{"gene":"VSIG2","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2023,"finding":"VSIG2 acts as a scaffold protein that simultaneously binds LAMTOR2 and mTOR, enhancing their interaction and resulting in elevated phosphorylation-mediated activation of mTOR and downstream signaling molecules, thereby promoting proliferation, invasion, and migration of pancreatic ductal adenocarcinoma cells.","method":"Mass spectrometry, co-immunoprecipitation, immunofluorescence, western blotting, CCK-8/colony formation/Transwell assays, subcutaneous xenograft tumor model, VSIG2 overexpression and knockdown","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and MS-identified interaction confirmed by IF and functional assays in single lab; no independent replication","pmids":["37626304"],"is_preprint":false},{"year":2025,"finding":"VSIG2 functions as an immunosuppressive ligand on the surface of activated antigen-presenting cells, specifically binding Nectin-2 (but not PD-1 or CTLA-4), and strongly inhibiting T cell activation and proliferation; this interaction regulates the STAT1/IRF1/GBP2 signaling pathway in T cells. VSIG2-Ig protein alleviated experimental autoimmune encephalomyelitis symptoms, and anti-VSIG2 antibodies inhibited pancreatic cancer growth in vivo.","method":"Binding assays (ligand-receptor interaction), T cell activation/proliferation assays, in vivo EAE model, in vivo pancreatic cancer model, pathway analysis (STAT1/IRF1/GBP2)","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay confirmed specificity for Nectin-2, functional in vivo and in vitro experiments, single lab with multiple orthogonal methods","pmids":["41350674"],"is_preprint":false},{"year":2025,"finding":"VSIG2 directly interacts with ANXA2 (Annexin A2) at the cell membrane in gastric cancer cells and competes with FBXW10 for binding to ANXA2. Highly expressed VSIG2 relies on FBXW10-mediated K63 polyubiquitination of ANXA2 to induce membrane localization of ANXA2, which inactivates NF-κB and suppresses gastric cancer cell proliferation and migration.","method":"Co-immunoprecipitation, immunofluorescence, ubiquitination assays, CCK-8, EdU, Transwell, wound healing assays, nude mouse subcutaneous tumor model, liver metastasis model, western blot, qRT-PCR, IHC","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus ubiquitination assay and in vivo validation in single lab with multiple orthogonal methods","pmids":["41185558"],"is_preprint":false}],"current_model":"VSIG2 is an immunoglobulin superfamily cell-surface protein with context-dependent roles: in pancreatic cancer it acts as a scaffold that bridges LAMTOR2 and mTOR to enhance mTOR phosphorylation and tumor progression; in gastric cancer it suppresses tumor growth by binding ANXA2, competing with FBXW10, and promoting FBXW10-mediated K63 polyubiquitination of ANXA2 to drive membrane localization of ANXA2 and NF-κB inactivation; and as a ligand on antigen-presenting cells it binds Nectin-2 to inhibit T cell activation and proliferation via the STAT1/IRF1/GBP2 pathway."},"narrative":{"mechanistic_narrative":"VSIG2 is an immunoglobulin-superfamily cell-surface protein that exerts context-dependent, tissue-specific roles in cancer progression and immune regulation [PMID:37626304, PMID:41350674, PMID:41185558]. As an immunosuppressive ligand on activated antigen-presenting cells, VSIG2 binds Nectin-2 — but not PD-1 or CTLA-4 — and strongly inhibits T cell activation and proliferation through the STAT1/IRF1/GBP2 signaling axis; a VSIG2-Ig fusion alleviated experimental autoimmune encephalomyelitis, while anti-VSIG2 antibodies suppressed pancreatic cancer growth in vivo [PMID:41350674]. In pancreatic ductal adenocarcinoma cells, VSIG2 acts intracellularly as a scaffold that simultaneously binds LAMTOR2 and mTOR, enhancing their interaction and driving mTOR phosphorylation and downstream signaling to promote proliferation, invasion, and migration [PMID:37626304]. In gastric cancer, by contrast, VSIG2 is tumor-suppressive: it directly binds ANXA2 at the membrane and competes with FBXW10, promoting FBXW10-mediated K63 polyubiquitination and membrane localization of ANXA2, thereby inactivating NF-κB and restraining proliferation and migration [PMID:41185558]. The structural basis of these interactions and how a single protein partitions between surface ligand and intracellular scaffold functions have not been characterized in the available corpus.","teleology":[{"year":2023,"claim":"Established the first molecular mechanism for VSIG2 in cancer by identifying it as an intracellular scaffold linking LAMTOR2 to mTOR activation.","evidence":"Mass spectrometry, reciprocal co-immunoprecipitation, immunofluorescence, functional assays and xenografts with VSIG2 overexpression/knockdown in pancreatic ductal adenocarcinoma cells","pmids":["37626304"],"confidence":"Medium","gaps":["No structural definition of the LAMTOR2/mTOR-bridging interface","Whether the scaffold function operates at a specific subcellular compartment is not resolved","Single lab, no independent replication"]},{"year":2025,"claim":"Identified VSIG2 as a tumor-suppressive partner of ANXA2 in gastric cancer, defining a competitive-binding/ubiquitination mechanism opposite to its pancreatic role.","evidence":"Reciprocal co-immunoprecipitation, ubiquitination assays, immunofluorescence, in vitro proliferation/migration assays and subcutaneous plus liver-metastasis mouse models in gastric cancer cells","pmids":["41185558"],"confidence":"Medium","gaps":["Mechanism by which K63-ubiquitinated ANXA2 inactivates NF-κB not detailed","Reason for opposite tumor role versus pancreatic cancer unexplained","Single lab, no independent replication"]},{"year":2025,"claim":"Defined VSIG2 as a cell-surface immunosuppressive ligand, identifying Nectin-2 as its receptor and the STAT1/IRF1/GBP2 axis as the downstream T cell pathway.","evidence":"Ligand-receptor binding assays, T cell activation/proliferation assays, in vivo EAE and pancreatic cancer models, pathway analysis","pmids":["41350674"],"confidence":"Medium","gaps":["Structural basis of VSIG2-Nectin-2 binding not determined","How surface ligand activity reconciles with reported intracellular scaffold function is unclear","Single lab, no independent replication"]},{"year":null,"claim":"How VSIG2 partitions between cell-surface immune-ligand and intracellular scaffold/adaptor functions, and what determines its opposing pro- versus anti-tumor roles across tissues, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model for any VSIG2 interaction","No reconciliation of surface versus intracellular localization across contexts","Determinants of context-dependent tumor outcome unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1]}],"complexes":[],"partners":["LAMTOR2","MTOR","ANXA2","FBXW10","NECTIN2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96IQ7","full_name":"V-set and immunoglobulin domain-containing protein 2","aliases":["Cortical thymocyte-like protein","CT-like protein"],"length_aa":327,"mass_kda":34.3,"function":"","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q96IQ7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VSIG2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VSIG2","total_profiled":1310},"omim":[{"mim_id":"611693","title":"COXSACKIEVIRUS- AND ADENOVIRUS RECEPTOR-LIKE MEMBRANE PROTEIN; CLMP","url":"https://www.omim.org/entry/611693"},{"mim_id":"606011","title":"V-SET AND IMMUNOGLOBULIN DOMAINS-CONTAINING PROTEIN 2; VSIG2","url":"https://www.omim.org/entry/606011"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"stomach 1","ntpm":584.2}],"url":"https://www.proteinatlas.org/search/VSIG2"},"hgnc":{"alias_symbol":["CTXL","CTH"],"prev_symbol":[]},"alphafold":{"accession":"Q96IQ7","domains":[{"cath_id":"2.60.40.10","chopping":"26-143","consensus_level":"high","plddt":91.4475,"start":26,"end":143},{"cath_id":"2.60.40.10","chopping":"150-233","consensus_level":"high","plddt":90.0786,"start":150,"end":233}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96IQ7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96IQ7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96IQ7-F1-predicted_aligned_error_v6.png","plddt_mean":80.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VSIG2","jax_strain_url":"https://www.jax.org/strain/search?query=VSIG2"},"sequence":{"accession":"Q96IQ7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96IQ7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96IQ7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96IQ7"}},"corpus_meta":[{"pmid":"20659327","id":"PMC_20659327","title":"Trait-stratified genome-wide association study identifies novel and diverse genetic associations with serologic and cytokine phenotypes in systemic lupus erythematosus.","date":"2010","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/20659327","citation_count":91,"is_preprint":false},{"pmid":"37140510","id":"PMC_37140510","title":"Myeloperoxidase Inhibition Reverses Biomarker Profiles Associated With Clinical Outcomes in HFpEF.","date":"2023","source":"JACC. 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and Major Cardiovascular Events in Older People With Advanced CKD: The European Quality (EQUAL) Study.","date":"2023","source":"Kidney medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38162538","citation_count":5,"is_preprint":false},{"pmid":"39568008","id":"PMC_39568008","title":"Knockdown of the long noncoding RNA VSIG2-1:1 promotes the angiogenic ability of human pulmonary microvascular endothelial cells by activating the VEGF/PI3K/AKT pathway.","date":"2024","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/39568008","citation_count":4,"is_preprint":false},{"pmid":"39586554","id":"PMC_39586554","title":"Protein signatures associated with loneliness and social isolation: Plasma proteome analyses in the English Longitudinal Study of Ageing, with causal evidence from Mendelian randomization.","date":"2024","source":"Brain, behavior, and 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2023,\n      \"finding\": \"VSIG2 acts as a scaffold protein that simultaneously binds LAMTOR2 and mTOR, enhancing their interaction and resulting in elevated phosphorylation-mediated activation of mTOR and downstream signaling molecules, thereby promoting proliferation, invasion, and migration of pancreatic ductal adenocarcinoma cells.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, immunofluorescence, western blotting, CCK-8/colony formation/Transwell assays, subcutaneous xenograft tumor model, VSIG2 overexpression and knockdown\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and MS-identified interaction confirmed by IF and functional assays in single lab; no independent replication\",\n      \"pmids\": [\"37626304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VSIG2 functions as an immunosuppressive ligand on the surface of activated antigen-presenting cells, specifically binding Nectin-2 (but not PD-1 or CTLA-4), and strongly inhibiting T cell activation and proliferation; this interaction regulates the STAT1/IRF1/GBP2 signaling pathway in T cells. VSIG2-Ig protein alleviated experimental autoimmune encephalomyelitis symptoms, and anti-VSIG2 antibodies inhibited pancreatic cancer growth in vivo.\",\n      \"method\": \"Binding assays (ligand-receptor interaction), T cell activation/proliferation assays, in vivo EAE model, in vivo pancreatic cancer model, pathway analysis (STAT1/IRF1/GBP2)\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay confirmed specificity for Nectin-2, functional in vivo and in vitro experiments, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41350674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VSIG2 directly interacts with ANXA2 (Annexin A2) at the cell membrane in gastric cancer cells and competes with FBXW10 for binding to ANXA2. Highly expressed VSIG2 relies on FBXW10-mediated K63 polyubiquitination of ANXA2 to induce membrane localization of ANXA2, which inactivates NF-κB and suppresses gastric cancer cell proliferation and migration.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, ubiquitination assays, CCK-8, EdU, Transwell, wound healing assays, nude mouse subcutaneous tumor model, liver metastasis model, western blot, qRT-PCR, IHC\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus ubiquitination assay and in vivo validation in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41185558\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VSIG2 is an immunoglobulin superfamily cell-surface protein with context-dependent roles: in pancreatic cancer it acts as a scaffold that bridges LAMTOR2 and mTOR to enhance mTOR phosphorylation and tumor progression; in gastric cancer it suppresses tumor growth by binding ANXA2, competing with FBXW10, and promoting FBXW10-mediated K63 polyubiquitination of ANXA2 to drive membrane localization of ANXA2 and NF-κB inactivation; and as a ligand on antigen-presenting cells it binds Nectin-2 to inhibit T cell activation and proliferation via the STAT1/IRF1/GBP2 pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VSIG2 is an immunoglobulin-superfamily cell-surface protein that exerts context-dependent, tissue-specific roles in cancer progression and immune regulation [#0, #1, #2]. As an immunosuppressive ligand on activated antigen-presenting cells, VSIG2 binds Nectin-2 — but not PD-1 or CTLA-4 — and strongly inhibits T cell activation and proliferation through the STAT1/IRF1/GBP2 signaling axis; a VSIG2-Ig fusion alleviated experimental autoimmune encephalomyelitis, while anti-VSIG2 antibodies suppressed pancreatic cancer growth in vivo [#1]. In pancreatic ductal adenocarcinoma cells, VSIG2 acts intracellularly as a scaffold that simultaneously binds LAMTOR2 and mTOR, enhancing their interaction and driving mTOR phosphorylation and downstream signaling to promote proliferation, invasion, and migration [#0]. In gastric cancer, by contrast, VSIG2 is tumor-suppressive: it directly binds ANXA2 at the membrane and competes with FBXW10, promoting FBXW10-mediated K63 polyubiquitination and membrane localization of ANXA2, thereby inactivating NF-\\u03baB and restraining proliferation and migration [#2]. The structural basis of these interactions and how a single protein partitions between surface ligand and intracellular scaffold functions have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"Established the first molecular mechanism for VSIG2 in cancer by identifying it as an intracellular scaffold linking LAMTOR2 to mTOR activation.\",\n      \"evidence\": \"Mass spectrometry, reciprocal co-immunoprecipitation, immunofluorescence, functional assays and xenografts with VSIG2 overexpression/knockdown in pancreatic ductal adenocarcinoma cells\",\n      \"pmids\": [\"37626304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural definition of the LAMTOR2/mTOR-bridging interface\",\n        \"Whether the scaffold function operates at a specific subcellular compartment is not resolved\",\n        \"Single lab, no independent replication\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified VSIG2 as a tumor-suppressive partner of ANXA2 in gastric cancer, defining a competitive-binding/ubiquitination mechanism opposite to its pancreatic role.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, ubiquitination assays, immunofluorescence, in vitro proliferation/migration assays and subcutaneous plus liver-metastasis mouse models in gastric cancer cells\",\n      \"pmids\": [\"41185558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which K63-ubiquitinated ANXA2 inactivates NF-\\u03baB not detailed\",\n        \"Reason for opposite tumor role versus pancreatic cancer unexplained\",\n        \"Single lab, no independent replication\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined VSIG2 as a cell-surface immunosuppressive ligand, identifying Nectin-2 as its receptor and the STAT1/IRF1/GBP2 axis as the downstream T cell pathway.\",\n      \"evidence\": \"Ligand-receptor binding assays, T cell activation/proliferation assays, in vivo EAE and pancreatic cancer models, pathway analysis\",\n      \"pmids\": [\"41350674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of VSIG2-Nectin-2 binding not determined\",\n        \"How surface ligand activity reconciles with reported intracellular scaffold function is unclear\",\n        \"Single lab, no independent replication\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VSIG2 partitions between cell-surface immune-ligand and intracellular scaffold/adaptor functions, and what determines its opposing pro- versus anti-tumor roles across tissues, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model for any VSIG2 interaction\",\n        \"No reconciliation of surface versus intracellular localization across contexts\",\n        \"Determinants of context-dependent tumor outcome unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LAMTOR2\", \"MTOR\", \"ANXA2\", \"FBXW10\", \"NECTIN2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}