{"gene":"RABGAP1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1999,"finding":"GAPCenA (RABGAP1) is a GAP specifically active in vitro on Rab6, and to a lesser extent on Rab4 and Rab2 GTPases. The GAP activity resides within a central ~200 amino acid TBC domain with similarity to yeast Rab-GAPs and spindle checkpoint proteins Bub2p/Cdc16p.","method":"In vitro GAP activity assay; primary sequence analysis; biochemical fractionation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic reconstitution, replicated in the founding characterization paper with substrate specificity established across multiple Rabs","pmids":["10202141"],"is_preprint":false},{"year":1999,"finding":"A minor pool of GAPCenA (RABGAP1) associates with the centrosome, as shown by immunofluorescence and cell fractionation. GAPCenA forms complexes with cytosolic gamma-tubulin and plays a role in microtubule nucleation, suggesting involvement in coordinating microtubule and Golgi dynamics during the cell cycle.","method":"Immunofluorescence; cell fractionation; co-immunoprecipitation with gamma-tubulin","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct localization by two orthogonal methods (IF and fractionation) plus co-IP with gamma-tubulin, single lab","pmids":["10202141"],"is_preprint":false},{"year":2000,"finding":"GAPCenA (RABGAP1) interacts with both Rab6A and Rab6A' isoforms. Rab6A' interaction with GAPCenA was demonstrated by co-precipitation, and the functional distinction between the two isoforms was mapped to a single amino acid (position 87: T vs A).","method":"Co-immunoprecipitation/pulldown; site-directed mutagenesis of Rab6 isoforms","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction confirmed by pulldown, mutagenesis to single residue, single lab","pmids":["11071909"],"is_preprint":false},{"year":2006,"finding":"GAPCenA (RABGAP1) depletion from cells phenocopies Rab6A' loss-of-function, causing metaphase block with activated Mad2-spindle checkpoint and retention of p150(Glued) (dynactin subunit) at kinetochores, placing RABGAP1 in the Rab6A'/p150(Glued)/GAPCenA pathway for metaphase-to-anaphase transition.","method":"siRNA depletion of GAPCenA; live-cell microscopy; kinetochore immunofluorescence; Mad2 checkpoint assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established by loss-of-function with specific molecular readouts (Mad2 activation, p150(Glued) localization), corroborated by parallel Rab6A' perturbation experiments","pmids":["16395330"],"is_preprint":false},{"year":2006,"finding":"RABGAP1 (GAPCenA) participates in a complex with Rab6A' and p150(Glued) (dynein/dynactin subunit) at kinetochores, regulating dynein/dynactin dynamics required for spindle checkpoint inactivation.","method":"Co-immunoprecipitation; immunofluorescence co-localization at kinetochores","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and IF co-localization in single lab, functionally supported by siRNA rescue context","pmids":["16395330"],"is_preprint":false},{"year":2006,"finding":"The PTB domain of RABGAP1 interacts with CARM1; co-overexpression of CARM1 rescues the cell cycle block induced by overexpression of the isolated RABGAP1 PTB domain, confirming functional relevance of this interaction in cell cycle progression.","method":"Yeast two-hybrid screen; overexpression dominant-negative rescue assay in NIH3T3 cells; cell cycle progression assay","journal":"Molecular & cellular proteomics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — interaction validated by functional rescue experiment in cells, single lab","pmids":["17124247"],"is_preprint":false},{"year":2010,"finding":"GAPCenA/TBC1D11 (RABGAP1) binds Rab36 via a domain other than its GAP domain (non-TBC domain interaction), identified through GST pulldown with 60 mammalian Rabs combined with mass spectrometry.","method":"GST pulldown with 60 Rab isoforms; mass spectrometric identification","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic GST pulldown screen with domain mapping, single lab, mass spec confirmation","pmids":["20070612"],"is_preprint":false},{"year":2015,"finding":"Drosophila ortholog of RabGap1 is required for autophagosome formation specifically in skeletal muscle cells, identified by RNAi knockdown in a primary myocyte system with rapamycin/chloroquine-induced autophagy.","method":"RNAi knockdown in Drosophila primary myocytes; autophagosome formation assay (fluorescent reporters); epistasis with ATG gene knockdowns","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function in defined cellular context with specific autophagy readout, single lab, ortholog study","pmids":["25692684"],"is_preprint":false},{"year":2017,"finding":"TBC1D11 (RABGAP1) co-localizes with transferrin receptor on recycling endosomes in mouse embryonic fibroblasts, establishing its recycling endosomal localization.","method":"Fluorescence co-localization with recycling endosome marker (transferrin receptor) in MEFs; systematic screen of 43 TBC proteins","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct imaging-based localization, part of systematic screen, no functional consequence linked in this paper","pmids":["28384198"],"is_preprint":false},{"year":2018,"finding":"TUFT1 physically interacts with RABGAP1, and this interaction modulates intracellular lysosomal positioning, vesicular trafficking, and promotes mTORC1 signaling. RABGAP1 acts downstream of TUFT1 in regulating mTORC1 pathway activity.","method":"Co-immunoprecipitation (TUFT1–RABGAP1 interaction); lysosomal positioning assay; vesicular trafficking assay; mTORC1 activity readouts (phospho-S6K etc.)","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus functional cellular assays (lysosomal positioning, mTORC1 signaling), single lab","pmids":["29423269"],"is_preprint":false},{"year":2020,"finding":"Rabgap1 (RABGAP1) promotes recycling of active (open conformation) β1 integrins to the plasma membrane. The PTB domain of Rabgap1 binds the membrane-proximal NPxY motif in the β1 integrin cytoplasmic tail on endosomes. Silencing Rabgap1 causes intracellular accumulation of active β1 integrins, altered focal adhesion formation, and decreased cell migration and cancer cell invasion. The mechanism involves Rabgap1 attenuating Rab11 activity to facilitate recycling.","method":"siRNA silencing; co-immunoprecipitation (PTB domain–β1 integrin NPxY); integrin recycling assay; focal adhesion immunofluorescence; migration and invasion assays in fibroblasts and breast cancer cells; Rab11 activity assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP mapping to NPxY motif, recycling assay, Rab11 activity, migration/invasion phenotype) in single rigorous study, with domain-specific interaction and functional rescue","pmids":["32843574"],"is_preprint":false},{"year":2022,"finding":"Loss-of-function of RABGAP1 in patient-derived lymphoblastoid cells causes downregulated mTOR signaling and abnormal localization of early endosomes and lysosomes. Rabgap1 knockout mice exhibit microcephaly, thinning of the corpus callosum, and ventriculomegaly, establishing RABGAP1 as necessary for normal endosomal/lysosomal positioning and mTOR signaling in vivo.","method":"Patient lymphoblastoid cell lines (functional studies); RNA sequencing; endosome/lysosome localization by immunofluorescence; mTOR pathway western blots; Rabgap1 KO mouse phenotyping","journal":"Genetics in medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — orthogonal human cell and mouse KO models with convergent mechanistic readouts (endosome localization, mTOR signaling), replicated across two experimental systems","pmids":["36083289"],"is_preprint":false},{"year":2025,"finding":"RABGAP1 directly interacts with the YENPTY motif in the cytosolic tail of amyloid precursor protein (APP), identified by unbiased interaction screen. RABGAP1 partially co-localizes with APP. Depletion or overexpression of RABGAP1 causes mistrafficking and misprocessing of endogenous APP in human and rodent neurons. This effect is dependent on the GAP activity of RABGAP1, indicating that RABGAP1 modulates RAB activity on endosomal subdomains to control APP trafficking.","method":"Unbiased interaction screen for APP cytosolic tail interactors; co-localization (immunofluorescence); direct interaction mapping to YENPTY motif; RABGAP1 depletion/overexpression in neurons; APP trafficking and processing assays; GAP-dead mutant functional rescue","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct interaction mapped to specific motif, GAP-dead mutagenesis establishing mechanistic dependency, loss- and gain-of-function in neurons with molecular trafficking/processing readouts, published peer-reviewed","pmids":["40859033"],"is_preprint":false}],"current_model":"RABGAP1 (GAPCenA/TBC1D11) is a TBC-domain Rab GTPase-activating protein that stimulates GTP hydrolysis primarily on Rab6 (and to a lesser extent Rab4/Rab2), localizes to the cytosol, recycling endosomes, and centrosome, and regulates multiple vesicle trafficking pathways: it attenuates Rab11 activity to promote conformation-specific (active) β1 integrin recycling to the plasma membrane; modulates RAB activity on endosomal subdomains to control amyloid precursor protein (APP) sorting and processing via its PTB-domain interaction with YENPTY/NPxY motifs; supports mTORC1 signaling by influencing lysosomal positioning (in complex with TUFT1); and participates in mitotic progression by acting downstream of Rab6A' to regulate dynein/dynactin (p150Glued) dynamics at kinetochores and inactivation of the Mad2 spindle checkpoint."},"narrative":{"mechanistic_narrative":"RABGAP1 (GAPCenA/TBC1D11) is a TBC-domain Rab GTPase-activating protein that couples Rab-GTP hydrolysis to the control of endosomal vesicle trafficking and mitotic progression [PMID:10202141, PMID:32843574]. Its catalytic activity is specific for Rab6, with weaker activity on Rab4 and Rab2, residing in a central ~200-residue TBC domain related to the Bub2p/Cdc16p spindle-checkpoint family [PMID:10202141]. A separate PTB domain confers cargo-recognition: it binds the NPxY motif of the β1 integrin cytoplasmic tail to promote recycling of active integrins to the plasma membrane by attenuating Rab11 activity, with loss of RABGAP1 causing intracellular accumulation of active β1 integrins, altered focal adhesions, and reduced migration and invasion [PMID:32843574]; and it binds the YENPTY motif of the amyloid precursor protein (APP) to control APP sorting and processing in neurons in a manner dependent on RABGAP1 GAP activity [PMID:40859033]. RABGAP1 also supports endosomal/lysosomal positioning and mTORC1 signaling, acting downstream of TUFT1, and its loss disrupts early endosome and lysosome localization and lowers mTOR activity in patient-derived cells and Rabgap1-knockout mice, which display microcephaly, corpus callosum thinning, and ventriculomegaly [PMID:29423269, PMID:36083289]. In mitosis, RABGAP1 functions within a Rab6A'/p150(Glued) pathway at kinetochores, where its depletion phenocopies Rab6A' loss, causing a metaphase block with persistent Mad2 checkpoint activation and retained dynactin at kinetochores [PMID:16395330]. A minor centrosomal pool associates with γ-tubulin, linking RABGAP1 to microtubule and Golgi dynamics during the cell cycle [PMID:10202141].","teleology":[{"year":1999,"claim":"Establishing that RABGAP1 is an enzyme answered what biochemical activity it carries, defining it as a Rab6-preferential GAP whose catalytic core is a TBC domain.","evidence":"In vitro GAP activity assays across multiple Rabs with primary sequence analysis","pmids":["10202141"],"confidence":"High","gaps":["Cellular substrate specificity in vivo not yet resolved","Did not address regulation of the GAP activity"]},{"year":1999,"claim":"Localizing a minor pool to the centrosome and tying it to γ-tubulin began to connect the GAP to microtubule and Golgi dynamics in the cell cycle.","evidence":"Immunofluorescence, cell fractionation, and co-IP with γ-tubulin","pmids":["10202141"],"confidence":"Medium","gaps":["Functional consequence of centrosomal localization not established","Single lab, no orthogonal interaction validation"]},{"year":2000,"claim":"Mapping interaction to both Rab6A and Rab6A' isoforms refined which Rab6 species RABGAP1 engages and pinpointed an isoform-distinguishing residue.","evidence":"Co-precipitation and site-directed mutagenesis of Rab6 (position 87)","pmids":["11071909"],"confidence":"Medium","gaps":["Functional distinction between isoform binding not linked to a pathway here","Single lab"]},{"year":2006,"claim":"Loss-of-function epistasis placed RABGAP1 in a Rab6A'/p150(Glued) pathway controlling the metaphase-to-anaphase transition, revealing a mitotic role beyond trafficking.","evidence":"siRNA depletion with live-cell microscopy, kinetochore IF, Mad2 checkpoint assays, and Co-IP of a Rab6A'/p150(Glued) complex","pmids":["16395330"],"confidence":"High","gaps":["Direct GAP substrate at kinetochores not defined","How dynactin dynamics are mechanistically regulated unresolved"]},{"year":2006,"claim":"Identifying CARM1 as a PTB-domain partner whose co-expression rescues a PTB-induced cell cycle block established functional relevance of this interaction.","evidence":"Yeast two-hybrid and overexpression rescue in NIH3T3 cells","pmids":["17124247"],"confidence":"Medium","gaps":["Mechanistic role of CARM1 in normal RABGAP1 function unclear","Single lab, overexpression-based"]},{"year":2010,"claim":"A systematic Rab screen showed RABGAP1 binds Rab36 through a non-TBC domain, indicating Rab engagement beyond its catalytic substrate.","evidence":"GST pulldown with 60 Rab isoforms and mass spectrometry","pmids":["20070612"],"confidence":"Medium","gaps":["Functional consequence of Rab36 binding untested","Whether RABGAP1 has GAP activity on Rab36 not addressed"]},{"year":2015,"claim":"The Drosophila ortholog requirement for autophagosome formation in muscle extended RABGAP1 function into autophagy.","evidence":"RNAi knockdown in Drosophila primary myocytes with autophagy reporters and ATG epistasis","pmids":["25692684"],"confidence":"Medium","gaps":["Mammalian RABGAP1 role in autophagy not confirmed","Molecular mechanism in autophagosome formation undefined"]},{"year":2017,"claim":"Co-localization with transferrin receptor placed RABGAP1 on recycling endosomes, anchoring its trafficking role to a defined compartment.","evidence":"Fluorescence co-localization in MEFs within a screen of 43 TBC proteins","pmids":["28384198"],"confidence":"Medium","gaps":["No functional consequence linked in this study","Imaging-based localization only"]},{"year":2018,"claim":"Identifying TUFT1 as a partner connected RABGAP1 to lysosomal positioning and mTORC1 signaling, situating it downstream of TUFT1 in this axis.","evidence":"Co-IP plus lysosomal positioning, vesicular trafficking, and mTORC1 activity assays","pmids":["29423269"],"confidence":"Medium","gaps":["Direct Rab substrate linking RABGAP1 to lysosome positioning unidentified","Single lab"]},{"year":2020,"claim":"Mapping the PTB domain to the β1 integrin NPxY motif and demonstrating Rab11 attenuation defined a concrete cargo-recognition mechanism driving active integrin recycling and cell migration.","evidence":"siRNA silencing, Co-IP NPxY mapping, recycling and Rab11 activity assays, focal adhesion IF, migration/invasion in fibroblasts and breast cancer cells","pmids":["32843574"],"confidence":"High","gaps":["Whether Rab11 is a direct RABGAP1 GAP substrate not biochemically established","Conformation-specificity mechanism for active integrins not fully resolved"]},{"year":2022,"claim":"Human patient cells and a knockout mouse established RABGAP1 as required in vivo for endosome/lysosome positioning and mTOR signaling, with a neurodevelopmental phenotype.","evidence":"Patient lymphoblastoid functional studies, RNA-seq, endosome/lysosome IF, mTOR western blots, and Rabgap1 KO mouse phenotyping (microcephaly, corpus callosum thinning, ventriculomegaly)","pmids":["36083289"],"confidence":"High","gaps":["Causative mutation-to-phenotype mechanism in brain not fully detailed","Cell-type-specific drivers of microcephaly unresolved"]},{"year":2025,"claim":"Identifying direct binding to the APP YENPTY motif and GAP-activity dependence of APP trafficking extended RABGAP1 cargo recognition to neuronal APP sorting and processing.","evidence":"Unbiased APP-tail interaction screen, motif mapping, co-localization, depletion/overexpression and GAP-dead rescue in human and rodent neurons with trafficking/processing assays","pmids":["40859033"],"confidence":"High","gaps":["Which endosomal Rab substrate mediates APP control not pinned down","Relevance to disease-related APP processing not established"]},{"year":null,"claim":"The unifying question is which specific Rab substrate(s) RABGAP1 inactivates in each cargo context (integrins, APP, lysosome positioning) and how its PTB-domain cargo recognition is coupled to spatially restricted GAP activity on endosomal subdomains.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Direct in-cell GAP substrate for each pathway unidentified","Coupling between PTB cargo binding and GAP catalysis unresolved","No structural model of the multidomain protein on membranes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,10,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10,12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[8,11]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[10,12]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,11]}],"complexes":["Rab6A'/p150(Glued)/RABGAP1 kinetochore complex"],"partners":["RAB6A","RAB6A'","RAB36","TUBG1","CARM1","TUFT1","ITGB1","APP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y3P9","full_name":"Rab GTPase-activating protein 1","aliases":["GAP and centrosome-associated protein","Rab6 GTPase-activating protein GAPCenA"],"length_aa":1069,"mass_kda":121.7,"function":"May act as a GTPase-activating protein of RAB6A. May play a role in microtubule nucleation by centrosome. May participate in a RAB6A-mediated pathway involved in the metaphase-anaphase transition","subcellular_location":"Cytoplasm, cytosol; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q9Y3P9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RABGAP1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000011454","cell_line_id":"CID000447","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"vesicles","grade":3},{"compartment":"golgi","grade":2}],"interactors":[{"gene":"RABGAP1L","stoichiometry":10.0},{"gene":"SEC61B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000447","total_profiled":1310},"omim":[{"mim_id":"615882","title":"RAB GTPase-ACTIVATING PROTEIN 1; RABGAP1","url":"https://www.omim.org/entry/615882"},{"mim_id":"615852","title":"RAS-ASSOCIATED PROTEIN RAB6B; RAB6B","url":"https://www.omim.org/entry/615852"},{"mim_id":"612465","title":"TBC1 DOMAIN FAMILY, MEMBER 4; TBC1D4","url":"https://www.omim.org/entry/612465"},{"mim_id":"609238","title":"RAB GTPase-ACTIVATING PROTEIN 1-LIKE; RABGAP1L","url":"https://www.omim.org/entry/609238"}],"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/RABGAP1"},"hgnc":{"alias_symbol":["GAPCenA","TBC1D11"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y3P9","domains":[{"cath_id":"2.30.29.30","chopping":"143-267","consensus_level":"high","plddt":87.4309,"start":143,"end":267},{"cath_id":"2.60.40","chopping":"288-461_471-480","consensus_level":"high","plddt":86.5496,"start":288,"end":480},{"cath_id":"1.10.8.270","chopping":"558-678","consensus_level":"medium","plddt":92.4141,"start":558,"end":678},{"cath_id":"1.10.472.80","chopping":"679-836","consensus_level":"medium","plddt":93.4439,"start":679,"end":836},{"cath_id":"1.20.5","chopping":"895-967","consensus_level":"medium","plddt":85.6256,"start":895,"end":967}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y3P9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y3P9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y3P9-F1-predicted_aligned_error_v6.png","plddt_mean":76.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RABGAP1","jax_strain_url":"https://www.jax.org/strain/search?query=RABGAP1"},"sequence":{"accession":"Q9Y3P9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y3P9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y3P9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y3P9"}},"corpus_meta":[{"pmid":"10202141","id":"PMC_10202141","title":"Characterization of GAPCenA, a GTPase activating protein for Rab6, part of which associates with the centrosome.","date":"1999","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/10202141","citation_count":126,"is_preprint":false},{"pmid":"21500097","id":"PMC_21500097","title":"The antiproliferative effect of dietary fiber phenolic compounds ferulic acid and p-coumaric acid on the cell cycle of Caco-2 cells.","date":"2011","source":"Nutrition and cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21500097","citation_count":110,"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":"11071909","id":"PMC_11071909","title":"Alternative splicing of the human Rab6A gene generates two close but functionally different 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The GAP activity resides within a central ~200 amino acid TBC domain with similarity to yeast Rab-GAPs and spindle checkpoint proteins Bub2p/Cdc16p.\",\n      \"method\": \"In vitro GAP activity assay; primary sequence analysis; biochemical fractionation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic reconstitution, replicated in the founding characterization paper with substrate specificity established across multiple Rabs\",\n      \"pmids\": [\"10202141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A minor pool of GAPCenA (RABGAP1) associates with the centrosome, as shown by immunofluorescence and cell fractionation. GAPCenA forms complexes with cytosolic gamma-tubulin and plays a role in microtubule nucleation, suggesting involvement in coordinating microtubule and Golgi dynamics during the cell cycle.\",\n      \"method\": \"Immunofluorescence; cell fractionation; co-immunoprecipitation with gamma-tubulin\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct localization by two orthogonal methods (IF and fractionation) plus co-IP with gamma-tubulin, single lab\",\n      \"pmids\": [\"10202141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"GAPCenA (RABGAP1) interacts with both Rab6A and Rab6A' isoforms. Rab6A' interaction with GAPCenA was demonstrated by co-precipitation, and the functional distinction between the two isoforms was mapped to a single amino acid (position 87: T vs A).\",\n      \"method\": \"Co-immunoprecipitation/pulldown; site-directed mutagenesis of Rab6 isoforms\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction confirmed by pulldown, mutagenesis to single residue, single lab\",\n      \"pmids\": [\"11071909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GAPCenA (RABGAP1) depletion from cells phenocopies Rab6A' loss-of-function, causing metaphase block with activated Mad2-spindle checkpoint and retention of p150(Glued) (dynactin subunit) at kinetochores, placing RABGAP1 in the Rab6A'/p150(Glued)/GAPCenA pathway for metaphase-to-anaphase transition.\",\n      \"method\": \"siRNA depletion of GAPCenA; live-cell microscopy; kinetochore immunofluorescence; Mad2 checkpoint assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established by loss-of-function with specific molecular readouts (Mad2 activation, p150(Glued) localization), corroborated by parallel Rab6A' perturbation experiments\",\n      \"pmids\": [\"16395330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RABGAP1 (GAPCenA) participates in a complex with Rab6A' and p150(Glued) (dynein/dynactin subunit) at kinetochores, regulating dynein/dynactin dynamics required for spindle checkpoint inactivation.\",\n      \"method\": \"Co-immunoprecipitation; immunofluorescence co-localization at kinetochores\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and IF co-localization in single lab, functionally supported by siRNA rescue context\",\n      \"pmids\": [\"16395330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The PTB domain of RABGAP1 interacts with CARM1; co-overexpression of CARM1 rescues the cell cycle block induced by overexpression of the isolated RABGAP1 PTB domain, confirming functional relevance of this interaction in cell cycle progression.\",\n      \"method\": \"Yeast two-hybrid screen; overexpression dominant-negative rescue assay in NIH3T3 cells; cell cycle progression assay\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — interaction validated by functional rescue experiment in cells, single lab\",\n      \"pmids\": [\"17124247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"GAPCenA/TBC1D11 (RABGAP1) binds Rab36 via a domain other than its GAP domain (non-TBC domain interaction), identified through GST pulldown with 60 mammalian Rabs combined with mass spectrometry.\",\n      \"method\": \"GST pulldown with 60 Rab isoforms; mass spectrometric identification\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic GST pulldown screen with domain mapping, single lab, mass spec confirmation\",\n      \"pmids\": [\"20070612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Drosophila ortholog of RabGap1 is required for autophagosome formation specifically in skeletal muscle cells, identified by RNAi knockdown in a primary myocyte system with rapamycin/chloroquine-induced autophagy.\",\n      \"method\": \"RNAi knockdown in Drosophila primary myocytes; autophagosome formation assay (fluorescent reporters); epistasis with ATG gene knockdowns\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function in defined cellular context with specific autophagy readout, single lab, ortholog study\",\n      \"pmids\": [\"25692684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TBC1D11 (RABGAP1) co-localizes with transferrin receptor on recycling endosomes in mouse embryonic fibroblasts, establishing its recycling endosomal localization.\",\n      \"method\": \"Fluorescence co-localization with recycling endosome marker (transferrin receptor) in MEFs; systematic screen of 43 TBC proteins\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct imaging-based localization, part of systematic screen, no functional consequence linked in this paper\",\n      \"pmids\": [\"28384198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TUFT1 physically interacts with RABGAP1, and this interaction modulates intracellular lysosomal positioning, vesicular trafficking, and promotes mTORC1 signaling. RABGAP1 acts downstream of TUFT1 in regulating mTORC1 pathway activity.\",\n      \"method\": \"Co-immunoprecipitation (TUFT1–RABGAP1 interaction); lysosomal positioning assay; vesicular trafficking assay; mTORC1 activity readouts (phospho-S6K etc.)\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus functional cellular assays (lysosomal positioning, mTORC1 signaling), single lab\",\n      \"pmids\": [\"29423269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rabgap1 (RABGAP1) promotes recycling of active (open conformation) β1 integrins to the plasma membrane. The PTB domain of Rabgap1 binds the membrane-proximal NPxY motif in the β1 integrin cytoplasmic tail on endosomes. Silencing Rabgap1 causes intracellular accumulation of active β1 integrins, altered focal adhesion formation, and decreased cell migration and cancer cell invasion. The mechanism involves Rabgap1 attenuating Rab11 activity to facilitate recycling.\",\n      \"method\": \"siRNA silencing; co-immunoprecipitation (PTB domain–β1 integrin NPxY); integrin recycling assay; focal adhesion immunofluorescence; migration and invasion assays in fibroblasts and breast cancer cells; Rab11 activity assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP mapping to NPxY motif, recycling assay, Rab11 activity, migration/invasion phenotype) in single rigorous study, with domain-specific interaction and functional rescue\",\n      \"pmids\": [\"32843574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss-of-function of RABGAP1 in patient-derived lymphoblastoid cells causes downregulated mTOR signaling and abnormal localization of early endosomes and lysosomes. Rabgap1 knockout mice exhibit microcephaly, thinning of the corpus callosum, and ventriculomegaly, establishing RABGAP1 as necessary for normal endosomal/lysosomal positioning and mTOR signaling in vivo.\",\n      \"method\": \"Patient lymphoblastoid cell lines (functional studies); RNA sequencing; endosome/lysosome localization by immunofluorescence; mTOR pathway western blots; Rabgap1 KO mouse phenotyping\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — orthogonal human cell and mouse KO models with convergent mechanistic readouts (endosome localization, mTOR signaling), replicated across two experimental systems\",\n      \"pmids\": [\"36083289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RABGAP1 directly interacts with the YENPTY motif in the cytosolic tail of amyloid precursor protein (APP), identified by unbiased interaction screen. RABGAP1 partially co-localizes with APP. Depletion or overexpression of RABGAP1 causes mistrafficking and misprocessing of endogenous APP in human and rodent neurons. This effect is dependent on the GAP activity of RABGAP1, indicating that RABGAP1 modulates RAB activity on endosomal subdomains to control APP trafficking.\",\n      \"method\": \"Unbiased interaction screen for APP cytosolic tail interactors; co-localization (immunofluorescence); direct interaction mapping to YENPTY motif; RABGAP1 depletion/overexpression in neurons; APP trafficking and processing assays; GAP-dead mutant functional rescue\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct interaction mapped to specific motif, GAP-dead mutagenesis establishing mechanistic dependency, loss- and gain-of-function in neurons with molecular trafficking/processing readouts, published peer-reviewed\",\n      \"pmids\": [\"40859033\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RABGAP1 (GAPCenA/TBC1D11) is a TBC-domain Rab GTPase-activating protein that stimulates GTP hydrolysis primarily on Rab6 (and to a lesser extent Rab4/Rab2), localizes to the cytosol, recycling endosomes, and centrosome, and regulates multiple vesicle trafficking pathways: it attenuates Rab11 activity to promote conformation-specific (active) β1 integrin recycling to the plasma membrane; modulates RAB activity on endosomal subdomains to control amyloid precursor protein (APP) sorting and processing via its PTB-domain interaction with YENPTY/NPxY motifs; supports mTORC1 signaling by influencing lysosomal positioning (in complex with TUFT1); and participates in mitotic progression by acting downstream of Rab6A' to regulate dynein/dynactin (p150Glued) dynamics at kinetochores and inactivation of the Mad2 spindle checkpoint.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RABGAP1 (GAPCenA/TBC1D11) is a TBC-domain Rab GTPase-activating protein that couples Rab-GTP hydrolysis to the control of endosomal vesicle trafficking and mitotic progression [#0, #10]. Its catalytic activity is specific for Rab6, with weaker activity on Rab4 and Rab2, residing in a central ~200-residue TBC domain related to the Bub2p/Cdc16p spindle-checkpoint family [#0]. A separate PTB domain confers cargo-recognition: it binds the NPxY motif of the \\u03b21 integrin cytoplasmic tail to promote recycling of active integrins to the plasma membrane by attenuating Rab11 activity, with loss of RABGAP1 causing intracellular accumulation of active \\u03b21 integrins, altered focal adhesions, and reduced migration and invasion [#10]; and it binds the YENPTY motif of the amyloid precursor protein (APP) to control APP sorting and processing in neurons in a manner dependent on RABGAP1 GAP activity [#12]. RABGAP1 also supports endosomal/lysosomal positioning and mTORC1 signaling, acting downstream of TUFT1, and its loss disrupts early endosome and lysosome localization and lowers mTOR activity in patient-derived cells and Rabgap1-knockout mice, which display microcephaly, corpus callosum thinning, and ventriculomegaly [#9, #11]. In mitosis, RABGAP1 functions within a Rab6A'/p150(Glued) pathway at kinetochores, where its depletion phenocopies Rab6A' loss, causing a metaphase block with persistent Mad2 checkpoint activation and retained dynactin at kinetochores [#3, #4]. A minor centrosomal pool associates with \\u03b3-tubulin, linking RABGAP1 to microtubule and Golgi dynamics during the cell cycle [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that RABGAP1 is an enzyme answered what biochemical activity it carries, defining it as a Rab6-preferential GAP whose catalytic core is a TBC domain.\",\n      \"evidence\": \"In vitro GAP activity assays across multiple Rabs with primary sequence analysis\",\n      \"pmids\": [\"10202141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular substrate specificity in vivo not yet resolved\", \"Did not address regulation of the GAP activity\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Localizing a minor pool to the centrosome and tying it to \\u03b3-tubulin began to connect the GAP to microtubule and Golgi dynamics in the cell cycle.\",\n      \"evidence\": \"Immunofluorescence, cell fractionation, and co-IP with \\u03b3-tubulin\",\n      \"pmids\": [\"10202141\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of centrosomal localization not established\", \"Single lab, no orthogonal interaction validation\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mapping interaction to both Rab6A and Rab6A' isoforms refined which Rab6 species RABGAP1 engages and pinpointed an isoform-distinguishing residue.\",\n      \"evidence\": \"Co-precipitation and site-directed mutagenesis of Rab6 (position 87)\",\n      \"pmids\": [\"11071909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional distinction between isoform binding not linked to a pathway here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Loss-of-function epistasis placed RABGAP1 in a Rab6A'/p150(Glued) pathway controlling the metaphase-to-anaphase transition, revealing a mitotic role beyond trafficking.\",\n      \"evidence\": \"siRNA depletion with live-cell microscopy, kinetochore IF, Mad2 checkpoint assays, and Co-IP of a Rab6A'/p150(Glued) complex\",\n      \"pmids\": [\"16395330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct GAP substrate at kinetochores not defined\", \"How dynactin dynamics are mechanistically regulated unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying CARM1 as a PTB-domain partner whose co-expression rescues a PTB-induced cell cycle block established functional relevance of this interaction.\",\n      \"evidence\": \"Yeast two-hybrid and overexpression rescue in NIH3T3 cells\",\n      \"pmids\": [\"17124247\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic role of CARM1 in normal RABGAP1 function unclear\", \"Single lab, overexpression-based\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"A systematic Rab screen showed RABGAP1 binds Rab36 through a non-TBC domain, indicating Rab engagement beyond its catalytic substrate.\",\n      \"evidence\": \"GST pulldown with 60 Rab isoforms and mass spectrometry\",\n      \"pmids\": [\"20070612\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Rab36 binding untested\", \"Whether RABGAP1 has GAP activity on Rab36 not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The Drosophila ortholog requirement for autophagosome formation in muscle extended RABGAP1 function into autophagy.\",\n      \"evidence\": \"RNAi knockdown in Drosophila primary myocytes with autophagy reporters and ATG epistasis\",\n      \"pmids\": [\"25692684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian RABGAP1 role in autophagy not confirmed\", \"Molecular mechanism in autophagosome formation undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Co-localization with transferrin receptor placed RABGAP1 on recycling endosomes, anchoring its trafficking role to a defined compartment.\",\n      \"evidence\": \"Fluorescence co-localization in MEFs within a screen of 43 TBC proteins\",\n      \"pmids\": [\"28384198\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence linked in this study\", \"Imaging-based localization only\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying TUFT1 as a partner connected RABGAP1 to lysosomal positioning and mTORC1 signaling, situating it downstream of TUFT1 in this axis.\",\n      \"evidence\": \"Co-IP plus lysosomal positioning, vesicular trafficking, and mTORC1 activity assays\",\n      \"pmids\": [\"29423269\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Rab substrate linking RABGAP1 to lysosome positioning unidentified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapping the PTB domain to the \\u03b21 integrin NPxY motif and demonstrating Rab11 attenuation defined a concrete cargo-recognition mechanism driving active integrin recycling and cell migration.\",\n      \"evidence\": \"siRNA silencing, Co-IP NPxY mapping, recycling and Rab11 activity assays, focal adhesion IF, migration/invasion in fibroblasts and breast cancer cells\",\n      \"pmids\": [\"32843574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Rab11 is a direct RABGAP1 GAP substrate not biochemically established\", \"Conformation-specificity mechanism for active integrins not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Human patient cells and a knockout mouse established RABGAP1 as required in vivo for endosome/lysosome positioning and mTOR signaling, with a neurodevelopmental phenotype.\",\n      \"evidence\": \"Patient lymphoblastoid functional studies, RNA-seq, endosome/lysosome IF, mTOR western blots, and Rabgap1 KO mouse phenotyping (microcephaly, corpus callosum thinning, ventriculomegaly)\",\n      \"pmids\": [\"36083289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causative mutation-to-phenotype mechanism in brain not fully detailed\", \"Cell-type-specific drivers of microcephaly unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying direct binding to the APP YENPTY motif and GAP-activity dependence of APP trafficking extended RABGAP1 cargo recognition to neuronal APP sorting and processing.\",\n      \"evidence\": \"Unbiased APP-tail interaction screen, motif mapping, co-localization, depletion/overexpression and GAP-dead rescue in human and rodent neurons with trafficking/processing assays\",\n      \"pmids\": [\"40859033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which endosomal Rab substrate mediates APP control not pinned down\", \"Relevance to disease-related APP processing not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying question is which specific Rab substrate(s) RABGAP1 inactivates in each cargo context (integrins, APP, lysosome positioning) and how its PTB-domain cargo recognition is coupled to spatially restricted GAP activity on endosomal subdomains.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct in-cell GAP substrate for each pathway unidentified\", \"Coupling between PTB cargo binding and GAP catalysis unresolved\", \"No structural model of the multidomain protein on membranes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 10, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [10, 12]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"complexes\": [\n      \"Rab6A'/p150(Glued)/RABGAP1 kinetochore complex\"\n    ],\n    \"partners\": [\n      \"RAB6A\",\n      \"RAB6A'\",\n      \"RAB36\",\n      \"TUBG1\",\n      \"CARM1\",\n      \"TUFT1\",\n      \"ITGB1\",\n      \"APP\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}