{"gene":"SLC35F6","run_date":"2026-06-10T07:46:33","timeline":{"discoveries":[{"year":2008,"finding":"C2orf18/SLC35F6 (ANT2BP) localizes to mitochondria and physically interacts with adenine nucleotide translocase 2 (ANT2), a protein involved in mitochondrial membrane potential maintenance and energy homeostasis; knockdown by siRNA induced apoptosis and suppressed cancer cell growth in pancreatic ductal adenocarcinoma cell lines.","method":"Immunolocalization (mitochondrial), co-immunoprecipitation/interaction assay with ANT2, siRNA knockdown with apoptosis/growth readout","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — subcellular localization and binding partner identified by direct experiment, siRNA phenotype with defined readout; single lab, methods described at abstract level only","pmids":["19154410"],"is_preprint":false},{"year":2024,"finding":"SLC35F6 localizes specifically to lysosomes (distinct from the recycling endosome localization of SLC35F1), and its lysosomal sorting depends on the EQERLL360 signal in its cytoplasmic C-terminal tail; swapping the C-terminal tail of SLC35F1 and SLC35F6 switched their respective localizations, demonstrating that C-terminal sorting signals are necessary and sufficient for their differential compartment targeting.","method":"Fluorescence microscopy, C-terminal tail domain-swap mutants, site-directed mutagenesis of sorting signals, cell surface biotinylation assays","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, domain swap, biotinylation, fluorescence microscopy) in a single focused study with rigorous controls","pmids":["38928424"],"is_preprint":false},{"year":2024,"finding":"SLC35F6 is involved in cell apoptosis through the Bcl2/BAX/caspase3 pathway and affects mitochondrial membrane potential, as demonstrated in functional validation experiments in a piglet diarrhea model.","method":"Functional validation assays measuring Bcl2/BAX/caspase3 pathway markers and mitochondrial membrane potential following SLC35F6 manipulation","journal":"Animal bioscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single study, methods described only at abstract level, limited mechanistic detail, non-human model system (pig)","pmids":["39482997"],"is_preprint":false},{"year":2025,"finding":"Knockdown of SLC35F6 in H22 and HepG2 hepatocellular carcinoma cells markedly reduced cell growth and elevated TP53 protein levels, placing SLC35F6 in a miR-542-3p/SLC35F6/TP53 regulatory axis; SLC35F6 is identified as a direct target gene of miR-542-3p.","method":"siRNA knockdown, western blot for TP53, miRNA target validation (miR-542-3p overexpression with SLC35F6 expression measurement), cell proliferation assays","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple methods (knockdown, miRNA manipulation, protein level measurement) in a single lab; direct mutual regulation between SLC35F6 and TP53 explicitly not confirmed by the authors","pmids":["40118430"],"is_preprint":false}],"current_model":"SLC35F6 (ANT2BP/C2orf18) is an orphan SLC35-family transporter that resides in lysosomes via a cytoplasmic C-terminal EQERLL sorting signal, physically interacts with the mitochondrial protein ANT2, participates in apoptotic regulation via the Bcl2/BAX/caspase3 pathway and mitochondrial membrane potential, and acts as a target of miR-542-3p to modulate TP53 levels and cell proliferation."},"narrative":{"mechanistic_narrative":"SLC35F6 (ANT2BP/C2orf18) is an orphan SLC35-family transporter implicated in apoptotic regulation and the control of cancer cell proliferation [PMID:19154410, PMID:40118430]. It localizes to lysosomes, with compartment targeting dictated by an EQERLL360 sorting signal in its cytoplasmic C-terminal tail that is both necessary and sufficient for lysosomal delivery, as shown by domain-swap experiments distinguishing it from the recycling-endosome-targeted SLC35F1 [PMID:38928424]. SLC35F6 physically interacts with the mitochondrial adenine nucleotide translocase ANT2, and its depletion triggers apoptosis and suppresses growth in pancreatic and hepatocellular carcinoma cells [PMID:19154410, PMID:40118430]. In hepatocellular carcinoma, SLC35F6 is a direct target of miR-542-3p, and its knockdown elevates TP53 protein levels, placing it within a miR-542-3p/SLC35F6/TP53 axis governing cell proliferation [PMID:40118430]. The transport substrate of SLC35F6 has not been identified in the available corpus, and the molecular link between its lysosomal localization and its mitochondrial/apoptotic functions remains uncharacterized.","teleology":[{"year":2008,"claim":"Established the first physical and functional partner for the orphan protein by showing it binds the mitochondrial nucleotide translocase ANT2 and is required for cancer cell survival.","evidence":"Mitochondrial immunolocalization, co-immunoprecipitation with ANT2, and siRNA knockdown with apoptosis/growth readouts in pancreatic carcinoma cells","pmids":["19154410"],"confidence":"Medium","gaps":["Interaction shown by single-lab Co-IP without reciprocal or structural validation","Mitochondrial localization later contrasted by lysosomal targeting evidence","No transport substrate identified"]},{"year":2024,"claim":"Resolved the steady-state localization of the protein, demonstrating lysosomal targeting driven by a defined C-terminal EQERLL sorting signal that distinguishes it from its paralog SLC35F1.","evidence":"Fluorescence microscopy, C-terminal domain-swap mutants, site-directed mutagenesis of sorting signals, and cell-surface biotinylation","pmids":["38928424"],"confidence":"High","gaps":["Does not reconcile lysosomal localization with the earlier reported mitochondrial localization and ANT2 interaction","Transported substrate remains unknown","Functional consequence of lysosomal targeting not tested"]},{"year":2024,"claim":"Linked SLC35F6 manipulation to apoptotic signaling through the Bcl2/BAX/caspase3 pathway and mitochondrial membrane potential in a non-human model.","evidence":"Functional validation of Bcl2/BAX/caspase3 markers and mitochondrial membrane potential in a piglet diarrhea model","pmids":["39482997"],"confidence":"Low","gaps":["Single study with abstract-level methods in a pig model, not independently confirmed in human cells","Mechanistic connection between SLC35F6 and the apoptotic pathway not defined","No direct molecular target identified"]},{"year":2025,"claim":"Placed SLC35F6 in a regulatory axis controlling proliferation, identifying it as a direct miR-542-3p target whose loss raises TP53 levels in hepatocellular carcinoma cells.","evidence":"siRNA knockdown, western blot for TP53, miR-542-3p target validation, and proliferation assays in H22 and HepG2 cells","pmids":["40118430"],"confidence":"Medium","gaps":["Direct mutual regulation between SLC35F6 and TP53 explicitly not confirmed by the authors","Mechanism by which SLC35F6 alters TP53 levels unknown","Single-lab study"]},{"year":null,"claim":"The transport substrate of SLC35F6 and the mechanistic bridge between its lysosomal localization, ANT2 binding, and apoptotic/TP53 regulation remain undefined.","evidence":"No discovery in the corpus identifies a transported molecule or a unifying molecular mechanism","pmids":[],"confidence":"Low","gaps":["No transport substrate identified","Mitochondrial versus lysosomal localization not reconciled","Causal mechanism linking the protein to Bcl2/BAX/caspase3 and TP53 unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[1]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,3]}],"complexes":[],"partners":["ANT2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N357","full_name":"Solute carrier family 35 member F6","aliases":["ANT2-binding protein","ANT2BP","Transport and Golgi organization 9 homolog"],"length_aa":371,"mass_kda":40.2,"function":"Involved in the maintenance of mitochondrial membrane potential in pancreatic ductal adenocarcinoma (PDAC) cells. Promotes pancreatic ductal adenocarcinoma (PDAC) cell growth. May play a role as a nucleotide-sugar transporter","subcellular_location":"Mitochondrion; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q8N357/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC35F6","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":[{"gene":"LAMP1","stoichiometry":0.2},{"gene":"TMEM106B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SLC35F6","total_profiled":1310},"omim":[{"mim_id":"619667","title":"SOLUTE CARRIER FAMILY 35, MEMBER F6; SLC35F6","url":"https://www.omim.org/entry/619667"},{"mim_id":"609955","title":"FIBROMATOSIS, GINGIVAL, 3; GINGF3","url":"https://www.omim.org/entry/609955"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SLC35F6"},"hgnc":{"alias_symbol":["FLJ20555","ANT2BP","TANGO9"],"prev_symbol":["C2orf18"]},"alphafold":{"accession":"Q8N357","domains":[{"cath_id":"-","chopping":"45-72_87-271_319-338","consensus_level":"high","plddt":89.6198,"start":45,"end":338}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N357","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N357-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N357-F1-predicted_aligned_error_v6.png","plddt_mean":84.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC35F6","jax_strain_url":"https://www.jax.org/strain/search?query=SLC35F6"},"sequence":{"accession":"Q8N357","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N357.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N357/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N357"}},"corpus_meta":[{"pmid":"32249461","id":"PMC_32249461","title":"Analysis of lncRNA UCA1-related downstream pathways and molecules of cisplatin resistance in lung adenocarcinoma.","date":"2020","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/32249461","citation_count":17,"is_preprint":false},{"pmid":"19154410","id":"PMC_19154410","title":"Identification of C2orf18, termed ANT2BP (ANT2-binding protein), as one of the key molecules involved in pancreatic carcinogenesis.","date":"2008","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/19154410","citation_count":16,"is_preprint":false},{"pmid":"40118430","id":"PMC_40118430","title":"Ulvan derived from Ulva lactuca suppresses hepatocellular carcinoma cell proliferation through miR-542-3p-mediated downregulation of SLC35F6.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40118430","citation_count":8,"is_preprint":false},{"pmid":"19633868","id":"PMC_19633868","title":"Refinement of the GINGF3 locus for hereditary gingival fibromatosis.","date":"2009","source":"European journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/19633868","citation_count":6,"is_preprint":false},{"pmid":"38928424","id":"PMC_38928424","title":"Residence of the Nucleotide Sugar Transporter Family Members SLC35F1 and SLC35F6 in the Endosomal/Lysosomal Pathway.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38928424","citation_count":5,"is_preprint":false},{"pmid":"39578844","id":"PMC_39578844","title":"Clinical significance and expression of SLC35F6 in bladder urothelial carcinoma.","date":"2024","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/39578844","citation_count":1,"is_preprint":false},{"pmid":"41284867","id":"PMC_41284867","title":"GWAS for behavioral traits in golden retrievers identifies genes implicated in human temperament, mental health, and cognition.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/41284867","citation_count":1,"is_preprint":false},{"pmid":"41516385","id":"PMC_41516385","title":"Molecular Modeling and Gene Ontology Implicate SLC35F4 and SLC35F5 as Golgi-Associated Importers of Flavin-Adenine-Dinucleotide.","date":"2026","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41516385","citation_count":0,"is_preprint":false},{"pmid":"39482997","id":"PMC_39482997","title":"Genome-wide association study and subsequent functional analysis reveal regulatory mechanism underlying piglet diarrhea.","date":"2024","source":"Animal bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/39482997","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6886,"output_tokens":1123,"usd":0.018752,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7706,"output_tokens":1959,"usd":0.043752,"stage2_stop_reason":"end_turn"},"total_usd":0.062504,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"C2orf18/SLC35F6 (ANT2BP) localizes to mitochondria and physically interacts with adenine nucleotide translocase 2 (ANT2), a protein involved in mitochondrial membrane potential maintenance and energy homeostasis; knockdown by siRNA induced apoptosis and suppressed cancer cell growth in pancreatic ductal adenocarcinoma cell lines.\",\n      \"method\": \"Immunolocalization (mitochondrial), co-immunoprecipitation/interaction assay with ANT2, siRNA knockdown with apoptosis/growth readout\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — subcellular localization and binding partner identified by direct experiment, siRNA phenotype with defined readout; single lab, methods described at abstract level only\",\n      \"pmids\": [\"19154410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLC35F6 localizes specifically to lysosomes (distinct from the recycling endosome localization of SLC35F1), and its lysosomal sorting depends on the EQERLL360 signal in its cytoplasmic C-terminal tail; swapping the C-terminal tail of SLC35F1 and SLC35F6 switched their respective localizations, demonstrating that C-terminal sorting signals are necessary and sufficient for their differential compartment targeting.\",\n      \"method\": \"Fluorescence microscopy, C-terminal tail domain-swap mutants, site-directed mutagenesis of sorting signals, cell surface biotinylation assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, domain swap, biotinylation, fluorescence microscopy) in a single focused study with rigorous controls\",\n      \"pmids\": [\"38928424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLC35F6 is involved in cell apoptosis through the Bcl2/BAX/caspase3 pathway and affects mitochondrial membrane potential, as demonstrated in functional validation experiments in a piglet diarrhea model.\",\n      \"method\": \"Functional validation assays measuring Bcl2/BAX/caspase3 pathway markers and mitochondrial membrane potential following SLC35F6 manipulation\",\n      \"journal\": \"Animal bioscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single study, methods described only at abstract level, limited mechanistic detail, non-human model system (pig)\",\n      \"pmids\": [\"39482997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Knockdown of SLC35F6 in H22 and HepG2 hepatocellular carcinoma cells markedly reduced cell growth and elevated TP53 protein levels, placing SLC35F6 in a miR-542-3p/SLC35F6/TP53 regulatory axis; SLC35F6 is identified as a direct target gene of miR-542-3p.\",\n      \"method\": \"siRNA knockdown, western blot for TP53, miRNA target validation (miR-542-3p overexpression with SLC35F6 expression measurement), cell proliferation assays\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple methods (knockdown, miRNA manipulation, protein level measurement) in a single lab; direct mutual regulation between SLC35F6 and TP53 explicitly not confirmed by the authors\",\n      \"pmids\": [\"40118430\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC35F6 (ANT2BP/C2orf18) is an orphan SLC35-family transporter that resides in lysosomes via a cytoplasmic C-terminal EQERLL sorting signal, physically interacts with the mitochondrial protein ANT2, participates in apoptotic regulation via the Bcl2/BAX/caspase3 pathway and mitochondrial membrane potential, and acts as a target of miR-542-3p to modulate TP53 levels and cell proliferation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC35F6 (ANT2BP/C2orf18) is an orphan SLC35-family transporter implicated in apoptotic regulation and the control of cancer cell proliferation [#0, #3]. It localizes to lysosomes, with compartment targeting dictated by an EQERLL360 sorting signal in its cytoplasmic C-terminal tail that is both necessary and sufficient for lysosomal delivery, as shown by domain-swap experiments distinguishing it from the recycling-endosome-targeted SLC35F1 [#1]. SLC35F6 physically interacts with the mitochondrial adenine nucleotide translocase ANT2, and its depletion triggers apoptosis and suppresses growth in pancreatic and hepatocellular carcinoma cells [#0, #3]. In hepatocellular carcinoma, SLC35F6 is a direct target of miR-542-3p, and its knockdown elevates TP53 protein levels, placing it within a miR-542-3p/SLC35F6/TP53 axis governing cell proliferation [#3]. The transport substrate of SLC35F6 has not been identified in the available corpus, and the molecular link between its lysosomal localization and its mitochondrial/apoptotic functions remains uncharacterized.\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established the first physical and functional partner for the orphan protein by showing it binds the mitochondrial nucleotide translocase ANT2 and is required for cancer cell survival.\",\n      \"evidence\": \"Mitochondrial immunolocalization, co-immunoprecipitation with ANT2, and siRNA knockdown with apoptosis/growth readouts in pancreatic carcinoma cells\",\n      \"pmids\": [\"19154410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction shown by single-lab Co-IP without reciprocal or structural validation\",\n        \"Mitochondrial localization later contrasted by lysosomal targeting evidence\",\n        \"No transport substrate identified\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the steady-state localization of the protein, demonstrating lysosomal targeting driven by a defined C-terminal EQERLL sorting signal that distinguishes it from its paralog SLC35F1.\",\n      \"evidence\": \"Fluorescence microscopy, C-terminal domain-swap mutants, site-directed mutagenesis of sorting signals, and cell-surface biotinylation\",\n      \"pmids\": [\"38928424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not reconcile lysosomal localization with the earlier reported mitochondrial localization and ANT2 interaction\",\n        \"Transported substrate remains unknown\",\n        \"Functional consequence of lysosomal targeting not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked SLC35F6 manipulation to apoptotic signaling through the Bcl2/BAX/caspase3 pathway and mitochondrial membrane potential in a non-human model.\",\n      \"evidence\": \"Functional validation of Bcl2/BAX/caspase3 markers and mitochondrial membrane potential in a piglet diarrhea model\",\n      \"pmids\": [\"39482997\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single study with abstract-level methods in a pig model, not independently confirmed in human cells\",\n        \"Mechanistic connection between SLC35F6 and the apoptotic pathway not defined\",\n        \"No direct molecular target identified\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed SLC35F6 in a regulatory axis controlling proliferation, identifying it as a direct miR-542-3p target whose loss raises TP53 levels in hepatocellular carcinoma cells.\",\n      \"evidence\": \"siRNA knockdown, western blot for TP53, miR-542-3p target validation, and proliferation assays in H22 and HepG2 cells\",\n      \"pmids\": [\"40118430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct mutual regulation between SLC35F6 and TP53 explicitly not confirmed by the authors\",\n        \"Mechanism by which SLC35F6 alters TP53 levels unknown\",\n        \"Single-lab study\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The transport substrate of SLC35F6 and the mechanistic bridge between its lysosomal localization, ANT2 binding, and apoptotic/TP53 regulation remain undefined.\",\n      \"evidence\": \"No discovery in the corpus identifies a transported molecule or a unifying molecular mechanism\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No transport substrate identified\",\n        \"Mitochondrial versus lysosomal localization not reconciled\",\n        \"Causal mechanism linking the protein to Bcl2/BAX/caspase3 and TP53 unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ANT2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":4,"faith_pct":75.0}}