{"gene":"TGFBRAP1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1990,"finding":"Yeast VPS3 (ortholog of TGFBRAP1) encodes a 117 kD hydrophilic cytoplasmic protein required for vacuolar protein sorting (carboxypeptidase Y) and vacuolar acidification; loss-of-function causes defective vacuolar morphology and impaired vacuolar segregation during the cell cycle, demonstrating its role in endosomal/vacuolar biogenesis.","method":"Gene cloning, deletion mutant analysis, temperature-conditional allele, fluorescence microscopy of vacuolar morphology, CPY sorting assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotypes (vacuolar sorting, acidification, morphology, segregation), multiple orthogonal assays, foundational study","pmids":["2202738"],"is_preprint":false},{"year":2010,"finding":"TGFBRAP1 (TRAP1/TGFBRAP1) is essential for early embryonic development in mice; homozygous knockout results in lethality either before the blastula stage or during gastrulation, demonstrating a non-redundant in vivo role for this TGF-β signaling adaptor.","method":"Mouse knockout generation, embryonic lethal phenotyping","journal":"Immunobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO with defined lethal phenotype, single lab, phenotype described but molecular pathway details limited in abstract","pmids":["20961651"],"is_preprint":false},{"year":2013,"finding":"Human TGFBRAP1 (hVps39-2/TRAP1) directly interacts with GTP-loaded Rab5 in vitro, co-localizes with co-expressed Rab5 in mammalian cells, and is proposed as the missing Vps3 subunit of the human CORVET endosomal tethering complex, acting as an effector of Rab5.","method":"In vitro Rab5-GTP binding assay (pulldown), co-localization by fluorescence microscopy in yeast and HEK293 cells, functional complementation assay in yeast","journal":"Cellular logistics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro binding assay plus co-localization in two cell systems, single lab but multiple orthogonal methods","pmids":["25750764"],"is_preprint":false},{"year":2013,"finding":"In yeast, the N-terminal domains of the CORVET-specific subunits Vps3 and Vps8 are required for endosomal localization and function of the CORVET complex; loss of both N-terminal domains mislocalizes CORVET to the cytosol and impairs endocytic protein sorting, though complex assembly is maintained.","method":"Truncation mutagenesis of Vps3 and Vps8, subcellular localization by fluorescence microscopy, endocytic protein sorting assay, CORVET assembly analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis with defined localization and functional readouts, multiple orthogonal assays in one rigorous study","pmids":["23840658"],"is_preprint":false},{"year":2018,"finding":"Mammalian Vps3 (TGFBRAP1 ortholog) and Vps8, as CORVET-specific subunits, localize to Rab4-positive recycling vesicles and co-localize with the CHEVI complex on Rab11-positive recycling endosomes; depletion of Vps3 or Vps8 delays delivery of internalised integrins to recycling endosomes and their return to the plasma membrane, causing defects in integrin-dependent cell adhesion, spreading, focal adhesion formation, and cell migration.","method":"siRNA depletion, fluorescence co-localization microscopy, integrin trafficking assays, cell adhesion/spreading/migration assays, focal adhesion staining","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-localization, depletion with multiple orthogonal functional readouts (trafficking, adhesion, migration, focal adhesions), published in high-quality journal","pmids":["29476049"],"is_preprint":false},{"year":2008,"finding":"Yeast Vps3 has an epistatic relationship with the multidrug transporter Pdr5; a double vps3/pdr5 deletion is no more drug-sensitive than either single mutant, yet vps3 mutation reduces rhodamine 6G efflux without affecting Pdr5 membrane localization or ATPase activity, suggesting Vps3 is required for routing xenobiotic compounds to plasma membrane transporters.","method":"Genetic epistasis (double deletion mutant), multidrug resistance phenotyping, subcellular fractionation, ATPase activity assay, rhodamine 6G efflux assay","journal":"Molecular genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus biochemical characterization of Pdr5 activity and localization, single lab with multiple methods","pmids":["18327613"],"is_preprint":false},{"year":2019,"finding":"TGFBRAP1 (CHIT1 interaction study, RETRACTED 2024): CHIT1 was reported to interact with TGFBRAP1 and to use this interaction to enhance TGF-β1 signaling and inhibit SMAD7 induction in pulmonary fibrosis. NOTE: The original paper (PMID 31085559) was subsequently retracted (PMID 39209538); this finding should be regarded as unreliable.","method":"Co-immunoprecipitation, knockdown experiments, TGF-β signaling assays — RETRACTED","journal":"Life science alliance","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, paper subsequently retracted; finding is unreliable","pmids":["31085559","39209538"],"is_preprint":false}],"current_model":"TGFBRAP1 (also known as VPS3) encodes a cytoplasmic/endosomal protein that functions as the CORVET-specific subunit responsible for Rab5-GTP binding and endosomal tethering: its N-terminal domain is required for endosomal localization and CORVET-dependent protein sorting, while in mammalian cells Vps3/TGFBRAP1 additionally controls vesicular transport from early to recycling endosomes to support integrin recycling, cell adhesion, and migration; in vivo, the protein is essential for early mouse embryogenesis, consistent with its proposed role as a modulator of TGF-β/Smad signaling."},"narrative":{"mechanistic_narrative":"TGFBRAP1 (VPS3) is the metazoan ortholog of yeast Vps3 and functions as a CORVET-specific endosomal tethering subunit that links Rab GTPase recognition to vesicular protein sorting [PMID:2202738, PMID:25750764, PMID:29476049]. The founding yeast studies established Vps3 as a cytoplasmic protein required for vacuolar protein sorting, vacuolar acidification, and inheritance of vacuolar morphology during the cell cycle [PMID:2202738], and showed that the N-terminal domains of the CORVET-specific subunits Vps3 and Vps8 are required for endosomal localization of the complex without affecting its assembly [PMID:23840658]. In human cells, TGFBRAP1 directly binds GTP-loaded Rab5 and co-localizes with Rab5, identifying it as the missing Vps3 subunit and a Rab5 effector of the human CORVET complex [PMID:25750764]. Beyond early-endosome tethering, mammalian Vps3 localizes to Rab4- and Rab11-positive recycling compartments and is required for delivery of internalized integrins to recycling endosomes and their return to the plasma membrane, so that its depletion impairs integrin-dependent adhesion, spreading, focal adhesion formation, and migration [PMID:29476049]. The protein is essential in vivo, as homozygous knockout mice die before the blastula stage or during gastrulation [PMID:20961651]. A reported interaction with CHIT1 in TGF-β/SMAD7 signaling derives from a retracted study and is not a reliable part of the mechanistic picture [PMID:31085559, PMID:39209538].","teleology":[{"year":1990,"claim":"Established the founding role of Vps3 by showing a single gene is required for delivery of vacuolar hydrolases, vacuolar acidification, and vacuolar inheritance, placing it at the core of endosomal/vacuolar biogenesis.","evidence":"Gene cloning, deletion and temperature-conditional alleles, CPY sorting assay, and vacuolar morphology microscopy in yeast","pmids":["2202738"],"confidence":"High","gaps":["No molecular partners or complex membership defined","Mechanism connecting Vps3 to sorting and acidification not resolved"]},{"year":2008,"claim":"Extended Vps3 function to xenobiotic handling by showing it is required to route compounds to plasma-membrane multidrug transporters rather than to regulate the transporter itself.","evidence":"Genetic epistasis with PDR5, rhodamine 6G efflux, subcellular fractionation, and Pdr5 ATPase assays in yeast","pmids":["18327613"],"confidence":"Medium","gaps":["Direct molecular mechanism of routing not defined","Relevance to mammalian Vps3 untested"]},{"year":2010,"claim":"Demonstrated a non-redundant in vivo requirement for the mammalian gene by showing knockout causes early embryonic lethality.","evidence":"Mouse knockout generation and embryonic phenotyping","pmids":["20961651"],"confidence":"Medium","gaps":["Molecular pathway underlying lethality not established","Cell-type and stage-specific requirements not dissected","Link between endosomal function and embryonic phenotype unresolved"]},{"year":2013,"claim":"Identified human TGFBRAP1 as the missing CORVET-specific Vps3 subunit and a Rab5 effector by demonstrating direct GTP-Rab5 binding and Rab5 co-localization.","evidence":"In vitro Rab5-GTP pulldown, co-localization in yeast and HEK293 cells, and yeast complementation","pmids":["25750764"],"confidence":"Medium","gaps":["Reconstitution of intact human CORVET not shown","Endogenous (untagged) complex composition not validated"]},{"year":2013,"claim":"Localized the determinant for CORVET endosomal targeting to the N-terminal domains of Vps3 and Vps8, separating membrane recruitment from complex assembly.","evidence":"Truncation mutagenesis with localization microscopy, endocytic sorting assays, and CORVET assembly analysis in yeast","pmids":["23840658"],"confidence":"High","gaps":["Structural basis of N-terminal membrane recruitment not defined","Conservation of the N-terminal requirement in mammals not tested"]},{"year":2018,"claim":"Expanded mammalian Vps3 function from early-endosome tethering to recycling-endosome transport, linking it directly to integrin trafficking and cell adhesion/migration.","evidence":"siRNA depletion, reciprocal co-localization with Rab4/Rab11/CHEVI, integrin trafficking, adhesion, spreading, focal adhesion, and migration assays","pmids":["29476049"],"confidence":"High","gaps":["Whether recycling role uses CORVET or a distinct complex unclear","Cargo selectivity beyond integrins not mapped"]},{"year":null,"claim":"How the endosomal/recycling function of TGFBRAP1 connects mechanistically to its proposed role in TGF-β/Smad signaling and to the embryonic lethality phenotype remains unresolved.","evidence":"No direct mechanistic evidence in the available corpus (the CHIT1/TGF-β interaction report is retracted)","pmids":[],"confidence":"Low","gaps":["No validated TGF-β signaling mechanism for TGFBRAP1 in the corpus","Tissue-level cause of embryonic lethality undefined","Direct human CORVET cargo repertoire incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,3,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005773","term_label":"vacuole","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[4]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,3,4]}],"complexes":["CORVET"],"partners":["RAB5","VPS8","RAB4","RAB11"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WUH2","full_name":"Transforming growth factor-beta receptor-associated protein 1","aliases":[],"length_aa":860,"mass_kda":97.2,"function":"Plays a role in the TGF-beta/activin signaling pathway. It associates with inactive heteromeric TGF-beta and activin receptor complexes, mainly through the type II receptor, and is released upon activation of signaling. May recruit SMAD4 to the vicinity of the receptor complex and facilitate its interaction with receptor-regulated Smads, such as SMAD2 Plays a role in vesicle-mediated protein trafficking of the endocytic membrane transport pathway. Believed to act as a component of the putative CORVET endosomal tethering complexes which is proposed to be involved in the Rab5-to-Rab7 endosome conversion probably implicating MON1A/B, and via binding SNAREs and SNARE complexes to mediate tethering and docking events during SNARE-mediated membrane fusion. The CORVET complex is proposed to function as a Rab5 effector to mediate early endosome fusion probably in specific endosome subpopulations (PubMed:25266290). Functions predominantly in APPL1-containing endosomes and in degradative but not recycling trafficking of endocytosed cargo (PubMed:25266290)","subcellular_location":"Cytoplasm; Early endosome","url":"https://www.uniprot.org/uniprotkb/Q8WUH2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TGFBRAP1","classification":"Not Classified","n_dependent_lines":199,"n_total_lines":1208,"dependency_fraction":0.16473509933774835},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000135966","cell_line_id":"CID001788","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"VPS18","stoichiometry":10.0},{"gene":"VPS8","stoichiometry":10.0},{"gene":"VPS11","stoichiometry":4.0},{"gene":"RPL32","stoichiometry":0.2},{"gene":"VPS16","stoichiometry":0.2},{"gene":"VPS33A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001788","total_profiled":1310},"omim":[{"mim_id":"612188","title":"VPS39 SUBUNIT OF HOPS COMPLEX; VPS39","url":"https://www.omim.org/entry/612188"},{"mim_id":"611919","title":"RIBOSOMAL OXYGENASE 1; RIOX1","url":"https://www.omim.org/entry/611919"},{"mim_id":"606237","title":"TRANSFORMING GROWTH FACTOR-BETA RECEPTOR-ASSOCIATED PROTEIN 1; TGFBRAP1","url":"https://www.omim.org/entry/606237"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TGFBRAP1"},"hgnc":{"alias_symbol":["TRAP-1","TRAP1","VPS3"],"prev_symbol":[]},"alphafold":{"accession":"Q8WUH2","domains":[{"cath_id":"-","chopping":"690-791","consensus_level":"medium","plddt":84.2441,"start":690,"end":791},{"cath_id":"-","chopping":"810-847","consensus_level":"high","plddt":80.8363,"start":810,"end":847}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUH2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUH2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUH2-F1-predicted_aligned_error_v6.png","plddt_mean":87.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TGFBRAP1","jax_strain_url":"https://www.jax.org/strain/search?query=TGFBRAP1"},"sequence":{"accession":"Q8WUH2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WUH2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WUH2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUH2"}},"corpus_meta":[{"pmid":"21878357","id":"PMC_21878357","title":"TRAP-1, the mitochondrial Hsp90.","date":"2011","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/21878357","citation_count":146,"is_preprint":false},{"pmid":"17853063","id":"PMC_17853063","title":"Tumor necrosis factor-associated protein 1 (TRAP-1) protects cells from oxidative stress and apoptosis.","date":"2007","source":"Stress (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/17853063","citation_count":144,"is_preprint":false},{"pmid":"24731398","id":"PMC_24731398","title":"Mitochondrial oxidative phosphorylation TRAP(1)ped in tumor cells.","date":"2014","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24731398","citation_count":111,"is_preprint":false},{"pmid":"19948822","id":"PMC_19948822","title":"Cytoprotective mitochondrial chaperone TRAP-1 as a novel molecular target in localized and metastatic prostate cancer.","date":"2009","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19948822","citation_count":104,"is_preprint":false},{"pmid":"2202738","id":"PMC_2202738","title":"Molecular analysis of the yeast VPS3 gene and the role of its product in vacuolar protein sorting and vacuolar segregation during the cell cycle.","date":"1990","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/2202738","citation_count":102,"is_preprint":false},{"pmid":"11010808","id":"PMC_11010808","title":"Immunoelectron microscopy provides evidence that tumor necrosis factor receptor-associated protein 1 (TRAP-1) is a mitochondrial protein which also localizes at specific extramitochondrial sites.","date":"2000","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/11010808","citation_count":79,"is_preprint":false},{"pmid":"25088416","id":"PMC_25088416","title":"Deletion of the mitochondrial chaperone TRAP-1 uncovers global reprogramming of metabolic networks.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25088416","citation_count":58,"is_preprint":false},{"pmid":"29476049","id":"PMC_29476049","title":"Vps3 and Vps8 control integrin trafficking from early to recycling endosomes and regulate integrin-dependent functions.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29476049","citation_count":41,"is_preprint":false},{"pmid":"23139614","id":"PMC_23139614","title":"Correlation between mitochondrial TRAP-1 expression and lymph node metastasis in colorectal cancer.","date":"2012","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/23139614","citation_count":38,"is_preprint":false},{"pmid":"20961651","id":"PMC_20961651","title":"The TGF-β signaling modulators TRAP1/TGFBRAP1 and VPS39/Vam6/TLP are essential for early embryonic development.","date":"2010","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/20961651","citation_count":32,"is_preprint":false},{"pmid":"31085559","id":"PMC_31085559","title":"Chitinase 1 regulates pulmonary fibrosis by modulating TGF-β/SMAD7 pathway via TGFBRAP1 and FOXO3.","date":"2019","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/31085559","citation_count":29,"is_preprint":false},{"pmid":"23418473","id":"PMC_23418473","title":"Effects of TRAP-1-like protein (TLP) gene on collagen synthesis induced by TGF-β/Smad signaling in human dermal fibroblasts.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23418473","citation_count":29,"is_preprint":false},{"pmid":"25750764","id":"PMC_25750764","title":"The Vps39-like TRAP1 is an effector of Rab5 and likely the missing Vps3 subunit of human CORVET.","date":"2014","source":"Cellular logistics","url":"https://pubmed.ncbi.nlm.nih.gov/25750764","citation_count":25,"is_preprint":false},{"pmid":"12372338","id":"PMC_12372338","title":"Unique behavior of a dictyostelium homologue of TRAP-1, coupling with differentiation of D. discoideum cells.","date":"2002","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/12372338","citation_count":21,"is_preprint":false},{"pmid":"23840658","id":"PMC_23840658","title":"The N-terminal domains of Vps3 and Vps8 are critical for localization and function of the CORVET tethering complex on endosomes.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23840658","citation_count":19,"is_preprint":false},{"pmid":"15652354","id":"PMC_15652354","title":"Involvement of the TRAP-1 homologue, Dd-TRAP1, in spore differentiation during Dictyostelium development.","date":"2004","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/15652354","citation_count":16,"is_preprint":false},{"pmid":"36828164","id":"PMC_36828164","title":"The mitochondrial chaperone TRAP-1 regulates the glutamine metabolism in tumor cells.","date":"2023","source":"Mitochondrion","url":"https://pubmed.ncbi.nlm.nih.gov/36828164","citation_count":11,"is_preprint":false},{"pmid":"29535540","id":"PMC_29535540","title":"Hepatitis C virus core impacts expression of miR122 and miR204 involved in carcinogenic progression via regulation of TGFBRAP1 and HOTTIP expression.","date":"2018","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29535540","citation_count":10,"is_preprint":false},{"pmid":"35025420","id":"PMC_35025420","title":"Development of Nanocarrier-Based Mitochondrial Chaperone, TRAP-1 Inhibitor to Combat Cancer Metabolism.","date":"2020","source":"ACS applied bio materials","url":"https://pubmed.ncbi.nlm.nih.gov/35025420","citation_count":9,"is_preprint":false},{"pmid":"33261638","id":"PMC_33261638","title":"Identification and characterization of a Babesia bigemina thrombospondin-related superfamily member, TRAP-1: a novel antigen containing neutralizing epitopes involved in merozoite invasion.","date":"2020","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/33261638","citation_count":9,"is_preprint":false},{"pmid":"33007376","id":"PMC_33007376","title":"The effects of FAR1 and TGFBRAP1 on the proliferation and apoptosis of follicular granulosa cells in goose (Anser cygnoides).","date":"2020","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/33007376","citation_count":8,"is_preprint":false},{"pmid":"33090425","id":"PMC_33090425","title":"Protective mechanisms of piperine against acetaminophen-induced hepatotoxicity may be mediated through TGFBRAP1.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33090425","citation_count":8,"is_preprint":false},{"pmid":"30461200","id":"PMC_30461200","title":"The variant at TGFBRAP1 is significantly associated with type 2 diabetes mellitus and affects diabetes-related miRNA expression.","date":"2018","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30461200","citation_count":7,"is_preprint":false},{"pmid":"25856002","id":"PMC_25856002","title":"Polymorphisms of the TGFBRAP1 gene in relation to blood pressure variability and plasma TGF-β1.","date":"2015","source":"Clinical and experimental hypertension (New York, N.Y. : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/25856002","citation_count":5,"is_preprint":false},{"pmid":"37920489","id":"PMC_37920489","title":"Mechanism of Nrf2/miR338-3p/TRAP-1 pathway involved in hyperactivation of synovial fibroblasts in patients with osteoarthritis.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/37920489","citation_count":5,"is_preprint":false},{"pmid":"31534460","id":"PMC_31534460","title":"The Variant at TGFBRAP1 but Not TGFBR2 Is Associated with Antituberculosis Drug-Induced Liver Injury.","date":"2019","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/31534460","citation_count":4,"is_preprint":false},{"pmid":"18327613","id":"PMC_18327613","title":"Pdr5-mediated multidrug resistance requires the CPY-vacuolar sorting protein Vps3: are xenobiotic compounds routed from the vacuole to plasma membrane transporters for efflux?","date":"2008","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/18327613","citation_count":4,"is_preprint":false},{"pmid":"37165028","id":"PMC_37165028","title":"Analysis and functional relevance of the chaperone TRAP-1 interactome in the metabolic regulation and mitochondrial integrity of cancer cells.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37165028","citation_count":4,"is_preprint":false},{"pmid":"37037591","id":"PMC_37037591","title":"Correction: Chitinase 1 regulates pulmonary fibrosis by modulating TGF-β/SMAD7 pathway via TGFBRAP1 and FOXO3.","date":"2023","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/37037591","citation_count":1,"is_preprint":false},{"pmid":"39209538","id":"PMC_39209538","title":"Retraction: Chitinase 1 regulates pulmonary fibrosis by modulating TGF-β/SMAD7 pathway via TGFBRAP1 and FOXO3.","date":"2024","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/39209538","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.23.619961","title":"Activating p53  <sup>Y220C</sup>  with a Mutant-Specific Small Molecule","date":"2024-10-28","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.23.619961","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16643,"output_tokens":2828,"usd":0.046175,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8790,"output_tokens":2485,"usd":0.053038,"stage2_stop_reason":"end_turn"},"total_usd":0.099213,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"I need to carefully classify each paper before extracting discoveries.\n\n**Classification notes:**\n- Papers 1-7, 9, 17, 19, 28: These are about mitochondrial TRAP-1 (HSP90 family chaperone) — this is a DIFFERENT protein from TGFBRAP1/TRAP-1 (TGF-β receptor associated protein 1, the Smad4-binding adaptor). These are alias collisions — the mitochondrial TRAP-1 is encoded by TRAP1 gene (HSP90L), NOT TGFBRAP1.\n- Paper 5, 15, 27: About yeast VPS3 — TGFBRAP1 is also known as VPS3 (alias). Need to check if yeast Vps3 is an ortholog. The yeast VPS3 encodes a vacuolar protein sorting protein in the CORVET complex — this IS the yeast ortholog context given the alias VPS3 is listed for TGFBRAP1.\n- Paper 8: About mammalian Vps3/Vps8 in CORVET — likely relevant.\n- Paper 13: hVps39-2/TRAP1 characterized as effector of Rab5 — this seems to be about TGFBRAP1 (VPS3 alias).\n- Paper 10: About TRAP1/TGFBRAP1 in TGF-β signaling and embryo development — directly names TGFBRAP1.\n- Paper 11/29/30: About TGFBRAP1 interaction with CHIT1 — paper 30 is a retraction of paper 11/29. Should note retraction.\n- Paper 12: About TLP (VPS39 homolog) — this is a paralog, not TGFBRAP1.\n- Papers 14, 16: Dictyostelium Dd-TRAP1 — ortholog context matches HSP90 family, not TGFBRAP1.\n- Paper 18: miRNA/TGFBRAP1 expression study — not mechanistic enough.\n- Paper 20: Babesia TRAP-1 — symbol collision (parasite protein).\n- Paper 21: Goose TGFBRAP1 — ortholog with functional experiments on granulosa cells.\n- Paper 25: Nrf2/miR338-3p/TRAP-1 — the TRAP-1 here refers to mitochondrial TRAP-1 (HSP90), not TGFBRAP1.\n- Paper 31: TRAP-1 compound name — alias collision (small molecule named TRAP-1).\n- Papers 22, 23, 24, 26: TGFBRAP1 genetic/expression studies — mostly biomarker/association, not mechanistic.\n\n**Key papers for TGFBRAP1:**\n- Paper 10: TGFBRAP1 required for embryogenesis, TGF-β/Smad signaling\n- Paper 13: hVps39-2/TRAP1 (=TGFBRAP1) is Rab5 effector, putative CORVET subunit\n- Paper 5: Yeast VPS3 in vacuolar protein sorting\n- Paper 8: Mammalian Vps3 in integrin recycling via CORVET\n- Paper 15: Yeast Vps3 N-terminal domain required for CORVET localization\n- Paper 27: Yeast Vps3 epistatic relationship with Pdr5\n- Paper 11/29: TGFBRAP1 interacts with CHIT1 — RETRACTED (paper 30)\n- Paper 21: Goose TGFBRAP1 in granulosa cell apoptosis\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"Yeast VPS3 (ortholog of TGFBRAP1) encodes a 117 kD hydrophilic cytoplasmic protein required for vacuolar protein sorting (carboxypeptidase Y) and vacuolar acidification; loss-of-function causes defective vacuolar morphology and impaired vacuolar segregation during the cell cycle, demonstrating its role in endosomal/vacuolar biogenesis.\",\n      \"method\": \"Gene cloning, deletion mutant analysis, temperature-conditional allele, fluorescence microscopy of vacuolar morphology, CPY sorting assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotypes (vacuolar sorting, acidification, morphology, segregation), multiple orthogonal assays, foundational study\",\n      \"pmids\": [\"2202738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TGFBRAP1 (TRAP1/TGFBRAP1) is essential for early embryonic development in mice; homozygous knockout results in lethality either before the blastula stage or during gastrulation, demonstrating a non-redundant in vivo role for this TGF-β signaling adaptor.\",\n      \"method\": \"Mouse knockout generation, embryonic lethal phenotyping\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO with defined lethal phenotype, single lab, phenotype described but molecular pathway details limited in abstract\",\n      \"pmids\": [\"20961651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Human TGFBRAP1 (hVps39-2/TRAP1) directly interacts with GTP-loaded Rab5 in vitro, co-localizes with co-expressed Rab5 in mammalian cells, and is proposed as the missing Vps3 subunit of the human CORVET endosomal tethering complex, acting as an effector of Rab5.\",\n      \"method\": \"In vitro Rab5-GTP binding assay (pulldown), co-localization by fluorescence microscopy in yeast and HEK293 cells, functional complementation assay in yeast\",\n      \"journal\": \"Cellular logistics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro binding assay plus co-localization in two cell systems, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"25750764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In yeast, the N-terminal domains of the CORVET-specific subunits Vps3 and Vps8 are required for endosomal localization and function of the CORVET complex; loss of both N-terminal domains mislocalizes CORVET to the cytosol and impairs endocytic protein sorting, though complex assembly is maintained.\",\n      \"method\": \"Truncation mutagenesis of Vps3 and Vps8, subcellular localization by fluorescence microscopy, endocytic protein sorting assay, CORVET assembly analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with defined localization and functional readouts, multiple orthogonal assays in one rigorous study\",\n      \"pmids\": [\"23840658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mammalian Vps3 (TGFBRAP1 ortholog) and Vps8, as CORVET-specific subunits, localize to Rab4-positive recycling vesicles and co-localize with the CHEVI complex on Rab11-positive recycling endosomes; depletion of Vps3 or Vps8 delays delivery of internalised integrins to recycling endosomes and their return to the plasma membrane, causing defects in integrin-dependent cell adhesion, spreading, focal adhesion formation, and cell migration.\",\n      \"method\": \"siRNA depletion, fluorescence co-localization microscopy, integrin trafficking assays, cell adhesion/spreading/migration assays, focal adhesion staining\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-localization, depletion with multiple orthogonal functional readouts (trafficking, adhesion, migration, focal adhesions), published in high-quality journal\",\n      \"pmids\": [\"29476049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Yeast Vps3 has an epistatic relationship with the multidrug transporter Pdr5; a double vps3/pdr5 deletion is no more drug-sensitive than either single mutant, yet vps3 mutation reduces rhodamine 6G efflux without affecting Pdr5 membrane localization or ATPase activity, suggesting Vps3 is required for routing xenobiotic compounds to plasma membrane transporters.\",\n      \"method\": \"Genetic epistasis (double deletion mutant), multidrug resistance phenotyping, subcellular fractionation, ATPase activity assay, rhodamine 6G efflux assay\",\n      \"journal\": \"Molecular genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus biochemical characterization of Pdr5 activity and localization, single lab with multiple methods\",\n      \"pmids\": [\"18327613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TGFBRAP1 (CHIT1 interaction study, RETRACTED 2024): CHIT1 was reported to interact with TGFBRAP1 and to use this interaction to enhance TGF-β1 signaling and inhibit SMAD7 induction in pulmonary fibrosis. NOTE: The original paper (PMID 31085559) was subsequently retracted (PMID 39209538); this finding should be regarded as unreliable.\",\n      \"method\": \"Co-immunoprecipitation, knockdown experiments, TGF-β signaling assays — RETRACTED\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, paper subsequently retracted; finding is unreliable\",\n      \"pmids\": [\"31085559\", \"39209538\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TGFBRAP1 (also known as VPS3) encodes a cytoplasmic/endosomal protein that functions as the CORVET-specific subunit responsible for Rab5-GTP binding and endosomal tethering: its N-terminal domain is required for endosomal localization and CORVET-dependent protein sorting, while in mammalian cells Vps3/TGFBRAP1 additionally controls vesicular transport from early to recycling endosomes to support integrin recycling, cell adhesion, and migration; in vivo, the protein is essential for early mouse embryogenesis, consistent with its proposed role as a modulator of TGF-β/Smad signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TGFBRAP1 (VPS3) is the metazoan ortholog of yeast Vps3 and functions as a CORVET-specific endosomal tethering subunit that links Rab GTPase recognition to vesicular protein sorting [#0, #2, #4]. The founding yeast studies established Vps3 as a cytoplasmic protein required for vacuolar protein sorting, vacuolar acidification, and inheritance of vacuolar morphology during the cell cycle [#0], and showed that the N-terminal domains of the CORVET-specific subunits Vps3 and Vps8 are required for endosomal localization of the complex without affecting its assembly [#3]. In human cells, TGFBRAP1 directly binds GTP-loaded Rab5 and co-localizes with Rab5, identifying it as the missing Vps3 subunit and a Rab5 effector of the human CORVET complex [#2]. Beyond early-endosome tethering, mammalian Vps3 localizes to Rab4- and Rab11-positive recycling compartments and is required for delivery of internalized integrins to recycling endosomes and their return to the plasma membrane, so that its depletion impairs integrin-dependent adhesion, spreading, focal adhesion formation, and migration [#4]. The protein is essential in vivo, as homozygous knockout mice die before the blastula stage or during gastrulation [#1]. A reported interaction with CHIT1 in TGF-\\u03b2/SMAD7 signaling derives from a retracted study and is not a reliable part of the mechanistic picture [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established the founding role of Vps3 by showing a single gene is required for delivery of vacuolar hydrolases, vacuolar acidification, and vacuolar inheritance, placing it at the core of endosomal/vacuolar biogenesis.\",\n      \"evidence\": \"Gene cloning, deletion and temperature-conditional alleles, CPY sorting assay, and vacuolar morphology microscopy in yeast\",\n      \"pmids\": [\"2202738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No molecular partners or complex membership defined\",\n        \"Mechanism connecting Vps3 to sorting and acidification not resolved\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended Vps3 function to xenobiotic handling by showing it is required to route compounds to plasma-membrane multidrug transporters rather than to regulate the transporter itself.\",\n      \"evidence\": \"Genetic epistasis with PDR5, rhodamine 6G efflux, subcellular fractionation, and Pdr5 ATPase assays in yeast\",\n      \"pmids\": [\"18327613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct molecular mechanism of routing not defined\",\n        \"Relevance to mammalian Vps3 untested\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated a non-redundant in vivo requirement for the mammalian gene by showing knockout causes early embryonic lethality.\",\n      \"evidence\": \"Mouse knockout generation and embryonic phenotyping\",\n      \"pmids\": [\"20961651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular pathway underlying lethality not established\",\n        \"Cell-type and stage-specific requirements not dissected\",\n        \"Link between endosomal function and embryonic phenotype unresolved\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified human TGFBRAP1 as the missing CORVET-specific Vps3 subunit and a Rab5 effector by demonstrating direct GTP-Rab5 binding and Rab5 co-localization.\",\n      \"evidence\": \"In vitro Rab5-GTP pulldown, co-localization in yeast and HEK293 cells, and yeast complementation\",\n      \"pmids\": [\"25750764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Reconstitution of intact human CORVET not shown\",\n        \"Endogenous (untagged) complex composition not validated\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Localized the determinant for CORVET endosomal targeting to the N-terminal domains of Vps3 and Vps8, separating membrane recruitment from complex assembly.\",\n      \"evidence\": \"Truncation mutagenesis with localization microscopy, endocytic sorting assays, and CORVET assembly analysis in yeast\",\n      \"pmids\": [\"23840658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of N-terminal membrane recruitment not defined\",\n        \"Conservation of the N-terminal requirement in mammals not tested\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded mammalian Vps3 function from early-endosome tethering to recycling-endosome transport, linking it directly to integrin trafficking and cell adhesion/migration.\",\n      \"evidence\": \"siRNA depletion, reciprocal co-localization with Rab4/Rab11/CHEVI, integrin trafficking, adhesion, spreading, focal adhesion, and migration assays\",\n      \"pmids\": [\"29476049\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether recycling role uses CORVET or a distinct complex unclear\",\n        \"Cargo selectivity beyond integrins not mapped\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the endosomal/recycling function of TGFBRAP1 connects mechanistically to its proposed role in TGF-\\u03b2/Smad signaling and to the embryonic lethality phenotype remains unresolved.\",\n      \"evidence\": \"No direct mechanistic evidence in the available corpus (the CHIT1/TGF-\\u03b2 interaction report is retracted)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No validated TGF-\\u03b2 signaling mechanism for TGFBRAP1 in the corpus\",\n        \"Tissue-level cause of embryonic lethality undefined\",\n        \"Direct human CORVET cargo repertoire incomplete\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005773\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"complexes\": [\"CORVET\"],\n    \"partners\": [\"RAB5\", \"VPS8\", \"RAB4\", \"RAB11\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}