ubiquitination of CD226 by the E3 ligase CBL-B, leading to internalization and proteasomal degradation of CD226. Mutation of Y319 prevents this degradation, resulting in increased CD226 surface expression and enhanced anti-tumor immunity. This represents a mechanism by which CD155 on tumor cells drives resistance to immunotherapy.\",\n      \"method\": \"CD226 Y319 point mutagenesis, phosphorylation assay, ubiquitination assay, co-immunoprecipitation (CBL-B interaction), flow cytometry (CD226 surface expression), in vivo tumor models, analysis of patient TILs\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis, biochemical ubiquitination/phosphorylation assays, Co-IP for CBL-B, in vivo validation, and human patient data, multiple orthogonal methods\",\n      \"pmids\": [\"33053330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Membrane-bound CD155 on tumor cells triggers CD226 internalization and degradation in NK cells, resulting in decreased NK cell-mediated tumor reactivity. IL-15 increases TIGIT and CD226 gene expression in tumor-infiltrating NK cells; combined IL-15 treatment with TIGIT blockade increases NK cell-mediated melanoma cytotoxicity in vitro and decreases tumor metastasis in two mouse melanoma models. CD226 blockade decreases the effects of IL-15 and TIGIT blockade.\",\n      \"method\": \"Flow cytometry (receptor internalization), in vitro cytotoxicity assay, two in vivo mouse melanoma models, genetic TIGIT deletion on transferred NK cells, IL-15 treatment\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — consistent mechanism across in vitro and two independent in vivo models, replicated directionally with PMID:33053330\",\n      \"pmids\": [\"32591463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PVRL1 (nectin-1) in hepatocellular carcinoma cells stabilizes cell-surface PVR/CD155 protein without affecting PVR mRNA levels. CD155 on HCC cells interacts with TIGIT on CD8+ effector memory T cells, suppressing anti-tumor immune response. Knockdown of Pvrl1 reduced cell-surface PVR levels and sensitized tumors to CD8+ T cell-mediated killing. Combined anti-PD1 and anti-TIGIT therapy significantly reduced tumor growth in mouse models.\",\n      \"method\": \"shRNA knockdown of Pvrl1, flow cytometry (surface PVR protein vs mRNA), co-culture cytotoxicity assays, CRISPR-Cas9 tumor models, in vivo antibody treatment (anti-TIGIT, anti-PD1, anti-CD8), mass cytometry (CyTOF)\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with biochemical and functional validation in vitro and in vivo, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"32275969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD155 loss in both host (Cd155-/- mice) and tumor cells reduces tumor growth and metastasis. Mechanistically, CD155 absence in the host leads to DNAM-1 (CD226) upregulation and enhanced effector function of CD8+ T and NK cells. CD155 deletion in tumor cells also reduces tumor growth (tumor-intrinsic role). Combined CD155 absence on host and tumor cells gives additive inhibition. PD-1 blockade is more effective in CD155-limiting settings.\",\n      \"method\": \"Cd155 germline knockout mice, CD155-deleted tumor cell lines, in vivo tumor growth and metastasis assays, flow cytometry (DNAM-1 expression, T/NK cell function), anti-PD-1 treatment\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout in both host and tumor compartments with multiple in vivo readouts and pathway validation, single lab\",\n      \"pmids\": [\"29757192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD155/PVR mediates a costimulatory signal in CD4+ T cells promoting Th1 differentiation via NF-κB-induced autocrine IFN-γ that triggers positive feedback through STAT1 activation, independent of IL-12. Cd155-/- mice or anti-CD155 antibody-treated mice showed attenuated Th1-type contact hypersensitivity.\",\n      \"method\": \"CD155 signaling in primary T cells, cytokine measurement (IFN-γ), NF-κB inhibition, STAT1 activation analysis, IL-12 neutralization, Cd155 germline knockout mice, contact hypersensitivity model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout plus pharmacological pathway dissection and functional in vivo model, single lab\",\n      \"pmids\": [\"25972481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIR2DL5 on human NK cells binds PVR without competing with TIGIT, CD96, or DNAM-1. KIR2DL5-PVR engagement induces inhibitory immune synapse formation. Both intracellular ITIM and ITSM of KIR2DL5 undergo tyrosine phosphorylation, recruiting SHP-1 and/or SHP-2, which then downregulate Vav1/ERK1/2/p90RSK/NF-κB signaling to suppress NK cytotoxicity.\",\n      \"method\": \"Binding competition assays, inhibitory synapse imaging, phosphorylation assays, Co-IP (SHP-1/SHP-2 recruitment), ITIM/ITSM mutagenesis, western blotting (Vav1, ERK, NF-κB), NK cell cytotoxicity assays, humanized tumor mouse models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis of ITIM/ITSM, Co-IP of phosphatase recruitment, signaling pathway analysis, and in vivo validation, single study with multiple orthogonal methods\",\n      \"pmids\": [\"36377656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TIGIT, upon binding to CD155 and being phosphorylated, inhibits NF-κB and ERK activation in CD8+ T cells by recruiting SHIP-1, resulting in downregulation of cytokine production. Blocking TIGIT attenuates the inhibitory effect of SHIP-1 and restores NF-κB and ERK activation.\",\n      \"method\": \"Western blotting (NF-κB, ERK phosphorylation, SHIP-1 interaction), co-culture with CD155+ tumor cells, TIGIT blockade, in vivo tumor model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — signaling pathway analysis with SHIP-1 co-IP and NF-κB/ERK readouts, single lab\",\n      \"pmids\": [\"35729552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Knockdown of Necl-5/CD155 in A172 GBM cells decreases invasion in a 3D matrix, reduces MMP-2 expression and activity, and diminishes basal Akt activation and ILK-dependent Akt activation in response to vitronectin. Necl-5, Akt, and ILK co-localize at focal contacts at the leading edge, suggesting integration of Akt signaling at the leading edge to induce MMP-2 expression.\",\n      \"method\": \"RNAi knockdown, 3D invasion assay, MMP-2 zymography, western blotting (Akt, ILK phosphorylation), immunofluorescence co-localization\",\n      \"journal\": \"Journal of neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with downstream signaling analysis and co-localization, single lab\",\n      \"pmids\": [\"20680398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Necl-5/CD155 enhances PDGF-induced growth of microtubules toward the plasma membrane at the leading edge of moving NIH3T3 cells in an integrin αVβ3-dependent manner. Necl-5 promotes PDGF-induced attraction of plus-end-tracking proteins (EB1, CLIP170, dynein intermediate chain, p150Glued/dynactin) near the plasma membrane at the leading edge.\",\n      \"method\": \"Live-cell imaging of GFP-tagged microtubule plus-end proteins, siRNA knockdown of Necl-5, integrin αVβ3 inhibition\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging combined with knockdown and pharmacological inhibition, single lab\",\n      \"pmids\": [\"20964795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD155 knockdown in colon cancer cells inhibited migration and invasion with reduced FAK, Src, and MMP-2 expression; suppressed proliferation; and increased Bax/Bcl-2 ratio resulting in increased apoptosis.\",\n      \"method\": \"shRNA lentiviral knockdown, migration/invasion assay, western blotting (FAK, Src, MMP-2, Bax, Bcl-2, cell cycle regulators), flow cytometry (apoptosis)\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — consistent with multiple prior studies, multiple readouts but single lab and single method approach per pathway\",\n      \"pmids\": [\"28816021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Aryl hydrocarbon receptor (AhR) transcriptionally regulates CD155 expression on tumor-associated macrophages in a co-regulated manner with PD-L1. AhR inhibition in vivo reduced CD155 expression and reversed tumor immunosuppression in a murine tumor model.\",\n      \"method\": \"AhR inhibitor treatment in vitro and in vivo, gene expression analysis, correlation with AhR activity markers in human glioblastoma data\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition in vitro and in vivo with expression readout, single lab; mechanism (direct transcriptional regulation) is somewhat inferred from abstract\",\n      \"pmids\": [\"33504618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"T cell-derived IL-22 induces high CD155 expression on cancer cells via IL-22 receptor signaling on tumor cells. Excessive CD226 activation by IL-22-induced CD155 leads to decreased CD226 surface levels and functionally impaired NK cells, elevating metastatic burden. Constitutional and T cell-specific deletion of Il22, or deletion of the IL-22 receptor on cancer cells, each reduced metastases to a similar degree.\",\n      \"method\": \"Conditional knockout mice (constitutional Il22 KO, T cell-specific Il22 KO, cancer cell IL-22 receptor KO), in vivo lung and breast cancer metastasis models, flow cytometry (NK cell CD226 expression and function)\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple conditional knockouts in independent compartments yielding consistent phenotype, rigorous in vivo data\",\n      \"pmids\": [\"36630913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Platelet contact with cancer cells transcriptionally upregulates CD155 via the FAK/JNK/c-Jun cascade. CD155 on circulating tumor cells inhibits NK cell cytotoxicity exclusively through TIGIT engagement, not through CD96 or DNAM-1. Antibody blockade of CD155-TIGIT interaction restored NK immunosurveillance and attenuated tumor metastasis.\",\n      \"method\": \"Single-cell RNA sequencing, multiplex immunofluorescence, in vitro/ex vivo co-culture cytotoxicity assays, in vivo metastasis models, competition assay (TIGIT vs CD96 vs DNAM-1 blocking), western blotting (FAK/JNK/c-Jun pathway)\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway dissection (FAK/JNK/c-Jun) plus receptor-specific competition assays identifying TIGIT as exclusive partner, in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38779918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Brain metastasis cancer-associated fibroblasts (bmCAFs) secrete fucosylated PVR/CD155 that enhances invasive capacity of breast cancer cells. Mechanistically, HIF1α transcriptionally upregulates fucosyltransferase 11, which fucosylates PVR, triggering its secretion. Secreted fucosylated PVR modulates cell-cell junction and actin cytoskeletal signaling in breast cancer cells.\",\n      \"method\": \"Patient-derived bmCAF conditioned medium experiments, HIF1α overexpression, fucosyltransferase 11 knockdown, global phosphoproteomics, functional invasion assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway with HIF1α-FUT11-PVR fucosylation-secretion axis validated by knockdown and phosphoproteomics, single lab\",\n      \"pmids\": [\"37995180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL1 mediates m7G methylation of PKM mRNA, enhancing PKM2 expression, which increases glycolysis and promotes H3K9 lactylation (H3K9la). Nuclear PKM2 dimer activates CD155 (PVR) transcription via H3K9la, promoting immune evasion in colorectal cancer. This creates a positive feedback loop (H3K9la activates METTL1 transcription). Knockdown of METTL1 reduced CD155 expression and enhanced CD8+ T cell-mediated tumor killing in vivo.\",\n      \"method\": \"m7G methylation assay, RNA stability analysis, RIP assay, ChIP (Cut&Run), western blotting, ECAR/lactate assays, in vivo knockout mouse model with CD155 blockade\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-step pathway with chromatin and RIP assays, in vivo validation; complex mechanism identified in single lab study\",\n      \"pmids\": [\"39741310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In giant cell arteritis (GCA), macrophages retain CD155 in the endoplasmic reticulum and fail to traffic it to the cell surface. This defective surface translocation of CD155 creates antigen-presenting cells that expand CD4+CD96+ T cells, which differentiate toward the Th9 lineage and release IL-9 to drive vasculitis.\",\n      \"method\": \"Immunofluorescence (ER retention of CD155), flow cytometry, humanized mouse model of GCA with recombinant IL-9 and anti-IL-9 antibody, T cell differentiation assays\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ER retention demonstrated by immunofluorescence with functional consequence in humanized mouse model, single lab\",\n      \"pmids\": [\"37075705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD155/PVR and B7-H6 (but not nectin-2/CD112) are critical and non-redundant ligands for formation of robust immunological synapses between AML cells and Vδ1+ γδ T (DOT) cells. CRISPR-mediated ablation of PVR or B7-H6 disrupted DOT-cell targeting of AML cells; PVR expression in primary AML samples predicted their elimination by DOT cells.\",\n      \"method\": \"CRISPR-Cas9 ablation of PVR, B7-H6, and CD112 in AML cell lines, immunological synapse imaging, in vitro cytotoxicity assays, primary AML sample analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR ablation of specific ligands with immunological synapse formation readout, validated in primary patient samples, single lab\",\n      \"pmids\": [\"38437507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD155 enhances proliferation of ras-mutated cells through the cytoplasmic region including the ITIM motif. CD155DeltaCP (lacking the cytoplasmic region including ITIM) has reduced ability to enhance serum responsiveness. siRNA knockdown of endogenous CD155 in DLD-1 cells (mutant K-ras) suppressed serum responsiveness.\",\n      \"method\": \"Cytoplasmic domain deletion mutant (CD155DeltaCP), siRNA knockdown, cell proliferation assay, cell cycle analysis\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion mutagenesis combined with knockdown and cell cycle readout, single lab\",\n      \"pmids\": [\"17893876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PITPNC1 regulates CD155 expression on the surface of tumor cells through FASN. Gene knockdown experiments showed that PITPNC1 upregulates FASN, which in turn increases CD155 surface expression. Co-immunoprecipitation and immunofluorescence confirmed co-localization of PITPNC1 and FASN. Silencing PITPNC1 suppressed FASN/CD155, enhanced CD8+ T cell immune function, and reduced radioresistance in colorectal cancer models.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, siRNA and lentiviral knockdown/overexpression, in vitro co-culture with CD8+ T cells, in vivo tumor-bearing model, western blotting\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional knockdown/rescue in vitro and in vivo, single lab\",\n      \"pmids\": [\"38291470\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PVR/CD155 is a multi-functional immunoglobulin superfamily transmembrane adhesion molecule that serves as the principal ligand for the activating receptor DNAM-1 (CD226) and inhibitory receptors TIGIT, CD96, and KIR2DL5 on NK and T cells; it promotes tumor cell migration and proliferation by co-localizing with integrin αVβ3 at the leading edge, interacting in cis with integrin αVβ3 and PDGF receptor to enhance Ras-Raf-MEK-ERK/Rac signaling and focal adhesion dynamics, while trans-interaction with nectin-3 triggers clathrin-mediated CD155 endocytosis and contact inhibition; its expression is transcriptionally driven by Sonic Hedgehog/GLI, oncogenic Ras/Raf-MEK-ERK-AP-1, TLR/NF-κB, AhR, IL-22/STAT3, and HIF1α pathways, whereas engagement with CD226 initiates Src-mediated Y319 phosphorylation enabling CBL-B ubiquitination and proteasomal degradation of CD226, thereby suppressing anti-tumor immunity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PVR (CD155/Necl-5) is an immunoglobulin-superfamily transmembrane adhesion molecule that functions at the interface of tumor cell motility and immune recognition [#0, #6]. As an immune ligand, PVR engages the activating receptor DNAM-1/CD226 on NK and T cells to promote target-cell lysis [#0, #1], while also serving as the shared ligand for the inhibitory receptors TIGIT, CD96, and KIR2DL5 [#26, #33, #34]; structural work defined the conserved 'lock-and-key' interface in CD155 D1 recognized by these receptors and the additional motifs that confer receptor specificity [#26, #27]. In tumors, surface PVR engages CD226 to drive Src-mediated phosphorylation of CD226 at Y319, enabling CBL-B-dependent ubiquitination and proteasomal degradation of CD226, thereby blunting anti-tumor NK and T cell responses [#28, #29], and host or tumor CD155 loss enhances CD8+ T and NK effector function and synergizes with PD-1 blockade [#31]. Independent of immunity, PVR drives directional cell migration and proliferation: it localizes to the leading edge where it interacts in cis with integrin \\u03b1V\\u03b23 and PDGF receptor \\u03b2 to amplify Ras-Raf-MEK-ERK and Rac/Cdc42 signaling, promote focal-complex and microtubule dynamics, and shorten G0/G1 [#5, #6, #13, #14], with knockdown reducing invasion, FAK/Src/MMP-2 signaling, and proliferation across multiple cancer types [#3, #8, #37]. Trans-interaction with nectin-3 triggers clathrin-dependent endocytosis of PVR and contact inhibition of movement and growth [#7]. PVR expression is transcriptionally controlled by Sonic Hedgehog/GLI, oncogenic Ras/Raf-MEK-ERK-AP-1, TLR/NF-\\u03baB, AhR, IL-22 receptor, and HIF1\\u03b1-linked pathways [#10, #11, #21, #38, #39, #41], and is further regulated post-transcriptionally by UPR/ERAD-mediated degradation and PVRL1-dependent surface stabilization [#25, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the first defined transcriptional input controlling CD155, linking it to a developmental morphogen pathway before its immune ligand role was known.\",\n      \"evidence\": \"Reporter assays, GLI-site promoter mutagenesis, and Gli1/Gli3 overexpression in human cells\",\n      \"pmids\": [\"11983699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether Shh-driven CD155 affects immune recognition\", \"Restricted to one cell line\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified CD155/PVR as the cell-surface ligand for the activating NK receptor DNAM-1, defining its core immune-recognition function.\",\n      \"evidence\": \"Protein purification, mass spectrometry, Fc-fusion binding, and NK cytotoxicity assays with blocking antibodies; independently replicated\",\n      \"pmids\": [\"12913096\", \"15607800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity and receptor competition with other DNAM-1 ligands not resolved here\", \"Structural basis of binding not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined PVR as a heterophilic trans-adhesion partner of nectin-3 that co-distributes with \\u03b1v integrin and promotes motility, distinguishing it from canonical afadin-binding nectins.\",\n      \"evidence\": \"Cell-based binding, motility assays, afadin-binding tests, and immunofluorescence in transformed fibroblasts\",\n      \"pmids\": [\"12740392\", \"12759359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoplasmic signaling consequences of nectin-3 trans-interaction unresolved\", \"Co-IP for dimerization only implied\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed PVR functions in both tumor invasion and physiological leukocyte trafficking, localizing to the migratory leading edge and to endothelial junctions where DNAM-1 engagement is required for monocyte diapedesis.\",\n      \"evidence\": \"FALI and RNAi loss-of-function, transwell migration, Fc-fusion endothelial binding, and in vitro transendothelial migration with blocking antibodies\",\n      \"pmids\": [\"15471548\", \"15136589\", \"15039383\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular signal transduced through endothelial PVR not yet defined\", \"Single-lab TEM data\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Dissected the cell-intrinsic motility/proliferation machinery of PVR, placing it downstream of PDGFR and upstream of Ras with cis-interactions with integrin \\u03b1V\\u03b23 and PDGFR\\u03b2 that amplify ERK and Rac/Cdc42 signaling and remodel focal adhesions and microtubules.\",\n      \"evidence\": \"Domain-deletion mutants, dominant-negatives, Co-IP, GTPase pull-downs, live-cell imaging, and signaling western blots in fibroblasts and glioma cells\",\n      \"pmids\": [\"15213219\", \"14871893\", \"16322240\", \"17446174\", \"18298801\", \"17352739\", \"16128743\", \"17893876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical mechanism of cis cytoplasmic signaling output incompletely defined\", \"Most data from a single fibroblast/glioma model system\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined a contact-inhibition mechanism whereby nectin-3 trans-engagement triggers clathrin-mediated endocytosis and surface down-regulation of PVR, curtailing movement and proliferation.\",\n      \"evidence\": \"Clathrin inhibition, co-culture contact experiments, and motility/proliferation assays\",\n      \"pmids\": [\"16216929\", \"17352739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adaptors recruiting clathrin to PVR not identified\", \"Fate of internalized PVR unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended PVR's growth-factor receptor partnerships to VEGFR2 and established a requirement in angiogenesis and post-ischemic neovascularization in vivo.\",\n      \"evidence\": \"Co-IP, siRNA in HUVECs, in vitro angiogenesis assays, and Necl-5 knockout mouse hindlimb-ischemia/Matrigel-plug models\",\n      \"pmids\": [\"22282193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether VEGFR2 coupling shares the integrin \\u03b1V\\u03b23 platform with PDGFR not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Broadened the regulatory map of PVR expression to innate/inflammatory and stress inputs, including TLR/NF-\\u03baB/IRF3, DNA-damage-response kinases, viral immediate-early proteins, and UPR/ERAD-mediated degradation.\",\n      \"evidence\": \"Genetic knockouts, pathway-specific inhibitors/siRNA, promoter analysis, and NK cytotoxicity readouts across APCs, myeloma, HCMV-infected, and HCC cells\",\n      \"pmids\": [\"23349877\", \"25609078\", \"27733551\", \"25209846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect transcriptional control by several factors not always distinguished\", \"Each mechanism from a single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided atomic-resolution definition of how the inhibitory receptor CD96 and activating receptor CD226 recognize CD155, explaining shared and receptor-specific binding determinants.\",\n      \"evidence\": \"X-ray crystallography of CD96-D1 and CD226-ectodomain complexes with CD155 D1, validated by mutagenesis and domain-deletion binding\",\n      \"pmids\": [\"30528596\", \"30591568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures of TIGIT and KIR2DL5 bound to CD155 not included here\", \"Affinity hierarchy across the full receptor set not co-determined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established the central immunosuppressive mechanism by which tumor PVR engages CD226 to drive its Src/CBL-B-dependent degradation, while PVR\\u2013TIGIT engagement recruits inhibitory phosphatases, defining PVR as a driver of immunotherapy resistance.\",\n      \"evidence\": \"CD226 Y319 mutagenesis, ubiquitination/phosphorylation assays, CBL-B Co-IP, in vivo tumor models, patient TIL analysis, PVRL1-stabilization knockdown, and combined checkpoint-blockade models\",\n      \"pmids\": [\"33053330\", \"32591463\", \"32275969\", \"29757192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of CD226 degradation vs TIGIT/CD96 inhibition across tumor types not resolved\", \"Triggers selecting activating vs inhibitory outcome unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified KIR2DL5 as a non-competing inhibitory PVR receptor and detailed the ITIM/ITSM-SHP and TIGIT-SHIP-1 signaling that suppresses NK and CD8+ T cell cytotoxicity.\",\n      \"evidence\": \"Binding-competition assays, ITIM/ITSM mutagenesis, SHP-1/SHP-2 and SHIP-1 Co-IP, signaling western blots, and humanized tumor mouse models\",\n      \"pmids\": [\"36377656\", \"35729552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single PVR ligand spatially partitions among DNAM-1/TIGIT/CD96/KIR2DL5 not resolved\", \"Inhibitory signaling for some receptors from single labs\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected PVR to additional disease and microenvironmental axes\\u2014IL-22, AhR, HIF1\\u03b1-FUT11-driven fucosylation/secretion, METTL1/PKM2-lactylation, PITPNC1/FASN, platelet-FAK/JNK/c-Jun, ER-retention vasculitis, and \\u03b3\\u03b4 T-cell synapse formation\\u2014revealing diverse routes that tune PVR abundance and function.\",\n      \"evidence\": \"Conditional knockouts, CRISPR ablation, knockdown/phosphoproteomics, ChIP/RIP, single-cell RNA-seq, and in vivo metastasis and humanized disease models\",\n      \"pmids\": [\"36630913\", \"33504618\", \"37995180\", \"39741310\", \"38291470\", \"38779918\", \"37075705\", \"38437507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Many regulatory mechanisms inferred from single studies\", \"Cross-talk and hierarchy among these inputs unmapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the same PVR molecule is dynamically partitioned between its pro-migratory cis-signaling complexes and its competing activating/inhibitory immune receptors to determine net biological outcome remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling cis-integrin/RTK signaling with trans-immune receptor engagement\", \"Spatiotemporal regulation of receptor choice in vivo unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [4, 9, 17]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 26, 27, 28]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13, 14, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 3, 9]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 6, 36]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [25, 43]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [12, 41]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 28, 31, 33]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 13, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [28, 30, 39, 40]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3, 8, 37]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [10, 11, 38, 42]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CD226\",\n      \"TIGIT\",\n      \"CD96\",\n      \"KIR2DL5\",\n      \"ITGAV/ITGB3\",\n      \"PDGFRB\",\n      \"KDR\",\n      \"PVRL3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}