{"gene":"TMEM208","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2017,"finding":"hSnd2 (TMEM208) functions as the first characterized human component of the SND (SRP-independent) ER targeting pathway, acting as a membrane-bound receptor that preferentially targets precursor proteins carrying C-terminal transmembrane domains to the ER. Genetic and physical interaction studies show hSnd2 is part of a complex network of targeting and translocation components.","method":"Genetic interaction studies, physical interaction (co-immunoprecipitation/pulldown), functional targeting assays in human cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and physical interaction studies in human cells, single lab, two orthogonal approaches (genetic + physical interactions)","pmids":["28862756"],"is_preprint":false},{"year":2021,"finding":"Human SND2 (hSnd2/TMEM208) mediates ER targeting of GPI-anchored proteins (GPI-APs) such as CD59, CD55, and CD109. The hydrophobicity of the C-terminal GPI attachment signal determines dependence on hSND2; GPI-APs with low-hydrophobicity GPI attachment signals preferentially use the hSND2-dependent pathway. Signal recognition particle receptors cooperate with hSND2 in this process.","method":"hSND2 knockdown/depletion with GPI-AP targeting assays, hydrophobicity mutant analysis, functional rescue experiments","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined substrate specificity, single lab, multiple GPI-AP substrates tested","pmids":["33838053"],"is_preprint":false},{"year":2022,"finding":"Proteomics after hSnd2 (TMEM208) depletion from HeLa cells identified the substrate spectrum of the human SND pathway: SND clients are predominantly membrane proteins with N-terminal, central, or C-terminal targeting signals (unlike SRP clients). TMEM109 was characterized as hSnd3, a novel component of the human SND pathway.","method":"hSnd2 depletion combined with quantitative proteomics and differential protein abundance analysis; comparison with SRP and TRC pathway clients","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics with pathway comparison, single lab, multiple orthogonal analyses","pmids":["36139500"],"is_preprint":false},{"year":2024,"finding":"Loss of Tmem208 in Drosophila (CG8320/Tmem208 null allele) causes lethality, wing and eye developmental defects consistent with impaired cell polarity, and mild ER stress. Tmem208 physically interacts with Frizzled (Fz), a planar cell polarity (PCP) receptor, and is required to maintain proper levels of Fz protein. Human TMEM208 fully rescues the fly null phenotype, confirming functional conservation.","method":"CRISPR-induced null allele generation, co-immunoprecipitation (physical interaction with Fz), rescue experiments with human TMEM208 and patient variants, ER stress assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR null allele, reciprocal physical interaction, cross-species rescue, patient variant loss-of-function testing, multiple orthogonal phenotypic readouts","pmids":["38381787"],"is_preprint":false},{"year":2024,"finding":"ZBTB14 transcriptionally represses TMEM208 expression in breast cancer cells; chromatin immunoprecipitation-qPCR and luciferase reporter assays demonstrated direct transcriptional repression of the TMEM208 promoter by ZBTB14. Upregulation of TMEM208 reversed the inhibitory effect of ZBTB14 overexpression on radiotherapy resistance.","method":"Chromatin immunoprecipitation (ChIP)-qPCR, luciferase reporter assay, overexpression and knockdown experiments","journal":"Journal of mammary gland biology and neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR and luciferase reporter assay are two orthogonal methods, single lab","pmids":["39692812"],"is_preprint":false}],"current_model":"TMEM208 (hSnd2) is an ER membrane-resident receptor that functions as a central component of the human SND (SRP-independent) ER targeting pathway, preferentially targeting membrane proteins with C-terminal transmembrane domains and GPI-anchored proteins with low-hydrophobicity GPI attachment signals to the ER; in vivo, it physically interacts with the planar cell polarity receptor Frizzled to maintain proper Fz levels and support cell polarity, and its expression is transcriptionally repressed by ZBTB14."},"narrative":{"mechanistic_narrative":"TMEM208 (hSnd2) is an endoplasmic reticulum membrane receptor that functions as a central component of the human SND (SRP-independent) ER protein targeting pathway [PMID:28862756]. It preferentially targets precursor proteins bearing C-terminal transmembrane domains to the ER, and proteomic profiling of its substrate spectrum shows that SND clients are predominantly membrane proteins carrying N-terminal, central, or C-terminal targeting signals, distinguishing them from SRP clients [PMID:28862756, PMID:36139500]. TMEM208 also mediates ER targeting of GPI-anchored proteins such as CD59, CD55, and CD109, with dependence governed by the hydrophobicity of the C-terminal GPI attachment signal: low-hydrophobicity signals preferentially route through the hSND2-dependent pathway, in cooperation with signal recognition particle receptors [PMID:33838053]. It operates within a network of targeting and translocation components, including TMEM109 (hSnd3) as a further pathway member [PMID:28862756, PMID:36139500]. Beyond protein targeting, TMEM208 physically interacts with the planar cell polarity receptor Frizzled and is required to maintain proper Frizzled protein levels, linking it to cell polarity in vivo; loss of the gene causes developmental defects and mild ER stress, and human TMEM208 fully rescues the Drosophila null phenotype, establishing functional conservation [PMID:38381787]. TMEM208 expression is directly repressed at the transcriptional level by ZBTB14, which binds and represses its promoter [PMID:39692812].","teleology":[{"year":2017,"claim":"Established that the human SND ER-targeting pathway exists and identified its first component, answering whether an SRP-independent targeting route operates in human cells.","evidence":"Genetic and physical interaction studies plus functional targeting assays in human cells","pmids":["28862756"],"confidence":"Medium","gaps":["Single lab; full set of pathway components not yet defined","Structural basis of substrate recognition not addressed","Quantitative scope of preferred substrates not yet mapped"]},{"year":2021,"claim":"Extended the pathway's substrate range to GPI-anchored proteins and defined GPI-signal hydrophobicity as the determinant of hSND2 dependence, clarifying which clients route through this pathway.","evidence":"hSND2 depletion with GPI-AP targeting assays, hydrophobicity mutant analysis, and functional rescue","pmids":["33838053"],"confidence":"Medium","gaps":["Molecular mechanism by which hydrophobicity is sensed not resolved","Nature of cooperation with SRP receptors not mechanistically defined"]},{"year":2022,"claim":"Defined the global substrate spectrum of the human SND pathway and identified an additional pathway component, distinguishing SND clients from SRP and TRC clients.","evidence":"hSnd2 depletion combined with quantitative proteomics and differential abundance analysis, with comparison to SRP/TRC pathways","pmids":["36139500"],"confidence":"Medium","gaps":["Single lab/cell type (HeLa); breadth across tissues unknown","Stoichiometry and architecture of the hSnd2/hSnd3 complex not resolved"]},{"year":2024,"claim":"Demonstrated an in vivo physiological role beyond ER targeting by linking TMEM208 to maintenance of the Frizzled planar cell polarity receptor and establishing cross-species functional conservation.","evidence":"Drosophila CRISPR null allele, co-immunoprecipitation with Frizzled, human TMEM208 and patient-variant rescue, and ER stress assays","pmids":["38381787"],"confidence":"High","gaps":["Whether Frizzled regulation reflects SND-dependent targeting or a separate activity unresolved","Mechanism by which TMEM208 maintains Frizzled protein levels not defined"]},{"year":2024,"claim":"Identified an upstream transcriptional regulator, showing TMEM208 is directly repressed by ZBTB14 with a functional consequence for radiotherapy resistance in breast cancer cells.","evidence":"ChIP-qPCR, luciferase reporter assay, and overexpression/knockdown experiments","pmids":["39692812"],"confidence":"Medium","gaps":["Single lab/cell context (breast cancer)","Mechanistic link between TMEM208 protein function and radioresistance not established"]},{"year":null,"claim":"How TMEM208 mechanistically recognizes diverse targeting signals and how its ER-targeting role relates to its in vivo control of Frizzled and cell polarity remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of TMEM208 or its complexes","Mechanism of substrate-signal discrimination not defined","Connection between protein-targeting activity and Frizzled/PCP function unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,3]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2]}],"complexes":["human SND targeting pathway complex"],"partners":["TMEM109","FRIZZLED","ZBTB14"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BTX3","full_name":"Transmembrane protein 208","aliases":[],"length_aa":173,"mass_kda":19.6,"function":"May function as a negative regulator of endoplasmic reticulum-stress induced autophagy","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9BTX3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM208","classification":"Not Classified","n_dependent_lines":99,"n_total_lines":1208,"dependency_fraction":0.08195364238410596},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000168701","cell_line_id":"CID001868","localizations":[{"compartment":"er","grade":3}],"interactors":[],"url":"https://opencell.sf.czbiohub.org/target/CID001868","total_profiled":1310},"omim":[{"mim_id":"620781","title":"TRANSMEMBRANE PROTEIN 208; TMEM208","url":"https://www.omim.org/entry/620781"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM208"},"hgnc":{"alias_symbol":["HSPC171","hSND2","SND2"],"prev_symbol":[]},"alphafold":{"accession":"Q9BTX3","domains":[{"cath_id":"-","chopping":"11-133","consensus_level":"high","plddt":82.8254,"start":11,"end":133}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BTX3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BTX3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BTX3-F1-predicted_aligned_error_v6.png","plddt_mean":78.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM208","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM208"},"sequence":{"accession":"Q9BTX3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BTX3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BTX3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BTX3"}},"corpus_meta":[{"pmid":"28862756","id":"PMC_28862756","title":"hSnd2 protein represents an alternative targeting factor to the endoplasmic reticulum in human cells.","date":"2017","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/28862756","citation_count":60,"is_preprint":false},{"pmid":"33838053","id":"PMC_33838053","title":"Human SND2 mediates ER targeting of GPI-anchored proteins with low hydrophobic GPI attachment signals.","date":"2021","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/33838053","citation_count":18,"is_preprint":false},{"pmid":"36139500","id":"PMC_36139500","title":"Proteomics Identifies Substrates and a Novel Component in hSnd2-Dependent ER Protein Targeting.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36139500","citation_count":16,"is_preprint":false},{"pmid":"38381787","id":"PMC_38381787","title":"Loss of the endoplasmic reticulum protein Tmem208 affects cell polarity, development, and viability.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/38381787","citation_count":8,"is_preprint":false},{"pmid":"28184026","id":"PMC_28184026","title":"Identification of TMEM208 and PQLC2 as reference genes for normalizing mRNA expression in colorectal cancer treated with aspirin.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28184026","citation_count":8,"is_preprint":false},{"pmid":"38670411","id":"PMC_38670411","title":"Unraveling the immune functions of large yellow croaker Tmem208 in response to Pseudomonas plecoglossicida: Insights from cloning, expression profiling, and transcriptome analysis.","date":"2024","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38670411","citation_count":7,"is_preprint":false},{"pmid":"37244496","id":"PMC_37244496","title":"Exogenous application of antagonistic Streptomyces sp. SND-2 triggers defense response in Vigna radiata (L.) R. Wilczek (mung bean) against anthracnose infection.","date":"2023","source":"Environmental research","url":"https://pubmed.ncbi.nlm.nih.gov/37244496","citation_count":3,"is_preprint":false},{"pmid":"39692812","id":"PMC_39692812","title":"Transcription Impairment of TMEM208 by ZBTB14 Suppresses Breast cancer Radiotherapy Resistance.","date":"2024","source":"Journal of mammary gland biology and neoplasia","url":"https://pubmed.ncbi.nlm.nih.gov/39692812","citation_count":2,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.05.25329021","title":"Genetically determined alterations in inflammation and infection-associated genes are associated with hydrocephalus in patients of African Ancestry","date":"2025-06-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.05.25329021","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6357,"output_tokens":1376,"usd":0.019856,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8083,"output_tokens":2245,"usd":0.04827,"stage2_stop_reason":"end_turn"},"total_usd":0.068126,"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\": 2017,\n      \"finding\": \"hSnd2 (TMEM208) functions as the first characterized human component of the SND (SRP-independent) ER targeting pathway, acting as a membrane-bound receptor that preferentially targets precursor proteins carrying C-terminal transmembrane domains to the ER. Genetic and physical interaction studies show hSnd2 is part of a complex network of targeting and translocation components.\",\n      \"method\": \"Genetic interaction studies, physical interaction (co-immunoprecipitation/pulldown), functional targeting assays in human cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and physical interaction studies in human cells, single lab, two orthogonal approaches (genetic + physical interactions)\",\n      \"pmids\": [\"28862756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human SND2 (hSnd2/TMEM208) mediates ER targeting of GPI-anchored proteins (GPI-APs) such as CD59, CD55, and CD109. The hydrophobicity of the C-terminal GPI attachment signal determines dependence on hSND2; GPI-APs with low-hydrophobicity GPI attachment signals preferentially use the hSND2-dependent pathway. Signal recognition particle receptors cooperate with hSND2 in this process.\",\n      \"method\": \"hSND2 knockdown/depletion with GPI-AP targeting assays, hydrophobicity mutant analysis, functional rescue experiments\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined substrate specificity, single lab, multiple GPI-AP substrates tested\",\n      \"pmids\": [\"33838053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Proteomics after hSnd2 (TMEM208) depletion from HeLa cells identified the substrate spectrum of the human SND pathway: SND clients are predominantly membrane proteins with N-terminal, central, or C-terminal targeting signals (unlike SRP clients). TMEM109 was characterized as hSnd3, a novel component of the human SND pathway.\",\n      \"method\": \"hSnd2 depletion combined with quantitative proteomics and differential protein abundance analysis; comparison with SRP and TRC pathway clients\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics with pathway comparison, single lab, multiple orthogonal analyses\",\n      \"pmids\": [\"36139500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of Tmem208 in Drosophila (CG8320/Tmem208 null allele) causes lethality, wing and eye developmental defects consistent with impaired cell polarity, and mild ER stress. Tmem208 physically interacts with Frizzled (Fz), a planar cell polarity (PCP) receptor, and is required to maintain proper levels of Fz protein. Human TMEM208 fully rescues the fly null phenotype, confirming functional conservation.\",\n      \"method\": \"CRISPR-induced null allele generation, co-immunoprecipitation (physical interaction with Fz), rescue experiments with human TMEM208 and patient variants, ER stress assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR null allele, reciprocal physical interaction, cross-species rescue, patient variant loss-of-function testing, multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"38381787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZBTB14 transcriptionally represses TMEM208 expression in breast cancer cells; chromatin immunoprecipitation-qPCR and luciferase reporter assays demonstrated direct transcriptional repression of the TMEM208 promoter by ZBTB14. Upregulation of TMEM208 reversed the inhibitory effect of ZBTB14 overexpression on radiotherapy resistance.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP)-qPCR, luciferase reporter assay, overexpression and knockdown experiments\",\n      \"journal\": \"Journal of mammary gland biology and neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR and luciferase reporter assay are two orthogonal methods, single lab\",\n      \"pmids\": [\"39692812\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM208 (hSnd2) is an ER membrane-resident receptor that functions as a central component of the human SND (SRP-independent) ER targeting pathway, preferentially targeting membrane proteins with C-terminal transmembrane domains and GPI-anchored proteins with low-hydrophobicity GPI attachment signals to the ER; in vivo, it physically interacts with the planar cell polarity receptor Frizzled to maintain proper Fz levels and support cell polarity, and its expression is transcriptionally repressed by ZBTB14.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM208 (hSnd2) is an endoplasmic reticulum membrane receptor that functions as a central component of the human SND (SRP-independent) ER protein targeting pathway [#0]. It preferentially targets precursor proteins bearing C-terminal transmembrane domains to the ER, and proteomic profiling of its substrate spectrum shows that SND clients are predominantly membrane proteins carrying N-terminal, central, or C-terminal targeting signals, distinguishing them from SRP clients [#0, #2]. TMEM208 also mediates ER targeting of GPI-anchored proteins such as CD59, CD55, and CD109, with dependence governed by the hydrophobicity of the C-terminal GPI attachment signal: low-hydrophobicity signals preferentially route through the hSND2-dependent pathway, in cooperation with signal recognition particle receptors [#1]. It operates within a network of targeting and translocation components, including TMEM109 (hSnd3) as a further pathway member [#0, #2]. Beyond protein targeting, TMEM208 physically interacts with the planar cell polarity receptor Frizzled and is required to maintain proper Frizzled protein levels, linking it to cell polarity in vivo; loss of the gene causes developmental defects and mild ER stress, and human TMEM208 fully rescues the Drosophila null phenotype, establishing functional conservation [#3]. TMEM208 expression is directly repressed at the transcriptional level by ZBTB14, which binds and represses its promoter [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that the human SND ER-targeting pathway exists and identified its first component, answering whether an SRP-independent targeting route operates in human cells.\",\n      \"evidence\": \"Genetic and physical interaction studies plus functional targeting assays in human cells\",\n      \"pmids\": [\"28862756\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single lab; full set of pathway components not yet defined\",\n        \"Structural basis of substrate recognition not addressed\",\n        \"Quantitative scope of preferred substrates not yet mapped\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the pathway's substrate range to GPI-anchored proteins and defined GPI-signal hydrophobicity as the determinant of hSND2 dependence, clarifying which clients route through this pathway.\",\n      \"evidence\": \"hSND2 depletion with GPI-AP targeting assays, hydrophobicity mutant analysis, and functional rescue\",\n      \"pmids\": [\"33838053\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Molecular mechanism by which hydrophobicity is sensed not resolved\",\n        \"Nature of cooperation with SRP receptors not mechanistically defined\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the global substrate spectrum of the human SND pathway and identified an additional pathway component, distinguishing SND clients from SRP and TRC clients.\",\n      \"evidence\": \"hSnd2 depletion combined with quantitative proteomics and differential abundance analysis, with comparison to SRP/TRC pathways\",\n      \"pmids\": [\"36139500\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single lab/cell type (HeLa); breadth across tissues unknown\",\n        \"Stoichiometry and architecture of the hSnd2/hSnd3 complex not resolved\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated an in vivo physiological role beyond ER targeting by linking TMEM208 to maintenance of the Frizzled planar cell polarity receptor and establishing cross-species functional conservation.\",\n      \"evidence\": \"Drosophila CRISPR null allele, co-immunoprecipitation with Frizzled, human TMEM208 and patient-variant rescue, and ER stress assays\",\n      \"pmids\": [\"38381787\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Whether Frizzled regulation reflects SND-dependent targeting or a separate activity unresolved\",\n        \"Mechanism by which TMEM208 maintains Frizzled protein levels not defined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified an upstream transcriptional regulator, showing TMEM208 is directly repressed by ZBTB14 with a functional consequence for radiotherapy resistance in breast cancer cells.\",\n      \"evidence\": \"ChIP-qPCR, luciferase reporter assay, and overexpression/knockdown experiments\",\n      \"pmids\": [\"39692812\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single lab/cell context (breast cancer)\",\n        \"Mechanistic link between TMEM208 protein function and radioresistance not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMEM208 mechanistically recognizes diverse targeting signals and how its ER-targeting role relates to its in vivo control of Frizzled and cell polarity remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No structure of TMEM208 or its complexes\",\n        \"Mechanism of substrate-signal discrimination not defined\",\n        \"Connection between protein-targeting activity and Frizzled/PCP function unestablished\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [\"human SND targeting pathway complex\"],\n    \"partners\": [\"TMEM109\", \"Frizzled\", \"ZBTB14\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}