{"gene":"TMF1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1999,"finding":"ARA160/TMF1 directly interacts with the androgen receptor (AR) N-terminal domain, and androgen enhances this interaction. ARA160/TMF1 functions as a coactivator for AR-mediated transactivation in prostate cancer cells and acts cooperatively 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 2 / Strong — multiple orthogonal methods (far-Western, Co-IP, pulldown, two-hybrid, reporter assay) in a single study establishing direct interaction and functional coactivation","pmids":["10428808"],"is_preprint":false},{"year":2002,"finding":"TMF1/ARA160 associates in vitro and in vivo with the ATPase subunits of the human SWI/SNF chromatin remodeling complex, hbrm/hSNF2α and BRG-1/hSNF2β. This interaction requires the conserved N-terminal regions of hbrm/BRG-1 and the C-terminal region of TMF1. TMF isoforms differentially localize to the Golgi apparatus and the nucleus.","method":"Co-immunoprecipitation (in vitro and in vivo), immunofluorescence, Western blot fractionation","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, plus localization data, single lab","pmids":["12044884"],"is_preprint":false},{"year":2004,"finding":"TMF1 is a Golgi-resident protein (golgin) that binds all three isoforms of the Rab6 GTPase via a conserved ~100-residue coiled-coil motif (the mammalian equivalent of yeast Sgm1). Depletion of TMF1 by RNAi causes modest dispersal of Golgi membranes, indicating a role in Golgi organisation.","method":"Protein binding assays, RNA interference (RNAi) knockdown, immunofluorescence microscopy","journal":"BMC cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assay identifying Rab6 interaction domain, RNAi phenotype, independently replicated by subsequent studies","pmids":["15128430"],"is_preprint":false},{"year":2004,"finding":"TMF1 contains a BC-box motif that mediates binding to elongin C, enabling TMF1 to act as an E3 ubiquitin ligase adaptor that directs ubiquitination and proteasomal degradation of STAT3. Under serum deprivation, cytoplasmic TMF1 transiently associates with the tyrosine kinase Fer and with STAT3. TMF1 lacking the BC-box fails to ubiquitinate or degrade STAT3.","method":"Co-immunoprecipitation, ectopic overexpression with BC-box mutant, ubiquitination assay, proteasome inhibitor experiments","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mutagenesis (BC-box deletion), Co-IP for complex, functional ubiquitination assay, replicated in downstream studies","pmids":["15467733"],"is_preprint":false},{"year":2007,"finding":"TMF1 is concentrated at budding structures at the tips of Golgi cisternae and is required for two Rab6-dependent retrograde transport processes: (1) retrograde transport of Shiga toxin from endosomes to the trans-Golgi network, and (2) Golgi retention of GalNAc-T2 (but not GalT). The cytoplasmic region of GalNAc-T2 is required for TMF-dependent Golgi retention.","method":"High-resolution immunofluorescence, immunoelectron microscopy, RNAi knockdown, chimeric protein analysis, Shiga toxin trafficking assay","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (immuno-EM, RNAi, chimeric proteins, toxin trafficking), single lab with rigorous controls","pmids":["17698061"],"is_preprint":false},{"year":2009,"finding":"TMF1 directs ubiquitination and proteasomal degradation of the NF-κB subunit p65/RelA in metabolically stressed cells, resulting in downregulation of pro-angiogenic NF-κB target genes (including IL-8 and IL-1β) and attenuation of tumor xenograft growth.","method":"Ectopic HA-TMF1 expression in PC3 cells, ubiquitination assay, xenograft mouse model, RNA expression profiling, immunohistochemistry","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay and in vivo xenograft with molecular readouts, single lab","pmids":["19330832"],"is_preprint":false},{"year":2010,"finding":"TMF1 is required for homing of Golgi-derived pro-acrosomal vesicles to the perinuclear surface of spermatids. In TMF1-null male mice, spermatids lack acrosome formation, fail to remove cytoplasm properly, and spermatozoa show misshapen heads, tail coiling, and lack of motility, establishing TMF1 as essential for mammalian spermiogenesis.","method":"TMF1 knockout mouse model (TMF-/- null mice), histology, immunofluorescence, electron microscopy","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined cellular phenotypes across multiple spermatogenic stages, multiple imaging modalities","pmids":["20691678"],"is_preprint":false},{"year":2012,"finding":"The COG complex interacts with both ends of the TMF1 golgin and with two different Rab GTPases, potentially bridging the distance between the distal golgin end and the target membrane. The central portion of TMF1 can bind to Golgi membranes freed of their COPI coat, suggesting a role in bringing vesicle and target membranes into close apposition prior to fusion.","method":"Protein interaction mapping (pulldown/binding assays), functional tethering analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding experiments mapping interaction domains, single lab with multiple interaction partners tested","pmids":["23239882"],"is_preprint":false},{"year":2012,"finding":"In the colon, TMF1 normally promotes p65/NF-κB-mediated suppression of MUC2 mucin expression. Loss of TMF1 leads to elevated p65/NF-κB in intestinal epithelial cells, 5-fold upregulation of MUC2 transcription, altered colonic mucus morphology refractory to bacterial colonization, and reduced susceptibility to DSS-induced acute colitis.","method":"TMF1 knockout mouse (TMF-/-), DSS colitis model, gene expression analysis, histology, bacterial colonization assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse with defined molecular and cellular phenotype, single lab","pmids":["22553199"],"is_preprint":false},{"year":2012,"finding":"Absence of TMF1 in male mice leads to significantly reduced serum testosterone levels, spermatid retention in testis, Leydig cell proliferation (with elevated LH), and apoptosis of epididymal epithelial cells. External testosterone administration reduced epididymal apoptosis in TMF1-/- mice, indicating TMF1 participates in control of testosterone levels.","method":"TMF1 knockout mouse (TMF-/-), hormone measurement (LH, testosterone), histology, testosterone supplementation rescue experiment","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with hormonal measurements and rescue experiment, single lab","pmids":["23000399"],"is_preprint":false},{"year":2015,"finding":"During spermiogenesis, TMF1 undergoes dynamic relocalization from the cis-Golgi to the trans-Golgi network and emerging vesicle surfaces. Absence of TMF1 causes abnormal spatial orientation of the Golgi and deviation of the trans-Golgi surface away from the nucleus, preventing pro-acrosomal vesicle tethering to the nuclear membrane and acroplaxome formation. TMF1 contains a microtubule-interacting (MIT) domain required for its stable Golgi association, and associates with microtubules in spermatogenic cells.","method":"TMF1 knockout mouse (TMF-/-), live/fixed fluorescence microscopy, electron microscopy, in silico domain analysis, MIT domain functional assay, microtubule co-sedimentation","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO model with multiple imaging modalities (light and EM), domain functional analysis, and direct microtubule association assay in a single rigorous study","pmids":["26701263"],"is_preprint":false},{"year":2021,"finding":"TMF1 is upregulated by insulin in myoblasts and is essential for the formation of insulin-responsive GLUT4-containing vesicles at the trans-Golgi. Absence of TMF1 causes retention of GLUT4 in perinuclear compartments, impaired insulin-stimulated GLUT4 trafficking to the plasma membrane, reduced glucose uptake, and hyperglycemia in TMF1-/- mice.","method":"TMF1 knockout myoblasts and mice (TMF1-/-), GLUT4 trafficking assay (live cell imaging/fractionation), glucose uptake assay, blood glucose measurement","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — both cellular KO and in vivo KO mouse with direct GLUT4 trafficking readout and functional glucose uptake measurements","pmids":["33475194"],"is_preprint":false}],"current_model":"TMF1 (ARA160/TMF) is a multifunctional Golgi-associated golgin that binds Rab6 via a conserved coiled-coil domain to tether retrograde vesicles and maintain Golgi organization; it also contains a microtubule-interacting domain enabling dynamic Golgi orientation during spermiogenesis; under metabolic stress it relocates to the cytoplasm where its BC-box motif recruits elongin C to direct ubiquitin-proteasomal degradation of STAT3 and NF-κB p65/RelA; it is essential for pro-acrosomal vesicle trafficking and acrosome formation in spermatids, for insulin-stimulated GLUT4 vesicle formation and glucose homeostasis, and for colonic mucus MUC2 regulation; and it was originally identified as an androgen-enhanced coactivator of the androgen receptor N-terminal domain that cooperates with SWI/SNF chromatin remodeling factors."},"narrative":{"mechanistic_narrative":"TMF1 (ARA160/TMF) is a Golgi-resident golgin that organizes the Golgi apparatus and tethers Rab6-dependent retrograde transport vesicles, thereby governing membrane traffic that underlies several specialized cellular programs [PMID:15128430, PMID:17698061]. It binds all three isoforms of the Rab6 GTPase through a conserved coiled-coil motif, concentrates at budding structures at the tips of Golgi cisternae, and is required for retrograde transport of Shiga toxin to the trans-Golgi network and for Golgi retention of GalNAc-T2 [PMID:15128430, PMID:17698061]; through interactions with the COG complex and with COPI-stripped Golgi membranes it brings vesicle and target membranes into apposition prior to fusion [PMID:23239882]. A microtubule-interacting (MIT) domain anchors TMF1 stably to the Golgi and lets it reorient the Golgi during specialized differentiation [PMID:26701263]. These trafficking functions make TMF1 essential in vivo: it is required for homing of pro-acrosomal vesicles to the spermatid nucleus and for acrosome formation during spermiogenesis [PMID:20691678, PMID:26701263], and for the formation of insulin-responsive GLUT4 vesicles at the trans-Golgi, with its loss causing impaired GLUT4 trafficking, reduced glucose uptake, and hyperglycemia [PMID:33475194]. Beyond its membrane role, TMF1 acts as an E3 ubiquitin ligase adaptor: under metabolic stress its BC-box motif recruits elongin C to direct ubiquitination and proteasomal degradation of STAT3 and of the NF-κB subunit p65/RelA, attenuating NF-κB target gene expression and tumor xenograft growth [PMID:15467733, PMID:19330832], and this p65 control also tunes MUC2 mucin expression in the colon [PMID:22553199]. TMF1 was originally identified as an androgen-enhanced coactivator of the androgen receptor N-terminal domain that cooperates with SWI/SNF chromatin-remodeling ATPases [PMID:10428808, PMID:12044884].","teleology":[{"year":1999,"claim":"Established the first molecular function for TMF1 by showing it acts as an androgen-dependent transcriptional coactivator, linking the protein to nuclear hormone signaling.","evidence":"Far-Western, Co-IP, pulldown, two-hybrid and reporter assays in prostate cancer cells","pmids":["10428808"],"confidence":"High","gaps":["Did not define the structural basis of AR N-terminal binding","Did not reconcile a nuclear coactivator role with later Golgi localization"]},{"year":2002,"claim":"Connected TMF1's coactivator function to chromatin remodeling and revealed dual subcellular distribution, raising the question of how one protein partitions between nucleus and Golgi.","evidence":"Reciprocal Co-IP with domain mapping plus immunofluorescence fractionation","pmids":["12044884"],"confidence":"Medium","gaps":["Single lab; functional consequence of SWI/SNF binding for transcription not established","Mechanism controlling isoform localization unresolved"]},{"year":2004,"claim":"Defined TMF1 as a bona fide golgin by identifying the Rab6-binding coiled-coil motif and a Golgi-organization phenotype, establishing its membrane-tethering identity.","evidence":"Direct binding assays and RNAi knockdown with immunofluorescence","pmids":["15128430"],"confidence":"High","gaps":["Specific retrograde cargoes not yet defined","Modest dispersal phenotype left functional importance unclear"]},{"year":2004,"claim":"Revealed an unexpected second activity — TMF1 as an E3 ubiquitin ligase adaptor that targets STAT3 — by mapping a BC-box that recruits elongin C.","evidence":"BC-box deletion mutagenesis, Co-IP, and ubiquitination assays under serum deprivation","pmids":["15467733"],"confidence":"High","gaps":["Identity of the full E3 complex (cullin/RBX) not defined","Trigger relocating TMF1 to cytoplasm not mechanistically resolved"]},{"year":2007,"claim":"Demonstrated the cargo-specific role of TMF1 in Rab6-dependent retrograde transport, distinguishing it from bulk Golgi maintenance.","evidence":"Immuno-EM, RNAi, chimeric proteins, and Shiga toxin trafficking assays","pmids":["17698061"],"confidence":"High","gaps":["Why only a subset of Golgi enzymes (GalNAc-T2 vs GalT) require TMF1 retention unexplained","Coupling between tethering and fusion machinery not defined"]},{"year":2009,"claim":"Extended the ubiquitin-adaptor function to NF-κB p65/RelA and linked it to suppression of pro-angiogenic gene expression and tumor growth.","evidence":"Ectopic TMF1 expression, ubiquitination assays, and xenograft mouse model with expression profiling","pmids":["19330832"],"confidence":"Medium","gaps":["Single lab; physiological stress conditions driving p65 degradation not fully defined","Selectivity between STAT3 and p65 substrates unresolved"]},{"year":2010,"claim":"Established the in vivo essentiality of TMF1 for spermiogenesis through a knockout, tying vesicle homing to acrosome biogenesis.","evidence":"TMF1-null mouse with histology, immunofluorescence, and electron microscopy","pmids":["20691678"],"confidence":"High","gaps":["Molecular tether linking pro-acrosomal vesicles to the nuclear surface not identified","Did not separate trafficking defect from downstream maturation failures"]},{"year":2012,"claim":"Positioned TMF1 within a tethering architecture by showing the COG complex and Rab GTPases bind both golgin ends, supporting a model that bridges vesicle to target membrane.","evidence":"Interaction-domain mapping and binding to COPI-stripped Golgi membranes","pmids":["23239882"],"confidence":"Medium","gaps":["Whether bridging directly precedes fusion not demonstrated in vivo","Stoichiometry and order of assembly with COG/Rab unknown"]},{"year":2012,"claim":"Showed that TMF1-dependent p65/NF-κB activity governs colonic MUC2 mucin expression, connecting its ubiquitin role to mucosal physiology.","evidence":"TMF1 knockout mouse with DSS colitis, expression analysis, and bacterial colonization assays","pmids":["22553199"],"confidence":"Medium","gaps":["Direct demonstration that p65 degradation (vs other effects) drives MUC2 change incomplete","Cell-autonomy in intestinal epithelium not isolated"]},{"year":2012,"claim":"Linked TMF1 loss to systemic endocrine disruption, indicating its testicular function extends beyond germ cells to hormone homeostasis.","evidence":"TMF1 knockout mouse with hormone measurements and testosterone rescue","pmids":["23000399"],"confidence":"Medium","gaps":["Whether reduced testosterone is a primary or secondary consequence unresolved","Molecular pathway connecting TMF1 to Leydig cell function unknown"]},{"year":2015,"claim":"Mechanistically explained the spermiogenesis defect by showing TMF1 reorients the Golgi via a microtubule-interacting domain to position vesicles at the nucleus.","evidence":"TMF1 knockout mouse with light and electron microscopy, domain analysis, and microtubule co-sedimentation","pmids":["26701263"],"confidence":"High","gaps":["How the MIT domain coordinates with Rab6 tethering not integrated","Regulation of dynamic cis-to-trans relocalization unknown"]},{"year":2021,"claim":"Generalized the trafficking role to metabolism by showing TMF1 is required for insulin-responsive GLUT4 vesicle formation and glucose homeostasis.","evidence":"TMF1 knockout myoblasts and mice with GLUT4 trafficking, glucose uptake, and blood glucose assays","pmids":["33475194"],"confidence":"High","gaps":["Whether GLUT4 vesicle formation uses the same Rab6/COG machinery as retrograde transport not tested","Mechanism of insulin-driven TMF1 upregulation unknown"]},{"year":null,"claim":"How TMF1 partitions and switches between its Golgi-tethering role and its cytoplasmic ubiquitin-adaptor / nuclear coactivator roles, and whether these functions share regulatory inputs, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating Rab6 coiled-coil, MIT, and BC-box domains","Signals controlling subcellular relocalization across functions not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[10]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,4,7]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2,4,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,4,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1]}],"complexes":["Golgi golgin tether"],"partners":["RAB6","ELOC","STAT3","RELA","FER","AR","SMARCA2","SMARCA4"],"other_free_text":[]}},"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":72,"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":48,"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":"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":"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":"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":9,"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":"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":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":6,"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":"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":"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":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":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":16544,"output_tokens":3189,"usd":0.048733,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10659,"output_tokens":3951,"usd":0.076035,"stage2_stop_reason":"end_turn"},"total_usd":0.124768,"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\": 1999,\n      \"finding\": \"ARA160/TMF1 directly interacts with the androgen receptor (AR) N-terminal domain, and androgen enhances this interaction. ARA160/TMF1 functions as a coactivator for AR-mediated transactivation in prostate cancer cells and acts cooperatively 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 2 / Strong — multiple orthogonal methods (far-Western, Co-IP, pulldown, two-hybrid, reporter assay) in a single study establishing direct interaction and functional coactivation\",\n      \"pmids\": [\"10428808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TMF1/ARA160 associates in vitro and in vivo with the ATPase subunits of the human SWI/SNF chromatin remodeling complex, hbrm/hSNF2α and BRG-1/hSNF2β. This interaction requires the conserved N-terminal regions of hbrm/BRG-1 and the C-terminal region of TMF1. TMF isoforms differentially localize to the Golgi apparatus and the nucleus.\",\n      \"method\": \"Co-immunoprecipitation (in vitro and in vivo), immunofluorescence, Western blot fractionation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, plus localization data, single lab\",\n      \"pmids\": [\"12044884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TMF1 is a Golgi-resident protein (golgin) that binds all three isoforms of the Rab6 GTPase via a conserved ~100-residue coiled-coil motif (the mammalian equivalent of yeast Sgm1). Depletion of TMF1 by RNAi causes modest dispersal of Golgi membranes, indicating a role in Golgi organisation.\",\n      \"method\": \"Protein binding assays, RNA interference (RNAi) knockdown, immunofluorescence microscopy\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assay identifying Rab6 interaction domain, RNAi phenotype, independently replicated by subsequent studies\",\n      \"pmids\": [\"15128430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TMF1 contains a BC-box motif that mediates binding to elongin C, enabling TMF1 to act as an E3 ubiquitin ligase adaptor that directs ubiquitination and proteasomal degradation of STAT3. Under serum deprivation, cytoplasmic TMF1 transiently associates with the tyrosine kinase Fer and with STAT3. TMF1 lacking the BC-box fails to ubiquitinate or degrade STAT3.\",\n      \"method\": \"Co-immunoprecipitation, ectopic overexpression with BC-box mutant, ubiquitination assay, proteasome inhibitor experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mutagenesis (BC-box deletion), Co-IP for complex, functional ubiquitination assay, replicated in downstream studies\",\n      \"pmids\": [\"15467733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TMF1 is concentrated at budding structures at the tips of Golgi cisternae and is required for two Rab6-dependent retrograde transport processes: (1) retrograde transport of Shiga toxin from endosomes to the trans-Golgi network, and (2) Golgi retention of GalNAc-T2 (but not GalT). The cytoplasmic region of GalNAc-T2 is required for TMF-dependent Golgi retention.\",\n      \"method\": \"High-resolution immunofluorescence, immunoelectron microscopy, RNAi knockdown, chimeric protein analysis, Shiga toxin trafficking assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (immuno-EM, RNAi, chimeric proteins, toxin trafficking), single lab with rigorous controls\",\n      \"pmids\": [\"17698061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TMF1 directs ubiquitination and proteasomal degradation of the NF-κB subunit p65/RelA in metabolically stressed cells, resulting in downregulation of pro-angiogenic NF-κB target genes (including IL-8 and IL-1β) and attenuation of tumor xenograft growth.\",\n      \"method\": \"Ectopic HA-TMF1 expression in PC3 cells, ubiquitination assay, xenograft mouse model, RNA expression profiling, immunohistochemistry\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay and in vivo xenograft with molecular readouts, single lab\",\n      \"pmids\": [\"19330832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TMF1 is required for homing of Golgi-derived pro-acrosomal vesicles to the perinuclear surface of spermatids. In TMF1-null male mice, spermatids lack acrosome formation, fail to remove cytoplasm properly, and spermatozoa show misshapen heads, tail coiling, and lack of motility, establishing TMF1 as essential for mammalian spermiogenesis.\",\n      \"method\": \"TMF1 knockout mouse model (TMF-/- null mice), histology, immunofluorescence, electron microscopy\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined cellular phenotypes across multiple spermatogenic stages, multiple imaging modalities\",\n      \"pmids\": [\"20691678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The COG complex interacts with both ends of the TMF1 golgin and with two different Rab GTPases, potentially bridging the distance between the distal golgin end and the target membrane. The central portion of TMF1 can bind to Golgi membranes freed of their COPI coat, suggesting a role in bringing vesicle and target membranes into close apposition prior to fusion.\",\n      \"method\": \"Protein interaction mapping (pulldown/binding assays), functional tethering analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding experiments mapping interaction domains, single lab with multiple interaction partners tested\",\n      \"pmids\": [\"23239882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In the colon, TMF1 normally promotes p65/NF-κB-mediated suppression of MUC2 mucin expression. Loss of TMF1 leads to elevated p65/NF-κB in intestinal epithelial cells, 5-fold upregulation of MUC2 transcription, altered colonic mucus morphology refractory to bacterial colonization, and reduced susceptibility to DSS-induced acute colitis.\",\n      \"method\": \"TMF1 knockout mouse (TMF-/-), DSS colitis model, gene expression analysis, histology, bacterial colonization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse with defined molecular and cellular phenotype, single lab\",\n      \"pmids\": [\"22553199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Absence of TMF1 in male mice leads to significantly reduced serum testosterone levels, spermatid retention in testis, Leydig cell proliferation (with elevated LH), and apoptosis of epididymal epithelial cells. External testosterone administration reduced epididymal apoptosis in TMF1-/- mice, indicating TMF1 participates in control of testosterone levels.\",\n      \"method\": \"TMF1 knockout mouse (TMF-/-), hormone measurement (LH, testosterone), histology, testosterone supplementation rescue experiment\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with hormonal measurements and rescue experiment, single lab\",\n      \"pmids\": [\"23000399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"During spermiogenesis, TMF1 undergoes dynamic relocalization from the cis-Golgi to the trans-Golgi network and emerging vesicle surfaces. Absence of TMF1 causes abnormal spatial orientation of the Golgi and deviation of the trans-Golgi surface away from the nucleus, preventing pro-acrosomal vesicle tethering to the nuclear membrane and acroplaxome formation. TMF1 contains a microtubule-interacting (MIT) domain required for its stable Golgi association, and associates with microtubules in spermatogenic cells.\",\n      \"method\": \"TMF1 knockout mouse (TMF-/-), live/fixed fluorescence microscopy, electron microscopy, in silico domain analysis, MIT domain functional assay, microtubule co-sedimentation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO model with multiple imaging modalities (light and EM), domain functional analysis, and direct microtubule association assay in a single rigorous study\",\n      \"pmids\": [\"26701263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TMF1 is upregulated by insulin in myoblasts and is essential for the formation of insulin-responsive GLUT4-containing vesicles at the trans-Golgi. Absence of TMF1 causes retention of GLUT4 in perinuclear compartments, impaired insulin-stimulated GLUT4 trafficking to the plasma membrane, reduced glucose uptake, and hyperglycemia in TMF1-/- mice.\",\n      \"method\": \"TMF1 knockout myoblasts and mice (TMF1-/-), GLUT4 trafficking assay (live cell imaging/fractionation), glucose uptake assay, blood glucose measurement\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — both cellular KO and in vivo KO mouse with direct GLUT4 trafficking readout and functional glucose uptake measurements\",\n      \"pmids\": [\"33475194\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMF1 (ARA160/TMF) is a multifunctional Golgi-associated golgin that binds Rab6 via a conserved coiled-coil domain to tether retrograde vesicles and maintain Golgi organization; it also contains a microtubule-interacting domain enabling dynamic Golgi orientation during spermiogenesis; under metabolic stress it relocates to the cytoplasm where its BC-box motif recruits elongin C to direct ubiquitin-proteasomal degradation of STAT3 and NF-κB p65/RelA; it is essential for pro-acrosomal vesicle trafficking and acrosome formation in spermatids, for insulin-stimulated GLUT4 vesicle formation and glucose homeostasis, and for colonic mucus MUC2 regulation; and it was originally identified as an androgen-enhanced coactivator of the androgen receptor N-terminal domain that cooperates with SWI/SNF chromatin remodeling factors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMF1 (ARA160/TMF) is a Golgi-resident golgin that organizes the Golgi apparatus and tethers Rab6-dependent retrograde transport vesicles, thereby governing membrane traffic that underlies several specialized cellular programs [#2, #4]. It binds all three isoforms of the Rab6 GTPase through a conserved coiled-coil motif, concentrates at budding structures at the tips of Golgi cisternae, and is required for retrograde transport of Shiga toxin to the trans-Golgi network and for Golgi retention of GalNAc-T2 [#2, #4]; through interactions with the COG complex and with COPI-stripped Golgi membranes it brings vesicle and target membranes into apposition prior to fusion [#7]. A microtubule-interacting (MIT) domain anchors TMF1 stably to the Golgi and lets it reorient the Golgi during specialized differentiation [#10]. These trafficking functions make TMF1 essential in vivo: it is required for homing of pro-acrosomal vesicles to the spermatid nucleus and for acrosome formation during spermiogenesis [#6, #10], and for the formation of insulin-responsive GLUT4 vesicles at the trans-Golgi, with its loss causing impaired GLUT4 trafficking, reduced glucose uptake, and hyperglycemia [#11]. Beyond its membrane role, TMF1 acts as an E3 ubiquitin ligase adaptor: under metabolic stress its BC-box motif recruits elongin C to direct ubiquitination and proteasomal degradation of STAT3 and of the NF-\\u03baB subunit p65/RelA, attenuating NF-\\u03baB target gene expression and tumor xenograft growth [#3, #5], and this p65 control also tunes MUC2 mucin expression in the colon [#8]. TMF1 was originally identified as an androgen-enhanced coactivator of the androgen receptor N-terminal domain that cooperates with SWI/SNF chromatin-remodeling ATPases [#0, #1].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the first molecular function for TMF1 by showing it acts as an androgen-dependent transcriptional coactivator, linking the protein to nuclear hormone signaling.\",\n      \"evidence\": \"Far-Western, Co-IP, pulldown, two-hybrid and reporter assays in prostate cancer cells\",\n      \"pmids\": [\"10428808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis of AR N-terminal binding\", \"Did not reconcile a nuclear coactivator role with later Golgi localization\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected TMF1's coactivator function to chromatin remodeling and revealed dual subcellular distribution, raising the question of how one protein partitions between nucleus and Golgi.\",\n      \"evidence\": \"Reciprocal Co-IP with domain mapping plus immunofluorescence fractionation\",\n      \"pmids\": [\"12044884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; functional consequence of SWI/SNF binding for transcription not established\", \"Mechanism controlling isoform localization unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined TMF1 as a bona fide golgin by identifying the Rab6-binding coiled-coil motif and a Golgi-organization phenotype, establishing its membrane-tethering identity.\",\n      \"evidence\": \"Direct binding assays and RNAi knockdown with immunofluorescence\",\n      \"pmids\": [\"15128430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific retrograde cargoes not yet defined\", \"Modest dispersal phenotype left functional importance unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed an unexpected second activity \\u2014 TMF1 as an E3 ubiquitin ligase adaptor that targets STAT3 \\u2014 by mapping a BC-box that recruits elongin C.\",\n      \"evidence\": \"BC-box deletion mutagenesis, Co-IP, and ubiquitination assays under serum deprivation\",\n      \"pmids\": [\"15467733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the full E3 complex (cullin/RBX) not defined\", \"Trigger relocating TMF1 to cytoplasm not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated the cargo-specific role of TMF1 in Rab6-dependent retrograde transport, distinguishing it from bulk Golgi maintenance.\",\n      \"evidence\": \"Immuno-EM, RNAi, chimeric proteins, and Shiga toxin trafficking assays\",\n      \"pmids\": [\"17698061\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why only a subset of Golgi enzymes (GalNAc-T2 vs GalT) require TMF1 retention unexplained\", \"Coupling between tethering and fusion machinery not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended the ubiquitin-adaptor function to NF-\\u03baB p65/RelA and linked it to suppression of pro-angiogenic gene expression and tumor growth.\",\n      \"evidence\": \"Ectopic TMF1 expression, ubiquitination assays, and xenograft mouse model with expression profiling\",\n      \"pmids\": [\"19330832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; physiological stress conditions driving p65 degradation not fully defined\", \"Selectivity between STAT3 and p65 substrates unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established the in vivo essentiality of TMF1 for spermiogenesis through a knockout, tying vesicle homing to acrosome biogenesis.\",\n      \"evidence\": \"TMF1-null mouse with histology, immunofluorescence, and electron microscopy\",\n      \"pmids\": [\"20691678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular tether linking pro-acrosomal vesicles to the nuclear surface not identified\", \"Did not separate trafficking defect from downstream maturation failures\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Positioned TMF1 within a tethering architecture by showing the COG complex and Rab GTPases bind both golgin ends, supporting a model that bridges vesicle to target membrane.\",\n      \"evidence\": \"Interaction-domain mapping and binding to COPI-stripped Golgi membranes\",\n      \"pmids\": [\"23239882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether bridging directly precedes fusion not demonstrated in vivo\", \"Stoichiometry and order of assembly with COG/Rab unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed that TMF1-dependent p65/NF-\\u03baB activity governs colonic MUC2 mucin expression, connecting its ubiquitin role to mucosal physiology.\",\n      \"evidence\": \"TMF1 knockout mouse with DSS colitis, expression analysis, and bacterial colonization assays\",\n      \"pmids\": [\"22553199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration that p65 degradation (vs other effects) drives MUC2 change incomplete\", \"Cell-autonomy in intestinal epithelium not isolated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked TMF1 loss to systemic endocrine disruption, indicating its testicular function extends beyond germ cells to hormone homeostasis.\",\n      \"evidence\": \"TMF1 knockout mouse with hormone measurements and testosterone rescue\",\n      \"pmids\": [\"23000399\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether reduced testosterone is a primary or secondary consequence unresolved\", \"Molecular pathway connecting TMF1 to Leydig cell function unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mechanistically explained the spermiogenesis defect by showing TMF1 reorients the Golgi via a microtubule-interacting domain to position vesicles at the nucleus.\",\n      \"evidence\": \"TMF1 knockout mouse with light and electron microscopy, domain analysis, and microtubule co-sedimentation\",\n      \"pmids\": [\"26701263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the MIT domain coordinates with Rab6 tethering not integrated\", \"Regulation of dynamic cis-to-trans relocalization unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Generalized the trafficking role to metabolism by showing TMF1 is required for insulin-responsive GLUT4 vesicle formation and glucose homeostasis.\",\n      \"evidence\": \"TMF1 knockout myoblasts and mice with GLUT4 trafficking, glucose uptake, and blood glucose assays\",\n      \"pmids\": [\"33475194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GLUT4 vesicle formation uses the same Rab6/COG machinery as retrograde transport not tested\", \"Mechanism of insulin-driven TMF1 upregulation unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMF1 partitions and switches between its Golgi-tethering role and its cytoplasmic ubiquitin-adaptor / nuclear coactivator roles, and whether these functions share regulatory inputs, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating Rab6 coiled-coil, MIT, and BC-box domains\", \"Signals controlling subcellular relocalization across functions not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 4, 7]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2, 4, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 4, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"Golgi golgin tether\"],\n    \"partners\": [\"RAB6\", \"ELOC\", \"STAT3\", \"RELA\", \"FER\", \"AR\", \"SMARCA2\", \"SMARCA4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}