{"gene":"SLC35F6","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2008,"finding":"C2orf18 (later identified as SLC35F6) localizes to the mitochondria and physically interacts with adenine nucleotide translocase 2 (ANT2), which is involved in maintenance of mitochondrial membrane potential and energy homeostasis; knockdown of C2orf18 in pancreatic cancer cell lines induced apoptosis and suppressed cancer cell growth.","method":"Subcellular fractionation/localization, co-immunoprecipitation (interaction with ANT2), siRNA knockdown with apoptosis/growth readout","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2-3 — single lab, localization plus pulldown/interaction data and functional KD phenotype, but limited orthogonal validation","pmids":["19154410"],"is_preprint":false},{"year":2024,"finding":"SLC35F6 is concentrated in lysosomes (distinct from SLC35F1 which resides in recycling endosomes), and its lysosomal sorting depends on the EQERLL360 signal in its cytoplasmic C-terminal tail; swapping C-terminal tails between SLC35F1 and SLC35F6 redirected their respective localizations, and site-directed mutagenesis of the EQERLL360 motif disrupted lysosomal targeting.","method":"Fluorescence microscopy, C-terminal tail swap experiments, site-directed mutagenesis, cell surface biotinylation assays","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (mutagenesis, domain swaps, biotinylation, microscopy) in a single 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 by functional validation in a piglet model.","method":"Functional gene validation (expression modulation) with apoptosis pathway readouts (Bcl2/BAX/caspase3 levels) and mitochondrial membrane potential assay","journal":"Animal bioscience","confidence":"Low","confidence_rationale":"Tier 3 — single study in a pig model with pathway readouts but limited mechanistic depth and no orthogonal methods","pmids":["39482997"],"is_preprint":false},{"year":2025,"finding":"SLC35F6 knockdown in HCC cell lines (H22 and HepG2) markedly reduced cell growth and elevated TP53 protein levels, placing SLC35F6 as a target gene of miR-542-3p within a miR-542-3p/SLC35F6/TP53 regulatory axis.","method":"siRNA knockdown, miRNA overexpression, Western blot for TP53, cell growth assay","journal":"International journal of biological macromolecules","confidence":"Low","confidence_rationale":"Tier 3 — single lab, functional KD with pathway placement but no direct biochemical interaction between SLC35F6 and TP53 confirmed","pmids":["40118430"],"is_preprint":false}],"current_model":"SLC35F6 is an orphan SLC35-family transporter that localizes to lysosomes via a cytoplasmic EQERLL360 sorting signal, physically interacts with the mitochondrial protein ANT2 (affecting mitochondrial membrane potential), and promotes cell survival through the Bcl2/BAX/caspase3 apoptosis pathway; its overexpression supports cancer cell proliferation, while its knockdown induces apoptosis and elevates TP53 levels."},"narrative":{"teleology":[{"year":2008,"claim":"The initial characterization of C2orf18/SLC35F6 established that it localizes to mitochondria, physically interacts with ANT2, and is required for cancer cell survival — linking an uncharacterized ORF to mitochondrial function and apoptosis regulation.","evidence":"Subcellular fractionation, co-immunoprecipitation with ANT2, and siRNA knockdown with apoptosis/growth readouts in pancreatic cancer cell lines","pmids":["19154410"],"confidence":"Medium","gaps":["Interaction with ANT2 demonstrated by co-IP only; no reciprocal or in vitro binding validation","Transport substrate of SLC35F6 not identified","Mitochondrial versus other organelle localization not resolved with high-resolution methods"]},{"year":2024,"claim":"Precise subcellular mapping resolved SLC35F6 as a lysosomal protein rather than exclusively mitochondrial, and identified the EQERLL360 cytoplasmic motif as both necessary and sufficient for lysosomal targeting — establishing the molecular basis of its trafficking.","evidence":"Fluorescence microscopy, C-terminal tail swaps between SLC35F1 and SLC35F6, site-directed mutagenesis of EQERLL360, and cell surface biotinylation","pmids":["38928424"],"confidence":"High","gaps":["Transport substrate remains unknown","Whether the earlier reported mitochondrial localization reflects a dual-organelle distribution or a methodological discrepancy is unresolved","Adaptor protein(s) recognizing the EQERLL signal not identified"]},{"year":2024,"claim":"An independent model (piglet) confirmed SLC35F6 involvement in apoptosis through Bcl2/BAX/caspase3 and mitochondrial membrane potential changes, extending the pro-survival role beyond cancer cell lines.","evidence":"Gene expression modulation with apoptosis pathway and mitochondrial membrane potential readouts in a pig model","pmids":["39482997"],"confidence":"Low","gaps":["Single study in a non-standard model with limited mechanistic depth; awaits independent replication","Direct biochemical mechanism connecting a lysosomal transporter to mitochondrial apoptosis signaling unknown","No reconstitution of SLC35F6 transport activity"]},{"year":2025,"claim":"SLC35F6 knockdown in hepatocellular carcinoma cells elevated TP53 levels and reduced growth, placing SLC35F6 within a miR-542-3p/SLC35F6/TP53 regulatory axis and suggesting it normally restrains TP53 accumulation.","evidence":"siRNA knockdown, miRNA overexpression, Western blot for TP53, and cell growth assays in HCC cell lines","pmids":["40118430"],"confidence":"Low","gaps":["No direct biochemical interaction between SLC35F6 and TP53 demonstrated; mechanism of TP53 regulation unknown","Pathway placement based on correlative expression changes in a single study","Relationship between lysosomal localization and TP53 regulation unexplained"]},{"year":null,"claim":"The transport substrate of SLC35F6 remains entirely unknown, leaving its primary molecular function unresolved despite clear links to apoptosis regulation and lysosomal localization.","evidence":"","pmids":[],"confidence":"High","gaps":["No substrate identification or transport reconstitution has been performed","Structural basis of SLC35F6 function not determined","How a lysosomal transporter mechanistically influences mitochondrial membrane potential and apoptotic signaling is unexplained"]}],"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]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["ANT2"],"other_free_text":[]},"mechanistic_narrative":"SLC35F6 is an orphan member of the SLC35 nucleotide-sugar transporter family that localizes to lysosomes through a cytoplasmic C-terminal EQERLL360 sorting signal, as demonstrated by domain-swap and mutagenesis experiments [PMID:38928424]. SLC35F6 physically interacts with the mitochondrial adenine nucleotide translocase ANT2 and influences mitochondrial membrane potential; its knockdown induces apoptosis via the Bcl2/BAX/caspase3 pathway and suppresses cancer cell proliferation [PMID:19154410, PMID:39482997]."},"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":7,"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":"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},{"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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6109,"output_tokens":1044,"usd":0.016994},"stage2":{"model":"claude-opus-4-6","input_tokens":4244,"output_tokens":1349,"usd":0.082418},"total_usd":0.099412,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"C2orf18 (later identified as SLC35F6) localizes to the mitochondria and physically interacts with adenine nucleotide translocase 2 (ANT2), which is involved in maintenance of mitochondrial membrane potential and energy homeostasis; knockdown of C2orf18 in pancreatic cancer cell lines induced apoptosis and suppressed cancer cell growth.\",\n      \"method\": \"Subcellular fractionation/localization, co-immunoprecipitation (interaction with ANT2), siRNA knockdown with apoptosis/growth readout\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — single lab, localization plus pulldown/interaction data and functional KD phenotype, but limited orthogonal validation\",\n      \"pmids\": [\"19154410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLC35F6 is concentrated in lysosomes (distinct from SLC35F1 which resides in recycling endosomes), and its lysosomal sorting depends on the EQERLL360 signal in its cytoplasmic C-terminal tail; swapping C-terminal tails between SLC35F1 and SLC35F6 redirected their respective localizations, and site-directed mutagenesis of the EQERLL360 motif disrupted lysosomal targeting.\",\n      \"method\": \"Fluorescence microscopy, C-terminal tail swap experiments, site-directed mutagenesis, cell surface biotinylation assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (mutagenesis, domain swaps, biotinylation, microscopy) in a single 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 by functional validation in a piglet model.\",\n      \"method\": \"Functional gene validation (expression modulation) with apoptosis pathway readouts (Bcl2/BAX/caspase3 levels) and mitochondrial membrane potential assay\",\n      \"journal\": \"Animal bioscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single study in a pig model with pathway readouts but limited mechanistic depth and no orthogonal methods\",\n      \"pmids\": [\"39482997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC35F6 knockdown in HCC cell lines (H22 and HepG2) markedly reduced cell growth and elevated TP53 protein levels, placing SLC35F6 as a target gene of miR-542-3p within a miR-542-3p/SLC35F6/TP53 regulatory axis.\",\n      \"method\": \"siRNA knockdown, miRNA overexpression, Western blot for TP53, cell growth assay\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, functional KD with pathway placement but no direct biochemical interaction between SLC35F6 and TP53 confirmed\",\n      \"pmids\": [\"40118430\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC35F6 is an orphan SLC35-family transporter that localizes to lysosomes via a cytoplasmic EQERLL360 sorting signal, physically interacts with the mitochondrial protein ANT2 (affecting mitochondrial membrane potential), and promotes cell survival through the Bcl2/BAX/caspase3 apoptosis pathway; its overexpression supports cancer cell proliferation, while its knockdown induces apoptosis and elevates TP53 levels.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SLC35F6 is an orphan member of the SLC35 nucleotide-sugar transporter family that localizes to lysosomes through a cytoplasmic C-terminal EQERLL360 sorting signal, as demonstrated by domain-swap and mutagenesis experiments [PMID:38928424]. SLC35F6 physically interacts with the mitochondrial adenine nucleotide translocase ANT2 and influences mitochondrial membrane potential; its knockdown induces apoptosis via the Bcl2/BAX/caspase3 pathway and suppresses cancer cell proliferation [PMID:19154410, PMID:39482997].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"The initial characterization of C2orf18/SLC35F6 established that it localizes to mitochondria, physically interacts with ANT2, and is required for cancer cell survival — linking an uncharacterized ORF to mitochondrial function and apoptosis regulation.\",\n      \"evidence\": \"Subcellular fractionation, co-immunoprecipitation with ANT2, and siRNA knockdown with apoptosis/growth readouts in pancreatic cancer cell lines\",\n      \"pmids\": [\"19154410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction with ANT2 demonstrated by co-IP only; no reciprocal or in vitro binding validation\",\n        \"Transport substrate of SLC35F6 not identified\",\n        \"Mitochondrial versus other organelle localization not resolved with high-resolution methods\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Precise subcellular mapping resolved SLC35F6 as a lysosomal protein rather than exclusively mitochondrial, and identified the EQERLL360 cytoplasmic motif as both necessary and sufficient for lysosomal targeting — establishing the molecular basis of its trafficking.\",\n      \"evidence\": \"Fluorescence microscopy, C-terminal tail swaps between SLC35F1 and SLC35F6, site-directed mutagenesis of EQERLL360, and cell surface biotinylation\",\n      \"pmids\": [\"38928424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Transport substrate remains unknown\",\n        \"Whether the earlier reported mitochondrial localization reflects a dual-organelle distribution or a methodological discrepancy is unresolved\",\n        \"Adaptor protein(s) recognizing the EQERLL signal not identified\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"An independent model (piglet) confirmed SLC35F6 involvement in apoptosis through Bcl2/BAX/caspase3 and mitochondrial membrane potential changes, extending the pro-survival role beyond cancer cell lines.\",\n      \"evidence\": \"Gene expression modulation with apoptosis pathway and mitochondrial membrane potential readouts in a pig model\",\n      \"pmids\": [\"39482997\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single study in a non-standard model with limited mechanistic depth; awaits independent replication\",\n        \"Direct biochemical mechanism connecting a lysosomal transporter to mitochondrial apoptosis signaling unknown\",\n        \"No reconstitution of SLC35F6 transport activity\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"SLC35F6 knockdown in hepatocellular carcinoma cells elevated TP53 levels and reduced growth, placing SLC35F6 within a miR-542-3p/SLC35F6/TP53 regulatory axis and suggesting it normally restrains TP53 accumulation.\",\n      \"evidence\": \"siRNA knockdown, miRNA overexpression, Western blot for TP53, and cell growth assays in HCC cell lines\",\n      \"pmids\": [\"40118430\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct biochemical interaction between SLC35F6 and TP53 demonstrated; mechanism of TP53 regulation unknown\",\n        \"Pathway placement based on correlative expression changes in a single study\",\n        \"Relationship between lysosomal localization and TP53 regulation unexplained\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The transport substrate of SLC35F6 remains entirely unknown, leaving its primary molecular function unresolved despite clear links to apoptosis regulation and lysosomal localization.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No substrate identification or transport reconstitution has been performed\",\n        \"Structural basis of SLC35F6 function not determined\",\n        \"How a lysosomal transporter mechanistically influences mitochondrial membrane potential and apoptotic signaling is unexplained\"\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    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ANT2\"],\n    \"other_free_text\": []\n  }\n}\n```"}