{"gene":"ITPRIPL1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2024,"finding":"ITPRIPL1 functions as an inhibitory ligand of CD3ε on T cells; binding of the ITPRIPL1 extracellular domain to CD3ε significantly decreases calcium influx and ZAP70 phosphorylation, impeding initial T cell activation ('signal one' phase).","method":"Binding assay (extracellular domain interaction), calcium influx measurement, ZAP70 phosphorylation assay, neutralizing antibody treatment in mouse tumor models with T cell infiltration readout","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (calcium influx, ZAP70 phosphorylation, in vivo tumor models, antibody neutralization) in a single rigorous study with clear mechanistic pathway placement","pmids":["38614099"],"is_preprint":false},{"year":2023,"finding":"ITPRIPL1 is overexpressed in non-small cell lung cancer tumor cells and its expression is negatively correlated with CD8+ T cell infiltration in situ, consistent with its role as an immune checkpoint ligand suppressing T cell activity in the tumor microenvironment.","method":"Immunohistochemistry with anti-ITPRIPL1 monoclonal antibody on patient tumor sections; correlation analysis with anti-CD8 staining","journal":"Frontiers in cell and developmental biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single IHC-based correlative study in patient samples; no direct mechanistic experiment beyond localization and correlation","pmids":["38188019"],"is_preprint":false}],"current_model":"ITPRIPL1 (CD3L1) acts as a tumor cell-surface inhibitory ligand that binds CD3ε on T cells via its extracellular domain, suppressing calcium influx and ZAP70 phosphorylation to block initial T cell activation, thereby enabling tumor immune evasion; neutralizing antibodies against ITPRIPL1 restore T cell infiltration and restrain tumor growth in vivo."},"narrative":{"mechanistic_narrative":"ITPRIPL1 (CD3L1) functions as a tumor cell-surface inhibitory ligand that suppresses T cell activation to promote immune evasion [PMID:38614099]. Its extracellular domain binds CD3ε on T cells, and this engagement decreases calcium influx and ZAP70 phosphorylation, thereby impeding the initial 'signal one' phase of T cell activation [PMID:38614099]. Consistent with a checkpoint role, neutralizing antibodies against ITPRIPL1 restore T cell infiltration and restrain tumor growth in mouse models [PMID:38614099]. Beyond this CD3ε-directed inhibitory ligand activity, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2024,"claim":"Established that ITPRIPL1 is a functional inhibitory ligand of the T cell receptor co-receptor CD3ε, defining a previously uncharacterized mechanism by which tumor cells dampen T cell activation at the earliest signaling step.","evidence":"Extracellular domain binding assays, calcium influx and ZAP70 phosphorylation readouts, and neutralizing antibody treatment in mouse tumor models","pmids":["38614099"],"confidence":"High","gaps":["Structural basis of the ITPRIPL1 extracellular domain–CD3ε interaction not resolved","Whether ITPRIPL1 acts only on CD3ε or engages other immune receptors is not established","Regulation of ITPRIPL1 surface expression and any signaling within the tumor cell is unknown"]},{"year":2023,"claim":"Provided correlative human evidence that ITPRIPL1 behaves as an immune checkpoint ligand by showing tumor overexpression that tracks with suppressed CD8+ T cell infiltration.","evidence":"Immunohistochemistry on NSCLC patient tumor sections with correlation against CD8 staining","pmids":["38188019"],"confidence":"Low","gaps":["Single IHC-based correlative study with no direct mechanistic experiment","Causality between ITPRIPL1 expression and reduced CD8 infiltration not demonstrated","Generalizability beyond NSCLC not assessed"]},{"year":null,"claim":"The structural details, full receptor repertoire, intrinsic signaling role within tumor cells, and broader physiological function of ITPRIPL1 remain undefined.","evidence":"No further discoveries in the available corpus","pmids":[],"confidence":"Low","gaps":["No structure of the ligand–receptor complex","No characterization of ITPRIPL1 function in normal tissues","Mechanism controlling ITPRIPL1 expression in tumors unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0]}],"complexes":[],"partners":["CD3E"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6GPH6","full_name":"Inositol 1,4,5-trisphosphate receptor-interacting protein-like 1","aliases":[],"length_aa":555,"mass_kda":63.4,"function":"Functions as a ligand of CD3E, inhibiting TCR-CD3 complex signaling to regulate T cell activation. Induces stable CD3E-NCK1 binding, thereby preventing the CD3E-ZAP70 interaction and subsequently inhibiting the activation of the downstream ERK-NFkB signaling cascade and calcium influx","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q6GPH6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITPRIPL1","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":[{"gene":"CANX","stoichiometry":0.2},{"gene":"RTN4","stoichiometry":0.2},{"gene":"STK4","stoichiometry":0.2},{"gene":"VAPA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ITPRIPL1","total_profiled":1310},"omim":[{"mim_id":"620821","title":"ITPRIP-LIKE PROTEIN 1; ITPRIPL1","url":"https://www.omim.org/entry/620821"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":26.1}],"url":"https://www.proteinatlas.org/search/ITPRIPL1"},"hgnc":{"alias_symbol":["D1B"],"prev_symbol":["KIAA1754L"]},"alphafold":{"accession":"Q6GPH6","domains":[{"cath_id":"1.10.1410.40","chopping":"157-178_403-434_443-547","consensus_level":"medium","plddt":90.9329,"start":157,"end":547},{"cath_id":"3.30.460.90","chopping":"182-278_295-398","consensus_level":"medium","plddt":86.3233,"start":182,"end":398}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6GPH6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6GPH6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6GPH6-F1-predicted_aligned_error_v6.png","plddt_mean":78.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITPRIPL1","jax_strain_url":"https://www.jax.org/strain/search?query=ITPRIPL1"},"sequence":{"accession":"Q6GPH6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6GPH6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6GPH6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6GPH6"}},"corpus_meta":[{"pmid":"14612495","id":"PMC_14612495","title":"An 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binding of the ITPRIPL1 extracellular domain to CD3ε significantly decreases calcium influx and ZAP70 phosphorylation, impeding initial T cell activation ('signal one' phase).\",\n      \"method\": \"Binding assay (extracellular domain interaction), calcium influx measurement, ZAP70 phosphorylation assay, neutralizing antibody treatment in mouse tumor models with T cell infiltration readout\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (calcium influx, ZAP70 phosphorylation, in vivo tumor models, antibody neutralization) in a single rigorous study with clear mechanistic pathway placement\",\n      \"pmids\": [\"38614099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ITPRIPL1 is overexpressed in non-small cell lung cancer tumor cells and its expression is negatively correlated with CD8+ T cell infiltration in situ, consistent with its role as an immune checkpoint ligand suppressing T cell activity in the tumor microenvironment.\",\n      \"method\": \"Immunohistochemistry with anti-ITPRIPL1 monoclonal antibody on patient tumor sections; correlation analysis with anti-CD8 staining\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single IHC-based correlative study in patient samples; no direct mechanistic experiment beyond localization and correlation\",\n      \"pmids\": [\"38188019\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITPRIPL1 (CD3L1) acts as a tumor cell-surface inhibitory ligand that binds CD3ε on T cells via its extracellular domain, suppressing calcium influx and ZAP70 phosphorylation to block initial T cell activation, thereby enabling tumor immune evasion; neutralizing antibodies against ITPRIPL1 restore T cell infiltration and restrain tumor growth in vivo.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITPRIPL1 (CD3L1) functions as a tumor cell-surface inhibitory ligand that suppresses T cell activation to promote immune evasion [#0]. Its extracellular domain binds CD3ε on T cells, and this engagement decreases calcium influx and ZAP70 phosphorylation, thereby impeding the initial 'signal one' phase of T cell activation [#0]. Consistent with a checkpoint role, neutralizing antibodies against ITPRIPL1 restore T cell infiltration and restrain tumor growth in mouse models [#0]. Beyond this CD3ε-directed inhibitory ligand activity, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2024,\n      \"claim\": \"Established that ITPRIPL1 is a functional inhibitory ligand of the T cell receptor co-receptor CD3ε, defining a previously uncharacterized mechanism by which tumor cells dampen T cell activation at the earliest signaling step.\",\n      \"evidence\": \"Extracellular domain binding assays, calcium influx and ZAP70 phosphorylation readouts, and neutralizing antibody treatment in mouse tumor models\",\n      \"pmids\": [\"38614099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the ITPRIPL1 extracellular domain–CD3ε interaction not resolved\",\n        \"Whether ITPRIPL1 acts only on CD3ε or engages other immune receptors is not established\",\n        \"Regulation of ITPRIPL1 surface expression and any signaling within the tumor cell is unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided correlative human evidence that ITPRIPL1 behaves as an immune checkpoint ligand by showing tumor overexpression that tracks with suppressed CD8+ T cell infiltration.\",\n      \"evidence\": \"Immunohistochemistry on NSCLC patient tumor sections with correlation against CD8 staining\",\n      \"pmids\": [\"38188019\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single IHC-based correlative study with no direct mechanistic experiment\",\n        \"Causality between ITPRIPL1 expression and reduced CD8 infiltration not demonstrated\",\n        \"Generalizability beyond NSCLC not assessed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural details, full receptor repertoire, intrinsic signaling role within tumor cells, and broader physiological function of ITPRIPL1 remain undefined.\",\n      \"evidence\": \"No further discoveries in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structure of the ligand–receptor complex\",\n        \"No characterization of ITPRIPL1 function in normal tissues\",\n        \"Mechanism controlling ITPRIPL1 expression in tumors unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD3E\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":3,"faith_total":3,"faith_pct":100.0}}