Affinage

TBC1D2B

TBC1 domain family member 2B · UniProt Q9UPU7

Length
963 aa
Mass
109.9 kDa
Annotated
2026-06-10
14 papers in source corpus 6 papers cited in narrative 6 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

TBC1D2B is a TBC-domain RAB-GTPase-activating protein (RABGAP) that operates on early endosomes to control endocytic membrane trafficking and the fate of internalized cargo (PMID:32623794, PMID:39051763). It is recruited to early endosomes by the small GTPases RAB31 and RAB22A, where it inactivates RAB7A; this RAB7A inactivation blocks fusion of multivesicular endosomes with lysosomes, instead routing intraluminal vesicles toward exosome secretion and diverting EGFR away from lysosomal degradation toward surface recycling and incorporation into microvesicles (PMID:32958903, PMID:39051763). TBC1D2B was originally identified as a RAB22-binding protein, with the RAB interaction occurring through a domain distinct from its catalytic GAP domain (PMID:20070612). Consistent with an early-endocytic role, it colocalizes with RAB5-positive early endosomes and is required for efficient EGF internalization (PMID:32623794). Beyond trafficking, TBC1D2B suppresses E-cadherin internalization, and its transcriptional silencing by the ZEB1/NuRD complex promotes cancer cell invasion and metastasis in non-small-cell lung cancer (PMID:31719531). It also participates in autophagy initiation through a functional LC3-interacting region that binds LC3/GABARAP and ATG12 conjugation complexes, is itself turned over by autophagy, and forms phase-separated condensates upon autophagy induction (PMID:38226533).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2010 Medium

    Established TBC1D2B as a RAB-interacting TBC-domain protein, placing it within the machinery that regulates Rab GTPases.

    Evidence Systematic GST pull-down against 60 mammalian Rabs with mass-spectrometry identification

    PMID:20070612

    Open questions at the time
    • GAP activity inferred from domain, not demonstrated biochemically
    • RAB22-binding domain not mapped beyond exclusion of the GAP domain
    • no cellular function assigned
  2. 2019 Medium

    Connected TBC1D2B to epithelial integrity and cancer by showing it suppresses E-cadherin internalization and is silenced by ZEB1/NuRD to drive metastasis.

    Evidence BioID proximity labeling, epigenome shRNA dropout screen, and E-cadherin internalization/metastasis assays in NSCLC models

    PMID:31719531

    Open questions at the time
    • mechanistic link between GAP activity and E-cadherin trafficking not resolved
    • specific Rab substrate in this context not defined
    • single-lab evidence
  3. 2020 Medium

    Localized TBC1D2B to early endosomes and demonstrated a functional requirement in early endocytosis.

    Evidence Immunofluorescence colocalization with RAB5, CRISPR/Cas9 knockout, and EGF internalization assay in HeLa cells

    PMID:32623794

    Open questions at the time
    • direct GAP substrate at the endosome not identified here
    • molecular mechanism linking TBC1D2B loss to reduced EGF uptake unclear
  4. 2020 Medium

    Defined a substrate and pathway role: RAB31 recruits TBC1D2B as a GAP for RAB7, controlling MVE-lysosome fusion and exosome secretion.

    Evidence Co-immunoprecipitation and functional assays of MVE-lysosome fusion and exosome secretion

    PMID:32958903

    Open questions at the time
    • direct biochemical GAP assay on RAB7 not shown
    • structural basis of RAB31-TBC1D2B recruitment unknown
    • single-lab finding
  5. 2024 Medium

    Generalized the recruitment-GAP model: RAB22A recruits TBC1D2B to inactivate RAB7A, redirecting EGFR from lysosomal degradation to recycling and microvesicle incorporation.

    Evidence RAB family screening, co-immunoprecipitation, and assays of RAB7A activity, EGFR trafficking, and microvesicle formation

    PMID:39051763

    Open questions at the time
    • relationship between RAB31- and RAB22A-mediated recruitment not reconciled
    • no structural model of the recruitment complex
    • single-lab finding
  6. 2024 Medium

    Extended TBC1D2B function beyond trafficking to autophagy initiation via a LIR motif and phase-separation behavior.

    Evidence LIR motif mutagenesis, co-IP with LC3/GABARAP and ATG12 complexes, autophagy reporter assays, and live-cell condensate imaging

    PMID:38226533

    Open questions at the time
    • how GAP activity relates to autophagy role is unresolved
    • functional significance of phase separation not mechanistically defined
    • single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TBC1D2B's RAB7A-directed GAP activity, its E-cadherin/metastasis role, and its autophagy-initiation function are mechanistically integrated remains unresolved.
  • no integrated model across endocytosis, autophagy, and cadherin regulation
  • no structural data on GAP-RAB7A complex
  • in vivo physiological role beyond cancer models undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2
Localization
GO:0005768 endosome 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-9612973 Autophagy 1
Partners
ATG12GABARAPLC3RAB22ARAB31RAB5RAB7A

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 RAB31 recruits TBC1D2B as a GTPase-activating protein (GAP) to inactivate RAB7, thereby preventing fusion of multivesicular endosomes (MVEs) with lysosomes and enabling secretion of intraluminal vesicles as exosomes. Co-immunoprecipitation, functional cell-based assays measuring MVE-lysosome fusion and exosome secretion Cell Research Medium 32958903
2010 TBC1D2B (mKIAA1055) was identified as a RAB22-binding protein via GST pull-down; its TBC domain-containing GAP activity is implicated in Rab GTPase regulation, but the interaction with RAB22 occurs via a domain other than the GAP domain. GST pull-down assay with 60 mammalian Rabs combined with mass spectrometry identification Traffic Medium 20070612
2019 TBC1D2B (a RAB22 GAP) is transcriptionally repressed by the ZEB1/NuRD complex, and TBC1D2B suppresses E-cadherin internalization; its loss via ZEB1/NuRD-mediated repression promotes cancer cell invasion and metastasis in NSCLC. BioID proximity labeling screen, epigenome shRNA dropout screen, loss-of-function studies measuring E-cadherin internalization and metastasis in NSCLC models Nature Communications Medium 31719531
2020 Ectopically expressed TBC1D2B colocalizes with RAB5-positive early endosomal vesicles; CRISPR/Cas9 knockout of TBC1D2B in HeLa cells significantly reduces EGF internalization, establishing a role for TBC1D2B in early endocytosis. Immunofluorescence colocalization, CRISPR/Cas9 knockout, EGF internalization assay Human Mutation Medium 32623794
2024 RAB22A recruits TBC1D2B (a GAP for RAB7A) to inactivate RAB7A on early endosomes, preventing EGFR transport to late endosomes/lysosomes and enabling EGFR recycling to the cell surface for incorporation into microvesicles. RAB GTPase family screening, co-immunoprecipitation, functional assays measuring RAB7A activity and EGFR trafficking/microvesicle formation Journal of Extracellular Vesicles Medium 39051763
2024 TBC1D2B contains a functional canonical LC3-interacting region (LIR) motif, binds both LC3/GABARAP and ATG12 conjugation complexes, acts at an early stage of autophagy initiation, is itself degraded by autophagy, and undergoes liquid-liquid phase separation (condensate formation) upon autophagy induction. LIR motif mutagenesis, co-immunoprecipitation with LC3/GABARAP and ATG12 complexes, autophagy reporter assays, live-cell imaging of condensate formation Journal of Cellular Biochemistry Medium 38226533

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 RAB31 marks and controls an ESCRT-independent exosome pathway. Cell research 395 32958903
2010 Comprehensive screening for novel rab-binding proteins by GST pull-down assay using 60 different mammalian Rabs. Traffic (Copenhagen, Denmark) 100 20070612
2019 ZEB1/NuRD complex suppresses TBC1D2b to stimulate E-cadherin internalization and promote metastasis in lung cancer. Nature communications 79 31719531
2006 Fine mapping of the keratoconus with cataract locus on chromosome 15q and candidate gene analysis. Molecular vision 39 16735990
2018 Weak sharing of genetic association signals in three lung cancer subtypes: evidence at the SNP, gene, regulation, and pathway levels. Genome medicine 33 29486777
2020 Biallelic loss-of-function variants in TBC1D2B cause a neurodevelopmental disorder with seizures and gingival overgrowth. Human mutation 14 32623794
2024 RAB22A sorts epithelial growth factor receptor (EGFR) from early endosomes to recycling endosomes for microvesicles release. Journal of extracellular vesicles 11 39051763
2016 Atlas of human diseases influenced by genetic variants with extreme allele frequency differences. Human genetics 10 27699474
2024 Loss of TBC1D2B causes a progressive neurological disorder with gingival overgrowth. European journal of human genetics : EJHG 4 38374468
2024 Genetic Variants in the TBC1D2B Gene Are Associated with Ramon Syndrome and Hereditary Gingival Fibromatosis. International journal of molecular sciences 3 39201553
2022 Biallelic frameshift variant in the TBC1D2B gene in two siblings with progressive gingival overgrowth, fibrous dysplasia of face, and mental deterioration. Clinical genetics 3 36029130
2024 TBC1D2B undergoes phase separation and mediates autophagy initiation. Journal of cellular biochemistry 2 38226533
2025 A Novel Homozygous TBC1D2B Variant Disrupts Functional Domains and Suggests Impaired Rab-GTPase Regulation in Neurodevelopmental Disorder. Developmental neurobiology 1 40898781
2025 Correction: Kularbkaew et al. Genetic Variants in the TBC1D2B Gene Are Associated with Ramon Syndrome and Hereditary Gingival Fibromatosis. Int. J. Mol. Sci. 2024, 25, 8867. International journal of molecular sciences 0 40244023

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