{"gene":"RABEP2","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1998,"finding":"RABEP2 (initially named Rabaptin-5beta) was identified as a novel 62 kDa coiled-coil protein that specifically interacts with the GTP-bound form of Rab5. Unlike Rabaptin-5, Rabaptin-5beta does not heterodimerize with Rabaptin-5 but forms a distinct complex with Rabex-5, the GDP/GTP exchange factor for Rab5. Immunodepletion experiments showed that the Rabaptin-5beta complex partially inhibits early endosome fusion in vitro, and maximal endocytic membrane fusion efficiency requires both Rabaptin-5 and Rabaptin-5beta complexes.","method":"Yeast two-hybrid screen, Co-immunoprecipitation, in vitro endosome fusion assay, immunodepletion","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — yeast two-hybrid identification confirmed by biochemical reconstitution (in vitro fusion assay) and immunodepletion with rescue; multiple orthogonal methods in single study","pmids":["9524116"],"is_preprint":false},{"year":2016,"finding":"RABEP2 was identified as an interaction partner of SDCCAG8 at the centrosome using affinity proteomics. RABEP2 localization at the centrosome is regulated by SDCCAG8, as loss of SDCCAG8 disrupts RABEP2 centrosomal localization. siRNA-mediated knockdown of RABEP2 in hTERT-RPE1 cells leads to defective ciliogenesis, demonstrating a critical role for RABEP2 in this process.","method":"Affinity proteomics (AP-MS), immunofluorescence localization, siRNA knockdown with ciliogenesis phenotypic readout","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — AP-MS interaction confirmed by localization studies and functional siRNA knockdown, single lab with multiple orthogonal methods","pmids":["27224062"],"is_preprint":false},{"year":2018,"finding":"RABEP2 interacts with the small GTPase Rab4 and regulates VEGFR2 endosomal trafficking to maintain cell-surface expression of VEGFR2 and VEGF signaling. Loss of RABEP2 leads to prolonged retention of VEGFR2 in Rab5-positive sorting endosomes, increasing VEGFR2 exposure to phosphotyrosine phosphatase 1b (PTP1b) and causing diminished VEGFR2 signaling. Additionally, loss of RABEP2 increases VEGFR2 degradation by diverting it to Rab7-positive endosomes destined for the lysosome.","method":"High-resolution microscopy, biochemical assays (Co-IP), siRNA knockdown, endosomal trafficking assays with Rab marker colocalization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP demonstrating Rab4 interaction, combined with high-resolution live imaging of endosomal compartments, loss-of-function with defined molecular and signaling phenotypes","pmids":["29425100"],"is_preprint":false}],"current_model":"RABEP2 is a Rab GTPase-binding effector protein that interacts with Rab5 (mediating early endosome fusion) and Rab4, regulating endosomal recycling of VEGFR2 to the cell surface; loss of RABEP2 diverts VEGFR2 to Rab5-positive sorting endosomes (where it is inactivated by PTP1b) and to Rab7-positive late endosomes for lysosomal degradation, thereby attenuating VEGF signaling, and RABEP2 also localizes to the centrosome in a SDCCAG8-dependent manner where it is required for ciliogenesis."},"narrative":{"teleology":[{"year":1998,"claim":"The discovery of Rabaptin-5β (RABEP2) as a Rab5-GTP effector that forms a distinct complex with Rabex-5 established that early endosome fusion relies on parallel, non-redundant Rab5 effector pathways rather than a single Rabaptin-5 complex.","evidence":"Yeast two-hybrid screen, co-immunoprecipitation, and in vitro endosome fusion assay with immunodepletion","pmids":["9524116"],"confidence":"High","gaps":["Cargo specificity of the RABEP2–Rabex-5 complex was not defined","Whether RABEP2 participates in recycling versus degradative sorting was unknown","Structural basis for selective Rab5-GTP binding was not resolved"]},{"year":2016,"claim":"Identification of RABEP2 at the centrosome, dependent on SDCCAG8, and its requirement for ciliogenesis extended RABEP2 function beyond endosome fusion to organelle biogenesis and revealed a non-endosomal cellular role.","evidence":"AP-MS proteomics of SDCCAG8, immunofluorescence localization, and siRNA knockdown of RABEP2 in hTERT-RPE1 cells with ciliogenesis readout","pmids":["27224062"],"confidence":"Medium","gaps":["No independent replication of the ciliogenesis phenotype in a second cell line or organism","Mechanism by which RABEP2 promotes cilium assembly (e.g., vesicle delivery vs. structural role) was not determined","Whether the centrosomal and endosomal pools of RABEP2 are functionally coupled is unknown"]},{"year":2018,"claim":"Demonstrating that RABEP2 binds Rab4 and controls VEGFR2 recycling resolved how RABEP2 connects endosomal sorting to receptor tyrosine kinase signaling output, explaining how loss of RABEP2 causes VEGFR2 misrouting, dephosphorylation by PTP1b, and lysosomal degradation.","evidence":"Reciprocal co-immunoprecipitation, siRNA knockdown, high-resolution live-cell imaging with Rab5/Rab7 markers, and VEGFR2 signaling readouts","pmids":["29425100"],"confidence":"High","gaps":["Whether RABEP2 regulates recycling of other receptor tyrosine kinases beyond VEGFR2 is untested","No in vivo (animal model) validation of vascular or angiogenic phenotypes upon RABEP2 loss","Structural basis for the Rab4 interaction and its relationship to the Rab5/Rabex-5 complex remains uncharacterized"]},{"year":null,"claim":"It remains unknown how RABEP2's endosomal recycling and centrosomal/ciliogenesis functions are coordinated, whether RABEP2 has additional cargo clients beyond VEGFR2, and what in vivo phenotypes result from RABEP2 loss in a whole organism.","evidence":"","pmids":[],"confidence":"Low","gaps":["No animal knockout or disease model for RABEP2 has been reported","No structural data exist for RABEP2 or its complexes","Functional relationship between Rab5- and Rab4-binding activities within RABEP2 is unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,2]},{"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":[0,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1]}],"complexes":[],"partners":["RAB5A","RABGEF1","RAB4A","SDCCAG8"],"other_free_text":[]},"mechanistic_narrative":"RABEP2 (Rabaptin-5β) is a coiled-coil Rab GTPase effector that participates in endosomal membrane trafficking and ciliogenesis. It binds GTP-loaded Rab5 and forms a complex with the Rab5 exchange factor Rabex-5 to promote early endosome fusion, while its interaction with Rab4 directs recycling of internalized VEGFR2 back to the plasma membrane; loss of RABEP2 traps VEGFR2 in Rab5-positive sorting endosomes (exposing it to PTP1b-mediated dephosphorylation) and diverts it to Rab7-positive late endosomes for lysosomal degradation, thereby attenuating VEGF signaling [PMID:9524116, PMID:29425100]. RABEP2 also localizes to the centrosome in an SDCCAG8-dependent manner and is required for ciliogenesis [PMID:27224062]."},"prefetch_data":{"uniprot":{"accession":"Q9H5N1","full_name":"Rab GTPase-binding effector protein 2","aliases":["Rabaptin-5beta"],"length_aa":569,"mass_kda":63.5,"function":"Plays a role in membrane trafficking and in homotypic early endosome fusion (PubMed:9524116). Participates in arteriogenesis by regulating vascular endothelial growth factor receptor 2/VEGFR2 cell surface expression and endosomal trafficking (PubMed:29425100). By interacting with SDCCAG8, localizes to centrosomes and plays a critical role in ciliogenesis (PubMed:27224062)","subcellular_location":"Cytoplasm; Early endosome; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/Q9H5N1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RABEP2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RABEP2","total_profiled":1310},"omim":[{"mim_id":"611869","title":"RABAPTIN, RAB GTPase-BINDING EFFECTOR PROTEIN 2; RABEP2","url":"https://www.omim.org/entry/611869"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RABEP2"},"hgnc":{"alias_symbol":["FRA","FLJ23282"],"prev_symbol":[]},"alphafold":{"accession":"Q9H5N1","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H5N1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H5N1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H5N1-F1-predicted_aligned_error_v6.png","plddt_mean":77.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RABEP2","jax_strain_url":"https://www.jax.org/strain/search?query=RABEP2"},"sequence":{"accession":"Q9H5N1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H5N1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H5N1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H5N1"}},"corpus_meta":[{"pmid":"3133553","id":"PMC_3133553","title":"fra-1: a serum-inducible, cellular immediate-early gene that encodes a fos-related antigen.","date":"1988","source":"Molecular and 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interactors.","date":"2024","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/38803224","citation_count":23,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49757,"output_tokens":630,"usd":0.079361},"stage2":{"model":"claude-opus-4-6","input_tokens":3793,"output_tokens":1087,"usd":0.06921},"total_usd":0.34569,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":62693,"output_tokens":1735,"usd":0.107052},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":4524,"output_tokens":1497,"usd":0.090067}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"RABEP2 interacts with the small GTPase Rab4 and regulates VEGFR2 endosomal trafficking to maintain cell-surface expression of VEGFR2 and VEGF signaling. Loss of RABEP2 causes prolonged retention of VEGFR2 in Rab5-positive sorting endosomes, increasing VEGFR2 exposure to PTP1b and diminishing signaling, and also diverts VEGFR2 to Rab7-positive lysosomes for degradation.\",\n      \"method\": \"High-resolution microscopy, biochemical assays, Co-IP, siRNA knockdown with defined endosomal trafficking readouts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (microscopy, biochemistry, KD) with specific mechanistic readouts in a single study\",\n      \"pmids\": [\"29425100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RABEP2 interacts with SDCCAG8 and localizes at the centrosome; SDCCAG8 regulates RABEP2 centrosomal localization. siRNA-mediated RABEP2 knockdown in hTERT-RPE1 cells leads to defective ciliogenesis, indicating a critical role for RABEP2 in this process.\",\n      \"method\": \"Affinity proteomics (Co-IP/MS), siRNA knockdown with ciliogenesis readout, immunofluorescence localization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — affinity proteomics plus functional KD phenotype, single study\",\n      \"pmids\": [\"27224062\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RABEP2 is a Rab GTPase-binding effector protein that interacts with Rab4 to promote recycling of VEGFR2 from early (Rab5-positive) endosomes back to the cell surface, thereby sustaining VEGFR2 signaling and preventing its lysosomal degradation via Rab7-positive endosomes; RABEP2 also localizes to the centrosome in a SDCCAG8-dependent manner and is required for ciliogenesis.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking through the corpus, I need to identify papers actually about RABEP2 (Rab GTPase-binding effector protein 2).\n\n**Classification:**\n\n- Papers [1]-[30] in the main corpus (fra-1, fra-2, fragile X, strawberry allergens, cyanobacterial Fra proteins, Chagas disease FRA, barley Fra, ash pollen Fra e 1): All EXCLUDE — alias collisions with unrelated genes/proteins sharing \"Fra\" abbreviation.\n\n- Paper [51] \"The Rab-effector protein RABEP2 regulates endosomal trafficking to mediate VEGFR2-dependent signaling\" (PMID:29425100): KEEP — directly about RABEP2.\n\n- Paper [95] \"SDCCAG8 Interacts with RAB Effector Proteins RABEP2 and ERC1 and Is Required for Hedgehog Signaling\" (PMID:27224062): KEEP — directly about RABEP2.\n\n**From curated papers:**\n- PMID:23128233 (IBD GWAS), PMID:12477932, PMID:26186194, PMID:28514442, PMID:26496610, PMID:14702039, PMID:33961781, PMID:21873635, PMID:23563607, PMID:15489334, PMID:22863883, PMID:23314748, PMID:27173435, PMID:21988832, PMID:21516116, PMID:29117863, PMID:28190767, PMID:10720461, PMID:9524116, PMID:27880917, PMID:33111431, PMID:25921289, PMID:36138187, PMID:25260751, PMID:33277362, PMID:30455363, PMID:36215168, PMID:17205062, PMID:33853758, PMID:38803224: Most are GWAS, interactome surveys, or unrelated mechanistic papers. \n\nKEEP from curated:\n- PMID:10720461 (Rab effector purification methodology — foundational for Rab biology but not specifically RABEP2)\n- PMID:9524116 (Rabaptin-5beta = RABEP2 precursor identification): KEEP\n- PMID:30455363 (RABEP2 upregulated by H. pylori — expression only, no mechanism): EXCLUDE\n- PMID:27224062 already in main corpus as [95]\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"RABEP2 (initially named Rabaptin-5beta) was identified as a novel 62 kDa coiled-coil protein that specifically interacts with the GTP-bound form of Rab5. Unlike Rabaptin-5, Rabaptin-5beta does not heterodimerize with Rabaptin-5 but forms a distinct complex with Rabex-5, the GDP/GTP exchange factor for Rab5. Immunodepletion experiments showed that the Rabaptin-5beta complex partially inhibits early endosome fusion in vitro, and maximal endocytic membrane fusion efficiency requires both Rabaptin-5 and Rabaptin-5beta complexes.\",\n      \"method\": \"Yeast two-hybrid screen, Co-immunoprecipitation, in vitro endosome fusion assay, immunodepletion\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — yeast two-hybrid identification confirmed by biochemical reconstitution (in vitro fusion assay) and immunodepletion with rescue; multiple orthogonal methods in single study\",\n      \"pmids\": [\"9524116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RABEP2 was identified as an interaction partner of SDCCAG8 at the centrosome using affinity proteomics. RABEP2 localization at the centrosome is regulated by SDCCAG8, as loss of SDCCAG8 disrupts RABEP2 centrosomal localization. siRNA-mediated knockdown of RABEP2 in hTERT-RPE1 cells leads to defective ciliogenesis, demonstrating a critical role for RABEP2 in this process.\",\n      \"method\": \"Affinity proteomics (AP-MS), immunofluorescence localization, siRNA knockdown with ciliogenesis phenotypic readout\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — AP-MS interaction confirmed by localization studies and functional siRNA knockdown, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27224062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RABEP2 interacts with the small GTPase Rab4 and regulates VEGFR2 endosomal trafficking to maintain cell-surface expression of VEGFR2 and VEGF signaling. Loss of RABEP2 leads to prolonged retention of VEGFR2 in Rab5-positive sorting endosomes, increasing VEGFR2 exposure to phosphotyrosine phosphatase 1b (PTP1b) and causing diminished VEGFR2 signaling. Additionally, loss of RABEP2 increases VEGFR2 degradation by diverting it to Rab7-positive endosomes destined for the lysosome.\",\n      \"method\": \"High-resolution microscopy, biochemical assays (Co-IP), siRNA knockdown, endosomal trafficking assays with Rab marker colocalization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP demonstrating Rab4 interaction, combined with high-resolution live imaging of endosomal compartments, loss-of-function with defined molecular and signaling phenotypes\",\n      \"pmids\": [\"29425100\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RABEP2 is a Rab GTPase-binding effector protein that interacts with Rab5 (mediating early endosome fusion) and Rab4, regulating endosomal recycling of VEGFR2 to the cell surface; loss of RABEP2 diverts VEGFR2 to Rab5-positive sorting endosomes (where it is inactivated by PTP1b) and to Rab7-positive late endosomes for lysosomal degradation, thereby attenuating VEGF signaling, and RABEP2 also localizes to the centrosome in a SDCCAG8-dependent manner where it is required for ciliogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RABEP2 is a Rab GTPase effector that interacts with Rab4 to direct VEGFR2 recycling from Rab5-positive sorting endosomes back to the plasma membrane, thereby sustaining cell-surface VEGFR2 levels and VEGF signaling; loss of RABEP2 prolongs VEGFR2 retention in sorting endosomes, increases its dephosphorylation by PTP1b, and diverts the receptor to Rab7-positive lysosomes for degradation [PMID:29425100]. RABEP2 also localizes to the centrosome in an SDCCAG8-dependent manner and is required for ciliogenesis in retinal pigment epithelial cells [PMID:27224062].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Whether RABEP2 functions beyond generic endosomal trafficking was unknown; the demonstration that it localizes to the centrosome via SDCCAG8 and is required for ciliogenesis established an unexpected role at the centrosome–cilium axis.\",\n      \"evidence\": \"Affinity proteomics (Co-IP/MS), immunofluorescence, and siRNA knockdown with ciliogenesis readout in hTERT-RPE1 cells\",\n      \"pmids\": [\"27224062\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study without independent replication of the ciliogenesis phenotype\",\n        \"Mechanism by which RABEP2 promotes ciliogenesis (cargo, membrane trafficking step) is undefined\",\n        \"Whether the centrosomal and endosomal functions of RABEP2 are linked or independent is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The specific endosomal trafficking step controlled by RABEP2 was undefined; this work showed that RABEP2 binds Rab4 and channels VEGFR2 from Rab5-positive sorting endosomes into a Rab4-dependent recycling route, preventing lysosomal degradation and sustaining VEGF signaling.\",\n      \"evidence\": \"High-resolution microscopy, Co-IP, biochemical assays, and siRNA knockdown with quantitative endosomal marker and VEGFR2 trafficking readouts\",\n      \"pmids\": [\"29425100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether RABEP2 acts on cargoes beyond VEGFR2 through the same Rab4-dependent mechanism is unknown\",\n        \"Structural basis of the RABEP2–Rab4 interaction has not been determined\",\n        \"In vivo validation of the VEGFR2-recycling phenotype in animal models is lacking\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how RABEP2's centrosomal/ciliogenesis role relates mechanistically to its Rab4-dependent endosomal recycling function, and whether additional Rab GTPases or cargoes are regulated by RABEP2.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural data for RABEP2 or its complexes exist\",\n        \"Physiological consequences of RABEP2 loss in vivo have not been characterized\",\n        \"Full spectrum of RABEP2-regulated endosomal cargoes is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RAB4A\",\n      \"SDCCAG8\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"RABEP2 (Rabaptin-5β) is a coiled-coil Rab GTPase effector that participates in endosomal membrane trafficking and ciliogenesis. It binds GTP-loaded Rab5 and forms a complex with the Rab5 exchange factor Rabex-5 to promote early endosome fusion, while its interaction with Rab4 directs recycling of internalized VEGFR2 back to the plasma membrane; loss of RABEP2 traps VEGFR2 in Rab5-positive sorting endosomes (exposing it to PTP1b-mediated dephosphorylation) and diverts it to Rab7-positive late endosomes for lysosomal degradation, thereby attenuating VEGF signaling [PMID:9524116, PMID:29425100]. RABEP2 also localizes to the centrosome in an SDCCAG8-dependent manner and is required for ciliogenesis [PMID:27224062].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"The discovery of Rabaptin-5β (RABEP2) as a Rab5-GTP effector that forms a distinct complex with Rabex-5 established that early endosome fusion relies on parallel, non-redundant Rab5 effector pathways rather than a single Rabaptin-5 complex.\",\n      \"evidence\": \"Yeast two-hybrid screen, co-immunoprecipitation, and in vitro endosome fusion assay with immunodepletion\",\n      \"pmids\": [\"9524116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cargo specificity of the RABEP2–Rabex-5 complex was not defined\",\n        \"Whether RABEP2 participates in recycling versus degradative sorting was unknown\",\n        \"Structural basis for selective Rab5-GTP binding was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of RABEP2 at the centrosome, dependent on SDCCAG8, and its requirement for ciliogenesis extended RABEP2 function beyond endosome fusion to organelle biogenesis and revealed a non-endosomal cellular role.\",\n      \"evidence\": \"AP-MS proteomics of SDCCAG8, immunofluorescence localization, and siRNA knockdown of RABEP2 in hTERT-RPE1 cells with ciliogenesis readout\",\n      \"pmids\": [\"27224062\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No independent replication of the ciliogenesis phenotype in a second cell line or organism\",\n        \"Mechanism by which RABEP2 promotes cilium assembly (e.g., vesicle delivery vs. structural role) was not determined\",\n        \"Whether the centrosomal and endosomal pools of RABEP2 are functionally coupled is unknown\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that RABEP2 binds Rab4 and controls VEGFR2 recycling resolved how RABEP2 connects endosomal sorting to receptor tyrosine kinase signaling output, explaining how loss of RABEP2 causes VEGFR2 misrouting, dephosphorylation by PTP1b, and lysosomal degradation.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, siRNA knockdown, high-resolution live-cell imaging with Rab5/Rab7 markers, and VEGFR2 signaling readouts\",\n      \"pmids\": [\"29425100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether RABEP2 regulates recycling of other receptor tyrosine kinases beyond VEGFR2 is untested\",\n        \"No in vivo (animal model) validation of vascular or angiogenic phenotypes upon RABEP2 loss\",\n        \"Structural basis for the Rab4 interaction and its relationship to the Rab5/Rabex-5 complex remains uncharacterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how RABEP2's endosomal recycling and centrosomal/ciliogenesis functions are coordinated, whether RABEP2 has additional cargo clients beyond VEGFR2, and what in vivo phenotypes result from RABEP2 loss in a whole organism.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No animal knockout or disease model for RABEP2 has been reported\",\n        \"No structural data exist for RABEP2 or its complexes\",\n        \"Functional relationship between Rab5- and Rab4-binding activities within RABEP2 is unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RAB5A\",\n      \"RABGEF1\",\n      \"RAB4A\",\n      \"SDCCAG8\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}