{"gene":"TBC1D2B","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2020,"finding":"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.","method":"Co-immunoprecipitation, functional cell-based assays measuring MVE-lysosome fusion and exosome secretion","journal":"Cell Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/interaction data with functional readout (MVE-lysosome fusion, exosome secretion), single lab, multiple orthogonal methods described in abstract","pmids":["32958903"],"is_preprint":false},{"year":2010,"finding":"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.","method":"GST pull-down assay with 60 mammalian Rabs combined with mass spectrometry identification","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic GST pull-down with MS identification, single lab, interaction domain inference from the screen design","pmids":["20070612"],"is_preprint":false},{"year":2019,"finding":"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.","method":"BioID proximity labeling screen, epigenome shRNA dropout screen, loss-of-function studies measuring E-cadherin internalization and metastasis in NSCLC models","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent screens (BioID + shRNA dropout) plus functional E-cadherin internalization assay, single lab","pmids":["31719531"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Immunofluorescence colocalization, CRISPR/Cas9 knockout, EGF internalization assay","journal":"Human Mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with defined cellular phenotype (EGF internalization), immunofluorescence localization, single lab, two orthogonal methods","pmids":["32623794"],"is_preprint":false},{"year":2024,"finding":"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.","method":"RAB GTPase family screening, co-immunoprecipitation, functional assays measuring RAB7A activity and EGFR trafficking/microvesicle formation","journal":"Journal of Extracellular Vesicles","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional trafficking assay, single lab, multiple readouts","pmids":["39051763"],"is_preprint":false},{"year":2024,"finding":"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.","method":"LIR motif mutagenesis, co-immunoprecipitation with LC3/GABARAP and ATG12 complexes, autophagy reporter assays, live-cell imaging of condensate formation","journal":"Journal of Cellular Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — LIR mutagenesis plus co-IP with multiple partners plus phase separation imaging, single lab, multiple orthogonal methods","pmids":["38226533"],"is_preprint":false}],"current_model":"TBC1D2B is a TBC-domain RAB-GTPase activating protein (RABGAP) that localizes to early endosomes (via RAB5 colocalization), functions in early endocytosis and endosomal trafficking by inactivating RAB7A (recruited by RAB31 or RAB22A to prevent MVE-lysosome fusion and promote exosome/microvesicle secretion), suppresses E-cadherin internalization downstream of ZEB1/NuRD transcriptional repression, and promotes autophagy initiation through a functional LIR motif that mediates binding to LC3/GABARAP and ATG12 complexes, with phase separation facilitating this autophagy-regulatory role."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2010,"claim":"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","pmids":["20070612"],"confidence":"Medium","gaps":["GAP activity inferred from domain, not demonstrated biochemically","RAB22-binding domain not mapped beyond exclusion of the GAP domain","no cellular function assigned"]},{"year":2019,"claim":"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","pmids":["31719531"],"confidence":"Medium","gaps":["mechanistic link between GAP activity and E-cadherin trafficking not resolved","specific Rab substrate in this context not defined","single-lab evidence"]},{"year":2020,"claim":"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","pmids":["32623794"],"confidence":"Medium","gaps":["direct GAP substrate at the endosome not identified here","molecular mechanism linking TBC1D2B loss to reduced EGF uptake unclear"]},{"year":2020,"claim":"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","pmids":["32958903"],"confidence":"Medium","gaps":["direct biochemical GAP assay on RAB7 not shown","structural basis of RAB31-TBC1D2B recruitment unknown","single-lab finding"]},{"year":2024,"claim":"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","pmids":["39051763"],"confidence":"Medium","gaps":["relationship between RAB31- and RAB22A-mediated recruitment not reconciled","no structural model of the recruitment complex","single-lab finding"]},{"year":2024,"claim":"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","pmids":["38226533"],"confidence":"Medium","gaps":["how GAP activity relates to autophagy role is unresolved","functional significance of phase separation not mechanistically defined","single-lab finding"]},{"year":null,"claim":"How TBC1D2B's RAB7A-directed GAP activity, its E-cadherin/metastasis role, and its autophagy-initiation function are mechanistically integrated remains unresolved.","evidence":"No single study links the trafficking, epithelial, and autophagy roles in one mechanism","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,3,4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[5]}],"complexes":[],"partners":["RAB31","RAB22A","RAB7A","RAB5","LC3","GABARAP","ATG12"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UPU7","full_name":"TBC1 domain family member 2B","aliases":[],"length_aa":963,"mass_kda":109.9,"function":"GTPase-activating protein that plays a role in the early steps of endocytosis (PubMed:32623794)","subcellular_location":"Early endosome","url":"https://www.uniprot.org/uniprotkb/Q9UPU7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TBC1D2B","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TBC1D2B","total_profiled":1310},"omim":[{"mim_id":"619323","title":"NEURODEVELOPMENTAL DISORDER WITH SEIZURES AND GINGIVAL OVERGROWTH; NEDSGO","url":"https://www.omim.org/entry/619323"},{"mim_id":"619152","title":"TBC1 DOMAIN FAMILY, MEMBER 2B; TBC1D2B","url":"https://www.omim.org/entry/619152"},{"mim_id":"612966","title":"RAS-ASSOCIATED PROTEIN RAB22A; RAB22A","url":"https://www.omim.org/entry/612966"},{"mim_id":"608411","title":"EXPORTIN 6; XPO6","url":"https://www.omim.org/entry/608411"},{"mim_id":"189909","title":"ZINC FINGER E BOX-BINDING HOMEOBOX 1; ZEB1","url":"https://www.omim.org/entry/189909"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TBC1D2B"},"hgnc":{"alias_symbol":["KIAA1055"],"prev_symbol":[]},"alphafold":{"accession":"Q9UPU7","domains":[{"cath_id":"2.30.29.30","chopping":"39-150_163-206","consensus_level":"high","plddt":70.0815,"start":39,"end":206},{"cath_id":"1.10.472.80","chopping":"786-946","consensus_level":"medium","plddt":94.7954,"start":786,"end":946},{"cath_id":"1.20.5","chopping":"417-446","consensus_level":"medium","plddt":89.7927,"start":417,"end":446}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPU7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPU7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPU7-F1-predicted_aligned_error_v6.png","plddt_mean":70.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TBC1D2B","jax_strain_url":"https://www.jax.org/strain/search?query=TBC1D2B"},"sequence":{"accession":"Q9UPU7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UPU7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UPU7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPU7"}},"corpus_meta":[{"pmid":"32958903","id":"PMC_32958903","title":"RAB31 marks and controls an ESCRT-independent exosome pathway.","date":"2020","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32958903","citation_count":395,"is_preprint":false},{"pmid":"20070612","id":"PMC_20070612","title":"Comprehensive screening for novel rab-binding proteins by GST pull-down assay using 60 different mammalian Rabs.","date":"2010","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/20070612","citation_count":100,"is_preprint":false},{"pmid":"31719531","id":"PMC_31719531","title":"ZEB1/NuRD complex suppresses TBC1D2b to stimulate E-cadherin internalization and promote metastasis in lung cancer.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31719531","citation_count":79,"is_preprint":false},{"pmid":"16735990","id":"PMC_16735990","title":"Fine mapping of the keratoconus with cataract locus on chromosome 15q and candidate gene analysis.","date":"2006","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/16735990","citation_count":39,"is_preprint":false},{"pmid":"29486777","id":"PMC_29486777","title":"Weak sharing of genetic association signals in three lung cancer subtypes: evidence at the SNP, gene, regulation, and pathway levels.","date":"2018","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29486777","citation_count":33,"is_preprint":false},{"pmid":"32623794","id":"PMC_32623794","title":"Biallelic loss-of-function variants in TBC1D2B cause a neurodevelopmental disorder with seizures and gingival overgrowth.","date":"2020","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/32623794","citation_count":14,"is_preprint":false},{"pmid":"39051763","id":"PMC_39051763","title":"RAB22A sorts epithelial growth factor receptor (EGFR) from early endosomes to recycling endosomes for microvesicles release.","date":"2024","source":"Journal of extracellular vesicles","url":"https://pubmed.ncbi.nlm.nih.gov/39051763","citation_count":11,"is_preprint":false},{"pmid":"27699474","id":"PMC_27699474","title":"Atlas of human diseases influenced by genetic variants with extreme allele frequency differences.","date":"2016","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27699474","citation_count":10,"is_preprint":false},{"pmid":"38374468","id":"PMC_38374468","title":"Loss of TBC1D2B causes a progressive neurological disorder with gingival overgrowth.","date":"2024","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/38374468","citation_count":4,"is_preprint":false},{"pmid":"36029130","id":"PMC_36029130","title":"Biallelic frameshift variant in the TBC1D2B gene in two siblings with progressive gingival overgrowth, fibrous dysplasia of face, and mental deterioration.","date":"2022","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36029130","citation_count":3,"is_preprint":false},{"pmid":"39201553","id":"PMC_39201553","title":"Genetic Variants in the TBC1D2B Gene Are Associated with Ramon Syndrome and Hereditary Gingival Fibromatosis.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39201553","citation_count":3,"is_preprint":false},{"pmid":"38226533","id":"PMC_38226533","title":"TBC1D2B undergoes phase separation and mediates autophagy initiation.","date":"2024","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38226533","citation_count":2,"is_preprint":false},{"pmid":"40898781","id":"PMC_40898781","title":"A Novel Homozygous TBC1D2B Variant Disrupts Functional Domains and Suggests Impaired Rab-GTPase Regulation in Neurodevelopmental Disorder.","date":"2025","source":"Developmental neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/40898781","citation_count":1,"is_preprint":false},{"pmid":"40244023","id":"PMC_40244023","title":"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.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40244023","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8752,"output_tokens":1539,"usd":0.024671,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8240,"output_tokens":2370,"usd":0.050225,"stage2_stop_reason":"end_turn"},"total_usd":0.074896,"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\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, functional cell-based assays measuring MVE-lysosome fusion and exosome secretion\",\n      \"journal\": \"Cell Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/interaction data with functional readout (MVE-lysosome fusion, exosome secretion), single lab, multiple orthogonal methods described in abstract\",\n      \"pmids\": [\"32958903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"GST pull-down assay with 60 mammalian Rabs combined with mass spectrometry identification\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic GST pull-down with MS identification, single lab, interaction domain inference from the screen design\",\n      \"pmids\": [\"20070612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"BioID proximity labeling screen, epigenome shRNA dropout screen, loss-of-function studies measuring E-cadherin internalization and metastasis in NSCLC models\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent screens (BioID + shRNA dropout) plus functional E-cadherin internalization assay, single lab\",\n      \"pmids\": [\"31719531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence colocalization, CRISPR/Cas9 knockout, EGF internalization assay\",\n      \"journal\": \"Human Mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with defined cellular phenotype (EGF internalization), immunofluorescence localization, single lab, two orthogonal methods\",\n      \"pmids\": [\"32623794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"RAB GTPase family screening, co-immunoprecipitation, functional assays measuring RAB7A activity and EGFR trafficking/microvesicle formation\",\n      \"journal\": \"Journal of Extracellular Vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional trafficking assay, single lab, multiple readouts\",\n      \"pmids\": [\"39051763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"LIR motif mutagenesis, co-immunoprecipitation with LC3/GABARAP and ATG12 complexes, autophagy reporter assays, live-cell imaging of condensate formation\",\n      \"journal\": \"Journal of Cellular Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LIR mutagenesis plus co-IP with multiple partners plus phase separation imaging, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38226533\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TBC1D2B is a TBC-domain RAB-GTPase activating protein (RABGAP) that localizes to early endosomes (via RAB5 colocalization), functions in early endocytosis and endosomal trafficking by inactivating RAB7A (recruited by RAB31 or RAB22A to prevent MVE-lysosome fusion and promote exosome/microvesicle secretion), suppresses E-cadherin internalization downstream of ZEB1/NuRD transcriptional repression, and promotes autophagy initiation through a functional LIR motif that mediates binding to LC3/GABARAP and ATG12 complexes, with phase separation facilitating this autophagy-regulatory role.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#3, #4]. 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 [#0, #4]. TBC1D2B was originally identified as a RAB22-binding protein, with the RAB interaction occurring through a domain distinct from its catalytic GAP domain [#1]. Consistent with an early-endocytic role, it colocalizes with RAB5-positive early endosomes and is required for efficient EGF internalization [#3]. 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 [#2]. 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 [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established TBC1D2B as a RAB-interacting TBC-domain protein, placing it within the machinery that regulates Rab GTPases.\",\n      \"evidence\": \"Systematic GST pull-down against 60 mammalian Rabs with mass-spectrometry identification\",\n      \"pmids\": [\"20070612\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GAP activity inferred from domain, not demonstrated biochemically\", \"RAB22-binding domain not mapped beyond exclusion of the GAP domain\", \"no cellular function assigned\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected TBC1D2B to epithelial integrity and cancer by showing it suppresses E-cadherin internalization and is silenced by ZEB1/NuRD to drive metastasis.\",\n      \"evidence\": \"BioID proximity labeling, epigenome shRNA dropout screen, and E-cadherin internalization/metastasis assays in NSCLC models\",\n      \"pmids\": [\"31719531\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanistic link between GAP activity and E-cadherin trafficking not resolved\", \"specific Rab substrate in this context not defined\", \"single-lab evidence\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Localized TBC1D2B to early endosomes and demonstrated a functional requirement in early endocytosis.\",\n      \"evidence\": \"Immunofluorescence colocalization with RAB5, CRISPR/Cas9 knockout, and EGF internalization assay in HeLa cells\",\n      \"pmids\": [\"32623794\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct GAP substrate at the endosome not identified here\", \"molecular mechanism linking TBC1D2B loss to reduced EGF uptake unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a substrate and pathway role: RAB31 recruits TBC1D2B as a GAP for RAB7, controlling MVE-lysosome fusion and exosome secretion.\",\n      \"evidence\": \"Co-immunoprecipitation and functional assays of MVE-lysosome fusion and exosome secretion\",\n      \"pmids\": [\"32958903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct biochemical GAP assay on RAB7 not shown\", \"structural basis of RAB31-TBC1D2B recruitment unknown\", \"single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Generalized the recruitment-GAP model: RAB22A recruits TBC1D2B to inactivate RAB7A, redirecting EGFR from lysosomal degradation to recycling and microvesicle incorporation.\",\n      \"evidence\": \"RAB family screening, co-immunoprecipitation, and assays of RAB7A activity, EGFR trafficking, and microvesicle formation\",\n      \"pmids\": [\"39051763\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"relationship between RAB31- and RAB22A-mediated recruitment not reconciled\", \"no structural model of the recruitment complex\", \"single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended TBC1D2B function beyond trafficking to autophagy initiation via a LIR motif and phase-separation behavior.\",\n      \"evidence\": \"LIR motif mutagenesis, co-IP with LC3/GABARAP and ATG12 complexes, autophagy reporter assays, and live-cell condensate imaging\",\n      \"pmids\": [\"38226533\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"how GAP activity relates to autophagy role is unresolved\", \"functional significance of phase separation not mechanistically defined\", \"single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TBC1D2B's RAB7A-directed GAP activity, its E-cadherin/metastasis role, and its autophagy-initiation function are mechanistically integrated remains unresolved.\",\n      \"evidence\": \"No single study links the trafficking, epithelial, and autophagy roles in one mechanism\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no integrated model across endocytosis, autophagy, and cadherin regulation\", \"no structural data on GAP-RAB7A complex\", \"in vivo physiological role beyond cancer models undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005096\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAB31\", \"RAB22A\", \"RAB7A\", \"RAB5\", \"LC3\", \"GABARAP\", \"ATG12\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}