Trans-Golgi golgin (TATA element modulatory factor 1 / ARA160). A long coiled-coil peripheral membrane protein recruited to the Golgi rim via a C-terminal Rab6-binding region, where it acts as a vesicle-tethering factor. Captures intra-Golgi transport vesicles via a conserved N-terminal motif (M-S-W-L/F, shared with the related intra-Golgi golgins GMAP-210 and golgin-84) and cooperates with the COG complex to dock retrograde vesicles. Required for Rab6-dependent retrograde transport from endosomes to the trans-Golgi network and from the Golgi to the ER (Shiga-toxin trafficking, GalNAc-T2 retention). Loss in mouse and Drosophila causes male-sterility acrosome biogenesis defects and altered Golgi-derived mucin glycosylation, consistent with a primary role in Golgi vesicle traffic. Despite the historical name and a small set of late-1990s overexpression studies that suggested a moonlighting role as a TBP-binding/androgen-receptor coactivator and a BC-box adaptor that targets STAT3 for proteasomal degradation, the bulk of mechanistically validated biology is at the Golgi and not in transcription.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005794 Golgi apparatus | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PAINT. TMF1 is a canonical golgin and the Golgi rim is its primary, conserved localization (UniProt SUBCELLULAR LOCATION; PMID:17698061; PMID:23239882; PMID:28122620). Accept as core localization. Supporting Evidence: PMID:17698061 TMF signal surrounded Rab6-positive Golgi structures and immunoelectron microscopy revealed that TMF is concentrated at the budding structures localized at the tips of cisternae. |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA from PAINT. TMF1 mediates Rab6-dependent retrograde transport from Golgi to ER (PMID:17698061), so it is transiently associated with ER-directed retrograde carriers, but it is not a steady-state ER-resident protein. Microscopy consistently shows the trans-Golgi rim, not the ER, as the primary localization. The annotation likely reflects over-propagation of yeast/fungal homolog data. Mark as over-annotated. |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from UniProt SubCell mapping. TMF1 is a peripheral Golgi-membrane protein concentrated at the tips of cisternae (UniProt SUBCELLULAR LOCATION; PMID:17698061). More precise than the bare Golgi apparatus annotation. Accept as core. Supporting Evidence: PMID:17698061 TMF is concentrated at the budding structures localized at the tips of cisternae. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | Summary: IEA from UniProt SubCell mapping. A nuclear pool of one TMF isoform was reported (PMID:12044884), but the dominant localization in every cell type examined is the Golgi (PMID:15467733 explicitly describes TMF/ARA160 as a Golgi-resident protein). The IEA over-emphasizes a minor, isoform-restricted fraction; the primary biology of the protein is not nuclear. Mark as over-annotated. Supporting Evidence: PMID:12044884 TMF isoforms differentially localize in the Golgi apparatus and the nucleus. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IEA from UniProt SubCell mapping. Generic parent term subsumed by the more specific Golgi membrane / cytosol annotations. Keep as non-core. |
| GO:0005515 protein binding | IPI PMID:20195357 A comprehensive resource of interacting protein regions for ... | MARK AS OVER ANNOTATED | Summary: High-throughput mRNA-display interactome screen reporting TMF1-NR3C1 binding. "Protein binding" is uninformative per project curation guidelines (CLAUDE.md). The relevant biology (interactions with Rab6, COG, AR, STAT3, FER, Elongin) is captured by more specific annotations. Mark as over-annotated. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: High-throughput Y2H reference map (HuRI). Reports binding to CMTM5 isoform Q96DZ9-2; no functional follow-up. Uninformative MF per project guidelines. Mark as over-annotated. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA via Ensembl ortholog transfer from mouse Tmf1 (UniProtKB:B9EKI3). Same concern as the IBA ER annotation: TMF1 mediates retrograde traffic to the ER but is not an ER-resident protein. Mark as over-annotated. |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000107 | ACCEPT | Summary: IEA via Ensembl ortholog transfer from mouse Tmf1. Redundant with the direct human IBA/IDA Golgi annotations but still correct. Accept. |
| GO:0061136 regulation of proteasomal protein catabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA via Ensembl ortholog transfer from mouse Tmf1. Reflects PMID:15467733, which showed that the BC-box motif of TMF/ARA160 mediates its binding to Elongin C and that ectopic expression in serum-starved C2C12 cells drives Stat3 ubiquitination and proteasomal degradation. This is a discrete, mechanistically supported moonlighting activity at the Golgi cytoplasmic face but is not the protein's core function. Keep as non-core. Supporting Evidence: PMID:15467733 Amino-acid sequence analysis identified a BC-box element in TMF/ARA160 that mediated the binding of this protein to elongin C. Ectopic expression of TMF/ARA160 in serum-starved C2C12 cells drove the ubiquitination and proteasomal degradation of Stat3. |
| GO:0005794 Golgi apparatus | IDA GO_REF:0000052 | ACCEPT | Summary: IDA from Human Protein Atlas immunofluorescence. Direct experimental confirmation of Golgi localization. Accept as core. |
| GO:0003713 transcription coactivator activity | IDA PMID:10428808 Isolation and characterization of ARA160 as the first androg... | MARK AS OVER ANNOTATED | Summary: IDA based on a single 1999 transient-transfection / reporter study in PC-3 cells. The same paper notes that a Gal4-DBD fusion to TMF1 fails to transactivate reporter genes (data not shown), which is inconsistent with a bona fide transcription coactivator (GO:0003713) sensu stricto - the authors propose that TMF acts only together with the AF-1 domain of steroid receptors. The mechanistically established function of TMF1 is at the Golgi (PMID:17698061; PMID:23239882; PMID:28122620); TMF1 has no DNA-binding domain (its "TMF_DNA_bd"/"TMF_TATA_bd" Pfam domains are operationally defined from the original 1992 HIV-1 LTR study and have not been validated as endogenous DNA-binding modules). The Pharos target development level is "Tbio" (no validated function). Down-rate from a core MF; flag as over-annotation pending orthogonal validation, but do not delete outright because a low-level moonlighting role at the AR cannot be formally excluded. Supporting Evidence: PMID:10428808 Transient transfection assays demonstrated that ARA160 might function as a coactivator for AR-mediated transactivation in human prostate cancer PC-3 cells. |
| GO:0030521 androgen receptor signaling pathway | IDA PMID:10428808 Isolation and characterization of ARA160 as the first androg... | MARK AS OVER ANNOTATED | Summary: IDA from the same single 1999 overexpression study (PMID:10428808). The mouse TMF-/- testosterone/spermatogenesis phenotype (PMID:23000399) is more compatible with disrupted Leydig cell secretion / Golgi-dependent acrosome biogenesis than with cell-autonomous loss of an AR coregulator. Mark as over-annotated. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:10428808 Isolation and characterization of ARA160 as the first androg... | MARK AS OVER ANNOTATED | Summary: IDA inferred from the same single transient transfection assay on an AR-responsive reporter in PC-3 cells. Not validated by orthogonal assays (ChIP-seq, KO RNA-seq) or independent groups. Mark as over-annotated. |
| GO:0050681 nuclear androgen receptor binding | IPI PMID:10428808 Isolation and characterization of ARA160 as the first androg... | KEEP AS NON CORE | Summary: IPI based on far-Western blotting and co-immunoprecipitation between AR N-terminal peptide and TMF1/ARA160 (PMID:10428808). The physical interaction is reproducibly observed, but in the context of TMF1's overall biology the AR-binding role is a moonlighting feature of a Golgi protein, not a core function. Keep as non-core. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6811431 | KEEP AS NON CORE | Summary: TAS from Reactome "RAB6:GTP binds the GARP and COG complexes, t-SNAREs and endosome-derived vesicles". Reflects the Reactome cytosolic-pool placeholder for tethering factors. The diffuse cytoplasmic distribution observed under low-serum conditions (PMID:15467733) is real but the protein is concentrated at Golgi membranes. Keep as non-core. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6814091 | KEEP AS NON CORE | Summary: TAS from Reactome "ARL1 recruits TGN Golgin homodimers". Same comment as the previous cytosol annotation - reflects the Reactome cytosolic-pool placeholder. Keep as non-core. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6814682 | KEEP AS NON CORE | Summary: TAS from Reactome "Fusion of early-endosome derived vesicles at the TGN". Same comment - Reactome placeholder for the cytosolic tethering pool. Keep as non-core. |
| GO:0061136 regulation of proteasomal protein catabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from manual transfer of mouse Tmf1 (UniProtKB:B9EKI3). Reflects PMID:15467733 (TMF/ARA160 BC-box-Elongin C-mediated Stat3 ubiquitination). Mechanistically supported but is a moonlighting activity of the Golgi pool, not the core function. Keep as non-core. Supporting Evidence: PMID:15467733 Amino-acid sequence analysis identified a BC-box element in TMF/ARA160 that mediated the binding of this protein to elongin C. |
| GO:7770062 vesicle membrane tethering activity | NAS | NEW | Summary: Added to align core_functions with existing annotations. Captures the vesicle-tethering bridging activity of TMF1. GO has now minted GO:7770062 vesicle membrane tethering activity (the MF formerly requested here as a proposed new term), which replaces the generic GO:0060090 molecular adaptor activity used previously and the obsoleted BP GO:0099041 vesicle tethering to Golgi. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:28122620 When relocated to mitochondria, TMF captures intra-Golgi transport vesicles. file:human/TMF1/TMF1-deep-research-falcon.md TMF1 is best supported as a **Golgi tether/scaffold (golgin) and Rab6 effector** that contributes to Golgi ribbon morphology and to specific retrograde trafficking pathways. |
| GO:0006891 intra-Golgi vesicle-mediated transport | NAS | NEW | Summary: Added to align core_functions with existing annotations. Supported by vesicle-capture assays (PMID:28122620), COG-TMF tethering model (PMID:23239882), and Drosophila in vivo data (PMID:36103876). Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:23239882 We find that the COG complex interacts with two different Rabs in addition to each end of the golgin "TATA element modulatory factor" (TMF). |
| GO:0031267 small GTPase binding | NAS | NEW | Summary: Added to align core_functions with existing annotations. Captures the Rab6-GTP binding activity that recruits TMF1 to the trans-Golgi. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:17698061 TMF signal surrounded Rab6-positive Golgi structures. |
| GO:0042147 retrograde transport, endosome to Golgi | NAS | NEW | Summary: Added to align core_functions with existing annotations. TMF1 knockdown blocks Rab6-dependent retrograde transport of Shiga toxin from early/recycling endosomes to the trans-Golgi network (PMID:17698061). Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:17698061 The knockdown of either TMF or Rab6 by RNA interference blocked retrograde transport of endocytosed Shiga toxin from early/recycling endosomes to the trans-Golgi network. |
| GO:0006890 retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum | NAS | NEW | Summary: Added to align core_functions with existing annotations. PMID:17698061 establishes a role for TMF1 in Rab6-dependent Golgi-to-ER retrograde traffic. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:17698061 critical roles for TMF in two Rab6-dependent retrograde transport processes - one from endosomes to the Golgi and the other from the Golgi to the ER. |
Loading supporting content…
Download this section (compressed HTML)Q: Is the apparent transcription-coactivator activity of TMF1 (PMID:10428808) a true endogenous function or an overexpression artefact? Has it been validated by AR ChIP-seq or by RNA-seq of TMF1 KO prostate cells?
Suggested experts: GO Consortium (R. Lovering, A. Lock, ARUK-UCL), Steroid-receptor coactivator field (e.g. C. Chang lab)
Q: Does any tissue/cell type maintain a functional nuclear pool of TMF1, and if so what is its target-gene repertoire?
Suggested experts: SWI/SNF / chromatin-remodeling researchers, Neuro-andrology / prostate-cancer transcription researchers
Experiment: ChIP-seq for endogenous TMF1 in LNCaP/22Rv1 (AR-positive prostate) cells +/- DHT, paired with AR ChIP-seq. Compute peak overlap with AR cistrome and motif enrichment. Validate top putative TMF1 chromatin sites by ChIP-qPCR after TMF1 knockdown. Couple with RNA-seq of TMF1 KO cells +/- DHT to ask whether AR target genes are preferentially affected.
Hypothesis: If TMF1 is an endogenous AR coactivator, AR-target promoters should be enriched among TMF1 ChIP-seq peaks; if not, TMF1 should occupy few or no chromatin sites and the existing IDA annotations to GO:0003713/GO:0045944/GO:0030521 should be retired rather than merely demoted.
Type: Genome-wide ChIP-seq for TMF1 in AR-positive prostate cells
Experiment: Generate stable lines expressing TurboID-TMF1 (full length and isoform P82094-2) at near-endogenous level. Perform 10-min biotin labelling, streptavidin enrichment and TMT-MS3 quantitation. Compare with TurboID-only and a TurboID-Rab6 control. Quantify the relative enrichment of trafficking vs. chromatin/transcription GO categories.
Hypothesis: TMF1 BioID interactomes will be dominated by Golgi-tethering machinery (Rab6, COG subunits, intra-Golgi cargo, glycosyltransferases) rather than by transcription/chromatin factors, reinforcing that the core function is at the Golgi.
Type: Quantitative proximity labelling (BioID/TurboID) at the trans-Golgi rim and at chromatin
Experiment: Cryo-electron tomography of vitrified Golgi-membrane-enriched HeLa extracts immuno-labelled for TMF1, with sub-tomogram averaging of TMF1-decorated vesicle-Golgi contacts. Compare WT to a TMF1 N-terminal motif (M-S-W-L/F) mutant and to Rab6-knockdown.
Hypothesis: TMF1 will be observed as elongated coiled-coil bridges between intra-Golgi transport vesicles and cisternal rims, with Rab6-binding ends anchored at the Golgi, providing a structural counterpart of the mitochondrial-relocation capture assay (PMID:28122620).
Type: Cryo-ET of TMF1 at intra-Golgi vesicle tethering sites
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)