1. Gene Aliases

PVR Cell Adhesion Molecule, Poliovirus Receptor, CD155, NECL5, HVED, PVS, Nectin-Like Protein 5, Necl-5, NECL-5, TAGE4, Nectin-Like 5, CD155 Antigen, Tage4

[https://www.genecards.org/cgi-bin/carddisp.pl?gene=PVR&keywords=Pvr]

2. Association with Toxicity and/or Disease at a Transcriptional Level

3. Summary of Protein Family and Structure

4. Proteins Known to Interact with Gene Product

Interactions with experimental support

The interactions list has been truncated to include only interactions with the strongest support from the literature.

5. Links to Gene Databases

6. GO Terms, MSigDB Signatures, Pathways Containing Gene with Descriptions of Gene Sets

Pathways:

Adherens junctions interactions: The adherens junctions (AJ) are multiprotein complexes that promote homotypic cell adhesion in nearly all types of tissue by linking membrane and cytoskeletal components at discrete contact regions (reviewed in Hartsock & Nelson 2008; Gumbiner 2005; Ebnet, 2008). The molecular constituents of adherens junctions form adhesive units which are organized into higher order junctional adhesions that create a zipper-like seal between adjacent cells. Junctional adhesions function in epithelial cell polarization and in the coupling of cytoskeletons in adjacent cells that allow coordinated movements. During embryonic development, AJs function in specifying adhesion between cells and contribute in the sorting of different cell types. AJs also regulate cell polarity and shape, promote cell-cell communication and help mediate contact inhibition of cell growth. This module covers transdimerization events involving AJ transmembrane proteins (cadherins and nectins) (Gumbiner 2005; Ebnet 2008; Hartsock & Nelson 2008).[https://reactome.org/PathwayBrowser/#/R-HSA-418990].

Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell: A number of receptors and cell adhesion molecules play a key role in modifying the response of cells of lymphoid origin (such as B-, T- and NK cells) to self and tumor antigens, as well as to pathogenic organisms.

Molecules such as KIRs and LILRs form part of a crucial surveillance system that looks out for any derangement, usually caused by cancer or viral infection, in MHC Class I presentation. Somatic cells are also able to report internal functional impairment by displaying surface stress markers such as MICA. The presence of these molecules on somatic cells is picked up by C-lectin NK immune receptors.

Lymphoid cells are able to regulate their location and movement in accordance to their state of activation, and home in on tissues expressing the appropriate complementary ligands. For example, lymphoid cells may fine tune the presence and concentration of adhesion molecules belonging to the IgSF, Selectin and Integrin class that interact with a number of vascular markers of inflammation.

Furthermore, there are a number of avenues through which lymphoid cells may interact with antigen. This may be presented directly to a specific T-cell receptor in the context of an MHC molecule. Antigen-antibody complexes may anchor to the cell via a small number of lymphoid-specific Fc receptors that may, in turn, influence cell function further. Activated complement factor C3d binds to both antigen and to cell surface receptor CD21. In such cases, the far-reaching influence of CD19 on B-lymphocyte function is tempered by its interaction with CD21 [https://reactome.org/PathwayBrowser/#/R-HSA-198933].

Nectin/Necl trans heterodimerization: Nectins and Nectin-like molecules (Necls) also undergo trans-heterophilic interactions to interact with other nectin or Necl family members. Besides these trans interactions among nectins and nectin-like family members, trans-homophilic interactions have also been described between nectins or Necls with other immunoglobulin-superfamily members like CD96, CD226 and CRTAM (Sakisaka et al., 2007; Takai et al., 2008). It should be noted that some of these interactions might not exist in epithelial cell-cell contacts but may occur in other cell-cell adhesion systems.[https://reactome.org/PathwayBrowser/#/R-HSA-420597].

GO terms:

cell migration [The controlled self-propelled movement of a cell from one site to a destination guided by molecular cues. GO:0016477]

cell-cell adhesion [The attachment of one cell to another cell via adhesion molecules. GO:0098609]

heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules [The attachment of an adhesion molecule in one cell to a nonidentical adhesion molecule in an adjacent cell. GO:0007157]

homophilic cell adhesion via plasma membrane adhesion molecules [The attachment of a plasma membrane adhesion molecule in one cell to an identical molecule in an adjacent cell. GO:0007156]

positive regulation of natural killer cell mediated cytotoxicity [Any process that activates or increases the frequency, rate or extent of natural killer cell mediated cytotoxicity. GO:0045954]

positive regulation of natural killer cell mediated cytotoxicity directed against tumor cell target [Any process that activates or increases the frequency, rate, or extent of natural killer cell mediated cytotoxicity directed against tumor cell target. GO:0002860]

susceptibility to T cell mediated cytotoxicity [The process of causing a cell to become susceptible to T cell mediated cytotoxicity. GO:0060370]

susceptibility to natural killer cell mediated cytotoxicity [The process of causing a cell to become susceptible to natural killer cell mediated cytotoxicity.|Note that this term is intended for cell-surface molecules on a target cell which interact with activating receptors on a natural killer cell to promote natural killer cell mediated cytotoxicity. GO:0042271]

viral entry into host cell [The process that occurs after viral attachment by which a virus, or viral nucleic acid, breaches the plasma membrane or cell envelope and enters the host cell. The process ends when the viral nucleic acid is released into the host cell cytoplasm.|Viral attachment to the host cell is not part of viral entry in GO because virus attachment does not always lead to viral entry: attachment can also result in the virion being carried by the host cell to another location. GO:0046718]

MSigDB Signatures:

ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN: Genes down-regulated in liver tumor compared to the normal adjacent tissue. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN.html]

STONER_ESOPHAGEAL_CARCINOGENESIS_UP: Genes up-regulated in esophagus by the carcinogen NMBA [PubChem=13643] and brought back to normal by a diet with PEITC [PubChem=16741] or black raspberries. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/STONER_ESOPHAGEAL_CARCINOGENESIS_UP.html]

REACTOME_ADAPTIVE_IMMUNE_SYSTEM: Adaptive Immune System [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_ADAPTIVE_IMMUNE_SYSTEM.html]

AMIT_SERUM_RESPONSE_480_MCF10A: Genes whose expression peaked at 480 min after stimulation of MCF10A cells with serum. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/AMIT_SERUM_RESPONSE_480_MCF10A.html]

AMIT_SERUM_RESPONSE_40_MCF10A: Genes whose expression peaked at 40 min after stimulation of MCF10A cells with serum. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/AMIT_SERUM_RESPONSE_40_MCF10A.html]

PID_NECTIN_PATHWAY: Nectin adhesion pathway [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/PID_NECTIN_PATHWAY.html]

PUJANA_BRCA1_PCC_NETWORK: Genes constituting the BRCA1-PCC network of transcripts whose expression positively correlated (Pearson correlation coefficient, PCC >= 0.4) with that of BRCA1 [GeneID=672] across a compendium of normal tissues. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/PUJANA_BRCA1_PCC_NETWORK.html]

REACTOME_NECTIN_NECL_TRANS_HETERODIMERIZATION: Nectin/Necl trans heterodimerization [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_NECTIN_NECL_TRANS_HETERODIMERIZATION.html]

REACTOME_CELL_CELL_COMMUNICATION: Cell-Cell communication [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_CELL_CELL_COMMUNICATION.html]

AMIT_EGF_RESPONSE_480_HELA: Genes whose expression peaked at 480 min after stimulation of HeLa cells with EGF [GeneID=1950]. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/AMIT_EGF_RESPONSE_480_HELA.html]

REACTOME_CELL_JUNCTION_ORGANIZATION: Cell junction organization [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_CELL_JUNCTION_ORGANIZATION.html]

RUTELLA_RESPONSE_TO_HGF_VS_CSF2RB_AND_IL4_DN: Genes down-regulated in peripheral blood mononucleocytes by HGF [GeneID=3082] compared to those regulated by CSF2RB (GM-CSF) and IL4 [GeneID=1437;3565]. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/RUTELLA_RESPONSE_TO_HGF_VS_CSF2RB_AND_IL4_DN.html]

REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS: Adherens junctions interactions [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS.html]

RIGGI_EWING_SARCOMA_PROGENITOR_UP: Genes up-regulated in mesenchymal stem cells (MSC) engineered to express EWS-FLI1 [GeneID=2130;2321] fusion protein. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/RIGGI_EWING_SARCOMA_PROGENITOR_UP.html]

REACTOME_CELL_CELL_JUNCTION_ORGANIZATION: Cell-cell junction organization [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_CELL_CELL_JUNCTION_ORGANIZATION.html]

ZWANG_CLASS_1_TRANSIENTLY_INDUCED_BY_EGF: Class I of genes transiently induced by EGF [GeneID =1950] in 184A1 cells (mammary epithelium). [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/ZWANG_CLASS_1_TRANSIENTLY_INDUCED_BY_EGF.html]

RUTELLA_RESPONSE_TO_HGF_UP: Genes up-regulated in peripheral blood monocytes by HGF [GeneID=3082]. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/RUTELLA_RESPONSE_TO_HGF_UP.html]

KEGG_CELL_ADHESION_MOLECULES_CAMS: Cell adhesion molecules (CAMs) [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_CELL_ADHESION_MOLECULES_CAMS.html]

7. Gene Descriptions

NCBI Gene Summary: The protein encoded by this gene is a transmembrane glycoprotein belonging to the immunoglobulin superfamily. The external domain mediates cell attachment to the extracellular matrix molecule vitronectin, while its intracellular domain interacts with the dynein light chain Tctex-1/DYNLT1. The gene is specific to the primate lineage, and serves as a cellular receptor for poliovirus in the first step of poliovirus replication. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

GeneCards Summary: PVR (PVR Cell Adhesion Molecule) is a Protein Coding gene. Diseases associated with PVR include Poliomyelitis and Paralytic Poliomyelitis. Among its related pathways are Regulation of CDH11 Expression and Function and Innate Immune System. Gene Ontology (GO) annotations related to this gene include signaling receptor activity and virus receptor activity. An important paralog of this gene is NECTIN2.

UniProtKB/Swiss-Prot Summary: 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. 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. Acts as a receptor for Pseudorabies virus. Is prevented to reach cell surface upon infection by Human cytomegalovirus /HHV-5, presumably to escape immune recognition of infected cell by NK cells.

8. Cellular Location of Gene Product

Membrane and cytoplasmic expression in several tissues. Positivity in plasma. Localized to the nucleoplasm, plasma membrane & vesicles. Predicted location: Secreted, Membrane, Intracellular (different isoforms) [https://www.proteinatlas.org/ENSG00000073008/subcellular]

9. Mechanistic Information

Summary

The PVR gene encodes a transmembrane glycoprotein that is involved in cell adhesion, immune response regulation and serves as a receptor for poliovirus [CS: 10]. Additionally, PVR participates in NK cell activation by binding to their receptors CD96 and CD226, triggering cytotoxic responses against cells expressing PVR [CS: 9]. Upregulation in response to liver injury or stress facilitates cellular attachment to vitronectin in the extracellular matrix [CS: 8]. This interaction could reinforce cellular stability and integrity during tissue repair, ensuring proper reestablishment of liver architecture and function after damage [CS: 7]. Moreover, the binding of PVR to CD226 on NK cells triggers NK cell effector functions, such as the release of lytic granules and IFN-gamma, which target and destroy damaged or aberrant cells - a critical step in mitigating the spread of injury or controlling potential malignant transformation in hepatocytes [CS: 8].

In HCC, the situation becomes more complicated, as the disease utilizes the unfolded protein response (UPR) to decrease PVR expression in order to suppress NK cell detection, thus promoting immune evasion [CS: 6]. In this manner, downregulation of PVR grants HCC cells a survival advantage, contrasting with the liver's usual mechanism of enhancing cell-mediated immunity through PVR in response to acute stress [CS: 6].

10. Upstream Regulators

11. Tissues/Cell Type Where Genes are Overexpressed

Tissue type enchanced: low tissue specificity [https://www.proteinatlas.org/ENSG00000073008/tissue]

Cell type enchanced: alveolar cells type 1 (cell type enhanced) [https://www.proteinatlas.org/ENSG00000073008/single+cell+type]

12. Role of Gene in Other Tissues

13. Chemicals Known to Elicit Transcriptional Response of Biomarker in Tissue of Interest

Compounds that increase expression of the gene:

14. DisGeNet Biomarker Associations to Disease in Organ of Interest

Most relevant biomarkers with lower score or lower probability of association with disease or organ of interest: