Affinage

TGFBRAP1

Transforming growth factor-beta receptor-associated protein 1 · UniProt Q8WUH2

Length
860 aa
Mass
97.2 kDa
Annotated
2026-06-10
30 papers in source corpus 8 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 1990 High

    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

    PMID:2202738

    Open questions at the time
    • No molecular partners or complex membership defined
    • Mechanism connecting Vps3 to sorting and acidification not resolved
  2. 2008 Medium

    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

    PMID:18327613

    Open questions at the time
    • Direct molecular mechanism of routing not defined
    • Relevance to mammalian Vps3 untested
  3. 2010 Medium

    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

    PMID:20961651

    Open questions at the time
    • Molecular pathway underlying lethality not established
    • Cell-type and stage-specific requirements not dissected
    • Link between endosomal function and embryonic phenotype unresolved
  4. 2013 Medium

    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

    PMID:25750764

    Open questions at the time
    • Reconstitution of intact human CORVET not shown
    • Endogenous (untagged) complex composition not validated
  5. 2013 High

    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

    PMID:23840658

    Open questions at the time
    • Structural basis of N-terminal membrane recruitment not defined
    • Conservation of the N-terminal requirement in mammals not tested
  6. 2018 High

    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

    PMID:29476049

    Open questions at the time
    • Whether recycling role uses CORVET or a distinct complex unclear
    • Cargo selectivity beyond integrins not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005768 endosome 3 GO:0005773 vacuole 1 GO:0005829 cytosol 1
Pathway
R-HSA-9609507 Protein localization 3 R-HSA-5653656 Vesicle-mediated transport 1
Partners
RAB11RAB4RAB5VPS8
Complex memberships
CORVET

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 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. Gene cloning, deletion mutant analysis, temperature-conditional allele, fluorescence microscopy of vacuolar morphology, CPY sorting assay The Journal of cell biology High 2202738
2010 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. Mouse knockout generation, embryonic lethal phenotyping Immunobiology Medium 20961651
2013 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. In vitro Rab5-GTP binding assay (pulldown), co-localization by fluorescence microscopy in yeast and HEK293 cells, functional complementation assay in yeast Cellular logistics Medium 25750764
2013 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. Truncation mutagenesis of Vps3 and Vps8, subcellular localization by fluorescence microscopy, endocytic protein sorting assay, CORVET assembly analysis PloS one High 23840658
2018 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. siRNA depletion, fluorescence co-localization microscopy, integrin trafficking assays, cell adhesion/spreading/migration assays, focal adhesion staining Nature communications High 29476049
2008 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. Genetic epistasis (double deletion mutant), multidrug resistance phenotyping, subcellular fractionation, ATPase activity assay, rhodamine 6G efflux assay Molecular genetics and genomics Medium 18327613
2019 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. Co-immunoprecipitation, knockdown experiments, TGF-β signaling assays — RETRACTED Life science alliance Low 31085559 39209538

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 TRAP-1, the mitochondrial Hsp90. Biochimica et biophysica acta 146 21878357
2007 Tumor necrosis factor-associated protein 1 (TRAP-1) protects cells from oxidative stress and apoptosis. Stress (Amsterdam, Netherlands) 144 17853063
2014 Mitochondrial oxidative phosphorylation TRAP(1)ped in tumor cells. Trends in cell biology 111 24731398
2009 Cytoprotective mitochondrial chaperone TRAP-1 as a novel molecular target in localized and metastatic prostate cancer. The American journal of pathology 104 19948822
1990 Molecular analysis of the yeast VPS3 gene and the role of its product in vacuolar protein sorting and vacuolar segregation during the cell cycle. The Journal of cell biology 102 2202738
2000 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. Experimental cell research 79 11010808
2014 Deletion of the mitochondrial chaperone TRAP-1 uncovers global reprogramming of metabolic networks. Cell reports 58 25088416
2018 Vps3 and Vps8 control integrin trafficking from early to recycling endosomes and regulate integrin-dependent functions. Nature communications 41 29476049
2012 Correlation between mitochondrial TRAP-1 expression and lymph node metastasis in colorectal cancer. World journal of gastroenterology 38 23139614
2010 The TGF-β signaling modulators TRAP1/TGFBRAP1 and VPS39/Vam6/TLP are essential for early embryonic development. Immunobiology 32 20961651
2019 Chitinase 1 regulates pulmonary fibrosis by modulating TGF-β/SMAD7 pathway via TGFBRAP1 and FOXO3. Life science alliance 29 31085559
2013 Effects of TRAP-1-like protein (TLP) gene on collagen synthesis induced by TGF-β/Smad signaling in human dermal fibroblasts. PloS one 29 23418473
2014 The Vps39-like TRAP1 is an effector of Rab5 and likely the missing Vps3 subunit of human CORVET. Cellular logistics 25 25750764
2002 Unique behavior of a dictyostelium homologue of TRAP-1, coupling with differentiation of D. discoideum cells. Experimental cell research 21 12372338
2013 The N-terminal domains of Vps3 and Vps8 are critical for localization and function of the CORVET tethering complex on endosomes. PloS one 19 23840658
2004 Involvement of the TRAP-1 homologue, Dd-TRAP1, in spore differentiation during Dictyostelium development. Experimental cell research 16 15652354
2023 The mitochondrial chaperone TRAP-1 regulates the glutamine metabolism in tumor cells. Mitochondrion 11 36828164
2018 Hepatitis C virus core impacts expression of miR122 and miR204 involved in carcinogenic progression via regulation of TGFBRAP1 and HOTTIP expression. OncoTargets and therapy 10 29535540
2020 Identification and characterization of a Babesia bigemina thrombospondin-related superfamily member, TRAP-1: a novel antigen containing neutralizing epitopes involved in merozoite invasion. Parasites & vectors 9 33261638
2020 Development of Nanocarrier-Based Mitochondrial Chaperone, TRAP-1 Inhibitor to Combat Cancer Metabolism. ACS applied bio materials 9 35025420
2020 The effects of FAR1 and TGFBRAP1 on the proliferation and apoptosis of follicular granulosa cells in goose (Anser cygnoides). Gene 8 33007376
2020 Protective mechanisms of piperine against acetaminophen-induced hepatotoxicity may be mediated through TGFBRAP1. European review for medical and pharmacological sciences 8 33090425
2018 The variant at TGFBRAP1 is significantly associated with type 2 diabetes mellitus and affects diabetes-related miRNA expression. Journal of cellular and molecular medicine 7 30461200
2023 Mechanism of Nrf2/miR338-3p/TRAP-1 pathway involved in hyperactivation of synovial fibroblasts in patients with osteoarthritis. Heliyon 5 37920489
2015 Polymorphisms of the TGFBRAP1 gene in relation to blood pressure variability and plasma TGF-β1. Clinical and experimental hypertension (New York, N.Y. : 1993) 5 25856002
2023 Analysis and functional relevance of the chaperone TRAP-1 interactome in the metabolic regulation and mitochondrial integrity of cancer cells. Scientific reports 4 37165028
2019 The Variant at TGFBRAP1 but Not TGFBR2 Is Associated with Antituberculosis Drug-Induced Liver Injury. Evidence-based complementary and alternative medicine : eCAM 4 31534460
2008 Pdr5-mediated multidrug resistance requires the CPY-vacuolar sorting protein Vps3: are xenobiotic compounds routed from the vacuole to plasma membrane transporters for efflux? Molecular genetics and genomics : MGG 4 18327613
2023 Correction: Chitinase 1 regulates pulmonary fibrosis by modulating TGF-β/SMAD7 pathway via TGFBRAP1 and FOXO3. Life science alliance 1 37037591
2024 Retraction: Chitinase 1 regulates pulmonary fibrosis by modulating TGF-β/SMAD7 pathway via TGFBRAP1 and FOXO3. Life science alliance 0 39209538

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