{"gene":"RABEP2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"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 caused prolonged retention of VEGFR2 in Rab5-positive sorting endosomes, increasing VEGFR2 exposure to phosphotyrosine phosphatase 1b (PTP1b) and diminishing VEGFR2 signaling. Loss of RABEP2 also increased VEGFR2 degradation by diverting it to Rab7-positive endosomes destined for the lysosome.","method":"High-resolution microscopy, biochemical assays (co-immunoprecipitation/pulldown), endosomal fractionation, loss-of-function (RABEP2 knockdown/knockout) with defined phenotypic readouts (VEGFR2 surface expression, signaling, degradation)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reciprocal biochemical assays and high-resolution microscopy in a single lab with multiple orthogonal methods, but no independent replication reported","pmids":["29425100"],"is_preprint":false}],"current_model":"RABEP2 is a Rab-effector protein that binds Rab4 and controls VEGFR2 endosomal trafficking in endothelial cells, directing VEGFR2 recycling back to the cell surface while preventing its retention in Rab5-positive sorting endosomes (where it is dephosphorylated by PTP1b) and diversion to Rab7-positive lysosomes for degradation, thereby sustaining VEGF signaling."},"narrative":{"mechanistic_narrative":"RABEP2 is a Rab-effector protein that governs the endosomal trafficking of VEGFR2 in endothelial cells to sustain VEGF signaling [PMID:29425100]. It binds the small GTPase Rab4 and directs VEGFR2 recycling to the cell surface; in its absence VEGFR2 is retained in Rab5-positive sorting endosomes, where increased exposure to the phosphotyrosine phosphatase PTP1b dampens signaling, and is additionally diverted to Rab7-positive endosomes destined for lysosomal degradation [PMID:29425100]. Beyond this single characterization of its role in VEGFR2 trafficking, no further mechanistic detail has been established in the available corpus.","teleology":[{"year":2018,"claim":"Whether and how a dedicated effector controls VEGFR2 fate after endocytosis was unresolved; this work established RABEP2 as a Rab4-binding effector that routes VEGFR2 toward recycling and away from phosphatase-mediated inactivation and lysosomal degradation.","evidence":"Co-immunoprecipitation/pulldown, high-resolution microscopy, endosomal fractionation, and RABEP2 loss-of-function with VEGFR2 surface-expression, signaling, and degradation readouts in endothelial cells","pmids":["29425100"],"confidence":"Medium","gaps":["Single-lab study without independent replication","Structural basis of the RABEP2–Rab4 interaction and the recycling step not defined","Whether RABEP2 acts on cargoes other than VEGFR2 not addressed"]},{"year":null,"claim":"It remains unknown whether RABEP2 functions in non-endothelial cell types or regulates additional receptor cargoes, and the molecular determinants of its Rab4-dependent recycling activity are uncharacterized.","evidence":"No further discoveries in the available corpus","pmids":[],"confidence":"Medium","gaps":["No structural model of RABEP2 or its Rab4 complex","No in vivo or organismal phenotype data captured","Mechanism by which RABEP2 selects recycling versus degradative routes unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":["RAB4","KDR"],"other_free_text":[]}},"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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Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/8883934","citation_count":39,"is_preprint":false},{"pmid":"15696094","id":"PMC_15696094","title":"Cloning, expression, and clinical significance of the major allergen from ash pollen, Fra e 1.","date":"2005","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15696094","citation_count":39,"is_preprint":false},{"pmid":"20427335","id":"PMC_20427335","title":"Fra-2 mediates oxygen-sensitive induction of transforming growth factor beta in cardiac fibroblasts.","date":"2010","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/20427335","citation_count":38,"is_preprint":false},{"pmid":"22364734","id":"PMC_22364734","title":"Intermittent hypoxia and systemic leptin administration induces pSTAT3 and Fos/Fra-1 in the carotid body.","date":"2012","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/22364734","citation_count":37,"is_preprint":false},{"pmid":"16490785","id":"PMC_16490785","title":"A Phosphatidylinositol 3-kinase-regulated Akt-independent signaling promotes cigarette smoke-induced FRA-1 expression.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16490785","citation_count":37,"is_preprint":false},{"pmid":"23625206","id":"PMC_23625206","title":"Effect of estrogen and tamoxifen on the expression pattern of AP-1 factors in MCF-7 cells: role of c-Jun, c-Fos, and Fra-1 in cell cycle regulation.","date":"2013","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23625206","citation_count":37,"is_preprint":false},{"pmid":"28566276","id":"PMC_28566276","title":"Fra-2 regulates B cell development by enhancing IRF4 and Foxo1 transcription.","date":"2017","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28566276","citation_count":36,"is_preprint":false},{"pmid":"14565943","id":"PMC_14565943","title":"DEP-induced fra-1 expression correlates with a distinct activation of AP-1-dependent gene transcription in the lung.","date":"2003","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/14565943","citation_count":36,"is_preprint":false},{"pmid":"37176013","id":"PMC_37176013","title":"FRA-1 as a Regulator of EMT and Metastasis in Breast Cancer.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37176013","citation_count":35,"is_preprint":false},{"pmid":"7566966","id":"PMC_7566966","title":"Cyclic AMP stimulates a JunD/Fra-2 AP-1 complex and inhibits the proliferation of interleukin-6-dependent cell lines.","date":"1995","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/7566966","citation_count":35,"is_preprint":false},{"pmid":"9294610","id":"PMC_9294610","title":"Structure and chromosomal assignment of the mouse fra-1 gene, and its exclusion as a candidate gene for oc (osteosclerosis).","date":"1997","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9294610","citation_count":34,"is_preprint":false},{"pmid":"22911824","id":"PMC_22911824","title":"Fra-1/AP-1 transcription factor negatively regulates pulmonary fibrosis in vivo.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22911824","citation_count":33,"is_preprint":false},{"pmid":"11316763","id":"PMC_11316763","title":"Parathyroid hormone stimulates fra-2 expression in osteoblastic cells in vitro and in vivo.","date":"2001","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11316763","citation_count":33,"is_preprint":false},{"pmid":"11254751","id":"PMC_11254751","title":"Cholesterol sulfate stimulates involucrin transcription in keratinocytes by increasing Fra-1, Fra-2, and Jun D.","date":"2001","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/11254751","citation_count":33,"is_preprint":false},{"pmid":"29382358","id":"PMC_29382358","title":"Integrin-uPAR signaling leads to FRA-1 phosphorylation and enhanced breast cancer invasion.","date":"2018","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/29382358","citation_count":32,"is_preprint":false},{"pmid":"15558021","id":"PMC_15558021","title":"MEKK1 regulates the AP-1 dimer repertoire via control of JunB transcription and Fra-2 protein stability.","date":"2005","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15558021","citation_count":30,"is_preprint":false},{"pmid":"12197835","id":"PMC_12197835","title":"Dual role for mitogen-activated protein kinase (Erk) in insulin-dependent regulation of Fra-1 (fos-related antigen-1) transcription and phosphorylation.","date":"2002","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12197835","citation_count":30,"is_preprint":false},{"pmid":"15596805","id":"PMC_15596805","title":"Induction of the RelB NF-kappaB subunit by the cytomegalovirus IE1 protein is mediated via Jun kinase and c-Jun/Fra-2 AP-1 complexes.","date":"2005","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/15596805","citation_count":29,"is_preprint":false},{"pmid":"17607691","id":"PMC_17607691","title":"Simultaneous generation of fra-2 conditional and fra-2 knock-out mice.","date":"2007","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/17607691","citation_count":27,"is_preprint":false},{"pmid":"33102485","id":"PMC_33102485","title":"Fra-1 Inhibits Cell Growth and the Warburg Effect in Cervical Cancer Cells via STAT1 Regulation of the p53 Signaling Pathway.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33102485","citation_count":27,"is_preprint":false},{"pmid":"18435914","id":"PMC_18435914","title":"ERK signaling regulates tumor promoter induced c-Jun recruitment at the Fra-1 promoter.","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18435914","citation_count":27,"is_preprint":false},{"pmid":"38657045","id":"PMC_38657045","title":"Liver cancer development driven by the AP-1/c-Jun~Fra-2 dimer through c-Myc.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/38657045","citation_count":26,"is_preprint":false},{"pmid":"34992218","id":"PMC_34992218","title":"NRG1 regulates Fra-1 transcription and metastasis of triple-negative breast cancer cells via the c-Myc ubiquitination as manipulated by ERK1/2-mediated Fbxw7 phosphorylation.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34992218","citation_count":26,"is_preprint":false},{"pmid":"30243808","id":"PMC_30243808","title":"MiR-124-3p suppresses glioma aggressiveness via targeting of Fra-2.","date":"2018","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/30243808","citation_count":26,"is_preprint":false},{"pmid":"2178237","id":"PMC_2178237","title":"Inhibition of PC-12 cell differentiation by the immediate early gene fra-1.","date":"1990","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/2178237","citation_count":26,"is_preprint":false},{"pmid":"36032067","id":"PMC_36032067","title":"The Fra-1: Novel role in regulating extensive immune cell states and affecting inflammatory diseases.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36032067","citation_count":25,"is_preprint":false},{"pmid":"1899576","id":"PMC_1899576","title":"Transcription of fra-2 mRNA and phosphorylation of Fra-2 protein are stimulated by serum.","date":"1991","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/1899576","citation_count":25,"is_preprint":false},{"pmid":"21480331","id":"PMC_21480331","title":"Transcription factor Fra-1 induces cholangitis and liver fibrosis.","date":"2011","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/21480331","citation_count":24,"is_preprint":false},{"pmid":"26734995","id":"PMC_26734995","title":"HDAC inhibitors suppress c-Jun/Fra-1-mediated proliferation through transcriptionally downregulating MKK7 and Raf1 in neuroblastoma cells.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26734995","citation_count":24,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50543,"output_tokens":717,"usd":0.081192,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6747,"output_tokens":1052,"usd":0.030017,"stage2_stop_reason":"end_turn"},"total_usd":0.111209,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about RABEP2 (also known as FRA, FLJ23282). The alias \"FRA\" here refers to RABEP2, not to \"Fos-related antigens\" (Fra-1, Fra-2, etc.). The vast majority of papers (1-100 except paper 51) are about the AP-1 transcription factor family members Fra-1 (FOSL1) and Fra-2 (FOSL2), which are completely different proteins from RABEP2. Paper 51 is the only one that directly describes RABEP2 (Rab GTPase-binding effector protein 2).\n\nPapers [18], [27], [38] are about folate receptor alpha (FRA/FOLR1) — a different protein, not RABEP2.\n\nPaper [73] is about Fra e 1, an ash pollen allergen — not relevant.\n\nOnly paper [51] describes the canonical RABEP2 protein.\n\n```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 caused prolonged retention of VEGFR2 in Rab5-positive sorting endosomes, increasing VEGFR2 exposure to phosphotyrosine phosphatase 1b (PTP1b) and diminishing VEGFR2 signaling. Loss of RABEP2 also increased VEGFR2 degradation by diverting it to Rab7-positive endosomes destined for the lysosome.\",\n      \"method\": \"High-resolution microscopy, biochemical assays (co-immunoprecipitation/pulldown), endosomal fractionation, loss-of-function (RABEP2 knockdown/knockout) with defined phenotypic readouts (VEGFR2 surface expression, signaling, degradation)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reciprocal biochemical assays and high-resolution microscopy in a single lab with multiple orthogonal methods, but no independent replication reported\",\n      \"pmids\": [\"29425100\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RABEP2 is a Rab-effector protein that binds Rab4 and controls VEGFR2 endosomal trafficking in endothelial cells, directing VEGFR2 recycling back to the cell surface while preventing its retention in Rab5-positive sorting endosomes (where it is dephosphorylated by PTP1b) and diversion to Rab7-positive lysosomes for degradation, thereby sustaining VEGF signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RABEP2 is a Rab-effector protein that governs the endosomal trafficking of VEGFR2 in endothelial cells to sustain VEGF signaling [#0]. It binds the small GTPase Rab4 and directs VEGFR2 recycling to the cell surface; in its absence VEGFR2 is retained in Rab5-positive sorting endosomes, where increased exposure to the phosphotyrosine phosphatase PTP1b dampens signaling, and is additionally diverted to Rab7-positive endosomes destined for lysosomal degradation [#0]. Beyond this single characterization of its role in VEGFR2 trafficking, no further mechanistic detail has been established in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Whether and how a dedicated effector controls VEGFR2 fate after endocytosis was unresolved; this work established RABEP2 as a Rab4-binding effector that routes VEGFR2 toward recycling and away from phosphatase-mediated inactivation and lysosomal degradation.\",\n      \"evidence\": \"Co-immunoprecipitation/pulldown, high-resolution microscopy, endosomal fractionation, and RABEP2 loss-of-function with VEGFR2 surface-expression, signaling, and degradation readouts in endothelial cells\",\n      \"pmids\": [\"29425100\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study without independent replication\",\n        \"Structural basis of the RABEP2\\u2013Rab4 interaction and the recycling step not defined\",\n        \"Whether RABEP2 acts on cargoes other than VEGFR2 not addressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether RABEP2 functions in non-endothelial cell types or regulates additional receptor cargoes, and the molecular determinants of its Rab4-dependent recycling activity are uncharacterized.\",\n      \"evidence\": \"No further discoveries in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of RABEP2 or its Rab4 complex\",\n        \"No in vivo or organismal phenotype data captured\",\n        \"Mechanism by which RABEP2 selects recycling versus degradative routes unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0]}\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\": [\"RAB4\", \"KDR\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":2,"faith_pct":100.0}}