{"gene":"RAB40A","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2015,"finding":"RAB40A forms a complex with Cullin 5 (RAB40A-Cullin 5 complex) that ubiquitinates RhoU, targeting it for degradation; PAK4 protects RhoU from this ubiquitination in a kinase-independent manner, thereby stabilizing RhoU protein levels and promoting cell adhesion turnover and migration.","method":"Co-immunoprecipitation, ubiquitination assays, RhoU rescue experiments, PAK4 depletion with phenotypic readout in breast cancer cells","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional rescue experiments in a single lab with two orthogonal methods (ubiquitination assay + rescue), but no in vitro reconstitution or structural validation","pmids":["26598620"],"is_preprint":false}],"current_model":"RAB40A functions as part of a RAB40A-Cullin 5 E3 ubiquitin ligase complex that ubiquitinates RhoU for proteasomal degradation, a process that is counteracted by PAK4 binding to stabilize RhoU and thereby regulate cell adhesion turnover and migration."},"narrative":{"mechanistic_narrative":"RAB40A is the substrate-recognition component of a RAB40A–Cullin 5 E3 ubiquitin ligase complex that ubiquitinates the small GTPase RhoU and targets it for proteasomal degradation [PMID:26598620]. Through this activity RAB40A controls RhoU protein levels, and the kinase PAK4 antagonizes RAB40A-mediated ubiquitination in a kinase-independent manner to stabilize RhoU, thereby regulating cell adhesion turnover and migration in breast cancer cells [PMID:26598620]. Beyond [PMID:26598620], no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2015,"claim":"Established that RAB40A is not merely a Rab GTPase but assembles with Cullin 5 into an E3 ubiquitin ligase that degrades RhoU, linking RAB40A to control of a migration-promoting GTPase.","evidence":"Co-immunoprecipitation, ubiquitination assays, and RhoU/PAK4 rescue and depletion experiments with phenotypic migration readout in breast cancer cells","pmids":["26598620"],"confidence":"Medium","gaps":["No in vitro reconstitution of the RAB40A-Cullin 5 ligase or direct demonstration of RhoU ubiquitination by purified components","No structural model of substrate recognition or of the PAK4-mediated protection mechanism","How PAK4 sterically or competitively blocks RAB40A binding to RhoU in a kinase-independent manner is undefined"]},{"year":null,"claim":"Whether RAB40A targets substrates beyond RhoU, how its ligase activity is regulated, and its subcellular localization remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No additional substrates identified","Regulation and activation of the RAB40A-Cullin 5 complex uncharacterized","Localization of RAB40A not established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]}],"complexes":["RAB40A-Cullin 5 E3 ubiquitin ligase complex"],"partners":["CUL5","RHOU","PAK4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WXH6","full_name":"Ras-related protein Rab-40A","aliases":["SOCS box-containing protein RAR2A","Protein Rar-2"],"length_aa":277,"mass_kda":31.1,"function":"RAB40A small GTPase acts as substrate-recognition component of the ECS(RAB40A) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:26598620). The Rab40 subfamily belongs to the Rab family that are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion (By similarity). As part of the ECS(RAB40A) complex, mediates RHOU 'Lys-48'-linked ubiquitination and degradation, thus inhibiting focal adhesion disassembly during cell migration (PubMed:26598620)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8WXH6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAB40A","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1047,"dependency_fraction":0.0009551098376313276},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RAB40A","total_profiled":1310},"omim":[{"mim_id":"619551","title":"RAB40C, MEMBER RAS ONCOGENE FAMILY; RAB40C","url":"https://www.omim.org/entry/619551"},{"mim_id":"619550","title":"RAB40B, MEMBER RAS ONCOGENE FAMILY; RAB40B","url":"https://www.omim.org/entry/619550"},{"mim_id":"301065","title":"RAB40A, MEMBER RAS ONCOGENE FAMILY; RAB40A","url":"https://www.omim.org/entry/301065"},{"mim_id":"300405","title":"RAS-ASSOCIATED PROTEIN RAB40A-LIKE; RAB40AL","url":"https://www.omim.org/entry/300405"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"epididymis","ntpm":7.6}],"url":"https://www.proteinatlas.org/search/RAB40A"},"hgnc":{"alias_symbol":["RAR2A","Rar-2"],"prev_symbol":[]},"alphafold":{"accession":"Q8WXH6","domains":[{"cath_id":"3.40.50.300","chopping":"14-182","consensus_level":"high","plddt":85.535,"start":14,"end":182},{"cath_id":"1.10.10","chopping":"191-236","consensus_level":"medium","plddt":79.1024,"start":191,"end":236}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WXH6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WXH6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WXH6-F1-predicted_aligned_error_v6.png","plddt_mean":73.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAB40A","jax_strain_url":"https://www.jax.org/strain/search?query=RAB40A"},"sequence":{"accession":"Q8WXH6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WXH6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WXH6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WXH6"}},"corpus_meta":[{"pmid":"32264724","id":"PMC_32264724","title":"Sex differences in autophagy-mediated diseases: toward precision medicine.","date":"2020","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/32264724","citation_count":75,"is_preprint":false},{"pmid":"26598620","id":"PMC_26598620","title":"PAK4 promotes kinase-independent stabilization of RhoU to modulate cell adhesion.","date":"2015","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26598620","citation_count":63,"is_preprint":false},{"pmid":"36814226","id":"PMC_36814226","title":"Relationship between red cell distribution width/albumin ratio and carotid plaque in different glucose metabolic states in patients with coronary heart disease: a RCSCD-TCM study in China.","date":"2023","source":"Cardiovascular diabetology","url":"https://pubmed.ncbi.nlm.nih.gov/36814226","citation_count":35,"is_preprint":false},{"pmid":"15160388","id":"PMC_15160388","title":"Vesicle transport in oligodendrocytes: probable role of Rab40c protein.","date":"2004","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/15160388","citation_count":33,"is_preprint":false},{"pmid":"38405142","id":"PMC_38405142","title":"Association between red cell distribution width-and-albumin ratio and the risk of peripheral artery disease in patients with diabetes.","date":"2024","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/38405142","citation_count":19,"is_preprint":false},{"pmid":"36368327","id":"PMC_36368327","title":"TCEAL1 loss-of-function results in an X-linked dominant neurodevelopmental syndrome and drives the neurological disease trait in Xq22.2 deletions.","date":"2022","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36368327","citation_count":15,"is_preprint":false},{"pmid":"6782472","id":"PMC_6782472","title":"Investigations on radiosensitive and radioresistant populations of Drosophila melanogaster. VIII. The system of relative radioresistance in immature oocytes of the irradiated population ROI4.","date":"1981","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/6782472","citation_count":9,"is_preprint":false},{"pmid":"6801500","id":"PMC_6801500","title":"Investigations on radiosensitive and radioresistant populations of Drosophila melanogaster. X. The resistance factor rar-3: genetics.","date":"1981","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/6801500","citation_count":6,"is_preprint":false},{"pmid":"6806648","id":"PMC_6806648","title":"Investigations on radiosensitive and radioresistant populations of Drosophila melanogaster. XIV. The genetic factor rar-1: effects in immature oocytes and their inhibition by caffeine.","date":"1982","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/6806648","citation_count":3,"is_preprint":false},{"pmid":"42221755","id":"PMC_42221755","title":"The association between red blood cell distribution width-to-albumin ratio and Helicobacter pylori seropositivity in U.S. adults: an observational study from NHANES 1999-2000 with external validation.","date":"2026","source":"Frontiers in nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/42221755","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7660,"output_tokens":355,"usd":0.014153,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6590,"output_tokens":981,"usd":0.028737,"stage2_stop_reason":"end_turn"},"total_usd":0.04289,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"RAB40A forms a complex with Cullin 5 (RAB40A-Cullin 5 complex) that ubiquitinates RhoU, targeting it for degradation; PAK4 protects RhoU from this ubiquitination in a kinase-independent manner, thereby stabilizing RhoU protein levels and promoting cell adhesion turnover and migration.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, RhoU rescue experiments, PAK4 depletion with phenotypic readout in breast cancer cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional rescue experiments in a single lab with two orthogonal methods (ubiquitination assay + rescue), but no in vitro reconstitution or structural validation\",\n      \"pmids\": [\"26598620\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAB40A functions as part of a RAB40A-Cullin 5 E3 ubiquitin ligase complex that ubiquitinates RhoU for proteasomal degradation, a process that is counteracted by PAK4 binding to stabilize RhoU and thereby regulate cell adhesion turnover and migration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAB40A is the substrate-recognition component of a RAB40A–Cullin 5 E3 ubiquitin ligase complex that ubiquitinates the small GTPase RhoU and targets it for proteasomal degradation [#0]. Through this activity RAB40A controls RhoU protein levels, and the kinase PAK4 antagonizes RAB40A-mediated ubiquitination in a kinase-independent manner to stabilize RhoU, thereby regulating cell adhesion turnover and migration in breast cancer cells [#0]. Beyond [#0], no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that RAB40A is not merely a Rab GTPase but assembles with Cullin 5 into an E3 ubiquitin ligase that degrades RhoU, linking RAB40A to control of a migration-promoting GTPase.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assays, and RhoU/PAK4 rescue and depletion experiments with phenotypic migration readout in breast cancer cells\",\n      \"pmids\": [\"26598620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro reconstitution of the RAB40A-Cullin 5 ligase or direct demonstration of RhoU ubiquitination by purified components\",\n        \"No structural model of substrate recognition or of the PAK4-mediated protection mechanism\",\n        \"How PAK4 sterically or competitively blocks RAB40A binding to RhoU in a kinase-independent manner is undefined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether RAB40A targets substrates beyond RhoU, how its ligase activity is regulated, and its subcellular localization remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No additional substrates identified\",\n        \"Regulation and activation of the RAB40A-Cullin 5 complex uncharacterized\",\n        \"Localization of RAB40A not established in the corpus\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"RAB40A-Cullin 5 E3 ubiquitin ligase complex\"],\n    \"partners\": [\"CUL5\", \"RHOU\", \"PAK4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"loss","faith_supported":1,"faith_total":2,"faith_pct":50.0}}