{"gene":"TMF1","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":1999,"finding":"TMF1/ARA160 directly interacts with the androgen receptor (AR) N-terminal domain and functions as an androgen-enhanced coactivator for AR-mediated transactivation in prostate cancer cells; interaction is enhanced by androgen and TMF1 cooperates with the AR C-terminal coactivator ARA70.","method":"Far-Western blotting, co-immunoprecipitation, affinity gel pull-down, mammalian two-hybrid assay, transient transfection reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (far-Western, Co-IP, pull-down, two-hybrid, reporter assay) in a single study; 118 citations","pmids":["10428808"],"is_preprint":false},{"year":2002,"finding":"TMF1/ARA160 physically associates with the ATPase subunits of human SWI/SNF chromatin remodeling complexes (hbrm/hSNF2α and BRG-1/hSNF2β) via their conserved N-terminal regions and the C-terminal region of TMF; different TMF isoforms differentially localize to the Golgi apparatus and the nucleus.","method":"In vitro binding assay, co-immunoprecipitation, immunofluorescence, Western blot fractionation","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2-3 — in vitro and in vivo binding shown with domain mapping, localization confirmed by imaging","pmids":["12044884"],"is_preprint":false},{"year":2004,"finding":"TMF1 is a Golgi-localized golgin that binds all three isoforms of the GTPase Rab6 (mammalian homologue of yeast Ypt6) via a conserved ~100-residue coiled-coil motif; depletion by RNAi causes dispersal of Golgi membranes, indicating a role in Golgi organization.","method":"Yeast two-hybrid (Sgm1/Ypt6 interaction), co-immunoprecipitation (Rab6 isoforms), RNA interference knockdown, immunofluorescence microscopy","journal":"BMC cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with multiple Rab6 isoforms, RNAi phenotype, evolutionary conservation argument; 85 citations","pmids":["15128430"],"is_preprint":false},{"year":2004,"finding":"TMF1/ARA160 contains a BC-box motif that mediates binding to elongin C; through this E3-ligase adaptor function, TMF1 directs ubiquitination and proteasomal degradation of Stat3 (but not Stat1) under serum-starvation conditions; BC-box deletion abolishes this activity.","method":"Co-immunoprecipitation, sequence motif analysis, ectopic overexpression with ubiquitination assay, proteasome inhibitor rescue, BC-box deletion mutagenesis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — domain mutagenesis combined with ubiquitination assay and proteasomal rescue, mechanistically well-defined","pmids":["15467733"],"is_preprint":false},{"year":2007,"finding":"TMF1 is concentrated at budding cisternae tips of the Golgi (shown by immunoelectron microscopy) and is required for two Rab6-dependent retrograde transport processes: (1) endosome-to-TGN transport of Shiga toxin, and (2) Golgi-to-ER retention of GalNAc-T2 (but not GalT); the cytoplasmic region of GalNAc-T2 mediates TMF-dependent Golgi retention.","method":"RNAi knockdown, high-resolution immunofluorescence, immunoelectron microscopy, Shiga toxin trafficking assay, chimeric protein domain-swap analysis","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (IEM, functional trafficking assay, domain-swap chimeras), clean mechanistic dissection; 57 citations","pmids":["17698061"],"is_preprint":false},{"year":2009,"finding":"Under metabolic stress, TMF1 directs ubiquitination and proteasomal degradation of the NF-κB subunit p65/RelA, thereby downregulating proangiogenic genes (IL-8, IL-1β) and attenuating tumor xenograft growth.","method":"Ectopic expression in PC3 cells, xenograft tumor model, ubiquitination assay, RNA expression profiling, immunohistochemistry","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — in vivo xenograft plus ubiquitination assay, mechanistic link to NF-κB degradation established","pmids":["19330832"],"is_preprint":false},{"year":2010,"finding":"TMF1 knockout male mice are sterile due to failure of proacrosomal vesicle homing to the perinuclear surface (acrosome absent), improper cytoplasm removal, misshapen sperm heads, and tail coiling; females are fertile and mice are otherwise healthy, establishing TMF1 as essential for spermiogenesis.","method":"TMF knockout mouse generation, histology, electron microscopy, fertility testing","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with specific spermatogenic phenotypes; 55 citations","pmids":["20691678"],"is_preprint":false},{"year":2012,"finding":"The COG tethering complex binds both ends of TMF1 and interacts with two Rab GTPases; the central portion of TMF1 can bind Golgi membranes stripped of COPI coat, suggesting TMF1 bridges vesicle–target membrane apposition prior to fusion.","method":"Co-immunoprecipitation, yeast two-hybrid, in vitro binding assays, domain mapping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple interaction methods with domain mapping; mechanistic model supported by functional context","pmids":["23239882"],"is_preprint":false},{"year":2012,"finding":"Loss of TMF1 in colonic goblet cells leads to altered MUC2 mucin secretion producing highly oligomerized gel-forming mucus refractory to bacterial colonization; TMF1 absence elevates p65/NF-κB and muc2 transcription in intestinal epithelial cells.","method":"TMF knockout mouse, DSS colitis model, gene expression analysis, mucus morphology assessment, bacterial colonization assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with multiple phenotypic readouts and gene expression data linking TMF1 to NF-κB/MUC2 axis","pmids":["22553199"],"is_preprint":false},{"year":2012,"finding":"TMF1 knockout leads to Leydig cell hyperproliferation, elevated LH, and significantly reduced serum testosterone, establishing a role for TMF1 in controlling testosterone production in the testis.","method":"TMF knockout mouse, hormone serum measurements (LH, testosterone), histological analysis, testosterone rescue experiment","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with hormonal rescue experiment","pmids":["23000399"],"is_preprint":false},{"year":2015,"finding":"During spermiogenesis, TMF1 dynamically translocates from cis-Golgi to trans-Golgi network to emerging vesicle surfaces; TMF1 contains a microtubule-interacting (MIT) domain that mediates association with microtubules, which is required for stable Golgi anchoring; loss of TMF1 causes aberrant Golgi orientation away from the nucleus, failure of proacrosomal vesicle targeting, and impaired acroplaxome and chromatoid body formation.","method":"TMF knockout mouse, immunofluorescence live/fixed imaging, electron microscopy, in-silico domain prediction, MIT domain mutation/deletion analysis, microtubule co-sedimentation","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (EM, imaging, domain mutagenesis) in KO model with defined mechanistic pathway","pmids":["26701263"],"is_preprint":false},{"year":2021,"finding":"TMF1 is upregulated by insulin in myoblasts and is required for formation of insulin-responsive GLUT4-containing vesicles; absence of TMF1 retains GLUT4 in perinuclear compartments, impairs GLUT4 trafficking to the plasma membrane, reduces glucose uptake, and causes hyperglycemia in TMF1-/- mice.","method":"TMF1 knockout myoblasts and mice, GLUT4 vesicle trafficking assay, glucose uptake assay, blood glucose measurement, immunofluorescence localization","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — both cell and mouse KO with functional readouts (GLUT4 trafficking, glucose uptake, in vivo glycemia)","pmids":["33475194"],"is_preprint":false}],"current_model":"TMF1 (TATA Element Modulatory Factor) is a multifunctional Golgi-associated golgin that (1) tethers retrograde transport vesicles via Rab6 binding and COG complex interaction to regulate Golgi-to-ER and endosome-to-TGN trafficking; (2) acts as a BC-box E3-ligase adaptor directing ubiquitin-proteasomal degradation of Stat3 and NF-κB p65/RelA under stress conditions; (3) interacts with microtubules through a MIT domain to maintain Golgi spatial orientation during spermiogenesis, where it is essential for proacrosomal vesicle targeting and acrosome formation; (4) facilitates formation of insulin-responsive GLUT4 vesicles for glucose uptake; and (5) coactivates androgen receptor transcription through direct N-terminal AR interaction."},"narrative":{"teleology":[{"year":1999,"claim":"The initial characterization of TMF1 revealed an unexpected nuclear function: it directly binds the androgen receptor N-terminus and coactivates AR-mediated transcription, establishing TMF1 as a transcriptional cofactor.","evidence":"Far-Western, Co-IP, pull-down, mammalian two-hybrid, and reporter assays in prostate cancer cells","pmids":["10428808"],"confidence":"High","gaps":["Physiological relevance of AR coactivation in vivo not tested","Whether TMF1 coactivation extends to other nuclear receptors unknown","Mechanism by which TMF1 shuttles between Golgi and nucleus not defined"]},{"year":2002,"claim":"Discovery that TMF1 physically associates with the ATPase subunits of SWI/SNF chromatin remodeling complexes (hbrm, BRG-1) suggested a mechanism for its nuclear transcriptional activity, while also confirming that different TMF1 isoforms partition between Golgi and nucleus.","evidence":"In vitro binding assays, Co-IP, immunofluorescence, and Western blot fractionation","pmids":["12044884"],"confidence":"Medium","gaps":["Functional consequence of SWI/SNF interaction on chromatin remodeling not demonstrated","Whether SWI/SNF interaction is linked to AR coactivation untested","Isoform-specific regulation not characterized"]},{"year":2004,"claim":"Two pivotal discoveries reframed TMF1's primary identity: it was shown to be a Golgi golgin that binds all three Rab6 isoforms via a coiled-coil domain and is needed for Golgi integrity, while independently it was found to contain a BC-box motif that recruits elongin C to direct ubiquitin-proteasomal degradation of Stat3.","evidence":"Yeast two-hybrid, reciprocal Co-IP with Rab6, RNAi-induced Golgi dispersal (Rab6); BC-box mutagenesis, ubiquitination assay, proteasome inhibitor rescue (Stat3 degradation)","pmids":["15128430","15467733"],"confidence":"High","gaps":["How TMF1 coordinates its Golgi-tethering and E3-adaptor functions is unknown","Structural basis of Rab6 binding not resolved","Whether Stat3 degradation occurs at the Golgi or in the cytosol undefined"]},{"year":2007,"claim":"High-resolution imaging and functional trafficking assays established that TMF1 localizes to budding cisternae tips and is required for two specific Rab6-dependent retrograde pathways — endosome-to-TGN transport of Shiga toxin and Golgi-to-ER retention of GalNAc-T2 — providing the first direct evidence that TMF1 acts as a vesicle tether.","evidence":"RNAi, immunoelectron microscopy, Shiga toxin trafficking assay, chimeric domain-swap analysis","pmids":["17698061"],"confidence":"High","gaps":["Whether TMF1 tethers other retrograde cargo beyond Shiga toxin and GalNAc-T2 unknown","SNARE partners mediating TMF1-dependent fusion not identified","Selectivity mechanism for GalNAc-T2 but not GalT not fully explained"]},{"year":2009,"claim":"Extending its E3-adaptor role, TMF1 was shown to ubiquitinate NF-κB p65/RelA under metabolic stress, downregulating proangiogenic genes and attenuating xenograft tumor growth, broadening the substrate repertoire of TMF1-mediated degradation.","evidence":"Ectopic expression in PC3 cells, xenograft tumor model, ubiquitination assay, RNA profiling","pmids":["19330832"],"confidence":"Medium","gaps":["Whether TMF1-mediated p65 degradation is relevant beyond the xenograft setting unknown","Specificity determinants distinguishing Stat3 vs. p65 as substrates not mapped","Upstream signals activating TMF1's E3-adaptor function undefined"]},{"year":2010,"claim":"Generation of TMF1-knockout mice revealed male-specific sterility caused by failure of proacrosomal vesicle homing, absent acrosome formation, and defective cytoplasm removal, establishing TMF1 as essential for spermiogenesis in vivo.","evidence":"TMF KO mouse, histology, electron microscopy, fertility testing","pmids":["20691678"],"confidence":"High","gaps":["Molecular cargo of proacrosomal vesicles requiring TMF1 not identified","Whether the spermiogenesis defect reflects Rab6-tethering loss, microtubule anchoring loss, or both not dissected","Rescue experiments not performed"]},{"year":2012,"claim":"Multiple studies refined TMF1's interaction network and physiological roles: the COG complex was shown to bind both ends of TMF1, supporting a model where TMF1 bridges vesicle–target membranes; TMF1 loss in goblet cells altered MUC2 mucin secretion via elevated NF-κB/p65; and TMF1 KO testes showed Leydig cell hyperproliferation with reduced testosterone, linking TMF1 to endocrine homeostasis.","evidence":"Co-IP and yeast two-hybrid for COG interaction; DSS colitis model in KO mice for mucin phenotype; hormone measurements and histology in KO mice for Leydig cell phenotype","pmids":["23239882","22553199","23000399"],"confidence":"Medium","gaps":["Whether COG–TMF1 interaction is required for the retrograde pathways defined in 2007 not tested","Mechanism linking TMF1 to Leydig cell proliferation unclear","Direct vesicle fusion reconstitution with TMF1 not achieved"]},{"year":2015,"claim":"Identification of a microtubule-interacting (MIT) domain in TMF1 explained how it anchors the Golgi near the nucleus during spermiogenesis; loss of MIT-mediated microtubule binding caused aberrant Golgi orientation, failed proacrosomal vesicle targeting, and impaired acroplaxome/chromatoid body formation.","evidence":"TMF KO mouse, immunofluorescence, electron microscopy, MIT domain mutation/deletion, microtubule co-sedimentation","pmids":["26701263"],"confidence":"High","gaps":["Crystal structure of the MIT domain not determined","Whether the MIT domain functions outside spermiogenesis not tested","Regulatory mechanisms controlling TMF1 translocation from cis- to trans-Golgi unknown"]},{"year":2021,"claim":"TMF1 was found to be insulin-upregulated and required for formation of insulin-responsive GLUT4 vesicles; its absence trapped GLUT4 in perinuclear compartments, reduced glucose uptake, and caused hyperglycemia, expanding TMF1's vesicle-sorting role to metabolic regulation.","evidence":"TMF1 KO myoblasts and mice, GLUT4 vesicle trafficking assay, glucose uptake assay, blood glucose measurement","pmids":["33475194"],"confidence":"High","gaps":["Whether TMF1 acts via Rab6 to form GLUT4 vesicles not determined","Sorting signals on GLUT4 recognized by TMF1 not identified","Contribution of TMF1 loss to systemic insulin resistance beyond glucose uptake not evaluated"]},{"year":null,"claim":"A unified structural and regulatory framework explaining how TMF1 coordinates its distinct roles — vesicle tethering, E3-ligase adaptor activity, microtubule anchoring, and transcriptional coactivation — remains unresolved, as does whether these functions are mutually exclusive or context-dependent.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of TMF1 or its complexes","No reconstituted vesicle tethering/fusion assay with purified TMF1","Post-translational modifications regulating TMF1 functional switching unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[10]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,5]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,2,4,10]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[4,11]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,4,7,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[6,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,11]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[11]}],"complexes":["Elongin BC-CUL5 E3 ligase complex"],"partners":["RAB6A","AR","SOCS1","SMARCA2","SMARCA4","COG3","ELOC"],"other_free_text":[]},"mechanistic_narrative":"TMF1 is a multifunctional golgin that serves as a Rab6-dependent vesicle tether at the Golgi apparatus, directing retrograde transport from endosomes to the TGN and from Golgi to the ER, while also interacting with the COG tethering complex to bridge vesicle–target membrane apposition [PMID:15128430, PMID:17698061, PMID:23239882]. Through a BC-box motif that recruits elongin C, TMF1 functions as an E3-ligase adaptor that targets Stat3 and NF-κB p65/RelA for ubiquitin-proteasomal degradation under stress conditions, thereby modulating inflammatory and angiogenic gene expression [PMID:15467733, PMID:19330832]. TMF1 contains a microtubule-interacting (MIT) domain essential for Golgi anchoring and spatial orientation during spermiogenesis; TMF1-knockout male mice are sterile due to failed proacrosomal vesicle targeting and absent acrosome formation [PMID:20691678, PMID:26701263]. TMF1 is also required for biogenesis of insulin-responsive GLUT4 vesicles, and its loss impairs GLUT4 trafficking to the plasma membrane and causes hyperglycemia [PMID:33475194]."},"prefetch_data":{"uniprot":{"accession":"P82094","full_name":"TATA element modulatory factor","aliases":["Androgen receptor coactivator 160 kDa protein","Androgen receptor-associated protein of 160 kDa"],"length_aa":1093,"mass_kda":122.8,"function":"Potential coactivator of the androgen receptor. Mediates STAT3 degradation. May play critical roles in two RAB6-dependent retrograde transport processes: one from endosomes to the Golgi and the other from the Golgi to the ER. This protein binds the HIV-1 TATA element and inhibits transcriptional activation by the TATA-binding protein (TBP)","subcellular_location":"Cytoplasm; Nucleus; Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/P82094/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMF1","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMF1","total_profiled":1310},"omim":[{"mim_id":"616824","title":"TMF1-REGULATED NUCLEAR PROTEIN 1; TRNP1","url":"https://www.omim.org/entry/616824"},{"mim_id":"609803","title":"ANKYRIN AND ARMADILLO REPEATS-CONTAINING PROTEIN; ANKAR","url":"https://www.omim.org/entry/609803"},{"mim_id":"607418","title":"GRIP AND COILED-COIL DOMAINS-CONTAINING PROTEIN 1; GCC1","url":"https://www.omim.org/entry/607418"},{"mim_id":"606918","title":"GOLGIN A5; GOLGA5","url":"https://www.omim.org/entry/606918"},{"mim_id":"604505","title":"THYROID HORMONE RECEPTOR INTERACTOR 11; TRIP11","url":"https://www.omim.org/entry/604505"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMF1"},"hgnc":{"alias_symbol":["ARA160","TMF"],"prev_symbol":[]},"alphafold":{"accession":"P82094","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P82094","model_url":"https://alphafold.ebi.ac.uk/files/AF-P82094-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P82094-F1-predicted_aligned_error_v6.png","plddt_mean":64.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMF1","jax_strain_url":"https://www.jax.org/strain/search?query=TMF1"},"sequence":{"accession":"P82094","fasta_url":"https://rest.uniprot.org/uniprotkb/P82094.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P82094/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P82094"}},"corpus_meta":[{"pmid":"10428808","id":"PMC_10428808","title":"Isolation and characterization of ARA160 as the first androgen receptor N-terminal-associated coactivator in human prostate cells.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10428808","citation_count":118,"is_preprint":false},{"pmid":"15128430","id":"PMC_15128430","title":"TMF is a golgin that binds Rab6 and influences Golgi morphology.","date":"2004","source":"BMC cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15128430","citation_count":85,"is_preprint":false},{"pmid":"23239882","id":"PMC_23239882","title":"Molecular insights into vesicle tethering at the Golgi by the conserved oligomeric Golgi (COG) complex and the golgin TATA element modulatory factor (TMF).","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23239882","citation_count":71,"is_preprint":false},{"pmid":"17698061","id":"PMC_17698061","title":"Functional involvement of TMF/ARA160 in Rab6-dependent retrograde membrane traffic.","date":"2007","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/17698061","citation_count":57,"is_preprint":false},{"pmid":"20691678","id":"PMC_20691678","title":"TMF/ARA160: A key regulator of sperm development.","date":"2010","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/20691678","citation_count":55,"is_preprint":false},{"pmid":"15467733","id":"PMC_15467733","title":"TMF/ARA160 is a BC-box-containing protein that mediates the degradation of Stat3.","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15467733","citation_count":47,"is_preprint":false},{"pmid":"24639530","id":"PMC_24639530","title":"Reprogrammed and transmissible intestinal microbiota confer diminished susceptibility to induced colitis in TMF-/- mice.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24639530","citation_count":44,"is_preprint":false},{"pmid":"28063362","id":"PMC_28063362","title":"Production of enzymes by a newly isolated Bacillus sp. TMF-1 in solid state fermentation on agricultural by-products: The evaluation of substrate pretreatment methods.","date":"2016","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/28063362","citation_count":39,"is_preprint":false},{"pmid":"12044884","id":"PMC_12044884","title":"A putative nuclear receptor coactivator (TMF/ARA160) associates with hbrm/hSNF2 alpha and BRG-1/hSNF2 beta and localizes in the Golgi apparatus.","date":"2002","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/12044884","citation_count":31,"is_preprint":false},{"pmid":"31354246","id":"PMC_31354246","title":"TMF inhibits miR-29a/Wnt/β-catenin signaling through upregulating Foxo3a activity in osteoarthritis chondrocytes.","date":"2019","source":"Drug design, development and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31354246","citation_count":24,"is_preprint":false},{"pmid":"31816985","id":"PMC_31816985","title":"The Anti-Proliferative Activity of the Hybrid TMS-TMF-4f Compound Against Human Cervical Cancer Involves Apoptosis Mediated by STAT3 Inactivation.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31816985","citation_count":21,"is_preprint":false},{"pmid":"26701263","id":"PMC_26701263","title":"TMF/ARA160 Governs the Dynamic Spatial Orientation of the Golgi Apparatus during Sperm Development.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26701263","citation_count":20,"is_preprint":false},{"pmid":"19330832","id":"PMC_19330832","title":"TMF/ARA160 downregulates proangiogenic genes and attenuates the progression of PC3 xenografts.","date":"2009","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19330832","citation_count":19,"is_preprint":false},{"pmid":"23000399","id":"PMC_23000399","title":"Testosterone deficiency accompanied by testicular and epididymal abnormalities in TMF(-/-) mice.","date":"2012","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23000399","citation_count":15,"is_preprint":false},{"pmid":"22553199","id":"PMC_22553199","title":"Loss of TMF/ARA160 protein renders colonic mucus refractory to bacterial colonization and diminishes intestinal susceptibility to acute colitis.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22553199","citation_count":15,"is_preprint":false},{"pmid":"28320093","id":"PMC_28320093","title":"TMF protects chondrocytes from ER stress-induced apoptosis by down-regulating GSK-3β.","date":"2017","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/28320093","citation_count":13,"is_preprint":false},{"pmid":"38554527","id":"PMC_38554527","title":"TMF inhibits extracellular matrix degradation by regulating the C/EBPβ/ADAMTS5 signaling pathway in osteoarthritis.","date":"2024","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/38554527","citation_count":8,"is_preprint":false},{"pmid":"33475194","id":"PMC_33475194","title":"TMF1 is upregulated by insulin and is required for a sustained glucose homeostasis.","date":"2021","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/33475194","citation_count":6,"is_preprint":false},{"pmid":"39997198","id":"PMC_39997198","title":"TMF Attenuates Cognitive Impairment and Neuroinflammation by Inhibiting the MAPK/NF-κB Pathway in Alzheimer's Disease: A Multi-Omics Analysis.","date":"2025","source":"Marine drugs","url":"https://pubmed.ncbi.nlm.nih.gov/39997198","citation_count":5,"is_preprint":false},{"pmid":"32738393","id":"PMC_32738393","title":"TMF, a natural dihydroflavonoid isolated from Scutellaria javanica Jungh, stimulates anticancer activity of s180 cancer-bearing mice, induces apoptosis, inhibits invasion and migration on HepG-2 cells.","date":"2020","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32738393","citation_count":5,"is_preprint":false},{"pmid":"12883631","id":"PMC_12883631","title":"Characterization of a new bradykinin-potentiating peptide (TmF) from Trimeresurus mucrosquamatus.","date":"2003","source":"Sheng wu hua xue yu sheng wu wu li xue bao Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/12883631","citation_count":5,"is_preprint":false},{"pmid":"37968761","id":"PMC_37968761","title":"Resequencing of the TMF-1 (TATA Element Modulatory Factor) regulated protein (TRNP1) gene in domestic and wild canids.","date":"2023","source":"Canine medicine and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37968761","citation_count":4,"is_preprint":false},{"pmid":"38800044","id":"PMC_38800044","title":"TMF suppresses chondrocyte hypertrophy in osteoarthritic cartilage by mediating the FOXO3a/BMPER pathway.","date":"2024","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38800044","citation_count":3,"is_preprint":false},{"pmid":"37137850","id":"PMC_37137850","title":"[Clinical efficacy analysis of TMF for the treatment of hyperviremia HBeAg-positive chronic hepatitis B patients with incomplete response to first-line oral antiviral nucleos(t)ide analogues].","date":"2023","source":"Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/37137850","citation_count":3,"is_preprint":false},{"pmid":"35324037","id":"PMC_35324037","title":"Computational analysis and in vitro evaluation of TMF 104, for its antioxidant, antimicrobial, and anticancer efficacies.","date":"2022","source":"Biotechnology and applied biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35324037","citation_count":2,"is_preprint":false},{"pmid":"39971496","id":"PMC_39971496","title":"[Switching to TMF rescue therapy in patients developing low-level viremia with ETV or TAF treatment].","date":"2024","source":"Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/39971496","citation_count":1,"is_preprint":false},{"pmid":"26796742","id":"PMC_26796742","title":"Objective Evaluation Tool for Texture-Modified Food (OET-TMF): Development of the Tool and Validation.","date":"2016","source":"Dysphagia","url":"https://pubmed.ncbi.nlm.nih.gov/26796742","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.13.25329470","title":"Implementation strategies and outcomes of intravenous iron use for treatment of anaemia during and after pregnancy in LMICs: a scoping review","date":"2025-06-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.13.25329470","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15786,"output_tokens":2941,"usd":0.045736},"stage2":{"model":"claude-opus-4-6","input_tokens":6314,"output_tokens":3063,"usd":0.162217},"total_usd":0.207953,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"TMF1/ARA160 directly interacts with the androgen receptor (AR) N-terminal domain and functions as an androgen-enhanced coactivator for AR-mediated transactivation in prostate cancer cells; interaction is enhanced by androgen and TMF1 cooperates with the AR C-terminal coactivator ARA70.\",\n      \"method\": \"Far-Western blotting, co-immunoprecipitation, affinity gel pull-down, mammalian two-hybrid assay, transient transfection reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (far-Western, Co-IP, pull-down, two-hybrid, reporter assay) in a single study; 118 citations\",\n      \"pmids\": [\"10428808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TMF1/ARA160 physically associates with the ATPase subunits of human SWI/SNF chromatin remodeling complexes (hbrm/hSNF2α and BRG-1/hSNF2β) via their conserved N-terminal regions and the C-terminal region of TMF; different TMF isoforms differentially localize to the Golgi apparatus and the nucleus.\",\n      \"method\": \"In vitro binding assay, co-immunoprecipitation, immunofluorescence, Western blot fractionation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vitro and in vivo binding shown with domain mapping, localization confirmed by imaging\",\n      \"pmids\": [\"12044884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TMF1 is a Golgi-localized golgin that binds all three isoforms of the GTPase Rab6 (mammalian homologue of yeast Ypt6) via a conserved ~100-residue coiled-coil motif; depletion by RNAi causes dispersal of Golgi membranes, indicating a role in Golgi organization.\",\n      \"method\": \"Yeast two-hybrid (Sgm1/Ypt6 interaction), co-immunoprecipitation (Rab6 isoforms), RNA interference knockdown, immunofluorescence microscopy\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with multiple Rab6 isoforms, RNAi phenotype, evolutionary conservation argument; 85 citations\",\n      \"pmids\": [\"15128430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TMF1/ARA160 contains a BC-box motif that mediates binding to elongin C; through this E3-ligase adaptor function, TMF1 directs ubiquitination and proteasomal degradation of Stat3 (but not Stat1) under serum-starvation conditions; BC-box deletion abolishes this activity.\",\n      \"method\": \"Co-immunoprecipitation, sequence motif analysis, ectopic overexpression with ubiquitination assay, proteasome inhibitor rescue, BC-box deletion mutagenesis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis combined with ubiquitination assay and proteasomal rescue, mechanistically well-defined\",\n      \"pmids\": [\"15467733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TMF1 is concentrated at budding cisternae tips of the Golgi (shown by immunoelectron microscopy) and is required for two Rab6-dependent retrograde transport processes: (1) endosome-to-TGN transport of Shiga toxin, and (2) Golgi-to-ER retention of GalNAc-T2 (but not GalT); the cytoplasmic region of GalNAc-T2 mediates TMF-dependent Golgi retention.\",\n      \"method\": \"RNAi knockdown, high-resolution immunofluorescence, immunoelectron microscopy, Shiga toxin trafficking assay, chimeric protein domain-swap analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (IEM, functional trafficking assay, domain-swap chimeras), clean mechanistic dissection; 57 citations\",\n      \"pmids\": [\"17698061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Under metabolic stress, TMF1 directs ubiquitination and proteasomal degradation of the NF-κB subunit p65/RelA, thereby downregulating proangiogenic genes (IL-8, IL-1β) and attenuating tumor xenograft growth.\",\n      \"method\": \"Ectopic expression in PC3 cells, xenograft tumor model, ubiquitination assay, RNA expression profiling, immunohistochemistry\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vivo xenograft plus ubiquitination assay, mechanistic link to NF-κB degradation established\",\n      \"pmids\": [\"19330832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TMF1 knockout male mice are sterile due to failure of proacrosomal vesicle homing to the perinuclear surface (acrosome absent), improper cytoplasm removal, misshapen sperm heads, and tail coiling; females are fertile and mice are otherwise healthy, establishing TMF1 as essential for spermiogenesis.\",\n      \"method\": \"TMF knockout mouse generation, histology, electron microscopy, fertility testing\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with specific spermatogenic phenotypes; 55 citations\",\n      \"pmids\": [\"20691678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The COG tethering complex binds both ends of TMF1 and interacts with two Rab GTPases; the central portion of TMF1 can bind Golgi membranes stripped of COPI coat, suggesting TMF1 bridges vesicle–target membrane apposition prior to fusion.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, in vitro binding assays, domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple interaction methods with domain mapping; mechanistic model supported by functional context\",\n      \"pmids\": [\"23239882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss of TMF1 in colonic goblet cells leads to altered MUC2 mucin secretion producing highly oligomerized gel-forming mucus refractory to bacterial colonization; TMF1 absence elevates p65/NF-κB and muc2 transcription in intestinal epithelial cells.\",\n      \"method\": \"TMF knockout mouse, DSS colitis model, gene expression analysis, mucus morphology assessment, bacterial colonization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with multiple phenotypic readouts and gene expression data linking TMF1 to NF-κB/MUC2 axis\",\n      \"pmids\": [\"22553199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TMF1 knockout leads to Leydig cell hyperproliferation, elevated LH, and significantly reduced serum testosterone, establishing a role for TMF1 in controlling testosterone production in the testis.\",\n      \"method\": \"TMF knockout mouse, hormone serum measurements (LH, testosterone), histological analysis, testosterone rescue experiment\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with hormonal rescue experiment\",\n      \"pmids\": [\"23000399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"During spermiogenesis, TMF1 dynamically translocates from cis-Golgi to trans-Golgi network to emerging vesicle surfaces; TMF1 contains a microtubule-interacting (MIT) domain that mediates association with microtubules, which is required for stable Golgi anchoring; loss of TMF1 causes aberrant Golgi orientation away from the nucleus, failure of proacrosomal vesicle targeting, and impaired acroplaxome and chromatoid body formation.\",\n      \"method\": \"TMF knockout mouse, immunofluorescence live/fixed imaging, electron microscopy, in-silico domain prediction, MIT domain mutation/deletion analysis, microtubule co-sedimentation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (EM, imaging, domain mutagenesis) in KO model with defined mechanistic pathway\",\n      \"pmids\": [\"26701263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TMF1 is upregulated by insulin in myoblasts and is required for formation of insulin-responsive GLUT4-containing vesicles; absence of TMF1 retains GLUT4 in perinuclear compartments, impairs GLUT4 trafficking to the plasma membrane, reduces glucose uptake, and causes hyperglycemia in TMF1-/- mice.\",\n      \"method\": \"TMF1 knockout myoblasts and mice, GLUT4 vesicle trafficking assay, glucose uptake assay, blood glucose measurement, immunofluorescence localization\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — both cell and mouse KO with functional readouts (GLUT4 trafficking, glucose uptake, in vivo glycemia)\",\n      \"pmids\": [\"33475194\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMF1 (TATA Element Modulatory Factor) is a multifunctional Golgi-associated golgin that (1) tethers retrograde transport vesicles via Rab6 binding and COG complex interaction to regulate Golgi-to-ER and endosome-to-TGN trafficking; (2) acts as a BC-box E3-ligase adaptor directing ubiquitin-proteasomal degradation of Stat3 and NF-κB p65/RelA under stress conditions; (3) interacts with microtubules through a MIT domain to maintain Golgi spatial orientation during spermiogenesis, where it is essential for proacrosomal vesicle targeting and acrosome formation; (4) facilitates formation of insulin-responsive GLUT4 vesicles for glucose uptake; and (5) coactivates androgen receptor transcription through direct N-terminal AR interaction.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TMF1 is a multifunctional golgin that serves as a Rab6-dependent vesicle tether at the Golgi apparatus, directing retrograde transport from endosomes to the TGN and from Golgi to the ER, while also interacting with the COG tethering complex to bridge vesicle–target membrane apposition [PMID:15128430, PMID:17698061, PMID:23239882]. Through a BC-box motif that recruits elongin C, TMF1 functions as an E3-ligase adaptor that targets Stat3 and NF-κB p65/RelA for ubiquitin-proteasomal degradation under stress conditions, thereby modulating inflammatory and angiogenic gene expression [PMID:15467733, PMID:19330832]. TMF1 contains a microtubule-interacting (MIT) domain essential for Golgi anchoring and spatial orientation during spermiogenesis; TMF1-knockout male mice are sterile due to failed proacrosomal vesicle targeting and absent acrosome formation [PMID:20691678, PMID:26701263]. TMF1 is also required for biogenesis of insulin-responsive GLUT4 vesicles, and its loss impairs GLUT4 trafficking to the plasma membrane and causes hyperglycemia [PMID:33475194].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"The initial characterization of TMF1 revealed an unexpected nuclear function: it directly binds the androgen receptor N-terminus and coactivates AR-mediated transcription, establishing TMF1 as a transcriptional cofactor.\",\n      \"evidence\": \"Far-Western, Co-IP, pull-down, mammalian two-hybrid, and reporter assays in prostate cancer cells\",\n      \"pmids\": [\"10428808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of AR coactivation in vivo not tested\", \"Whether TMF1 coactivation extends to other nuclear receptors unknown\", \"Mechanism by which TMF1 shuttles between Golgi and nucleus not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Discovery that TMF1 physically associates with the ATPase subunits of SWI/SNF chromatin remodeling complexes (hbrm, BRG-1) suggested a mechanism for its nuclear transcriptional activity, while also confirming that different TMF1 isoforms partition between Golgi and nucleus.\",\n      \"evidence\": \"In vitro binding assays, Co-IP, immunofluorescence, and Western blot fractionation\",\n      \"pmids\": [\"12044884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of SWI/SNF interaction on chromatin remodeling not demonstrated\", \"Whether SWI/SNF interaction is linked to AR coactivation untested\", \"Isoform-specific regulation not characterized\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Two pivotal discoveries reframed TMF1's primary identity: it was shown to be a Golgi golgin that binds all three Rab6 isoforms via a coiled-coil domain and is needed for Golgi integrity, while independently it was found to contain a BC-box motif that recruits elongin C to direct ubiquitin-proteasomal degradation of Stat3.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP with Rab6, RNAi-induced Golgi dispersal (Rab6); BC-box mutagenesis, ubiquitination assay, proteasome inhibitor rescue (Stat3 degradation)\",\n      \"pmids\": [\"15128430\", \"15467733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TMF1 coordinates its Golgi-tethering and E3-adaptor functions is unknown\", \"Structural basis of Rab6 binding not resolved\", \"Whether Stat3 degradation occurs at the Golgi or in the cytosol undefined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"High-resolution imaging and functional trafficking assays established that TMF1 localizes to budding cisternae tips and is required for two specific Rab6-dependent retrograde pathways — endosome-to-TGN transport of Shiga toxin and Golgi-to-ER retention of GalNAc-T2 — providing the first direct evidence that TMF1 acts as a vesicle tether.\",\n      \"evidence\": \"RNAi, immunoelectron microscopy, Shiga toxin trafficking assay, chimeric domain-swap analysis\",\n      \"pmids\": [\"17698061\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TMF1 tethers other retrograde cargo beyond Shiga toxin and GalNAc-T2 unknown\", \"SNARE partners mediating TMF1-dependent fusion not identified\", \"Selectivity mechanism for GalNAc-T2 but not GalT not fully explained\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extending its E3-adaptor role, TMF1 was shown to ubiquitinate NF-κB p65/RelA under metabolic stress, downregulating proangiogenic genes and attenuating xenograft tumor growth, broadening the substrate repertoire of TMF1-mediated degradation.\",\n      \"evidence\": \"Ectopic expression in PC3 cells, xenograft tumor model, ubiquitination assay, RNA profiling\",\n      \"pmids\": [\"19330832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TMF1-mediated p65 degradation is relevant beyond the xenograft setting unknown\", \"Specificity determinants distinguishing Stat3 vs. p65 as substrates not mapped\", \"Upstream signals activating TMF1's E3-adaptor function undefined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Generation of TMF1-knockout mice revealed male-specific sterility caused by failure of proacrosomal vesicle homing, absent acrosome formation, and defective cytoplasm removal, establishing TMF1 as essential for spermiogenesis in vivo.\",\n      \"evidence\": \"TMF KO mouse, histology, electron microscopy, fertility testing\",\n      \"pmids\": [\"20691678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular cargo of proacrosomal vesicles requiring TMF1 not identified\", \"Whether the spermiogenesis defect reflects Rab6-tethering loss, microtubule anchoring loss, or both not dissected\", \"Rescue experiments not performed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Multiple studies refined TMF1's interaction network and physiological roles: the COG complex was shown to bind both ends of TMF1, supporting a model where TMF1 bridges vesicle–target membranes; TMF1 loss in goblet cells altered MUC2 mucin secretion via elevated NF-κB/p65; and TMF1 KO testes showed Leydig cell hyperproliferation with reduced testosterone, linking TMF1 to endocrine homeostasis.\",\n      \"evidence\": \"Co-IP and yeast two-hybrid for COG interaction; DSS colitis model in KO mice for mucin phenotype; hormone measurements and histology in KO mice for Leydig cell phenotype\",\n      \"pmids\": [\"23239882\", \"22553199\", \"23000399\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether COG–TMF1 interaction is required for the retrograde pathways defined in 2007 not tested\", \"Mechanism linking TMF1 to Leydig cell proliferation unclear\", \"Direct vesicle fusion reconstitution with TMF1 not achieved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of a microtubule-interacting (MIT) domain in TMF1 explained how it anchors the Golgi near the nucleus during spermiogenesis; loss of MIT-mediated microtubule binding caused aberrant Golgi orientation, failed proacrosomal vesicle targeting, and impaired acroplaxome/chromatoid body formation.\",\n      \"evidence\": \"TMF KO mouse, immunofluorescence, electron microscopy, MIT domain mutation/deletion, microtubule co-sedimentation\",\n      \"pmids\": [\"26701263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of the MIT domain not determined\", \"Whether the MIT domain functions outside spermiogenesis not tested\", \"Regulatory mechanisms controlling TMF1 translocation from cis- to trans-Golgi unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"TMF1 was found to be insulin-upregulated and required for formation of insulin-responsive GLUT4 vesicles; its absence trapped GLUT4 in perinuclear compartments, reduced glucose uptake, and caused hyperglycemia, expanding TMF1's vesicle-sorting role to metabolic regulation.\",\n      \"evidence\": \"TMF1 KO myoblasts and mice, GLUT4 vesicle trafficking assay, glucose uptake assay, blood glucose measurement\",\n      \"pmids\": [\"33475194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TMF1 acts via Rab6 to form GLUT4 vesicles not determined\", \"Sorting signals on GLUT4 recognized by TMF1 not identified\", \"Contribution of TMF1 loss to systemic insulin resistance beyond glucose uptake not evaluated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified structural and regulatory framework explaining how TMF1 coordinates its distinct roles — vesicle tethering, E3-ligase adaptor activity, microtubule anchoring, and transcriptional coactivation — remains unresolved, as does whether these functions are mutually exclusive or context-dependent.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of TMF1 or its complexes\", \"No reconstituted vesicle tethering/fusion assay with purified TMF1\", \"Post-translational modifications regulating TMF1 functional switching unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 2, 4, 10]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [4, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 4, 7, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [6, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 11]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [\n      \"Elongin BC-CUL5 E3 ligase complex\"\n    ],\n    \"partners\": [\n      \"RAB6A\",\n      \"AR\",\n      \"SOCS1\",\n      \"SMARCA2\",\n      \"SMARCA4\",\n      \"COG3\",\n      \"ELOC\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}