{"gene":"TCAF2","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2015,"finding":"TCAF2 physically binds to the TRPM8 channel and promotes its trafficking to the cell surface, while exerting opposing effects on TRPM8 gating properties compared to TCAF1 (TCAF1 reduces channel activity; TCAF2 promotes it). TCAF2 also promotes migration of prostate cancer cells, in contrast to TCAF1 which reduces migration speed and directionality.","method":"Co-immunoprecipitation (binding), cell surface trafficking assays, electrophysiology (gating), and cell migration assays (Transwell/scratch); loss- and gain-of-function experiments in prostate cancer cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for binding, functional trafficking assay, electrophysiology for gating, and migration assays in a single focused study; foundational paper replicated in subsequent work","pmids":["25559186"],"is_preprint":false},{"year":2023,"finding":"In tumor pericytes, TCAF2 inhibits the expression and activity of TRPM8, leading to Wnt5a secretion from pericytes, which in turn activates the STAT3 signaling pathway in tumor cells to facilitate epithelial-mesenchymal transition (EMT) and colorectal cancer liver metastasis. Pericyte-conditional Tcaf2 knockout in mice attenuates metastasis, and the TRPM8 agonist menthol suppresses Wnt5a secretion and metastasis.","method":"Gain- and loss-of-function experiments in pericytes, pericyte-conditional Tcaf2-knockout mice, proteomic analysis, TRPM8 activity assays, Wnt5a secretion measurement, STAT3 phosphorylation western blot, in vivo metastasis models","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mouse model with defined metastatic phenotype, multiple orthogonal mechanistic readouts (TRPM8 activity, Wnt5a secretion, STAT3 signaling), replicated with pharmacological rescue","pmids":["37635201"],"is_preprint":false},{"year":2023,"finding":"Elevated TCAF2 expression promotes glioma cell migration and invasion through an EMT-like process mediated by activation of the STAT3 signaling pathway.","method":"Transwell and scratch assays for migration/invasion, western blotting for EMT markers and STAT3 phosphorylation, gain- and loss-of-function in glioma cell lines, immunohistochemistry on glioma tissue microarray","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD/OE with defined cellular phenotype and pathway placement via western blot, single lab, no in vivo validation","pmids":["38019450"],"is_preprint":false},{"year":2025,"finding":"PDE12 positively regulates TCAF2 expression in gastric cancer cells, and TCAF2 functions downstream of PDE12 to promote gastric cancer cell proliferation, migration, invasion, and EMT via activation of the JAK2/STAT3 signaling pathway. TCAF2 knockdown reverses the pro-tumorigenic effects of PDE12 overexpression, placing TCAF2 as a required intermediate in the PDE12/JAK2/STAT3 axis.","method":"Gain- and loss-of-function experiments (overexpression and knockdown of PDE12 and TCAF2), western blotting for JAK2/STAT3 phosphorylation and EMT markers, proliferation and migration/invasion assays, cell cycle analysis","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by rescue experiment (TCAF2 KD reverses PDE12 OE phenotype), multiple orthogonal cellular assays, single lab","pmids":["40628363"],"is_preprint":false},{"year":2020,"finding":"FAM115C (TCAF2) inhibition promotes pancreatic ductal adenocarcinoma (PDAC) cell migration and invasion in vitro without affecting proliferation, suggesting a tumor-suppressive role in restraining cell motility in PDAC. Protein was localized mainly to the nucleus but also the cytoplasm in PDAC cells.","method":"siRNA-mediated knockdown of FAM115C/TCAF2, migration and invasion assays, proliferation assay, immunohistochemistry for subcellular localization","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined migration/invasion phenotype and subcellular localization, but single lab, limited mechanistic pathway detail","pmids":["32127956"],"is_preprint":false}],"current_model":"TCAF2 is a TRPM8 channel-associated factor that physically binds TRPM8, promotes its trafficking to the cell surface, and enhances its gating activity; in pericytes and cancer cells, TCAF2 suppresses TRPM8 activity to drive Wnt5a secretion and activate JAK2/STAT3 signaling, thereby promoting epithelial-mesenchymal transition, cell migration/invasion, and tumor metastasis, placing TCAF2 as a pro-migratory, oncogenic regulator downstream of TRPM8 channel inhibition and upstream of STAT3 activation."},"narrative":{"mechanistic_narrative":"TCAF2 is a TRPM8 channel-associated factor that governs cell migration and invasion across multiple cancer contexts by coupling regulation of TRPM8 to downstream STAT3 signaling [PMID:25559186, PMID:37635201]. It physically binds the TRPM8 channel and promotes its trafficking to the cell surface while potentiating its gating activity, in contrast to its paralog TCAF1, which reduces channel activity; functionally, TCAF2 promotes migration of prostate cancer cells [PMID:25559186]. In tumor pericytes, TCAF2 inhibits TRPM8 expression and activity, driving Wnt5a secretion that activates STAT3 in adjacent tumor cells to promote epithelial-mesenchymal transition and colorectal cancer liver metastasis, a phenotype attenuated by pericyte-specific Tcaf2 knockout and by the TRPM8 agonist menthol [PMID:37635201]. The pro-migratory, EMT-promoting role of TCAF2 via JAK2/STAT3 activation extends to glioma [PMID:38019450] and to gastric cancer, where TCAF2 acts as a required intermediate downstream of PDE12 [PMID:40628363]. Context-dependence is evident, as TCAF2 inhibition instead promotes migration and invasion in pancreatic ductal adenocarcinoma, indicating a motility-restraining role in that setting [PMID:32127956].","teleology":[{"year":2015,"claim":"Established that TCAF2 is a physical partner and trafficking/gating regulator of the TRPM8 channel, distinguishing it functionally from its paralog TCAF1 and linking it to cancer cell migration.","evidence":"Reciprocal Co-IP, cell surface trafficking assays, electrophysiology, and migration assays with loss-/gain-of-function in prostate cancer cells","pmids":["25559186"],"confidence":"High","gaps":["Molecular basis for the opposing gating effects of TCAF2 versus TCAF1 not resolved","Signaling pathway linking TRPM8 modulation to migration not defined in this study"]},{"year":2023,"claim":"Connected TCAF2 to a paracrine metastatic mechanism, showing it suppresses TRPM8 to drive pericyte Wnt5a secretion and tumor-cell STAT3-dependent EMT in vivo.","evidence":"Pericyte-conditional Tcaf2-knockout mice, proteomics, TRPM8 activity and Wnt5a secretion assays, STAT3 phosphorylation western blot, in vivo metastasis models with menthol rescue","pmids":["37635201"],"confidence":"High","gaps":["Mechanism by which TCAF2 inhibits TRPM8 expression not defined","How TRPM8 activity controls Wnt5a secretion mechanistically unresolved"]},{"year":2023,"claim":"Extended the TCAF2-STAT3-EMT axis to glioma, supporting a generalizable pro-migratory function across tumor types.","evidence":"Transwell/scratch assays, EMT marker and STAT3 western blots, gain-/loss-of-function in glioma lines, IHC on tissue microarray","pmids":["38019450"],"confidence":"Medium","gaps":["No in vivo validation","TRPM8 involvement in glioma not tested","Single lab"]},{"year":2025,"claim":"Placed TCAF2 as a required intermediate in a PDE12/JAK2/STAT3 oncogenic axis in gastric cancer via epistasis.","evidence":"PDE12 and TCAF2 overexpression/knockdown with rescue, JAK2/STAT3 and EMT marker western blots, proliferation/migration/invasion and cell cycle assays","pmids":["40628363"],"confidence":"Medium","gaps":["Mechanism by which PDE12 regulates TCAF2 expression unknown","No in vivo validation","Direct biochemical link of TCAF2 to JAK2 not established"]},{"year":2020,"claim":"Revealed context-dependent function, with TCAF2 inhibition promoting rather than restraining migration in pancreatic cancer.","evidence":"siRNA knockdown, migration/invasion and proliferation assays, IHC for subcellular localization in PDAC cells","pmids":["32127956"],"confidence":"Medium","gaps":["Mechanistic pathway not defined","Reason for opposite directionality versus other cancers unresolved","Single lab"]},{"year":null,"claim":"How TCAF2 reconciles its dual context-dependent roles—promoting versus restraining migration—and the molecular basis of its TRPM8-independent signaling remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying mechanism explaining tissue-specific opposite phenotypes","Direct biochemical link between TCAF2 and JAK2/STAT3 not established","No structural model of TCAF2-TRPM8 interaction"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":["TRPM8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A6NFQ2","full_name":"TRPM8 channel-associated factor 2","aliases":["TRP channel-associated factor 2"],"length_aa":919,"mass_kda":100.9,"function":"Negatively regulates the plasma membrane cation channel TRPM8 activity. Involved in the recruitment of TRPM8 to the cell surface. Promotes prostate cancer cell migration stimulation in a TRPM8-dependent manner","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/A6NFQ2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TCAF2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":77,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TCAF2","total_profiled":1310},"omim":[{"mim_id":"616252","title":"TRPM8 CHANNEL-ASSOCIATED FACTOR 2; TCAF2","url":"https://www.omim.org/entry/616252"},{"mim_id":"616251","title":"TRPM8 CHANNEL-ASSOCIATED FACTOR 1; TCAF1","url":"https://www.omim.org/entry/616251"},{"mim_id":"606678","title":"TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY M, MEMBER 8; TRPM8","url":"https://www.omim.org/entry/606678"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TCAF2"},"hgnc":{"alias_symbol":["FLJ40722","GATD9B"],"prev_symbol":["FAM139A","FAM115C"]},"alphafold":{"accession":"A6NFQ2","domains":[{"cath_id":"-","chopping":"6-189","consensus_level":"high","plddt":93.6451,"start":6,"end":189},{"cath_id":"-","chopping":"214-406","consensus_level":"high","plddt":94.4516,"start":214,"end":406},{"cath_id":"-","chopping":"419-504","consensus_level":"medium","plddt":90.5614,"start":419,"end":504},{"cath_id":"3.40.390.80","chopping":"639-764","consensus_level":"medium","plddt":95.586,"start":639,"end":764},{"cath_id":"1.10.390.30","chopping":"768-918","consensus_level":"high","plddt":95.4928,"start":768,"end":918}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A6NFQ2","model_url":"https://alphafold.ebi.ac.uk/files/AF-A6NFQ2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A6NFQ2-F1-predicted_aligned_error_v6.png","plddt_mean":92.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TCAF2","jax_strain_url":"https://www.jax.org/strain/search?query=TCAF2"},"sequence":{"accession":"A6NFQ2","fasta_url":"https://rest.uniprot.org/uniprotkb/A6NFQ2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A6NFQ2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A6NFQ2"}},"corpus_meta":[{"pmid":"25559186","id":"PMC_25559186","title":"TRP channel-associated factors are a novel protein family that regulates TRPM8 trafficking and activity.","date":"2015","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25559186","citation_count":83,"is_preprint":false},{"pmid":"37635201","id":"PMC_37635201","title":"TCAF2 in Pericytes Promotes Colorectal Cancer Liver Metastasis via Inhibiting Cold-Sensing TRPM8 Channel.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37635201","citation_count":24,"is_preprint":false},{"pmid":"34433829","id":"PMC_34433829","title":"Evidence for opposing selective forces operating on human-specific duplicated TCAF genes in Neanderthals and humans.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34433829","citation_count":17,"is_preprint":false},{"pmid":"29167762","id":"PMC_29167762","title":"LncRNA Expression in CD4+ T Cells in Neurosyphilis Patients.","date":"2017","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/29167762","citation_count":12,"is_preprint":false},{"pmid":"32127956","id":"PMC_32127956","title":"FAM115C could be a novel tumor suppressor associated with prolonged survival in pancreatic cancer patients.","date":"2020","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32127956","citation_count":10,"is_preprint":false},{"pmid":"36012311","id":"PMC_36012311","title":"The Association between TRP Channels Expression and Clinicopathological Characteristics of Patients with Pancreatic Adenocarcinoma.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36012311","citation_count":9,"is_preprint":false},{"pmid":"31151297","id":"PMC_31151297","title":"Identification of Proteins Differentially Expressed by Adipose-derived Mesenchymal Stem Cells Isolated from Immunodeficient Mice.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31151297","citation_count":7,"is_preprint":false},{"pmid":"35641902","id":"PMC_35641902","title":"Hypoxia classifier for transcriptome datasets.","date":"2022","source":"BMC bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/35641902","citation_count":6,"is_preprint":false},{"pmid":"39446287","id":"PMC_39446287","title":"Key Genes Involved in the Beneficial Mechanism of Hyperbaric Oxygen for Glioblastoma and Predictive Indicators of Hyperbaric Oxygen Prolonging Survival in Glioblastoma Patients.","date":"2024","source":"Current medical science","url":"https://pubmed.ncbi.nlm.nih.gov/39446287","citation_count":5,"is_preprint":false},{"pmid":"38019450","id":"PMC_38019450","title":"TCAF2 drives glioma cellular migratory/invasion properties through STAT3 signaling.","date":"2023","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38019450","citation_count":3,"is_preprint":false},{"pmid":"40628363","id":"PMC_40628363","title":"Phosphodiesterase 12 facilitates the growth and metastatic capabilities of gastric cancer cells by activating the TCAF2/JAK2/STAT3 axis.","date":"2025","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/40628363","citation_count":0,"is_preprint":false},{"pmid":"39263936","id":"PMC_39263936","title":"When is an SNP not an SNP?","date":"2024","source":"BioTechniques","url":"https://pubmed.ncbi.nlm.nih.gov/39263936","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8243,"output_tokens":1536,"usd":0.023884,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8305,"output_tokens":2174,"usd":0.047938,"stage2_stop_reason":"end_turn"},"total_usd":0.071822,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"TCAF2 physically binds to the TRPM8 channel and promotes its trafficking to the cell surface, while exerting opposing effects on TRPM8 gating properties compared to TCAF1 (TCAF1 reduces channel activity; TCAF2 promotes it). TCAF2 also promotes migration of prostate cancer cells, in contrast to TCAF1 which reduces migration speed and directionality.\",\n      \"method\": \"Co-immunoprecipitation (binding), cell surface trafficking assays, electrophysiology (gating), and cell migration assays (Transwell/scratch); loss- and gain-of-function experiments in prostate cancer cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for binding, functional trafficking assay, electrophysiology for gating, and migration assays in a single focused study; foundational paper replicated in subsequent work\",\n      \"pmids\": [\"25559186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In tumor pericytes, TCAF2 inhibits the expression and activity of TRPM8, leading to Wnt5a secretion from pericytes, which in turn activates the STAT3 signaling pathway in tumor cells to facilitate epithelial-mesenchymal transition (EMT) and colorectal cancer liver metastasis. Pericyte-conditional Tcaf2 knockout in mice attenuates metastasis, and the TRPM8 agonist menthol suppresses Wnt5a secretion and metastasis.\",\n      \"method\": \"Gain- and loss-of-function experiments in pericytes, pericyte-conditional Tcaf2-knockout mice, proteomic analysis, TRPM8 activity assays, Wnt5a secretion measurement, STAT3 phosphorylation western blot, in vivo metastasis models\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mouse model with defined metastatic phenotype, multiple orthogonal mechanistic readouts (TRPM8 activity, Wnt5a secretion, STAT3 signaling), replicated with pharmacological rescue\",\n      \"pmids\": [\"37635201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Elevated TCAF2 expression promotes glioma cell migration and invasion through an EMT-like process mediated by activation of the STAT3 signaling pathway.\",\n      \"method\": \"Transwell and scratch assays for migration/invasion, western blotting for EMT markers and STAT3 phosphorylation, gain- and loss-of-function in glioma cell lines, immunohistochemistry on glioma tissue microarray\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD/OE with defined cellular phenotype and pathway placement via western blot, single lab, no in vivo validation\",\n      \"pmids\": [\"38019450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PDE12 positively regulates TCAF2 expression in gastric cancer cells, and TCAF2 functions downstream of PDE12 to promote gastric cancer cell proliferation, migration, invasion, and EMT via activation of the JAK2/STAT3 signaling pathway. TCAF2 knockdown reverses the pro-tumorigenic effects of PDE12 overexpression, placing TCAF2 as a required intermediate in the PDE12/JAK2/STAT3 axis.\",\n      \"method\": \"Gain- and loss-of-function experiments (overexpression and knockdown of PDE12 and TCAF2), western blotting for JAK2/STAT3 phosphorylation and EMT markers, proliferation and migration/invasion assays, cell cycle analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by rescue experiment (TCAF2 KD reverses PDE12 OE phenotype), multiple orthogonal cellular assays, single lab\",\n      \"pmids\": [\"40628363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM115C (TCAF2) inhibition promotes pancreatic ductal adenocarcinoma (PDAC) cell migration and invasion in vitro without affecting proliferation, suggesting a tumor-suppressive role in restraining cell motility in PDAC. Protein was localized mainly to the nucleus but also the cytoplasm in PDAC cells.\",\n      \"method\": \"siRNA-mediated knockdown of FAM115C/TCAF2, migration and invasion assays, proliferation assay, immunohistochemistry for subcellular localization\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined migration/invasion phenotype and subcellular localization, but single lab, limited mechanistic pathway detail\",\n      \"pmids\": [\"32127956\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TCAF2 is a TRPM8 channel-associated factor that physically binds TRPM8, promotes its trafficking to the cell surface, and enhances its gating activity; in pericytes and cancer cells, TCAF2 suppresses TRPM8 activity to drive Wnt5a secretion and activate JAK2/STAT3 signaling, thereby promoting epithelial-mesenchymal transition, cell migration/invasion, and tumor metastasis, placing TCAF2 as a pro-migratory, oncogenic regulator downstream of TRPM8 channel inhibition and upstream of STAT3 activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TCAF2 is a TRPM8 channel-associated factor that governs cell migration and invasion across multiple cancer contexts by coupling regulation of TRPM8 to downstream STAT3 signaling [#0, #1]. It physically binds the TRPM8 channel and promotes its trafficking to the cell surface while potentiating its gating activity, in contrast to its paralog TCAF1, which reduces channel activity; functionally, TCAF2 promotes migration of prostate cancer cells [#0]. In tumor pericytes, TCAF2 inhibits TRPM8 expression and activity, driving Wnt5a secretion that activates STAT3 in adjacent tumor cells to promote epithelial-mesenchymal transition and colorectal cancer liver metastasis, a phenotype attenuated by pericyte-specific Tcaf2 knockout and by the TRPM8 agonist menthol [#1]. The pro-migratory, EMT-promoting role of TCAF2 via JAK2/STAT3 activation extends to glioma [#2] and to gastric cancer, where TCAF2 acts as a required intermediate downstream of PDE12 [#3]. Context-dependence is evident, as TCAF2 inhibition instead promotes migration and invasion in pancreatic ductal adenocarcinoma, indicating a motility-restraining role in that setting [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that TCAF2 is a physical partner and trafficking/gating regulator of the TRPM8 channel, distinguishing it functionally from its paralog TCAF1 and linking it to cancer cell migration.\",\n      \"evidence\": \"Reciprocal Co-IP, cell surface trafficking assays, electrophysiology, and migration assays with loss-/gain-of-function in prostate cancer cells\",\n      \"pmids\": [\"25559186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular basis for the opposing gating effects of TCAF2 versus TCAF1 not resolved\",\n        \"Signaling pathway linking TRPM8 modulation to migration not defined in this study\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected TCAF2 to a paracrine metastatic mechanism, showing it suppresses TRPM8 to drive pericyte Wnt5a secretion and tumor-cell STAT3-dependent EMT in vivo.\",\n      \"evidence\": \"Pericyte-conditional Tcaf2-knockout mice, proteomics, TRPM8 activity and Wnt5a secretion assays, STAT3 phosphorylation western blot, in vivo metastasis models with menthol rescue\",\n      \"pmids\": [\"37635201\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which TCAF2 inhibits TRPM8 expression not defined\",\n        \"How TRPM8 activity controls Wnt5a secretion mechanistically unresolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the TCAF2-STAT3-EMT axis to glioma, supporting a generalizable pro-migratory function across tumor types.\",\n      \"evidence\": \"Transwell/scratch assays, EMT marker and STAT3 western blots, gain-/loss-of-function in glioma lines, IHC on tissue microarray\",\n      \"pmids\": [\"38019450\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vivo validation\",\n        \"TRPM8 involvement in glioma not tested\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed TCAF2 as a required intermediate in a PDE12/JAK2/STAT3 oncogenic axis in gastric cancer via epistasis.\",\n      \"evidence\": \"PDE12 and TCAF2 overexpression/knockdown with rescue, JAK2/STAT3 and EMT marker western blots, proliferation/migration/invasion and cell cycle assays\",\n      \"pmids\": [\"40628363\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which PDE12 regulates TCAF2 expression unknown\",\n        \"No in vivo validation\",\n        \"Direct biochemical link of TCAF2 to JAK2 not established\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed context-dependent function, with TCAF2 inhibition promoting rather than restraining migration in pancreatic cancer.\",\n      \"evidence\": \"siRNA knockdown, migration/invasion and proliferation assays, IHC for subcellular localization in PDAC cells\",\n      \"pmids\": [\"32127956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanistic pathway not defined\",\n        \"Reason for opposite directionality versus other cancers unresolved\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TCAF2 reconciles its dual context-dependent roles—promoting versus restraining migration—and the molecular basis of its TRPM8-independent signaling remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No unifying mechanism explaining tissue-specific opposite phenotypes\",\n        \"Direct biochemical link between TCAF2 and JAK2/STAT3 not established\",\n        \"No structural model of TCAF2-TRPM8 interaction\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TRPM8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}