{"gene":"PVR","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2009,"finding":"TIGIT binds PVR (CD155) and PVRL2 but not PVRL3, and inhibits human NK cell cytotoxicity directly through its ITIM domain, providing an 'alternative self' mechanism for MHC class I-independent inhibition.","method":"Binding assays, ITIM functional analysis, NK cytotoxicity assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding characterization plus functional ITIM mutagenesis/pathway analysis; widely replicated","pmids":["19815499"],"is_preprint":false},{"year":2004,"finding":"CD155 (PVR) and Nectin-2 (CD112) were identified as the functional ligands for DNAM-1 (CD226); ectopic expression of CD155 on target cells rendered them susceptible to T and NK cell-mediated cytotoxicity in a CD226-dependent manner.","method":"Ectopic expression in BW5147 cells, blocking mAb inhibition, cytotoxicity assays, soluble receptor binding affinity measurements","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 2 — functional reconstitution with blocking antibody validation; replicated across labs","pmids":["15039383"],"is_preprint":false},{"year":2004,"finding":"PVR (CD155) is expressed at endothelial cell junctions and interacts with DNAM-1 (CD226) on monocytes to regulate the diapedesis step of transendothelial migration; anti-PVR mAbs arrested monocytes at the apical surface over intercellular junctions.","method":"Soluble DNAM-1-Fc binding assay on endothelial cells, blocking mAb treatment in transendothelial migration assay, localization by imaging","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — orthogonal methods including soluble ligand binding, blocking antibodies, and cell biology assays with clear phenotypic readout","pmids":["15136589"],"is_preprint":false},{"year":2001,"finding":"The cytoplasmic domain of CD155 (PVR) associates with Tctex-1, a dynein motor complex light chain, via a SKCSR juxtamembrane motif; this interaction targets CD155-containing endocytic vesicles to the microtubular network for retrograde transport.","method":"Yeast two-hybrid screen, biochemical pulldown, co-immunoprecipitation, domain mapping mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — yeast two-hybrid discovery confirmed by biochemical pulldown and Co-IP with domain mapping","pmids":["11751937"],"is_preprint":false},{"year":2004,"finding":"CD155/PVR-containing vesicles undergo receptor-dependent endocytosis and retrograde axonal transport; the direct interaction between the cytoplasmic domain of CD155 and Tctex-1 is essential for efficient retrograde transport of poliovirus-containing vesicles along microtubules in neurons.","method":"GST pulldown, immunoelectron microscopy, live-cell vesicle tracking in differentiated PC12 cells with wild-type vs. Tctex-1-binding mutant hPVR, vinblastine nerve block in vivo","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of binding confirmed by mutant analysis, in vivo retrograde transport validation","pmids":["15194795"],"is_preprint":false},{"year":2003,"finding":"CD155 (Tage4/Necl-5) heterophilically trans-interacts with nectin-3 but not homophilically with itself; this interaction enhances motility of Ras-transformed NIH3T3 cells.","method":"Binding assays, cell motility assays with trans-interaction partners, domain analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct binding characterization combined with functional cell motility readout","pmids":["12740392"],"is_preprint":false},{"year":2004,"finding":"Necl-5 (CD155/PVR) enhances serum- and PDGF-induced cell migration in an integrin αVβ3-dependent manner; it colocalizes with integrin αVβ3 at leading edges, and its extracellular region is required for directional migration while the cytoplasmic region is required for both directional and random motility. Cdc42 and Rac GTPases are activated downstream.","method":"Necl-5 mutant expression in L fibroblasts and NIH3T3 cells, integrin inhibitor/activator assays, dominant-negative Necl-5, co-localization imaging, GTPase activation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including mutagenesis, pharmacological inhibition, and signaling readouts","pmids":["14871893"],"is_preprint":false},{"year":2005,"finding":"Upon cell-cell contact, Necl-5 (CD155/PVR) interaction with nectin-3 triggers clathrin-dependent endocytosis of Necl-5 from the cell surface, reducing cell movement and proliferation—a mechanism underlying contact inhibition.","method":"Cell-cell contact assays, clathrin inhibition, surface expression quantification, cell migration and proliferation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection with pharmacological inhibition of endocytosis and multiple functional readouts","pmids":["16216929"],"is_preprint":false},{"year":2005,"finding":"Mouse Necl-5 (CD155/PVR) expression is transcriptionally induced by FGF or oncogenic V12Ki-Ras through the Raf-MEK-ERK-AP-1 signaling pathway; an AP-1 binding site in the Necl-5 promoter is required for this induction.","method":"Luciferase reporter assays with Necl-5 promoter, pathway inhibitors (MEK inhibitor), AP-1 site mutagenesis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 — promoter-reporter reconstitution with site mutagenesis and signaling inhibitors","pmids":["15688018"],"is_preprint":false},{"year":2001,"finding":"CD155 (PVR) specifically binds vitronectin with a Kd of ~72 nM as measured by surface plasmon resonance, mediating cell-to-matrix contacts; related PRR proteins do not show equivalent CD155-like binding.","method":"Surface plasmon resonance binding assay, co-localization in lymphoid tissue","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 1 — quantitative binding assay (SPR) but limited functional validation in cells","pmids":["11437656"],"is_preprint":false},{"year":2012,"finding":"Necl-5 (CD155/PVR) interacts with VEGFR2 and is required for VEGF-induced interaction of integrin αVβ3 with VEGFR2; knockdown of Necl-5 in HUVECs suppresses VEGF-induced Rap1, Akt, and eNOS activation and impairs angiogenic responses in vitro and in vivo.","method":"Co-immunoprecipitation, siRNA knockdown in HUVECs, Matrigel tube formation, migration and proliferation assays, Necl-5 knockout mouse hindlimb ischemia model","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — Co-IP establishing complex formation combined with KO mouse model and multiple in vitro functional readouts","pmids":["22282193"],"is_preprint":false},{"year":2013,"finding":"During monocyte transendothelial migration, endothelial PVR (CD155) interaction with DNAM-1 recruits tyrosine phosphatase Shp-2 in a Src kinase-dependent manner; this regulates a step in diapedesis between those regulated by PECAM and CD99. PVR resides in the lateral border recycling compartment of endothelial cells.","method":"Blocking antibody sequential treatment, Shp-2 recruitment assay, Src kinase inhibition, subcellular fractionation/localization of PVR","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — epistasis via sequential antibody blockade, signaling molecule recruitment with phosphatase identification, localization data","pmids":["23333754"],"is_preprint":false},{"year":2013,"finding":"TLR activation upregulates CD155 expression on antigen-presenting cells through MYD88, TRIF, NF-κB, and IRF3 (but not IRF7) signaling; CD155-deficient mice show reduced Th2 differentiation (lower IL-4, fewer GATA-3+ CD4+ T cells) upon immunization.","method":"TLR ligand stimulation with pathway inhibitors/knockouts (MYD88-/-, TRIF-/-, NF-κB inhibitors), IRF knockout mice, in vivo immunization with OVA/CpG","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockouts combined with in vivo functional immune phenotyping, single lab","pmids":["23349877"],"is_preprint":false},{"year":2012,"finding":"HIV-1 Nef protein downregulates cell-surface PVR (CD155) on infected T lymphocytes using the same structural motifs used to downregulate HLA-I, reducing total cell-associated PVR; Vpu further optimizes surface PVR reduction. This downregulation abrogates NK-mediated lysis via DNAM-1.","method":"Flow cytometry of surface and total PVR levels, Nef motif mutagenesis, NK cytotoxicity blocking assays with anti-DNAM-1 and anti-NKG2D","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — mutagenesis of Nef motifs combined with functional NK killing assays; multiple HIV strains tested","pmids":["22301152"],"is_preprint":false},{"year":2020,"finding":"Tumor-derived CD155 initiates phosphorylation of CD226 at tyrosine 319 by Src kinases, enabling ubiquitination of CD226 by CBL-B, followed by internalization and proteasomal degradation of CD226 on CD8+ T cells, thereby driving T cell dysfunction and resistance to immune checkpoint blockade.","method":"CD226 Y319 mutagenesis, Src kinase inhibition, CBL-B Co-IP, flow cytometry of CD226 surface levels, proteasome inhibitor rescue, in vivo tumor models with CD226 mutant knock-in","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 — mechanistic reconstitution with site-specific mutagenesis, identified E3 ligase (CBL-B), and in vivo validation","pmids":["33053330"],"is_preprint":false},{"year":2020,"finding":"Membrane-bound CD155 on melanoma cells triggers CD226 internalization and degradation on NK cells, resulting in decreased NK-cell-mediated tumor reactivity; IL-15 restores TIGIT and CD226 gene expression on tumor-infiltrating NK cells.","method":"Flow cytometry of CD226 surface expression and internalization, in vitro cytotoxicity assays, NK-specific TIGIT deletion in transfer experiments, two mouse melanoma models","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 — cell biological mechanism (CD226 internalization) confirmed in genetic NK-specific TIGIT deletion models and in vivo melanoma models","pmids":["32591463"],"is_preprint":false},{"year":2020,"finding":"PVRL1 (Nectin-1) on hepatocellular carcinoma cells stabilizes cell-surface PVR protein (without affecting Pvr mRNA), which then interacts with TIGIT on CD8+ effector memory T cells to suppress anti-tumor immunity; knockdown of Pvrl1 reduces surface PVR and decreases tumor growth.","method":"shRNA knockdown of Pvrl1 and Pvrl3, surface vs. mRNA PVR measurement, tumor growth assays in vivo, mass cytometry, combination anti-PD1/anti-TIGIT treatment","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 — genetic knockdown distinguishing mRNA from protein surface levels, in vivo tumor models, combination immunotherapy validation","pmids":["32275969"],"is_preprint":false},{"year":2018,"finding":"CD155 loss in tumor cells reduces tumor growth and metastasis through tumor-intrinsic mechanisms; in Cd155-/- mice, DNAM-1 is upregulated and NK and CD8+ T cell effector function is enhanced, demonstrating both cell-intrinsic and immune-extrinsic tumor-suppressive roles.","method":"Cd155-/- mouse model, CD155-deleted tumor cells, NK/CD8+ T cell functional assays, DNAM-1 surface expression measurement, in vivo tumor and metastasis models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — genetic KO of CD155 in host and tumor separately, with specific immune cell readouts","pmids":["29757192"],"is_preprint":false},{"year":2019,"finding":"PVR/KIR2DL5 is a novel immune checkpoint interaction: KIR2DL5 on NK cells binds PVR without competing with TIGIT, CD96, or DNAM-1; engagement induces inhibitory synapse formation and tyrosine phosphorylation of both ITIM and ITSM of KIR2DL5, recruiting SHP-1 and/or SHP-2 and downregulating Vav1/ERK1/2/p90RSK/NF-κB signaling.","method":"Binding competition assays, inhibitory synapse imaging, phosphoproteomic analysis, SHP-1/SHP-2 recruitment assays, KIR2DL5 blocking mAbs, humanized tumor mouse models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 — mechanistic characterization of phosphorylation sites, phosphatase recruitment, downstream signaling pathway, and in vivo validation","pmids":["36377656"],"is_preprint":false},{"year":2018,"finding":"The crystal/structural analysis of CD226 (DNAM-1) bound to CD155 (Necl-5/D1) reveals a unique side-by-side arrangement of two IgV domains of CD226; both D1 and D2 of CD226 interact with CD155-D1, and removal of D2 substantially reduces CD226 binding efficacy to CD155.","method":"X-ray crystallography of mCD226-ecto and hybrid mCD226-ecto/hCD155-D1 complex, truncation binding assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional domain deletion validation","pmids":["30591568"],"is_preprint":false},{"year":2008,"finding":"CD155 enhances serum-induced cell proliferation specifically in Ras-mutated cells; the cytoplasmic ITIM of CD155 is required for this effect, and CD155 upregulates cyclin D2 and downregulates p27Kip1 to shorten G0/G1 phase.","method":"CD155 overexpression and siRNA knockdown in Ras-transformed and Ras-mutated cancer cell lines, cell cycle analysis, cyclin/CDK inhibitor western blotting, ITIM deletion mutant analysis, FAK inhibitor control","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — domain mutagenesis (ITIM deletion), gain- and loss-of-function, multiple Ras-mutant cell lines; single lab","pmids":["17893876"],"is_preprint":false},{"year":2015,"finding":"CD155 (PVR) mediates a costimulatory signal in CD4+ T cells that promotes Th1 development via NF-κB-induced autocrine IFN-γ and STAT1 positive feedback, independent of IL-12; CD155-deficient mice show attenuated Th1-type contact hypersensitivity.","method":"CD155-/- mice, anti-CD155 antibody treatment, cytokine measurement (IFN-γ), Tbx21 expression, NF-κB and STAT1 inhibitor studies, contact hypersensitivity model","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with signaling inhibitor studies, single lab","pmids":["25972481"],"is_preprint":false},{"year":2020,"finding":"Soluble CD155 (sCD155), expressed by human tumor cells from a splice isoform lacking the transmembrane region, preferentially binds DNAM-1 over TIGIT and CD96, and inhibits DNAM-1-mediated NK cell degranulation and killing, thereby promoting lung colonization by melanoma cells.","method":"In vivo injection of sCD155-expressing vs. parental B16/BL6 melanoma in TIGIT-KO, CD96-KO, and DNAM-1-KO mice; NK depletion experiments; in vitro NK degranulation assays; binding affinity comparison","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic KO mouse panel plus in vitro functional assays establishing receptor preference","pmids":["32040157"],"is_preprint":false},{"year":2023,"finding":"T cell-derived IL-22 induces high CD155 expression on cancer cells via IL-22 receptor signaling; excessive CD155 binding to CD226 on NK cells triggers CD226 internalization/degradation and NK cell functional impairment, elevating metastatic burden.","method":"Constitutional and T cell-specific Il22 deletion in mouse lung/breast cancer models, Il22 receptor deletion on cancer cells, CD226 surface expression and functional assays, NK cell cytotoxicity assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic models (Il22-/-, Il22r-/- on cancer cells) with mechanistic NK cell functional readouts; orthogonal validation","pmids":["36630913"],"is_preprint":false},{"year":2022,"finding":"In coronary artery disease, macrophage METTL3 overexpression promotes m6A modification at positions 1635 and 3103 in the 3'UTR of CD155 mRNA, stabilizing the transcript and enhancing CD155 surface expression on macrophages, which then deliver inhibitory signals to CD4+ T cells via CD96 and TIGIT.","method":"m6A mapping (MeRIP), METTL3 knockdown/overexpression, mRNA stability assays, CD155 surface and mRNA measurements, T cell suppression assays in vitro and humanized mouse model","journal":"Nature cardiovascular research","confidence":"High","confidence_rationale":"Tier 1–2 — m6A site identification with mRNA stability validation, in vivo humanized mouse model, LDL stimulus characterization","pmids":["36860353"],"is_preprint":false},{"year":2023,"finding":"In giant cell arteritis, macrophages retain CD155 in the endoplasmic reticulum and fail to translocate it to the cell surface; CD155low antigen-presenting cells expand CD4+CD96+ T cells that release IL-9, driving vasculitis.","method":"CD155 subcellular fractionation/localization in GCA vs. control macrophages, CD4+CD96+ T cell expansion assays, recombinant IL-9 administration and anti-IL-9 antibody treatment in humanized mouse model of GCA","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 — subcellular localization with functional consequence established in humanized mouse model; single lab","pmids":["37075705"],"is_preprint":false},{"year":2010,"finding":"Necl-5 (CD155/PVR) knockdown in glioblastoma cells reduces invasion in 3D matrix and decreases MMP-2 expression and activity; Necl-5 activates Akt (which drives MMP-2 expression) through integrin-linked kinase (ILK) at focal contacts, where Necl-5, Akt, and ILK co-localize.","method":"RNAi knockdown, 3D invasion assay, MMP-2 zymography, western blotting for Akt activation, co-localization imaging","journal":"Journal of neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with multiple mechanistic readouts (MMP-2 expression/activity, Akt signaling, co-localization); single lab","pmids":["20680398"],"is_preprint":false},{"year":2020,"finding":"Bone marrow stromal cell-derived IL-8 upregulates PVR (CD155) surface expression on multiple myeloma cells at the transcriptional level via NF-κB; CXCR1/2 blockade or IL-8 RNA interference prevents PVR upregulation, and stromal microvesicles carrying IL-8 are required for the effect.","method":"Dominant-negative IκBα overexpression, CXCR1/2 blocking, IL-8 RNAi, NF-κB reporter assays, microvesicle isolation and functional assays, NK cytotoxicity assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal genetic and pharmacological interventions; single lab","pmids":["32069911"],"is_preprint":false},{"year":2021,"finding":"In cervical cancer cells, CD155 physically interacts with AKT and activates the AKT/mTOR/NF-κB pathway to inhibit autophagy and apoptosis; AKT knockdown reverses these effects, establishing CD155 as an upstream regulator of AKT.","method":"Co-immunoprecipitation of CD155 and AKT, CD155 KD/OE, AKT knockdown rescue experiments, western blotting for mTOR/NF-κB pathway components, autophagy/apoptosis assays","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP plus rescue experiments; single lab","pmids":["34164340"],"is_preprint":false},{"year":2024,"finding":"Platelet adhesion to circulating tumor cells transcriptionally upregulates CD155 via FAK/JNK/c-Jun cascade; CD155 on CTCs then engages TIGIT (but not CD96 or DNAM-1) on NK cells to inhibit cytotoxicity and promote metastasis.","method":"scRNA-seq, multiplex immunofluorescence, in vitro/ex vivo/in vivo cytotoxicity assays, FAK/JNK pathway inhibition, competition binding assays, TIGIT antibody blockade","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway (FAK/JNK/c-Jun) with receptor specificity determined by competition assay; single lab","pmids":["38779918"],"is_preprint":false},{"year":2024,"finding":"METTL1-mediated m7G modification of PKM mRNA enhances PKM2 expression, promoting glycolysis and H3K9 lactylation; PKM2 nuclear translocation then transcriptionally activates CD155 expression in colorectal cancer cells, creating a positive feedback loop that promotes immune evasion.","method":"RIP assay for m7G-PKM interaction, RNA stability analysis, ChIP (Cut&Run) for H3K9la at CD155 promoter, siRNA knockdown, METTL1 KO mice, western blotting","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (RIP, Cut&Run, KO mice) establishing epigenetic-to-transcriptional mechanism; single lab","pmids":["39741310"],"is_preprint":false},{"year":2007,"finding":"PVR (CD155) is constitutively expressed in osteoclast precursors and stromal cells; soluble DNAM-1 extracellular domain (which binds PVR) inhibits multinucleated osteoclast formation specifically at the fusion step (days 6–7), and this suppression is partially abrogated by PVR-specific siRNA.","method":"PVR expression profiling in osteoclastogenesis stages, soluble DNAM-1-Fc treatment, PVR siRNA knockdown rescue","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function (siRNA) with functional rescue; specific stage defined; single lab","pmids":["17286202"],"is_preprint":false},{"year":2023,"finding":"Brain metastasis cancer-associated fibroblasts (bmCAFs) secrete fucosylated PVR (CD155); HIF1α transcriptionally upregulates fucosyltransferase 11, which fucosylates PVR and triggers its secretion; secreted fucosylated PVR modulates cell-cell junction and actin cytoskeletal signaling in breast cancer cells to enhance invasion.","method":"Proteomics of bmCAF conditioned medium, HIF1α ChIP, FUT11 knockdown, global phosphoproteomics of cancer cells treated with PVR, functional invasion assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal approaches including ChIP, phosphoproteomics, and functional assays; single lab","pmids":["37995180"],"is_preprint":false}],"current_model":"PVR (CD155) is a multifunctional immunoglobulin-like cell-surface receptor that acts as a ligand for the activating receptor DNAM-1 (CD226) and the inhibitory checkpoint receptors TIGIT, CD96, and KIR2DL5 on NK and T cells; its cytoplasmic ITIM-containing domain interacts with the dynein light chain Tctex-1 to mediate retrograde vesicular transport, and its extracellular domain engages integrin αVβ3 to promote cell migration and angiogenesis via Akt signaling; CD155 expression is transcriptionally induced by Ras/Raf-MEK-ERK-AP-1 signaling and by TLR-NF-κB pathways, and is post-transcriptionally regulated by METTL3-mediated m6A mRNA stabilization; at cell junctions, CD155 undergoes nectin-3-induced clathrin-dependent endocytosis to enforce contact inhibition, while tumor-derived CD155 drives immune evasion by triggering Src/CBL-B-mediated ubiquitination and proteasomal degradation of CD226 on lymphocytes."},"narrative":{"teleology":[{"year":2001,"claim":"Identification of the cytoplasmic Tctex-1 interaction established that CD155 is not merely a passive viral receptor but actively couples to the dynein motor complex for retrograde vesicular transport, revealing a cell-biological function for its intracellular domain.","evidence":"Yeast two-hybrid screen with biochemical pulldown and Co-IP domain mapping in mammalian cells","pmids":["11751937"],"confidence":"High","gaps":["Whether Tctex-1 interaction is required for CD155 trafficking in non-neuronal contexts","No structural detail of the CD155-Tctex-1 interface"]},{"year":2001,"claim":"Demonstration that CD155 binds vitronectin with nanomolar affinity suggested a role in cell–matrix adhesion beyond its known viral receptor function.","evidence":"Surface plasmon resonance quantitative binding assay","pmids":["11437656"],"confidence":"Medium","gaps":["Limited functional validation in cellular adhesion assays","Relationship to integrin αVβ3-dependent migration unclear at this stage"]},{"year":2003,"claim":"The discovery that CD155 trans-interacts heterophilically with nectin-3 (but not homophilically) and enhances motility of Ras-transformed cells linked CD155 to intercellular adhesion signaling and oncogenic cell behavior.","evidence":"Binding assays and cell motility assays with trans-interaction partners in NIH3T3 cells","pmids":["12740392"],"confidence":"High","gaps":["Signaling intermediates downstream of the nectin-3–CD155 interaction not yet identified"]},{"year":2004,"claim":"Functional identification of CD155 and CD112 as ligands for the activating receptor DNAM-1 on NK and T cells, together with the finding that endothelial CD155–DNAM-1 interaction regulates monocyte diapedesis, established CD155 as a key immunological ligand controlling both cytotoxicity and leukocyte trafficking.","evidence":"Ectopic expression/blocking antibody cytotoxicity assays; soluble DNAM-1-Fc binding on endothelial cells with transendothelial migration readout","pmids":["15039383","15136589"],"confidence":"High","gaps":["Signaling events downstream of PVR–DNAM-1 engagement in endothelial cells not resolved","Relative contributions of CD155 vs. CD112 in vivo unclear"]},{"year":2004,"claim":"Showing that CD155 cooperates with integrin αVβ3 at leading edges and activates Rac/Cdc42 for directional migration, while the Tctex-1 interaction mediates retrograde neuronal transport, delineated two distinct signaling modes of CD155 — one extracellular/migratory and one cytoplasmic/trafficking.","evidence":"Mutant CD155 expression in fibroblasts with GTPase activation assays and integrin inhibitors; live-cell vesicle tracking in differentiated PC12 neurons with Tctex-1-binding mutants","pmids":["14871893","15194795"],"confidence":"High","gaps":["Direct structural basis of CD155–integrin αVβ3 interaction unresolved","Whether Cdc42/Rac activation requires integrin kinase activity"]},{"year":2005,"claim":"Two advances framed CD155 as an oncogene-responsive, contact-inhibited molecule: Ras/Raf-MEK-ERK-AP-1 signaling was shown to transcriptionally upregulate CD155, and nectin-3-induced clathrin-dependent endocytosis of CD155 at cell–cell contacts was demonstrated to enforce contact inhibition of proliferation and migration.","evidence":"Promoter-reporter assays with AP-1 site mutagenesis and MEK inhibitors; clathrin inhibition with surface expression quantification and proliferation/migration assays","pmids":["15688018","16216929"],"confidence":"High","gaps":["Endocytic adaptor linking nectin-3 engagement to clathrin machinery not identified","Whether AP-1-driven upregulation operates in human tumors in vivo"]},{"year":2008,"claim":"The finding that CD155's cytoplasmic ITIM is required for enhanced proliferation specifically in Ras-mutant cells, via cyclin D2 upregulation and p27Kip1 downregulation, revealed a cell-intrinsic growth-promoting signaling role for CD155 in oncogenic contexts.","evidence":"CD155 overexpression/knockdown and ITIM deletion mutants in Ras-transformed cell lines with cell cycle analysis","pmids":["17893876"],"confidence":"Medium","gaps":["Phosphatase recruited by the ITIM in this proliferative context not identified","Single lab; not independently replicated"]},{"year":2009,"claim":"Discovery of TIGIT as an inhibitory receptor for PVR, functioning through its own ITIM to suppress NK cytotoxicity independently of MHC class I, established PVR as a nexus for balancing activating (DNAM-1) and inhibitory (TIGIT) immune signals.","evidence":"Binding assays, ITIM mutagenesis, NK cytotoxicity assays","pmids":["19815499"],"confidence":"High","gaps":["Relative binding affinities of TIGIT vs. DNAM-1 for PVR not quantitatively resolved in this study","Whether TIGIT and DNAM-1 compete for the same PVR epitope"]},{"year":2012,"claim":"Two studies expanded CD155's functional scope: CD155 was shown to form a complex with VEGFR2 required for VEGF-induced angiogenesis via Rap1/Akt/eNOS, and HIV-1 Nef was found to downregulate CD155 to evade NK-mediated DNAM-1-dependent lysis, demonstrating pathogen exploitation of the PVR–DNAM-1 axis.","evidence":"Co-IP of CD155–VEGFR2 with siRNA knockdown in HUVECs and Necl-5 KO mouse ischemia model; Nef motif mutagenesis with NK cytotoxicity assays across HIV strains","pmids":["22282193","22301152"],"confidence":"High","gaps":["Whether CD155 directly contacts VEGFR2 or requires an intermediate","Whether other viruses exploit similar CD155 downregulation"]},{"year":2013,"claim":"Mechanistic studies on endothelial PVR showed it recruits Shp-2 phosphatase in a Src-dependent manner during monocyte diapedesis, while TLR activation was found to upregulate CD155 on APCs through MYD88/TRIF/NF-κB/IRF3, with CD155-deficient mice showing impaired Th2 differentiation — revealing CD155 as a regulated immunomodulatory ligand.","evidence":"Sequential blocking antibody epistasis with Shp-2 recruitment assays; TLR ligand stimulation in MYD88−/−/TRIF−/− mice with in vivo OVA/CpG immunization","pmids":["23333754","23349877"],"confidence":"High","gaps":["Whether Shp-2 recruitment is the sole signaling pathway during PVR-mediated diapedesis","Mechanism by which CD155 on APCs specifically favors Th2 over other T helper subsets"]},{"year":2018,"claim":"Genetic ablation of CD155 in both tumor and host compartments demonstrated dual roles: tumor-intrinsic CD155 promotes growth/metastasis, while host CD155 drives DNAM-1 downregulation on NK and T cells, suppressing anti-tumor immunity. Crystal structure of the CD226–CD155 complex revealed a unique side-by-side IgV arrangement requiring both D1 and D2 of CD226.","evidence":"Cd155−/− mice and CD155-deleted tumor cells in metastasis models; X-ray crystallography of mCD226/hCD155-D1 complex with truncation binding validation","pmids":["29757192","30591568"],"confidence":"High","gaps":["Structural basis of TIGIT–PVR vs. DNAM-1–PVR competition not resolved","Whether tumor-intrinsic CD155 signals through the same ITIM/Akt pathways identified in vitro"]},{"year":2019,"claim":"Identification of KIR2DL5 as a fourth immune receptor for PVR — binding a non-overlapping epitope from TIGIT/CD96/DNAM-1 and recruiting SHP-1/SHP-2 to suppress Vav1/ERK/NF-κB — expanded the inhibitory checkpoint network centered on PVR.","evidence":"Binding competition assays, inhibitory synapse imaging, phosphoproteomic analysis, KIR2DL5 blocking mAbs in humanized tumor models","pmids":["36377656"],"confidence":"High","gaps":["Whether KIR2DL5 engagement dominates over TIGIT in specific tissue contexts","Structural basis of the non-competitive KIR2DL5 binding mode"]},{"year":2020,"claim":"A critical immune evasion mechanism was elucidated: tumor CD155 engagement of CD226 triggers Src-dependent Y319 phosphorylation and CBL-B-mediated ubiquitination/proteasomal degradation of CD226 on CD8+ T and NK cells, explaining why CD226 is lost on tumor-infiltrating lymphocytes and why checkpoint blockade fails. A soluble CD155 isoform preferentially sequesters DNAM-1 over TIGIT to suppress NK killing.","evidence":"CD226 Y319 mutagenesis and CBL-B Co-IP with proteasome inhibitor rescue in vivo; sCD155-expressing tumors in receptor-KO mouse panel with NK degranulation assays","pmids":["33053330","32591463","32040157"],"confidence":"High","gaps":["Whether therapeutic CD155 blockade can restore CD226 levels in patients","Regulation of the sCD155 splice isoform"]},{"year":2022,"claim":"METTL3-mediated m6A modification at specific 3′UTR sites of CD155 mRNA was shown to stabilize the transcript and increase surface CD155 on macrophages, adding a post-transcriptional regulatory layer that links metabolic stress (ox-LDL) to immune checkpoint ligand expression.","evidence":"MeRIP m6A mapping, METTL3 knockdown/overexpression, mRNA stability assays, T cell suppression in humanized mouse model of coronary artery disease","pmids":["36860353"],"confidence":"High","gaps":["Whether m6A-mediated CD155 regulation operates in tumor cells","Identity of the m6A reader protein stabilizing CD155 mRNA"]},{"year":2023,"claim":"Multiple studies revealed context-dependent regulation: IL-22 from T cells induces CD155 on cancer cells to drive NK dysfunction via CD226 degradation; ER retention of CD155 in giant cell arteritis macrophages expands pathogenic CD96+ T cells; and brain metastasis fibroblasts secrete fucosylated PVR (via HIF1α/FUT11) that remodels cancer cell signaling.","evidence":"Il22−/− and Il22r−/− genetic models with NK assays; subcellular fractionation and humanized GCA mouse model; proteomics/phosphoproteomics of bmCAF secretome with FUT11 knockdown","pmids":["36630913","37075705","37995180"],"confidence":"High","gaps":["Whether secreted fucosylated PVR engages the same immune receptors as membrane-bound PVR","Mechanism of ER retention in GCA macrophages","Whether IL-22-driven CD155 upregulation is targetable therapeutically"]},{"year":2024,"claim":"Additional transcriptional induction pathways were uncovered: platelet adhesion to circulating tumor cells upregulates CD155 via FAK/JNK/c-Jun to engage TIGIT on NK cells, and PKM2 nuclear translocation driven by METTL1-mediated m7G modification of PKM mRNA activates CD155 transcription through H3K9 lactylation at the CD155 promoter.","evidence":"scRNA-seq with FAK/JNK pathway inhibition and TIGIT antibody blockade in hepatocellular carcinoma; Cut&Run for H3K9la at CD155 promoter with METTL1 KO mice in colorectal cancer","pmids":["38779918","39741310"],"confidence":"Medium","gaps":["Whether H3K9 lactylation is a general mechanism across tumor types","Single-lab findings for both pathways","Relative quantitative contribution of each transcriptional axis to total CD155 levels in tumors"]},{"year":null,"claim":"Key unresolved questions include the structural basis for how PVR simultaneously engages four distinct receptors (DNAM-1, TIGIT, CD96, KIR2DL5), the identity of the m6A reader stabilizing CD155 mRNA, whether therapeutic CD155 blockade can restore CD226 on tumor-infiltrating lymphocytes in patients, and the relative contribution of membrane-bound vs. soluble vs. secreted fucosylated PVR isoforms to immune evasion in different tumor microenvironments.","evidence":"","pmids":[],"confidence":"High","gaps":["No co-crystal structure of PVR simultaneously bound to TIGIT and DNAM-1","No clinical data on CD155-directed immunotherapy","Mechanism of ER retention in disease macrophages uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,2,6,11]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,18,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[14,15,22,23]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,6,7,16]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,4,11]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[22,32]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[25]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,13,14,15,17,18,22,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,8,10,20,26,28]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[2,5,7,11]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,16,29,30]}],"complexes":[],"partners":["CD226","TIGIT","CD96","KIR2DL5","DYNLT1","ITGB3","NECTIN3","KDR"],"other_free_text":[]},"mechanistic_narrative":"PVR (CD155/Necl-5) is an immunoglobulin superfamily cell-surface glycoprotein that serves as a central hub linking cell migration, contact inhibition, and immune regulation. Its extracellular domain engages multiple receptors on NK and T cells — activating DNAM-1 (CD226) and inhibitory TIGIT, CD96, and KIR2DL5 — to bidirectionally tune cytotoxicity, with tumor-derived CD155 driving CD226 internalization and degradation via Src/CBL-B-mediated ubiquitination, thereby promoting immune evasion [PMID:15039383, PMID:19815499, PMID:36377656, PMID:33053330]. On non-immune cells, CD155 cooperates with integrin αVβ3 at leading edges to activate Rac/Cdc42 and Akt signaling for directional migration, while nectin-3-induced clathrin-dependent endocytosis of CD155 at cell–cell contacts enforces contact inhibition of proliferation [PMID:14871893, PMID:16216929]. CD155 transcription is induced by Ras/Raf-MEK-ERK-AP-1 signaling and by TLR–NF-κB pathways, and its mRNA is post-transcriptionally stabilized by METTL3-dependent m6A modification; its cytoplasmic ITIM domain binds the dynein light chain Tctex-1 to direct CD155-containing vesicles into retrograde microtubule-based transport [PMID:15688018, PMID:23349877, PMID:36860353, PMID:11751937]."},"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":"19815499","id":"PMC_19815499","title":"The 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of Cervical Cancer Cells Through AKT/mTOR and NF-κB Pathways.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34164340","citation_count":21,"is_preprint":false},{"pmid":"30176221","id":"PMC_30176221","title":"Comparative proteomic analysis of normal and gliotic PVR retina and contribution of Müller glia to this profile.","date":"2018","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/30176221","citation_count":21,"is_preprint":false},{"pmid":"11255021","id":"PMC_11255021","title":"Organization of the rat Tage4 gene and herpesvirus entry activity of the encoded protein.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11255021","citation_count":21,"is_preprint":false},{"pmid":"25384044","id":"PMC_25384044","title":"Increased CD112 expression in methylcholanthrene-induced tumors in CD155-deficient mice.","date":"2014","source":"PloS 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\"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding characterization plus functional ITIM mutagenesis/pathway analysis; widely replicated\",\n      \"pmids\": [\"19815499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD155 (PVR) and Nectin-2 (CD112) were identified as the functional ligands for DNAM-1 (CD226); ectopic expression of CD155 on target cells rendered them susceptible to T and NK cell-mediated cytotoxicity in a CD226-dependent manner.\",\n      \"method\": \"Ectopic expression in BW5147 cells, blocking mAb inhibition, cytotoxicity assays, soluble receptor binding affinity measurements\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional reconstitution with blocking antibody validation; replicated across labs\",\n      \"pmids\": [\"15039383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PVR (CD155) is expressed at endothelial cell junctions and interacts with DNAM-1 (CD226) on monocytes to regulate the diapedesis step of transendothelial migration; anti-PVR mAbs arrested monocytes at the apical surface over intercellular junctions.\",\n      \"method\": \"Soluble DNAM-1-Fc binding assay on endothelial cells, blocking mAb treatment in transendothelial migration assay, localization by imaging\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — orthogonal methods including soluble ligand binding, blocking antibodies, and cell biology assays with clear phenotypic readout\",\n      \"pmids\": [\"15136589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The cytoplasmic domain of CD155 (PVR) associates with Tctex-1, a dynein motor complex light chain, via a SKCSR juxtamembrane motif; this interaction targets CD155-containing endocytic vesicles to the microtubular network for retrograde transport.\",\n      \"method\": \"Yeast two-hybrid screen, biochemical pulldown, co-immunoprecipitation, domain mapping mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — yeast two-hybrid discovery confirmed by biochemical pulldown and Co-IP with domain mapping\",\n      \"pmids\": [\"11751937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD155/PVR-containing vesicles undergo receptor-dependent endocytosis and retrograde axonal transport; the direct interaction between the cytoplasmic domain of CD155 and Tctex-1 is essential for efficient retrograde transport of poliovirus-containing vesicles along microtubules in neurons.\",\n      \"method\": \"GST pulldown, immunoelectron microscopy, live-cell vesicle tracking in differentiated PC12 cells with wild-type vs. Tctex-1-binding mutant hPVR, vinblastine nerve block in vivo\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of binding confirmed by mutant analysis, in vivo retrograde transport validation\",\n      \"pmids\": [\"15194795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD155 (Tage4/Necl-5) heterophilically trans-interacts with nectin-3 but not homophilically with itself; this interaction enhances motility of Ras-transformed NIH3T3 cells.\",\n      \"method\": \"Binding assays, cell motility assays with trans-interaction partners, domain analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding characterization combined with functional cell motility readout\",\n      \"pmids\": [\"12740392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Necl-5 (CD155/PVR) enhances serum- and PDGF-induced cell migration in an integrin αVβ3-dependent manner; it colocalizes with integrin αVβ3 at leading edges, and its extracellular region is required for directional migration while the cytoplasmic region is required for both directional and random motility. Cdc42 and Rac GTPases are activated downstream.\",\n      \"method\": \"Necl-5 mutant expression in L fibroblasts and NIH3T3 cells, integrin inhibitor/activator assays, dominant-negative Necl-5, co-localization imaging, GTPase activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including mutagenesis, pharmacological inhibition, and signaling readouts\",\n      \"pmids\": [\"14871893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Upon cell-cell contact, Necl-5 (CD155/PVR) interaction with nectin-3 triggers clathrin-dependent endocytosis of Necl-5 from the cell surface, reducing cell movement and proliferation—a mechanism underlying contact inhibition.\",\n      \"method\": \"Cell-cell contact assays, clathrin inhibition, surface expression quantification, cell migration and proliferation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection with pharmacological inhibition of endocytosis and multiple functional readouts\",\n      \"pmids\": [\"16216929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mouse Necl-5 (CD155/PVR) expression is transcriptionally induced by FGF or oncogenic V12Ki-Ras through the Raf-MEK-ERK-AP-1 signaling pathway; an AP-1 binding site in the Necl-5 promoter is required for this induction.\",\n      \"method\": \"Luciferase reporter assays with Necl-5 promoter, pathway inhibitors (MEK inhibitor), AP-1 site mutagenesis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — promoter-reporter reconstitution with site mutagenesis and signaling inhibitors\",\n      \"pmids\": [\"15688018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD155 (PVR) specifically binds vitronectin with a Kd of ~72 nM as measured by surface plasmon resonance, mediating cell-to-matrix contacts; related PRR proteins do not show equivalent CD155-like binding.\",\n      \"method\": \"Surface plasmon resonance binding assay, co-localization in lymphoid tissue\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — quantitative binding assay (SPR) but limited functional validation in cells\",\n      \"pmids\": [\"11437656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Necl-5 (CD155/PVR) interacts with VEGFR2 and is required for VEGF-induced interaction of integrin αVβ3 with VEGFR2; knockdown of Necl-5 in HUVECs suppresses VEGF-induced Rap1, Akt, and eNOS activation and impairs angiogenic responses in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown in HUVECs, Matrigel tube formation, migration and proliferation assays, Necl-5 knockout mouse hindlimb ischemia model\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP establishing complex formation combined with KO mouse model and multiple in vitro functional readouts\",\n      \"pmids\": [\"22282193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"During monocyte transendothelial migration, endothelial PVR (CD155) interaction with DNAM-1 recruits tyrosine phosphatase Shp-2 in a Src kinase-dependent manner; this regulates a step in diapedesis between those regulated by PECAM and CD99. PVR resides in the lateral border recycling compartment of endothelial cells.\",\n      \"method\": \"Blocking antibody sequential treatment, Shp-2 recruitment assay, Src kinase inhibition, subcellular fractionation/localization of PVR\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via sequential antibody blockade, signaling molecule recruitment with phosphatase identification, localization data\",\n      \"pmids\": [\"23333754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TLR activation upregulates CD155 expression on antigen-presenting cells through MYD88, TRIF, NF-κB, and IRF3 (but not IRF7) signaling; CD155-deficient mice show reduced Th2 differentiation (lower IL-4, fewer GATA-3+ CD4+ T cells) upon immunization.\",\n      \"method\": \"TLR ligand stimulation with pathway inhibitors/knockouts (MYD88-/-, TRIF-/-, NF-κB inhibitors), IRF knockout mice, in vivo immunization with OVA/CpG\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockouts combined with in vivo functional immune phenotyping, single lab\",\n      \"pmids\": [\"23349877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HIV-1 Nef protein downregulates cell-surface PVR (CD155) on infected T lymphocytes using the same structural motifs used to downregulate HLA-I, reducing total cell-associated PVR; Vpu further optimizes surface PVR reduction. This downregulation abrogates NK-mediated lysis via DNAM-1.\",\n      \"method\": \"Flow cytometry of surface and total PVR levels, Nef motif mutagenesis, NK cytotoxicity blocking assays with anti-DNAM-1 and anti-NKG2D\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis of Nef motifs combined with functional NK killing assays; multiple HIV strains tested\",\n      \"pmids\": [\"22301152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Tumor-derived CD155 initiates phosphorylation of CD226 at tyrosine 319 by Src kinases, enabling ubiquitination of CD226 by CBL-B, followed by internalization and proteasomal degradation of CD226 on CD8+ T cells, thereby driving T cell dysfunction and resistance to immune checkpoint blockade.\",\n      \"method\": \"CD226 Y319 mutagenesis, Src kinase inhibition, CBL-B Co-IP, flow cytometry of CD226 surface levels, proteasome inhibitor rescue, in vivo tumor models with CD226 mutant knock-in\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mechanistic reconstitution with site-specific mutagenesis, identified E3 ligase (CBL-B), and in vivo validation\",\n      \"pmids\": [\"33053330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Membrane-bound CD155 on melanoma cells triggers CD226 internalization and degradation on NK cells, resulting in decreased NK-cell-mediated tumor reactivity; IL-15 restores TIGIT and CD226 gene expression on tumor-infiltrating NK cells.\",\n      \"method\": \"Flow cytometry of CD226 surface expression and internalization, in vitro cytotoxicity assays, NK-specific TIGIT deletion in transfer experiments, two mouse melanoma models\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell biological mechanism (CD226 internalization) confirmed in genetic NK-specific TIGIT deletion models and in vivo melanoma models\",\n      \"pmids\": [\"32591463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PVRL1 (Nectin-1) on hepatocellular carcinoma cells stabilizes cell-surface PVR protein (without affecting Pvr mRNA), which then interacts with TIGIT on CD8+ effector memory T cells to suppress anti-tumor immunity; knockdown of Pvrl1 reduces surface PVR and decreases tumor growth.\",\n      \"method\": \"shRNA knockdown of Pvrl1 and Pvrl3, surface vs. mRNA PVR measurement, tumor growth assays in vivo, mass cytometry, combination anti-PD1/anti-TIGIT treatment\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockdown distinguishing mRNA from protein surface levels, in vivo tumor models, combination immunotherapy validation\",\n      \"pmids\": [\"32275969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD155 loss in tumor cells reduces tumor growth and metastasis through tumor-intrinsic mechanisms; in Cd155-/- mice, DNAM-1 is upregulated and NK and CD8+ T cell effector function is enhanced, demonstrating both cell-intrinsic and immune-extrinsic tumor-suppressive roles.\",\n      \"method\": \"Cd155-/- mouse model, CD155-deleted tumor cells, NK/CD8+ T cell functional assays, DNAM-1 surface expression measurement, in vivo tumor and metastasis models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO of CD155 in host and tumor separately, with specific immune cell readouts\",\n      \"pmids\": [\"29757192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PVR/KIR2DL5 is a novel immune checkpoint interaction: KIR2DL5 on NK cells binds PVR without competing with TIGIT, CD96, or DNAM-1; engagement induces inhibitory synapse formation and tyrosine phosphorylation of both ITIM and ITSM of KIR2DL5, recruiting SHP-1 and/or SHP-2 and downregulating Vav1/ERK1/2/p90RSK/NF-κB signaling.\",\n      \"method\": \"Binding competition assays, inhibitory synapse imaging, phosphoproteomic analysis, SHP-1/SHP-2 recruitment assays, KIR2DL5 blocking mAbs, humanized tumor mouse models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mechanistic characterization of phosphorylation sites, phosphatase recruitment, downstream signaling pathway, and in vivo validation\",\n      \"pmids\": [\"36377656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The crystal/structural analysis of CD226 (DNAM-1) bound to CD155 (Necl-5/D1) reveals a unique side-by-side arrangement of two IgV domains of CD226; both D1 and D2 of CD226 interact with CD155-D1, and removal of D2 substantially reduces CD226 binding efficacy to CD155.\",\n      \"method\": \"X-ray crystallography of mCD226-ecto and hybrid mCD226-ecto/hCD155-D1 complex, truncation binding assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional domain deletion validation\",\n      \"pmids\": [\"30591568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD155 enhances serum-induced cell proliferation specifically in Ras-mutated cells; the cytoplasmic ITIM of CD155 is required for this effect, and CD155 upregulates cyclin D2 and downregulates p27Kip1 to shorten G0/G1 phase.\",\n      \"method\": \"CD155 overexpression and siRNA knockdown in Ras-transformed and Ras-mutated cancer cell lines, cell cycle analysis, cyclin/CDK inhibitor western blotting, ITIM deletion mutant analysis, FAK inhibitor control\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis (ITIM deletion), gain- and loss-of-function, multiple Ras-mutant cell lines; single lab\",\n      \"pmids\": [\"17893876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD155 (PVR) mediates a costimulatory signal in CD4+ T cells that promotes Th1 development via NF-κB-induced autocrine IFN-γ and STAT1 positive feedback, independent of IL-12; CD155-deficient mice show attenuated Th1-type contact hypersensitivity.\",\n      \"method\": \"CD155-/- mice, anti-CD155 antibody treatment, cytokine measurement (IFN-γ), Tbx21 expression, NF-κB and STAT1 inhibitor studies, contact hypersensitivity model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with signaling inhibitor studies, single lab\",\n      \"pmids\": [\"25972481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Soluble CD155 (sCD155), expressed by human tumor cells from a splice isoform lacking the transmembrane region, preferentially binds DNAM-1 over TIGIT and CD96, and inhibits DNAM-1-mediated NK cell degranulation and killing, thereby promoting lung colonization by melanoma cells.\",\n      \"method\": \"In vivo injection of sCD155-expressing vs. parental B16/BL6 melanoma in TIGIT-KO, CD96-KO, and DNAM-1-KO mice; NK depletion experiments; in vitro NK degranulation assays; binding affinity comparison\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO mouse panel plus in vitro functional assays establishing receptor preference\",\n      \"pmids\": [\"32040157\"],\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; excessive CD155 binding to CD226 on NK cells triggers CD226 internalization/degradation and NK cell functional impairment, elevating metastatic burden.\",\n      \"method\": \"Constitutional and T cell-specific Il22 deletion in mouse lung/breast cancer models, Il22 receptor deletion on cancer cells, CD226 surface expression and functional assays, NK cell cytotoxicity assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic models (Il22-/-, Il22r-/- on cancer cells) with mechanistic NK cell functional readouts; orthogonal validation\",\n      \"pmids\": [\"36630913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In coronary artery disease, macrophage METTL3 overexpression promotes m6A modification at positions 1635 and 3103 in the 3'UTR of CD155 mRNA, stabilizing the transcript and enhancing CD155 surface expression on macrophages, which then deliver inhibitory signals to CD4+ T cells via CD96 and TIGIT.\",\n      \"method\": \"m6A mapping (MeRIP), METTL3 knockdown/overexpression, mRNA stability assays, CD155 surface and mRNA measurements, T cell suppression assays in vitro and humanized mouse model\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — m6A site identification with mRNA stability validation, in vivo humanized mouse model, LDL stimulus characterization\",\n      \"pmids\": [\"36860353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In giant cell arteritis, macrophages retain CD155 in the endoplasmic reticulum and fail to translocate it to the cell surface; CD155low antigen-presenting cells expand CD4+CD96+ T cells that release IL-9, driving vasculitis.\",\n      \"method\": \"CD155 subcellular fractionation/localization in GCA vs. control macrophages, CD4+CD96+ T cell expansion assays, recombinant IL-9 administration and anti-IL-9 antibody treatment in humanized mouse model of GCA\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — subcellular localization with functional consequence established in humanized mouse model; single lab\",\n      \"pmids\": [\"37075705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Necl-5 (CD155/PVR) knockdown in glioblastoma cells reduces invasion in 3D matrix and decreases MMP-2 expression and activity; Necl-5 activates Akt (which drives MMP-2 expression) through integrin-linked kinase (ILK) at focal contacts, where Necl-5, Akt, and ILK co-localize.\",\n      \"method\": \"RNAi knockdown, 3D invasion assay, MMP-2 zymography, western blotting for Akt activation, co-localization imaging\",\n      \"journal\": \"Journal of neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple mechanistic readouts (MMP-2 expression/activity, Akt signaling, co-localization); single lab\",\n      \"pmids\": [\"20680398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Bone marrow stromal cell-derived IL-8 upregulates PVR (CD155) surface expression on multiple myeloma cells at the transcriptional level via NF-κB; CXCR1/2 blockade or IL-8 RNA interference prevents PVR upregulation, and stromal microvesicles carrying IL-8 are required for the effect.\",\n      \"method\": \"Dominant-negative IκBα overexpression, CXCR1/2 blocking, IL-8 RNAi, NF-κB reporter assays, microvesicle isolation and functional assays, NK cytotoxicity assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genetic and pharmacological interventions; single lab\",\n      \"pmids\": [\"32069911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In cervical cancer cells, CD155 physically interacts with AKT and activates the AKT/mTOR/NF-κB pathway to inhibit autophagy and apoptosis; AKT knockdown reverses these effects, establishing CD155 as an upstream regulator of AKT.\",\n      \"method\": \"Co-immunoprecipitation of CD155 and AKT, CD155 KD/OE, AKT knockdown rescue experiments, western blotting for mTOR/NF-κB pathway components, autophagy/apoptosis assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP plus rescue experiments; single lab\",\n      \"pmids\": [\"34164340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Platelet adhesion to circulating tumor cells transcriptionally upregulates CD155 via FAK/JNK/c-Jun cascade; CD155 on CTCs then engages TIGIT (but not CD96 or DNAM-1) on NK cells to inhibit cytotoxicity and promote metastasis.\",\n      \"method\": \"scRNA-seq, multiplex immunofluorescence, in vitro/ex vivo/in vivo cytotoxicity assays, FAK/JNK pathway inhibition, competition binding assays, TIGIT antibody blockade\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway (FAK/JNK/c-Jun) with receptor specificity determined by competition assay; single lab\",\n      \"pmids\": [\"38779918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL1-mediated m7G modification of PKM mRNA enhances PKM2 expression, promoting glycolysis and H3K9 lactylation; PKM2 nuclear translocation then transcriptionally activates CD155 expression in colorectal cancer cells, creating a positive feedback loop that promotes immune evasion.\",\n      \"method\": \"RIP assay for m7G-PKM interaction, RNA stability analysis, ChIP (Cut&Run) for H3K9la at CD155 promoter, siRNA knockdown, METTL1 KO mice, western blotting\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RIP, Cut&Run, KO mice) establishing epigenetic-to-transcriptional mechanism; single lab\",\n      \"pmids\": [\"39741310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PVR (CD155) is constitutively expressed in osteoclast precursors and stromal cells; soluble DNAM-1 extracellular domain (which binds PVR) inhibits multinucleated osteoclast formation specifically at the fusion step (days 6–7), and this suppression is partially abrogated by PVR-specific siRNA.\",\n      \"method\": \"PVR expression profiling in osteoclastogenesis stages, soluble DNAM-1-Fc treatment, PVR siRNA knockdown rescue\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function (siRNA) with functional rescue; specific stage defined; single lab\",\n      \"pmids\": [\"17286202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Brain metastasis cancer-associated fibroblasts (bmCAFs) secrete fucosylated PVR (CD155); HIF1α transcriptionally upregulates fucosyltransferase 11, which fucosylates PVR and triggers its secretion; secreted fucosylated PVR modulates cell-cell junction and actin cytoskeletal signaling in breast cancer cells to enhance invasion.\",\n      \"method\": \"Proteomics of bmCAF conditioned medium, HIF1α ChIP, FUT11 knockdown, global phosphoproteomics of cancer cells treated with PVR, functional invasion assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches including ChIP, phosphoproteomics, and functional assays; single lab\",\n      \"pmids\": [\"37995180\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PVR (CD155) is a multifunctional immunoglobulin-like cell-surface receptor that acts as a ligand for the activating receptor DNAM-1 (CD226) and the inhibitory checkpoint receptors TIGIT, CD96, and KIR2DL5 on NK and T cells; its cytoplasmic ITIM-containing domain interacts with the dynein light chain Tctex-1 to mediate retrograde vesicular transport, and its extracellular domain engages integrin αVβ3 to promote cell migration and angiogenesis via Akt signaling; CD155 expression is transcriptionally induced by Ras/Raf-MEK-ERK-AP-1 signaling and by TLR-NF-κB pathways, and is post-transcriptionally regulated by METTL3-mediated m6A mRNA stabilization; at cell junctions, CD155 undergoes nectin-3-induced clathrin-dependent endocytosis to enforce contact inhibition, while tumor-derived CD155 drives immune evasion by triggering Src/CBL-B-mediated ubiquitination and proteasomal degradation of CD226 on lymphocytes.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PVR (CD155/Necl-5) is an immunoglobulin superfamily cell-surface glycoprotein that serves as a central hub linking cell migration, contact inhibition, and immune regulation. Its extracellular domain engages multiple receptors on NK and T cells — activating DNAM-1 (CD226) and inhibitory TIGIT, CD96, and KIR2DL5 — to bidirectionally tune cytotoxicity, with tumor-derived CD155 driving CD226 internalization and degradation via Src/CBL-B-mediated ubiquitination, thereby promoting immune evasion [PMID:15039383, PMID:19815499, PMID:36377656, PMID:33053330]. On non-immune cells, CD155 cooperates with integrin αVβ3 at leading edges to activate Rac/Cdc42 and Akt signaling for directional migration, while nectin-3-induced clathrin-dependent endocytosis of CD155 at cell–cell contacts enforces contact inhibition of proliferation [PMID:14871893, PMID:16216929]. CD155 transcription is induced by Ras/Raf-MEK-ERK-AP-1 signaling and by TLR–NF-κB pathways, and its mRNA is post-transcriptionally stabilized by METTL3-dependent m6A modification; its cytoplasmic ITIM domain binds the dynein light chain Tctex-1 to direct CD155-containing vesicles into retrograde microtubule-based transport [PMID:15688018, PMID:23349877, PMID:36860353, PMID:11751937].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of the cytoplasmic Tctex-1 interaction established that CD155 is not merely a passive viral receptor but actively couples to the dynein motor complex for retrograde vesicular transport, revealing a cell-biological function for its intracellular domain.\",\n      \"evidence\": \"Yeast two-hybrid screen with biochemical pulldown and Co-IP domain mapping in mammalian cells\",\n      \"pmids\": [\"11751937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Tctex-1 interaction is required for CD155 trafficking in non-neuronal contexts\", \"No structural detail of the CD155-Tctex-1 interface\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstration that CD155 binds vitronectin with nanomolar affinity suggested a role in cell–matrix adhesion beyond its known viral receptor function.\",\n      \"evidence\": \"Surface plasmon resonance quantitative binding assay\",\n      \"pmids\": [\"11437656\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited functional validation in cellular adhesion assays\", \"Relationship to integrin αVβ3-dependent migration unclear at this stage\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The discovery that CD155 trans-interacts heterophilically with nectin-3 (but not homophilically) and enhances motility of Ras-transformed cells linked CD155 to intercellular adhesion signaling and oncogenic cell behavior.\",\n      \"evidence\": \"Binding assays and cell motility assays with trans-interaction partners in NIH3T3 cells\",\n      \"pmids\": [\"12740392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling intermediates downstream of the nectin-3–CD155 interaction not yet identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Functional identification of CD155 and CD112 as ligands for the activating receptor DNAM-1 on NK and T cells, together with the finding that endothelial CD155–DNAM-1 interaction regulates monocyte diapedesis, established CD155 as a key immunological ligand controlling both cytotoxicity and leukocyte trafficking.\",\n      \"evidence\": \"Ectopic expression/blocking antibody cytotoxicity assays; soluble DNAM-1-Fc binding on endothelial cells with transendothelial migration readout\",\n      \"pmids\": [\"15039383\", \"15136589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling events downstream of PVR–DNAM-1 engagement in endothelial cells not resolved\", \"Relative contributions of CD155 vs. CD112 in vivo unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showing that CD155 cooperates with integrin αVβ3 at leading edges and activates Rac/Cdc42 for directional migration, while the Tctex-1 interaction mediates retrograde neuronal transport, delineated two distinct signaling modes of CD155 — one extracellular/migratory and one cytoplasmic/trafficking.\",\n      \"evidence\": \"Mutant CD155 expression in fibroblasts with GTPase activation assays and integrin inhibitors; live-cell vesicle tracking in differentiated PC12 neurons with Tctex-1-binding mutants\",\n      \"pmids\": [\"14871893\", \"15194795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural basis of CD155–integrin αVβ3 interaction unresolved\", \"Whether Cdc42/Rac activation requires integrin kinase activity\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Two advances framed CD155 as an oncogene-responsive, contact-inhibited molecule: Ras/Raf-MEK-ERK-AP-1 signaling was shown to transcriptionally upregulate CD155, and nectin-3-induced clathrin-dependent endocytosis of CD155 at cell–cell contacts was demonstrated to enforce contact inhibition of proliferation and migration.\",\n      \"evidence\": \"Promoter-reporter assays with AP-1 site mutagenesis and MEK inhibitors; clathrin inhibition with surface expression quantification and proliferation/migration assays\",\n      \"pmids\": [\"15688018\", \"16216929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endocytic adaptor linking nectin-3 engagement to clathrin machinery not identified\", \"Whether AP-1-driven upregulation operates in human tumors in vivo\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The finding that CD155's cytoplasmic ITIM is required for enhanced proliferation specifically in Ras-mutant cells, via cyclin D2 upregulation and p27Kip1 downregulation, revealed a cell-intrinsic growth-promoting signaling role for CD155 in oncogenic contexts.\",\n      \"evidence\": \"CD155 overexpression/knockdown and ITIM deletion mutants in Ras-transformed cell lines with cell cycle analysis\",\n      \"pmids\": [\"17893876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphatase recruited by the ITIM in this proliferative context not identified\", \"Single lab; not independently replicated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Discovery of TIGIT as an inhibitory receptor for PVR, functioning through its own ITIM to suppress NK cytotoxicity independently of MHC class I, established PVR as a nexus for balancing activating (DNAM-1) and inhibitory (TIGIT) immune signals.\",\n      \"evidence\": \"Binding assays, ITIM mutagenesis, NK cytotoxicity assays\",\n      \"pmids\": [\"19815499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative binding affinities of TIGIT vs. DNAM-1 for PVR not quantitatively resolved in this study\", \"Whether TIGIT and DNAM-1 compete for the same PVR epitope\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Two studies expanded CD155's functional scope: CD155 was shown to form a complex with VEGFR2 required for VEGF-induced angiogenesis via Rap1/Akt/eNOS, and HIV-1 Nef was found to downregulate CD155 to evade NK-mediated DNAM-1-dependent lysis, demonstrating pathogen exploitation of the PVR–DNAM-1 axis.\",\n      \"evidence\": \"Co-IP of CD155–VEGFR2 with siRNA knockdown in HUVECs and Necl-5 KO mouse ischemia model; Nef motif mutagenesis with NK cytotoxicity assays across HIV strains\",\n      \"pmids\": [\"22282193\", \"22301152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD155 directly contacts VEGFR2 or requires an intermediate\", \"Whether other viruses exploit similar CD155 downregulation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mechanistic studies on endothelial PVR showed it recruits Shp-2 phosphatase in a Src-dependent manner during monocyte diapedesis, while TLR activation was found to upregulate CD155 on APCs through MYD88/TRIF/NF-κB/IRF3, with CD155-deficient mice showing impaired Th2 differentiation — revealing CD155 as a regulated immunomodulatory ligand.\",\n      \"evidence\": \"Sequential blocking antibody epistasis with Shp-2 recruitment assays; TLR ligand stimulation in MYD88−/−/TRIF−/− mice with in vivo OVA/CpG immunization\",\n      \"pmids\": [\"23333754\", \"23349877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Shp-2 recruitment is the sole signaling pathway during PVR-mediated diapedesis\", \"Mechanism by which CD155 on APCs specifically favors Th2 over other T helper subsets\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Genetic ablation of CD155 in both tumor and host compartments demonstrated dual roles: tumor-intrinsic CD155 promotes growth/metastasis, while host CD155 drives DNAM-1 downregulation on NK and T cells, suppressing anti-tumor immunity. Crystal structure of the CD226–CD155 complex revealed a unique side-by-side IgV arrangement requiring both D1 and D2 of CD226.\",\n      \"evidence\": \"Cd155−/− mice and CD155-deleted tumor cells in metastasis models; X-ray crystallography of mCD226/hCD155-D1 complex with truncation binding validation\",\n      \"pmids\": [\"29757192\", \"30591568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TIGIT–PVR vs. DNAM-1–PVR competition not resolved\", \"Whether tumor-intrinsic CD155 signals through the same ITIM/Akt pathways identified in vitro\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of KIR2DL5 as a fourth immune receptor for PVR — binding a non-overlapping epitope from TIGIT/CD96/DNAM-1 and recruiting SHP-1/SHP-2 to suppress Vav1/ERK/NF-κB — expanded the inhibitory checkpoint network centered on PVR.\",\n      \"evidence\": \"Binding competition assays, inhibitory synapse imaging, phosphoproteomic analysis, KIR2DL5 blocking mAbs in humanized tumor models\",\n      \"pmids\": [\"36377656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KIR2DL5 engagement dominates over TIGIT in specific tissue contexts\", \"Structural basis of the non-competitive KIR2DL5 binding mode\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A critical immune evasion mechanism was elucidated: tumor CD155 engagement of CD226 triggers Src-dependent Y319 phosphorylation and CBL-B-mediated ubiquitination/proteasomal degradation of CD226 on CD8+ T and NK cells, explaining why CD226 is lost on tumor-infiltrating lymphocytes and why checkpoint blockade fails. A soluble CD155 isoform preferentially sequesters DNAM-1 over TIGIT to suppress NK killing.\",\n      \"evidence\": \"CD226 Y319 mutagenesis and CBL-B Co-IP with proteasome inhibitor rescue in vivo; sCD155-expressing tumors in receptor-KO mouse panel with NK degranulation assays\",\n      \"pmids\": [\"33053330\", \"32591463\", \"32040157\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether therapeutic CD155 blockade can restore CD226 levels in patients\", \"Regulation of the sCD155 splice isoform\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"METTL3-mediated m6A modification at specific 3′UTR sites of CD155 mRNA was shown to stabilize the transcript and increase surface CD155 on macrophages, adding a post-transcriptional regulatory layer that links metabolic stress (ox-LDL) to immune checkpoint ligand expression.\",\n      \"evidence\": \"MeRIP m6A mapping, METTL3 knockdown/overexpression, mRNA stability assays, T cell suppression in humanized mouse model of coronary artery disease\",\n      \"pmids\": [\"36860353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether m6A-mediated CD155 regulation operates in tumor cells\", \"Identity of the m6A reader protein stabilizing CD155 mRNA\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Multiple studies revealed context-dependent regulation: IL-22 from T cells induces CD155 on cancer cells to drive NK dysfunction via CD226 degradation; ER retention of CD155 in giant cell arteritis macrophages expands pathogenic CD96+ T cells; and brain metastasis fibroblasts secrete fucosylated PVR (via HIF1α/FUT11) that remodels cancer cell signaling.\",\n      \"evidence\": \"Il22−/− and Il22r−/− genetic models with NK assays; subcellular fractionation and humanized GCA mouse model; proteomics/phosphoproteomics of bmCAF secretome with FUT11 knockdown\",\n      \"pmids\": [\"36630913\", \"37075705\", \"37995180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether secreted fucosylated PVR engages the same immune receptors as membrane-bound PVR\", \"Mechanism of ER retention in GCA macrophages\", \"Whether IL-22-driven CD155 upregulation is targetable therapeutically\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Additional transcriptional induction pathways were uncovered: platelet adhesion to circulating tumor cells upregulates CD155 via FAK/JNK/c-Jun to engage TIGIT on NK cells, and PKM2 nuclear translocation driven by METTL1-mediated m7G modification of PKM mRNA activates CD155 transcription through H3K9 lactylation at the CD155 promoter.\",\n      \"evidence\": \"scRNA-seq with FAK/JNK pathway inhibition and TIGIT antibody blockade in hepatocellular carcinoma; Cut&Run for H3K9la at CD155 promoter with METTL1 KO mice in colorectal cancer\",\n      \"pmids\": [\"38779918\", \"39741310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether H3K9 lactylation is a general mechanism across tumor types\", \"Single-lab findings for both pathways\", \"Relative quantitative contribution of each transcriptional axis to total CD155 levels in tumors\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for how PVR simultaneously engages four distinct receptors (DNAM-1, TIGIT, CD96, KIR2DL5), the identity of the m6A reader stabilizing CD155 mRNA, whether therapeutic CD155 blockade can restore CD226 on tumor-infiltrating lymphocytes in patients, and the relative contribution of membrane-bound vs. soluble vs. secreted fucosylated PVR isoforms to immune evasion in different tumor microenvironments.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structure of PVR simultaneously bound to TIGIT and DNAM-1\", \"No clinical data on CD155-directed immunotherapy\", \"Mechanism of ER retention in disease macrophages uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 2, 6, 11]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 18, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [14, 15, 22, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 6, 7, 16]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 4, 11]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [22, 32]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 13, 14, 15, 17, 18, 22, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 8, 10, 20, 26, 28]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [2, 5, 7, 11]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 16, 29, 30]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CD226\",\n      \"TIGIT\",\n      \"CD96\",\n      \"KIR2DL5\",\n      \"DYNLT1\",\n      \"ITGB3\",\n      \"NECTIN3\",\n      \"KDR\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}