Affinage

RABGAP1

Rab GTPase-activating protein 1 · UniProt Q9Y3P9

Length
1069 aa
Mass
121.7 kDa
Annotated
2026-06-10
31 papers in source corpus 11 papers cited in narrative 13 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

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1999 High

    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

    PMID:10202141

    Open questions at the time
    • Cellular substrate specificity in vivo not yet resolved
    • Did not address regulation of the GAP activity
  2. 1999 Medium

    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

    PMID:10202141

    Open questions at the time
    • Functional consequence of centrosomal localization not established
    • Single lab, no orthogonal interaction validation
  3. 2000 Medium

    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)

    PMID:11071909

    Open questions at the time
    • Functional distinction between isoform binding not linked to a pathway here
    • Single lab
  4. 2006 High

    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

    PMID:16395330

    Open questions at the time
    • Direct GAP substrate at kinetochores not defined
    • How dynactin dynamics are mechanistically regulated unresolved
  5. 2006 Medium

    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

    PMID:17124247

    Open questions at the time
    • Mechanistic role of CARM1 in normal RABGAP1 function unclear
    • Single lab, overexpression-based
  6. 2010 Medium

    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

    PMID:20070612

    Open questions at the time
    • Functional consequence of Rab36 binding untested
    • Whether RABGAP1 has GAP activity on Rab36 not addressed
  7. 2015 Medium

    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

    PMID:25692684

    Open questions at the time
    • Mammalian RABGAP1 role in autophagy not confirmed
    • Molecular mechanism in autophagosome formation undefined
  8. 2017 Medium

    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

    PMID:28384198

    Open questions at the time
    • No functional consequence linked in this study
    • Imaging-based localization only
  9. 2018 Medium

    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

    PMID:29423269

    Open questions at the time
    • Direct Rab substrate linking RABGAP1 to lysosome positioning unidentified
    • Single lab
  10. 2020 High

    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

    PMID:32843574

    Open questions at the time
    • Whether Rab11 is a direct RABGAP1 GAP substrate not biochemically established
    • Conformation-specificity mechanism for active integrins not fully resolved
  11. 2022 High

    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)

    PMID:36083289

    Open questions at the time
    • Causative mutation-to-phenotype mechanism in brain not fully detailed
    • Cell-type-specific drivers of microcephaly unresolved
  12. 2025 High

    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

    PMID:40859033

    Open questions at the time
    • Which endosomal Rab substrate mediates APP control not pinned down
    • Relevance to disease-related APP processing not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005768 endosome 2 GO:0005815 microtubule organizing center 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
APPCARM1ITGB1RAB36RAB6ARAB6A'TUBG1TUFT1
Complex memberships
Rab6A'/p150(Glued)/RABGAP1 kinetochore complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 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. In vitro GAP activity assay; primary sequence analysis; biochemical fractionation The EMBO journal High 10202141
1999 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. Immunofluorescence; cell fractionation; co-immunoprecipitation with gamma-tubulin The EMBO journal Medium 10202141
2000 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). Co-immunoprecipitation/pulldown; site-directed mutagenesis of Rab6 isoforms Molecular biology of the cell Medium 11071909
2006 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. siRNA depletion of GAPCenA; live-cell microscopy; kinetochore immunofluorescence; Mad2 checkpoint assay The EMBO journal High 16395330
2006 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. Co-immunoprecipitation; immunofluorescence co-localization at kinetochores The EMBO journal Medium 16395330
2006 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. Yeast two-hybrid screen; overexpression dominant-negative rescue assay in NIH3T3 cells; cell cycle progression assay Molecular & cellular proteomics Medium 17124247
2010 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. GST pulldown with 60 Rab isoforms; mass spectrometric identification Traffic Medium 20070612
2015 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. RNAi knockdown in Drosophila primary myocytes; autophagosome formation assay (fluorescent reporters); epistasis with ATG gene knockdowns PLoS genetics Medium 25692684
2017 TBC1D11 (RABGAP1) co-localizes with transferrin receptor on recycling endosomes in mouse embryonic fibroblasts, establishing its recycling endosomal localization. Fluorescence co-localization with recycling endosome marker (transferrin receptor) in MEFs; systematic screen of 43 TBC proteins PloS one Medium 28384198
2018 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. Co-immunoprecipitation (TUFT1–RABGAP1 interaction); lysosomal positioning assay; vesicular trafficking assay; mTORC1 activity readouts (phospho-S6K etc.) Cell discovery Medium 29423269
2020 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. 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 of cell science High 32843574
2022 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. Patient lymphoblastoid cell lines (functional studies); RNA sequencing; endosome/lysosome localization by immunofluorescence; mTOR pathway western blots; Rabgap1 KO mouse phenotyping Genetics in medicine High 36083289
2025 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. 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 The EMBO journal High 40859033

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Characterization of GAPCenA, a GTPase activating protein for Rab6, part of which associates with the centrosome. The EMBO journal 126 10202141
2011 The antiproliferative effect of dietary fiber phenolic compounds ferulic acid and p-coumaric acid on the cell cycle of Caco-2 cells. Nutrition and cancer 110 21500097
2010 Comprehensive screening for novel rab-binding proteins by GST pull-down assay using 60 different mammalian Rabs. Traffic (Copenhagen, Denmark) 100 20070612
2000 Alternative splicing of the human Rab6A gene generates two close but functionally different isoforms. Molecular biology of the cell 98 11071909
2019 Identification of crucial genes in abdominal aortic aneurysm by WGCNA. PeerJ 88 31608184
2015 Type 2 diabetes alters metabolic and transcriptional signatures of glucose and amino acid metabolism during exercise and recovery. Diabetologia 72 26067360
2006 A role for the Rab6A' GTPase in the inactivation of the Mad2-spindle checkpoint. The EMBO journal 67 16395330
2013 Identification of microRNAs regulated by isothiocyanates and association of polymorphisms inside their target sites with risk of sporadic colorectal cancer. Nutrition and cancer 43 23441612
2018 TUFT1 interacts with RABGAP1 and regulates mTORC1 signaling. Cell discovery 40 29423269
2006 Identification of the ligands of protein interaction domains through a functional approach. Molecular & cellular proteomics : MCP 29 17124247
2015 Regulators of autophagosome formation in Drosophila muscles. PLoS genetics 26 25692684
2019 Whole Exome Sequencing of Ulcerative Colitis-associated Colorectal Cancer Based on Novel Somatic Mutations Identified in Chinese Patients. Inflammatory bowel diseases 21 30794281
2020 Rabgap1 promotes recycling of active β1 integrins to support effective cell migration. Journal of cell science 18 32843574
2017 TBC1D12 is a novel Rab11-binding protein that modulates neurite outgrowth of PC12 cells. PloS one 18 28384198
2023 Knockout mouse models as a resource for the study of rare diseases. Mammalian genome : official journal of the International Mammalian Genome Society 17 37160609
2020 GWA-based pleiotropic analysis identified potential SNPs and genes related to type 2 diabetes and obesity. Journal of human genetics 13 32948839
2014 The JNK1/JNK3 interactome--contributions by the JNK3 unique N-terminus and JNK common docking site residues. Biochemical and biophysical research communications 11 25301550
2022 Biallelic loss-of-function variants in RABGAP1 cause a novel neurodevelopmental syndrome. Genetics in medicine : official journal of the American College of Medical Genetics 10 36083289
2017 Bovine ovarian follicular growth and development correlate with lysophosphatidic acid expression. Theriogenology 9 29028570
2023 Differential DNA methylation associated with multiple sclerosis and disease modifying treatments in an underrepresented minority population. Frontiers in genetics 8 36685876
2017 Dissecting the genetic components of a quantitative trait locus for blood pressure and renal pathology on rat chromosome 3. Journal of hypertension 7 27755386
2016 GPR21 KO mice demonstrate no resistance to high fat diet induced obesity or improved glucose tolerance. F1000Research 7 27081476
2007 Simple repeat evolution includes dramatic primary sequence changes that conserve folding potential. Biochemical and biophysical research communications 7 17320822
2019 Predication of hub target genes of differentially expressed microRNAs contributing to Helicobacter pylori infection in gastric non-cancerous tissue. Gastroenterology and hepatology from bed to bench 4 32099601
2015 RECURRENT RAB3GAP1 MUTATIONS IN THE TURKISH POPULATION. Genetic counseling (Geneva, Switzerland) 4 26852512
2009 Derivation of a novel undifferentiated human foetal phenotype in serum-free cultures with BMP-2. Journal of cellular and molecular medicine 4 19438813
2025 Association and shared biological bases between birth weight and cortical structure. Translational psychiatry 3 40044659
2024 Genetic Findings in Short Turkish Children Born to Consanguineous Parents. Hormone research in paediatrics 2 38838658
2025 The effect of high-level dietary Laminaria digitata on the muscle proteome and metabolome of weaned piglets. Research in veterinary science 1 40199047
2025 RABGAP1 is a sensor that facilitates the sorting and processing of amyloid precursor protein. The EMBO journal 1 40859033
2023 Rare 15q21.1q22.31 Duplication Due to a Familial Chromosomal Insertion and Diagnostic Investigation in a Carrier of Balanced Chromosomal Rearrangement and Intellectual Disability. Genes 1 37107643

Missed literature

Know a paper Affinage missed for RABGAP1? Flag it for the maintainers and the community.

No submissions yet.