{"gene":"F2RL1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2026,"finding":"Extracellular granzyme K (GZMK) cleaves F2RL1 (PAR-2) on tumor cells, activating downstream AKT/GSK-3β/β-catenin and JAK2/STAT1 signaling pathways. This leads to nuclear accumulation of β-catenin and phosphorylated STAT1, driving PD-L1 transcription. Additionally, F2RL1 signaling upregulates COPS8, which stabilizes PD-L1 by inhibiting its ubiquitin-mediated degradation, thereby facilitating tumor immune evasion in lung adenocarcinoma.","method":"Recombinant human GZMK treatment in tumor-CD8+ T cell co-culture systems, Western blotting for signaling proteins, flow cytometry for PD-L1 expression and CD8+ T-cell function, in vivo mouse tumor models with GZMK inhibitor + anti-PD-1 combination therapy","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (co-culture, Western blot for pathway activation, in vivo models) in a single lab; mechanistic pathway defined but no reconstitution or structural validation","pmids":["41526166"],"is_preprint":false},{"year":2024,"finding":"F2RL1 knockdown in palmitate-stimulated HK-2 renal tubular epithelial cells significantly reduced the inflammatory response, and mechanistic analysis suggested F2RL1 exacerbates lipotoxicity-induced injury through modulation of the Hippo signaling pathway in diabetic kidney disease.","method":"siRNA knockdown of F2RL1 in HK-2 cells stimulated with palmitate; measurement of inflammatory factor expression; in vivo and in vitro DKD models","journal":"Inflammation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown with phenotypic readout but pathway placement (Hippo) described as mechanistic inference rather than directly demonstrated by epistasis or rescue experiments","pmids":["39738821"],"is_preprint":false},{"year":2024,"finding":"F2RL1 knockdown combined with melittin treatment in glioma U251 cells increased G1-phase arrest, reduced cell proliferation, migration, and invasion, and altered expression of apoptosis and cell cycle arrest genes, establishing that melittin inhibits glioma cell proliferation at least partly by suppressing F2RL1 expression.","method":"Lentiviral F2RL1 knockdown, MTT and EdU proliferation assays, flow cytometry for apoptosis and cell cycle, qRT-PCR for gene expression, xenograft mouse model","journal":"Applied biochemistry and biotechnology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, loss-of-function with phenotypic readout but no direct molecular mechanism or pathway placement beyond F2RL1 expression level","pmids":["38252207"],"is_preprint":false}],"current_model":"F2RL1 (PAR-2) is a G protein-coupled proteinase-activated receptor that can be cleaved by extracellular serine proteases such as granzyme K; upon cleavage, it activates AKT/GSK-3β/β-catenin and JAK2/STAT1 signaling to drive PD-L1 transcription and, via COPS8 upregulation, stabilizes PD-L1 against ubiquitin-mediated degradation, thereby promoting immune evasion; F2RL1 also participates in inflammatory signaling in renal tubular cells (via the Hippo pathway) and in glioma cell proliferation, though the precise downstream mechanisms in these contexts remain less well defined."},"narrative":{"mechanistic_narrative":"F2RL1 (PAR-2) is a proteinase-activated receptor that couples extracellular serine-protease cleavage to intracellular signaling cascades controlling tumor immune evasion, inflammation, and proliferation [PMID:41526166]. In lung adenocarcinoma, extracellular granzyme K cleaves F2RL1 on tumor cells, activating AKT/GSK-3β/β-catenin and JAK2/STAT1 signaling; this drives nuclear accumulation of β-catenin and phosphorylated STAT1 to promote PD-L1 transcription, and additionally upregulates COPS8, which stabilizes PD-L1 by inhibiting its ubiquitin-mediated degradation, together suppressing CD8+ T-cell function [PMID:41526166]. Beyond this immune-evasion axis, F2RL1 contributes to lipotoxic inflammatory injury in renal tubular epithelial cells and to glioma cell proliferation, but the downstream mechanisms in these contexts have not been resolved in the available corpus [PMID:39738821, PMID:38252207].","teleology":[{"year":2026,"claim":"Established that F2RL1 functions as a protease-activated signaling hub linking extracellular granzyme K to PD-L1-mediated tumor immune evasion, defining a mechanistic basis for combining protease inhibition with checkpoint blockade.","evidence":"Recombinant GZMK treatment in tumor-CD8+ T cell co-cultures, Western blot for AKT/GSK-3β/β-catenin and JAK2/STAT1, flow cytometry for PD-L1, and in vivo mouse models with GZMK inhibitor plus anti-PD-1","pmids":["41526166"],"confidence":"Medium","gaps":["No reconstitution or structural validation of GZMK-mediated F2RL1 cleavage","Relative contributions of the β-catenin versus STAT1 arms to PD-L1 transcription not dissected","Mechanism by which F2RL1 signaling upregulates COPS8 unknown"]},{"year":2024,"claim":"Implicated F2RL1 in lipotoxicity-driven renal tubular inflammation, extending its role beyond cancer to diabetic kidney disease.","evidence":"siRNA knockdown of F2RL1 in palmitate-stimulated HK-2 cells with inflammatory factor readouts and DKD models","pmids":["39738821"],"confidence":"Low","gaps":["Hippo pathway placement is mechanistic inference, not demonstrated by epistasis or rescue","No identification of the activating protease in this context","No direct molecular link between F2RL1 and the measured inflammatory output"]},{"year":2024,"claim":"Showed F2RL1 supports glioma cell proliferation and is a target of melittin-mediated growth inhibition.","evidence":"Lentiviral F2RL1 knockdown plus melittin in U251 cells, proliferation/migration/invasion assays, cell-cycle and apoptosis flow cytometry, qRT-PCR, and xenografts","pmids":["38252207"],"confidence":"Low","gaps":["No direct molecular mechanism beyond F2RL1 expression level","No pathway placement for the proliferative effect","Whether melittin acts on F2RL1 directly is not established"]},{"year":null,"claim":"How F2RL1 signaling is differentially wired across cancer, renal, and glial contexts, and what physiological proteases activate it, remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of receptor activation or cleavage","Endogenous activating proteases beyond GZMK not defined","Context-specific downstream effectors (e.g., Hippo, cell-cycle genes) not mechanistically linked to F2RL1"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P55085","full_name":"Proteinase-activated receptor 2","aliases":["Coagulation factor II receptor-like 1","G-protein coupled receptor 11","Thrombin receptor-like 1"],"length_aa":397,"mass_kda":44.1,"function":"Receptor for trypsin and trypsin-like enzymes coupled to G proteins (PubMed:28445455). Its function is mediated through the activation of several signaling pathways including phospholipase C (PLC), intracellular calcium, mitogen-activated protein kinase (MAPK), I-kappaB kinase/NF-kappaB and Rho (PubMed:28445455). Can also be transactivated by cleaved F2R/PAR1. Involved in modulation of inflammatory responses and regulation of innate and adaptive immunity, and acts as a sensor for proteolytic enzymes generated during infection. Generally is promoting inflammation. Can signal synergistically with TLR4 and probably TLR2 in inflammatory responses and modulates TLR3 signaling. Has a protective role in establishing the endothelial barrier; the activity involves coagulation factor X. Regulates endothelial cell barrier integrity during neutrophil extravasation, probably following proteolytic cleavage by PRTN3 (PubMed:23202369). Proposed to have a bronchoprotective role in airway epithelium, but also shown to compromise the airway epithelial barrier by interrupting E-cadherin adhesion (PubMed:10086357). Involved in the regulation of vascular tone; activation results in hypotension presumably mediated by vasodilation. Associates with a subset of G proteins alpha subunits such as GNAQ, GNA11, GNA14, GNA12 and GNA13, but probably not with G(o)-alpha, G(i) subunit alpha-1 and G(i) subunit alpha-2. However, according to PubMed:21627585 can signal through G(i) subunit alpha. Believed to be a class B receptor which internalizes as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptor, for extended periods of time. Mediates inhibition of TNF stimulated JNK phosphorylation via coupling to GNAQ and GNA11; the function involves dissociation of RIPK1 and TRADD from TNFR1. Mediates phosphorylation of nuclear factor NF-kappa-B RELA subunit at 'Ser-536'; the function involves IKBKB and is predominantly independent of G proteins. Involved in cellular migration. Involved in cytoskeletal rearrangement and chemotaxis through beta-arrestin-promoted scaffolds; the function is independent of GNAQ and GNA11 and involves promotion of cofilin dephosphorylation and actin filament severing. Induces redistribution of COPS5 from the plasma membrane to the cytosol and activation of the JNK cascade is mediated by COPS5. Involved in the recruitment of leukocytes to the sites of inflammation and is the major PAR receptor capable of modulating eosinophil function such as pro-inflammatory cytokine secretion, superoxide production and degranulation. During inflammation promotes dendritic cell maturation, trafficking to the lymph nodes and subsequent T-cell activation. Involved in antimicrobial response of innate immune cells; activation enhances phagocytosis of Gram-positive and killing of Gram-negative bacteria. Acts synergistically with interferon-gamma in enhancing antiviral responses. Implicated in a number of acute and chronic inflammatory diseases such as of the joints, lungs, brain, gastrointestinal tract, periodontium, skin, and vascular systems, and in autoimmune disorders. Probably mediates activation of pro-inflammatory and pro-fibrotic responses in fibroblasts, triggered by coagulation factor Xa (F10) (By similarity). Mediates activation of barrier protective signaling responses in endothelial cells, triggered by coagulation factor Xa (F10) (PubMed:22409427)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P55085/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/F2RL1","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/F2RL1","total_profiled":1310},"omim":[{"mim_id":"610499","title":"RAP GUANINE NUCLEOTIDE EXCHANGE FACTOR 6; RAPGEF6","url":"https://www.omim.org/entry/610499"},{"mim_id":"607092","title":"SPHINGOSINE KINASE 2; SPHK2","url":"https://www.omim.org/entry/607092"},{"mim_id":"607003","title":"THYMIC STROMAL LYMPHOPOIETIN; TSLP","url":"https://www.omim.org/entry/607003"},{"mim_id":"603730","title":"SPHINGOSINE KINASE 1; SPHK1","url":"https://www.omim.org/entry/603730"},{"mim_id":"601974","title":"SPHINGOSINE-1-PHOSPHATE RECEPTOR 1; S1PR1","url":"https://www.omim.org/entry/601974"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":55.6},{"tissue":"stomach 1","ntpm":41.6}],"url":"https://www.proteinatlas.org/search/F2RL1"},"hgnc":{"alias_symbol":["PAR2"],"prev_symbol":["GPR11"]},"alphafold":{"accession":"P55085","domains":[{"cath_id":"1.20.1070.10","chopping":"57-354","consensus_level":"medium","plddt":91.098,"start":57,"end":354}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P55085","model_url":"https://alphafold.ebi.ac.uk/files/AF-P55085-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P55085-F1-predicted_aligned_error_v6.png","plddt_mean":82.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=F2RL1","jax_strain_url":"https://www.jax.org/strain/search?query=F2RL1"},"sequence":{"accession":"P55085","fasta_url":"https://rest.uniprot.org/uniprotkb/P55085.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P55085/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P55085"}},"corpus_meta":[{"pmid":"22914544","id":"PMC_22914544","title":"Variants in CXADR and F2RL1 are associated with blood pressure and obesity in African-Americans in regions identified through admixture mapping.","date":"2012","source":"Journal of hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/22914544","citation_count":26,"is_preprint":false},{"pmid":"20008081","id":"PMC_20008081","title":"GPR11, a putative seven-transmembrane G protein-coupled receptor, controls zoospore development and virulence of Phytophthora sojae.","date":"2009","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/20008081","citation_count":23,"is_preprint":false},{"pmid":"33765896","id":"PMC_33765896","title":"Cold pain sensitivity is associated with single-nucleotide polymorphisms of PAR2/F2RL1 and TRPM8.","date":"2021","source":"Molecular pain","url":"https://pubmed.ncbi.nlm.nih.gov/33765896","citation_count":11,"is_preprint":false},{"pmid":"19080851","id":"PMC_19080851","title":"[Influence of mutations of proteinase-activated receptors F2R/PAR1 and F2RL1/PAR2 on inflammatory bowel disease].","date":"2008","source":"Medicina clinica","url":"https://pubmed.ncbi.nlm.nih.gov/19080851","citation_count":4,"is_preprint":false},{"pmid":"38252207","id":"PMC_38252207","title":"Melitoxin Inhibits Proliferation, Metastasis, and Invasion of Glioma U251 Cells by Down-regulating F2RL1.","date":"2024","source":"Applied biochemistry and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/38252207","citation_count":3,"is_preprint":false},{"pmid":"38308375","id":"PMC_38308375","title":"Association of single nucleotide polymorphisms in the F2RL1 gene with clinical and inflammatory characteristics of patients with asthma.","date":"2024","source":"Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38308375","citation_count":3,"is_preprint":false},{"pmid":"39738821","id":"PMC_39738821","title":"F2RL1 Inhibition Alleviates Lipotoxicity-Induced Kidney Injury Through the Hippo Pathway in Diabetic Kidney Disease.","date":"2024","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/39738821","citation_count":3,"is_preprint":false},{"pmid":"40931492","id":"PMC_40931492","title":"Proteinase-activated receptor 2 (PAR-2) expression and F2RL1 genetic variants are associated with asthma: a case-control study in the Chinese population.","date":"2025","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/40931492","citation_count":1,"is_preprint":false},{"pmid":"40142692","id":"PMC_40142692","title":"The Expression of F2RL1, P2RX2, P2RX3 and P2RY2 in the Esophagus of Patients with Gastroesophageal Reflux Disease and Their Relationship to Reflux Symptoms-A Pilot Study.","date":"2025","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40142692","citation_count":1,"is_preprint":false},{"pmid":"41526166","id":"PMC_41526166","title":"Extracellular granzyme K enhances PD-L1 transcription and stability via F2RL1 activation to facilitate tumor immune evasion in lung adenocarcinoma.","date":"2026","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41526166","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7671,"output_tokens":1036,"usd":0.019276,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7593,"output_tokens":1683,"usd":0.04002,"stage2_stop_reason":"end_turn"},"total_usd":0.059296,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2026,\n      \"finding\": \"Extracellular granzyme K (GZMK) cleaves F2RL1 (PAR-2) on tumor cells, activating downstream AKT/GSK-3β/β-catenin and JAK2/STAT1 signaling pathways. This leads to nuclear accumulation of β-catenin and phosphorylated STAT1, driving PD-L1 transcription. Additionally, F2RL1 signaling upregulates COPS8, which stabilizes PD-L1 by inhibiting its ubiquitin-mediated degradation, thereby facilitating tumor immune evasion in lung adenocarcinoma.\",\n      \"method\": \"Recombinant human GZMK treatment in tumor-CD8+ T cell co-culture systems, Western blotting for signaling proteins, flow cytometry for PD-L1 expression and CD8+ T-cell function, in vivo mouse tumor models with GZMK inhibitor + anti-PD-1 combination therapy\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (co-culture, Western blot for pathway activation, in vivo models) in a single lab; mechanistic pathway defined but no reconstitution or structural validation\",\n      \"pmids\": [\"41526166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"F2RL1 knockdown in palmitate-stimulated HK-2 renal tubular epithelial cells significantly reduced the inflammatory response, and mechanistic analysis suggested F2RL1 exacerbates lipotoxicity-induced injury through modulation of the Hippo signaling pathway in diabetic kidney disease.\",\n      \"method\": \"siRNA knockdown of F2RL1 in HK-2 cells stimulated with palmitate; measurement of inflammatory factor expression; in vivo and in vitro DKD models\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown with phenotypic readout but pathway placement (Hippo) described as mechanistic inference rather than directly demonstrated by epistasis or rescue experiments\",\n      \"pmids\": [\"39738821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"F2RL1 knockdown combined with melittin treatment in glioma U251 cells increased G1-phase arrest, reduced cell proliferation, migration, and invasion, and altered expression of apoptosis and cell cycle arrest genes, establishing that melittin inhibits glioma cell proliferation at least partly by suppressing F2RL1 expression.\",\n      \"method\": \"Lentiviral F2RL1 knockdown, MTT and EdU proliferation assays, flow cytometry for apoptosis and cell cycle, qRT-PCR for gene expression, xenograft mouse model\",\n      \"journal\": \"Applied biochemistry and biotechnology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, loss-of-function with phenotypic readout but no direct molecular mechanism or pathway placement beyond F2RL1 expression level\",\n      \"pmids\": [\"38252207\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"F2RL1 (PAR-2) is a G protein-coupled proteinase-activated receptor that can be cleaved by extracellular serine proteases such as granzyme K; upon cleavage, it activates AKT/GSK-3β/β-catenin and JAK2/STAT1 signaling to drive PD-L1 transcription and, via COPS8 upregulation, stabilizes PD-L1 against ubiquitin-mediated degradation, thereby promoting immune evasion; F2RL1 also participates in inflammatory signaling in renal tubular cells (via the Hippo pathway) and in glioma cell proliferation, though the precise downstream mechanisms in these contexts remain less well defined.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"F2RL1 (PAR-2) is a proteinase-activated receptor that couples extracellular serine-protease cleavage to intracellular signaling cascades controlling tumor immune evasion, inflammation, and proliferation [#0]. In lung adenocarcinoma, extracellular granzyme K cleaves F2RL1 on tumor cells, activating AKT/GSK-3\\u03b2/\\u03b2-catenin and JAK2/STAT1 signaling; this drives nuclear accumulation of \\u03b2-catenin and phosphorylated STAT1 to promote PD-L1 transcription, and additionally upregulates COPS8, which stabilizes PD-L1 by inhibiting its ubiquitin-mediated degradation, together suppressing CD8+ T-cell function [#0]. Beyond this immune-evasion axis, F2RL1 contributes to lipotoxic inflammatory injury in renal tubular epithelial cells and to glioma cell proliferation, but the downstream mechanisms in these contexts have not been resolved in the available corpus [#1, #2].\",\n  \"teleology\": [\n    {\n      \"year\": 2026,\n      \"claim\": \"Established that F2RL1 functions as a protease-activated signaling hub linking extracellular granzyme K to PD-L1-mediated tumor immune evasion, defining a mechanistic basis for combining protease inhibition with checkpoint blockade.\",\n      \"evidence\": \"Recombinant GZMK treatment in tumor-CD8+ T cell co-cultures, Western blot for AKT/GSK-3\\u03b2/\\u03b2-catenin and JAK2/STAT1, flow cytometry for PD-L1, and in vivo mouse models with GZMK inhibitor plus anti-PD-1\",\n      \"pmids\": [\"41526166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No reconstitution or structural validation of GZMK-mediated F2RL1 cleavage\",\n        \"Relative contributions of the \\u03b2-catenin versus STAT1 arms to PD-L1 transcription not dissected\",\n        \"Mechanism by which F2RL1 signaling upregulates COPS8 unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated F2RL1 in lipotoxicity-driven renal tubular inflammation, extending its role beyond cancer to diabetic kidney disease.\",\n      \"evidence\": \"siRNA knockdown of F2RL1 in palmitate-stimulated HK-2 cells with inflammatory factor readouts and DKD models\",\n      \"pmids\": [\"39738821\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Hippo pathway placement is mechanistic inference, not demonstrated by epistasis or rescue\",\n        \"No identification of the activating protease in this context\",\n        \"No direct molecular link between F2RL1 and the measured inflammatory output\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed F2RL1 supports glioma cell proliferation and is a target of melittin-mediated growth inhibition.\",\n      \"evidence\": \"Lentiviral F2RL1 knockdown plus melittin in U251 cells, proliferation/migration/invasion assays, cell-cycle and apoptosis flow cytometry, qRT-PCR, and xenografts\",\n      \"pmids\": [\"38252207\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct molecular mechanism beyond F2RL1 expression level\",\n        \"No pathway placement for the proliferative effect\",\n        \"Whether melittin acts on F2RL1 directly is not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How F2RL1 signaling is differentially wired across cancer, renal, and glial contexts, and what physiological proteases activate it, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of receptor activation or cleavage\",\n        \"Endogenous activating proteases beyond GZMK not defined\",\n        \"Context-specific downstream effectors (e.g., Hippo, cell-cycle genes) not mechanistically linked to F2RL1\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":2,"faith_pct":100.0}}