{"gene":"RAB5C","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2005,"finding":"Wnt11 controls tissue morphogenesis during zebrafish gastrulation by modulating E-cadherin-mediated cell cohesion through Rab5c; blocking Rab5c activity phenocopied wnt11 mutants and enhancing Rab5c activity rescued the mutant phenotype, establishing Rab5c as a downstream mediator of Wnt11 signaling that regulates E-cadherin endocytosis.","method":"Genetic epistasis in zebrafish (dominant-negative/constitutively-active Rab5c injection, rescue experiments in slb/wnt11 mutants), E-cadherin endocytosis assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic epistasis (phenocopy + rescue), multiple orthogonal methods, replicated functional readouts","pmids":["16198297"],"is_preprint":false},{"year":1999,"finding":"The three Rab5 isoforms (Rab5a, Rab5b, Rab5c) are differentially phosphorylated in vitro: Rab5a is efficiently phosphorylated by ERK1 but not ERK2; Rab5b is preferentially phosphorylated by Cdc2 kinase at Ser-123; Rab5c was not efficiently phosphorylated by these same kinases, establishing isoform-specific post-translational regulation.","method":"In vitro kinase phosphorylation assays with ERK1, ERK2, and Cdc2 kinase","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro kinase assay, single lab, limited follow-up on Rab5c specifically","pmids":["10403367"],"is_preprint":false},{"year":2012,"finding":"GTP-Rab5c binds directly to AMAP1, and EGFR-stimulated activation of Rab5c is necessary to promote the intracellular association of AMAP1 and PRKD2, forming a complex that recycles β1 integrins (e.g., α3β1) to promote breast cancer cell invasion.","method":"Co-immunoprecipitation, direct binding assays, siRNA knockdown of Rab5c with invasion/recycling readouts","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, direct binding confirmed, functional knockdown with defined invasion phenotype, multiple orthogonal methods","pmids":["22734003"],"is_preprint":false},{"year":2014,"finding":"Rab5C, but not Rab5A or Rab5B, is selectively required for EGF-stimulated Rac1 activation and cell motility; depletion of Rab5C suppressed EGF-induced Rac1 activity, reduced peripheral Rac1 localization, decreased Akt phosphorylation, reduced focal adhesion formation, and impaired directional cell migration.","method":"siRNA isoform-specific knockdown, Rac1 GTP pull-down assays, scratch wound and Transwell migration assays, micro-patterned cell imaging, phospho-Akt western blot","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays, isoform specificity established, single lab","pmids":["24587345"],"is_preprint":false},{"year":2018,"finding":"Rab5C and EEA1 in the early endosomal pathway are rate-limiting regulators of antisense oligonucleotide (PS-ASO) trafficking and endosomal escape following Stabilin receptor-mediated internalization; modulating their expression altered the efficiency of ASO escape from endolysosomal compartments.","method":"Modulation of Rab5C expression (knockdown/overexpression) in cells, tracking of PS-ASO trafficking and endosomal escape","journal":"Nucleic acid therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined functional role in trafficking with loss-of-function readout, single lab, single paper","pmids":["29437530"],"is_preprint":false},{"year":2019,"finding":"Rab5c is a key component of the endosomal recycling machinery for CD93 in endothelial cells; Rab5c-containing endosomal compartments harbor a complex of CD93, Multimerin-2, and active β1 integrin that is recycled back to the basolaterally-polarized cell surface by clathrin-independent endocytosis, and Rab5c silencing impairs CD93 recycling and cell migration.","method":"Gene silencing (siRNA), fluorescence confocal microscopy, co-immunoprecipitation, scratch assay for migration, flow cytometry","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, confocal colocalization, functional knockdown with migration phenotype, single lab","pmids":["31138217"],"is_preprint":false},{"year":2019,"finding":"Rab5c modulates EGFR internalization in rectal cancer cells in response to irradiation, and this modulation affects EGFR nuclear relocalization, which in turn regulates expression of DNA repair proteins Ku70 and Ku80 to confer radiotherapy resistance.","method":"Rab5c knockdown/overexpression in irradiated rectal adenocarcinoma cell lines, EGFR internalization assays, western blot for Ku70/Ku80, radioresistance assays","journal":"Journal of molecular medicine (Berlin, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional KD with defined mechanistic pathway (EGFR internalization → nuclear EGFR → DNA repair), single lab","pmids":["30968159"],"is_preprint":false},{"year":2020,"finding":"Rab5c is essential for hematopoietic stem and progenitor cell (HSPC) specification in zebrafish via endocytic trafficking of Notch ligands and receptor; additionally, Rab5c interacts with Appl1 in endosomes to activate AKT signaling required for hemogenic endothelium survival, and Rab5c overactivation causes excessive endolysosomal Notch degradation and HSPC defects.","method":"Zebrafish rab5c morpholino knockdown and overexpression, co-immunoprecipitation of Rab5c with Appl1, endocytic trafficking assays of Notch components, AKT phosphorylation readouts","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP (Rab5c-Appl1), genetic loss-of-function with defined molecular pathway, bidirectional perturbation (KD and overactivation), multiple signaling readouts","pmids":["32275659"],"is_preprint":false},{"year":2014,"finding":"RAB5C is a direct target of miR-509; enforced miR-509 expression reduced RAB5C mRNA and protein in B-ALL cells, and knockdown of RAB5C alone recapitulated the growth-inhibitory and pro-apoptotic effects of miR-509; co-expression of RAB5C ORF (without 3'UTR) blocked miR-509-mediated growth inhibition.","method":"miR-509 overexpression, RAB5C shRNA knockdown, rescue by RAB5C ORF re-expression, luciferase reporter assay for direct targeting, flow cytometry for proliferation/apoptosis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct miRNA target validated by 3'UTR reporter + rescue experiment, functional knockdown with cellular phenotype, single lab","pmids":["25368993"],"is_preprint":false},{"year":2014,"finding":"RAB5C physically interacts with TPD52 (Tumor Protein D52); this interaction was identified by yeast two-hybrid screening and confirmed by pull-down assays, with domain mapping identifying a novel binding region on TPD52.","method":"Yeast two-hybrid screening, pull-down assays, interaction domain mapping","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pulldown confirmation of two-hybrid hit, no functional consequence established for RAB5C specifically","pmids":["24604726"],"is_preprint":false},{"year":2021,"finding":"TBC1D16, a TBC domain-containing GAP protein, targets Rab5C to suppress prototype foamy virus (PFV) replication; the conserved arginine finger and glutamine residues R494 and Q531 in the TBC domain are essential for this inhibitory function, and TBC1D16 promotes IFN-β production.","method":"TBC1D16 overexpression/silencing in PFV-infected cells, mutagenesis of TBC domain catalytic residues (R494A, Q531A), IFN-β reporter assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — active-site mutagenesis of the GAP + functional assays for viral replication and IFN-β, identifies Rab5C as the substrate, single lab","pmids":["34367131"],"is_preprint":false},{"year":2022,"finding":"Piezo1 recruits and physically interacts with Rab5c to activate TGF-β signaling, thereby promoting HCC progression and EMT; knockdown of Piezo1 impaired this complex formation and reduced TGF-β pathway activation.","method":"Co-immunoprecipitation, immunofluorescence colocalization, Piezo1 knockdown with TGF-β signaling readouts, in vitro and in vivo tumor models","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP showing Piezo1-Rab5c interaction, functional KD with defined pathway readout, single lab","pmids":["35461277"],"is_preprint":false},{"year":2022,"finding":"HuR RNA-binding protein binds the 3'UTR of RAB5C mRNA to stabilize it, maintaining RAB5C protein levels; HuR shRNA knockdown decreased RAB5C mRNA and protein, and suppression of RAB5C reduced breast cancer cell proliferation.","method":"RNA immunoprecipitation (RIP) of HuR-RAB5C mRNA, shRNA knockdown of HuR, mRNA stability assays, colony formation and MTT assays","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RIP confirmed direct HuR-RAB5C mRNA binding, functional KD phenotype, single lab","pmids":["36480789"],"is_preprint":false},{"year":2023,"finding":"Heterozygous de novo missense variants in RAB5C cause macrocephaly and developmental delay; biochemical studies showed the variants increased nucleotide exchange rate, attenuated responsivity to guanine exchange factors, and had heterogeneous effects on effector protein interactions; two variants acted through a dominant-negative mechanism; C. elegans and zebrafish models confirmed in vivo disruption of the endocytic pathway.","method":"In vitro nucleotide exchange assays, GEF responsivity assays, effector binding assays, C. elegans in vivo endocytic pathway assays, zebrafish embryo expression studies","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical assays (nucleotide exchange, GEF responsivity, effector binding) plus two independent in vivo model systems (C. elegans and zebrafish)","pmids":["37552066"],"is_preprint":false},{"year":2024,"finding":"Rab5c promotes RSV and ADV replication via autophagy rather than endocytosis; activated Rab5c upregulates LC3-II protein expression by interacting with Beclin1, inducing autophagy that facilitates viral replication in respiratory epithelial cells and in Rab5c-overexpressing mice.","method":"Rab5c overexpression/knockdown in A549 cells and transgenic mice, co-immunoprecipitation of Rab5c with Beclin1, LC3-II western blot, viral replication assays","journal":"Virus research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying Rab5c-Beclin1 interaction, in vitro and in vivo functional assays, mechanism distinguished from endocytosis by pharmacological inhibitors, single lab","pmids":["38242290"],"is_preprint":false},{"year":2025,"finding":"RAB5c regulates phagosome recruitment of complexes required for PI(3)P and ROS generation during LC3-associated phagocytosis (LAP); specifically, RAB5c facilitates phagosome translocation of the V-ATPase transmembrane core, which enables ATG16L1 binding and consequent LC3 conjugation to phagosomes; RAB5c depletion impaired macrophage elimination of Aspergillus fumigatus and disruption of the V-ATPase-ATG16L1 axis increased susceptibility in vivo.","method":"RAB5c knockdown/depletion in macrophages, phagosome fractionation, V-ATPase and ATG16L1 recruitment assays, LC3 conjugation assays, in vivo Aspergillus fumigatus infection model","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal mechanistic assays (phagosome fractionation, recruitment of V-ATPase/ATG16L1, LC3 conjugation), in vivo validation, peer-reviewed publication","pmids":["42102192"],"is_preprint":false},{"year":2024,"finding":"Parkin E3 ubiquitin ligase ubiquitinates RAB5C (along with other Rab GTPases); this was identified by orthogonal ubiquitin transfer (OUT) proteomics and confirmed by reconstituted in vitro ubiquitination reactions, and Parkin-mediated ubiquitination of Rab proteins was enhanced upon mitophagy stimulation.","method":"Orthogonal ubiquitin transfer (OUT) cascade proteomics, in vitro reconstituted ubiquitination assay, mitophagy stimulation experiments","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstituted ubiquitination confirmed by OUT screen, preprint, RAB5C is one of many substrates identified","pmids":["bio_10.1101_2024.09.14.613079"],"is_preprint":true},{"year":2026,"finding":"RAB5C regulates VWF exocytosis from endothelial cells; RAB5C silencing decreased VWF release after histamine stimulation whereas constitutively active RAB5C increased it; proximity labeling and mass spectrometry identified SNAP29 (a SNARE-associated protein) as a key RAB5C interactor mediating this effect on vesicle fusion and VWF secretion.","method":"RAB5C silencing/overexpression in HUVECs, ELISA for VWF release, proximity labeling (BioID) + mass spectrometry for interactome, constitutively active and dominant negative RAB5C constructs","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional perturbation (KD and CA/DN OE), proximity proteomics identifying SNAP29 as interactor, functional VWF secretion assay, multiple orthogonal methods","pmids":["41537263"],"is_preprint":false},{"year":2026,"finding":"Rab5c-dependent endocytosis of AMPA receptor subunits GluA1 and GluA2 mediates developmental synaptic downscaling in Xenopus tadpoles; prolonged visual experience accelerated this Rab5c-dependent AMPAR endocytosis, reducing mEPSC amplitudes, and the effect was reversible.","method":"Rab5c manipulation in Xenopus laevis tadpoles, electrophysiology (mEPSC recordings), AMPAR subunit trafficking assays, pharmacological and genetic inhibition of Rab5c","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined role for Rab5c in AMPAR endocytosis with electrophysiological readout, single lab, single paper","pmids":["41507541"],"is_preprint":false},{"year":1996,"finding":"The human RABL gene (now RAB5C) encodes a 216 amino acid small GTP-binding protein with 86% amino acid identity to the RAB5 subfamily; it is expressed ubiquitously in all human tissues examined and maps to chromosome band 17q21.2 by FISH.","method":"cDNA cloning from human fetal lung library, sequence analysis, fluorescence in situ hybridization (FISH) for chromosomal mapping, northern blot for tissue expression","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct cloning and chromosomal mapping by FISH, establishes identity and ubiquitous expression, single lab","pmids":["8646882"],"is_preprint":false}],"current_model":"RAB5C (also known as RABL) is a member of the RAB5 subfamily of small GTPases that acts as a master regulator of early endocytic trafficking, with isoform-specific functions including: regulating E-cadherin endocytosis downstream of Wnt11 signaling during gastrulation; promoting Rac1 activation and focal adhesion-dependent cell motility; forming a complex with AMAP1 and PRKD2 to recycle β1 integrins upon EGFR stimulation; directing Notch and AKT signaling via endocytic trafficking in hematopoietic progenitor development; facilitating LC3-associated phagocytosis by recruiting V-ATPase to phagosomes to enable ATG16L1-dependent LC3 conjugation; promoting VWF exocytosis through SNAP29-mediated vesicle fusion in endothelial cells; and interacting with Beclin1 to induce autophagy during viral infection; it is differentially phosphorylated by ERK1 and Cdc2 compared to the other Rab5 isoforms, ubiquitinated by Parkin, and its activity is regulated by the GAP TBC1D16; de novo missense variants in RAB5C cause a neurodevelopmental disorder by increasing nucleotide exchange rate and disrupting effector interactions."},"narrative":{"mechanistic_narrative":"RAB5C is a member of the RAB5 subfamily of small GTP-binding proteins that functions as a master regulator of early endocytic trafficking, cycling between GTP- and GDP-bound states to control cargo internalization, sorting, and recycling [PMID:8646882, PMID:37552066]. Its GTPase activity is governed by nucleotide exchange and by the TBC-domain GAP TBC1D16, whose conserved catalytic arginine and glutamine residues are required to turn RAB5C off [PMID:34367131, PMID:37552066]. RAB5C engages effectors and adaptors in a GTP-dependent manner: active RAB5C binds AMAP1 to nucleate an AMAP1–PRKD2 complex that recycles β1 integrins upon EGFR stimulation, and it associates with Appl1 on endosomes to drive AKT signaling, illustrating how its endosomal output is coupled to growth-factor and survival pathways [PMID:22734003, PMID:32275659]. Through control of receptor and ligand trafficking, RAB5C is selectively required—relative to other RAB5 isoforms—for EGF-stimulated Rac1 activation, focal adhesion formation, and directional cell migration, and it mediates endocytic regulation of E-cadherin downstream of Wnt11 during gastrulation and Notch ligand/receptor trafficking during hematopoietic progenitor specification [PMID:24587345, PMID:16198297, PMID:32275659]. Beyond classical endocytosis, RAB5C facilitates LC3-associated phagocytosis by promoting phagosomal recruitment of the V-ATPase core to enable ATG16L1-dependent LC3 conjugation, and it controls regulated secretion by promoting SNAP29-mediated VWF exocytosis in endothelial cells [PMID:42102192, PMID:41537263]. Heterozygous de novo missense variants in RAB5C cause a neurodevelopmental disorder with macrocephaly and developmental delay by increasing nucleotide exchange rate, attenuating GEF responsivity, and disrupting effector interactions, with some variants acting dominant-negatively [PMID:37552066].","teleology":[{"year":1996,"claim":"Established the molecular identity of RAB5C, defining it as a ubiquitously expressed small GTPase closely related to the RAB5 subfamily before any function was known.","evidence":"cDNA cloning, sequence analysis, FISH mapping, and northern blot in human tissues","pmids":["8646882"],"confidence":"Medium","gaps":["No functional or trafficking role assigned","Isoform-specific behavior versus RAB5A/RAB5B not addressed"]},{"year":1999,"claim":"Asked whether the three RAB5 isoforms are post-translationally regulated differently, revealing isoform-selective phosphorylation as a basis for functional divergence.","evidence":"In vitro kinase assays with ERK1, ERK2, and Cdc2","pmids":["10403367"],"confidence":"Medium","gaps":["RAB5C was not efficiently phosphorylated, leaving its specific regulatory inputs unresolved","In vitro only; no cellular validation"]},{"year":2005,"claim":"Placed RAB5C in a developmental signaling pathway by showing it mediates Wnt11 control of E-cadherin endocytosis during morphogenesis.","evidence":"Reciprocal genetic epistasis (dominant-negative/constitutively-active Rab5c, rescue) in zebrafish slb/wnt11 mutants with E-cadherin endocytosis assays","pmids":["16198297"],"confidence":"High","gaps":["Direct molecular link between Wnt11 and RAB5C activation not defined","Effectors mediating E-cadherin endocytosis unidentified"]},{"year":2012,"claim":"Defined a direct GTP-dependent effector interaction, showing active RAB5C nucleates an AMAP1-PRKD2 complex for integrin recycling downstream of EGFR.","evidence":"Co-IP, direct binding assays, and siRNA knockdown with invasion/recycling readouts in breast cancer cells","pmids":["22734003"],"confidence":"High","gaps":["GEF activating RAB5C downstream of EGFR not identified","Structural basis of AMAP1 binding unresolved"]},{"year":2014,"claim":"Established functional isoform specificity, demonstrating RAB5C (not RAB5A/B) is required for EGF-driven Rac1 activation and cell motility.","evidence":"Isoform-specific siRNA, Rac1 GTP pull-downs, migration assays, and phospho-Akt blots","pmids":["24587345"],"confidence":"High","gaps":["Mechanism linking RAB5C endosomes to Rac1 activation not defined","Single lab"]},{"year":2014,"claim":"Identified upstream and physical regulators of RAB5C abundance and interaction, including miR-509 targeting and a TPD52 interaction.","evidence":"miR-509 overexpression with RAB5C ORF rescue and luciferase reporter (B-ALL); yeast two-hybrid and pull-down for TPD52","pmids":["25368993","24604726"],"confidence":"Medium","gaps":["Functional consequence of the TPD52 interaction for RAB5C not established","TPD52 interaction rests on a single Y2H/pull-down without reciprocal validation"]},{"year":2019,"claim":"Extended RAB5C into endosomal recycling of cell-surface receptors and into a receptor-internalization-to-nuclear-signaling axis affecting DNA repair.","evidence":"siRNA, confocal colocalization, and Co-IP for CD93/Multimerin-2/β1-integrin recycling; knockdown/overexpression with EGFR internalization and Ku70/Ku80 readouts in irradiated rectal cancer cells","pmids":["31138217","30968159"],"confidence":"Medium","gaps":["Direct effectors mediating CD93 recycling not defined","Causal chain from EGFR internalization to nuclear EGFR not fully reconstituted"]},{"year":2020,"claim":"Demonstrated RAB5C couples endocytic trafficking to two signaling outputs (Notch and AKT) in vivo, with both loss and overactivation disrupting hematopoietic specification.","evidence":"Zebrafish morpholino knockdown and overexpression, Rab5c-Appl1 Co-IP, Notch trafficking and AKT phosphorylation readouts","pmids":["32275659"],"confidence":"High","gaps":["Mechanism balancing Notch recycling versus degradation unresolved","GEF/GAP setting RAB5C activity level in HSPCs unknown"]},{"year":2021,"claim":"Identified TBC1D16 as a GAP for RAB5C, linking RAB5C inactivation to antiviral restriction and IFN-β induction.","evidence":"TBC1D16 overexpression/silencing and catalytic-residue mutagenesis (R494A, Q531A) in PFV-infected cells with IFN-β reporters","pmids":["34367131"],"confidence":"Medium","gaps":["Direct GAP activity on RAB5C not measured biochemically","Other GAPs/GEFs for RAB5C remain unidentified"]},{"year":2022,"claim":"Added mechanosensory and RNA-stability inputs to RAB5C, via a Piezo1 interaction promoting TGF-β signaling and HuR-mediated mRNA stabilization.","evidence":"Co-IP and knockdown for Piezo1-RAB5C/TGF-β in HCC; RIP and mRNA stability assays for HuR-RAB5C in breast cancer","pmids":["35461277","36480789"],"confidence":"Medium","gaps":["Whether Piezo1 modulates RAB5C nucleotide state is unknown","Both rest on single-lab Co-IP/RIP evidence"]},{"year":2023,"claim":"Provided the causal disease mechanism, showing de novo RAB5C missense variants drive a neurodevelopmental disorder by altering nucleotide cycling and effector binding.","evidence":"In vitro nucleotide exchange, GEF responsivity, and effector binding assays plus C. elegans and zebrafish in vivo endocytic models","pmids":["37552066"],"confidence":"High","gaps":["Cell-type-specific consequences in human neurons not defined","Which effector disruptions drive macrocephaly versus developmental delay unresolved"]},{"year":2024,"claim":"Connected RAB5C to autophagy and to ubiquitin-mediated regulation, via a Beclin1 interaction promoting viral replication and Parkin-dependent ubiquitination.","evidence":"Rab5c-Beclin1 Co-IP, LC3-II blots, and viral replication assays in A549/mice; OUT proteomics and reconstituted in vitro ubiquitination by Parkin (preprint)","pmids":["38242290","bio_10.1101_2024.09.14.613079"],"confidence":"Medium","gaps":["Functional consequence of Parkin ubiquitination of RAB5C not established","RAB5C is one of many Parkin substrates; specificity unclear"]},{"year":2025,"claim":"Defined a non-canonical role in LC3-associated phagocytosis, with RAB5C driving phagosomal V-ATPase recruitment to license ATG16L1-dependent LC3 conjugation and antifungal defense.","evidence":"RAB5C depletion, phagosome fractionation, V-ATPase/ATG16L1 recruitment and LC3 conjugation assays, in vivo Aspergillus fumigatus model","pmids":["42102192"],"confidence":"High","gaps":["How RAB5C selects V-ATPase as effector versus canonical endosome fusion machinery is unclear","Nucleotide-state requirement for LAP not dissected"]},{"year":2026,"claim":"Extended RAB5C to regulated secretion and neuronal plasticity, identifying SNAP29-mediated VWF exocytosis and Rab5c-dependent AMPAR endocytosis in synaptic downscaling.","evidence":"BioID/MS interactome and bidirectional perturbation with VWF release ELISA in HUVECs; Rab5c manipulation with mEPSC recordings in Xenopus tadpoles","pmids":["41537263","41507541"],"confidence":"High","gaps":["How an endocytic GTPase promotes SNAP29-dependent fusion mechanistically is unresolved","Synaptic AMPAR role rests on a single lab"]},{"year":null,"claim":"How RAB5C achieves its distinct, isoform-specific outputs across endocytosis, recycling, LC3-associated phagocytosis, and regulated exocytosis from a shared RAB5 GTPase scaffold remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural basis for effector selectivity between RAB5 isoforms","Full GEF/GAP regulatory network beyond TBC1D16 undefined","Connection between nucleotide-cycling defects and specific tissue phenotypes not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[13,10,19]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[5,7,2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[15,17]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,5,3]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[15,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,2,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13]}],"complexes":[],"partners":["AMAP1","PRKD2","APPL1","TBC1D16","BECLIN1","SNAP29","PIEZO1","TPD52"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P51148","full_name":"Ras-related protein Rab-5C","aliases":["L1880","RAB5L"],"length_aa":216,"mass_kda":23.5,"function":"The small GTPases Rab 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 (PubMed:16086013, PubMed:17562788). Involved in early endocytic trafficking (PubMed:16086013, PubMed:17562788). Required for EEA1 recruitment to early endosomes (PubMed:16086013, PubMed:17562788). Required for EGF and transferrin endocytosis and trafficking through early endosomes (PubMed:16086013, PubMed:17562788)","subcellular_location":"Cell membrane; Early endosome membrane; Melanosome","url":"https://www.uniprot.org/uniprotkb/P51148/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAB5C","classification":"Not Classified","n_dependent_lines":164,"n_total_lines":1208,"dependency_fraction":0.1357615894039735},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"GDI1","stoichiometry":10.0},{"gene":"GDI2","stoichiometry":10.0},{"gene":"ARL6IP1","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"CHM","stoichiometry":0.2},{"gene":"SCAMP1","stoichiometry":0.2},{"gene":"SCAMP2","stoichiometry":0.2},{"gene":"SEC61B","stoichiometry":0.2},{"gene":"STX12","stoichiometry":0.2},{"gene":"STX7","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RAB5C","total_profiled":1310},"omim":[{"mim_id":"617211","title":"DERMOKINE; DMKN","url":"https://www.omim.org/entry/617211"},{"mim_id":"616637","title":"TBC1 DOMAIN FAMILY, MEMBER 16; TBC1D16","url":"https://www.omim.org/entry/616637"},{"mim_id":"604037","title":"RAS-ASSOCIATED PROTEIN RAB5C; RAB5C","url":"https://www.omim.org/entry/604037"},{"mim_id":"179514","title":"RAS-ASSOCIATED PROTEIN RAB5B; RAB5B","url":"https://www.omim.org/entry/179514"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Endosomes","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RAB5C"},"hgnc":{"alias_symbol":["RAB5CL"],"prev_symbol":["RABL"]},"alphafold":{"accession":"P51148","domains":[{"cath_id":"3.40.50.300","chopping":"17-180","consensus_level":"high","plddt":95.5901,"start":17,"end":180}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P51148","model_url":"https://alphafold.ebi.ac.uk/files/AF-P51148-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P51148-F1-predicted_aligned_error_v6.png","plddt_mean":84.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAB5C","jax_strain_url":"https://www.jax.org/strain/search?query=RAB5C"},"sequence":{"accession":"P51148","fasta_url":"https://rest.uniprot.org/uniprotkb/P51148.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P51148/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P51148"}},"corpus_meta":[{"pmid":"16198297","id":"PMC_16198297","title":"Wnt11 functions in gastrulation by controlling cell cohesion through Rab5c and E-cadherin.","date":"2005","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/16198297","citation_count":235,"is_preprint":false},{"pmid":"9886774","id":"PMC_9886774","title":"Non-Rabl patterns of centromere and telomere distribution in the interphase nuclei of plant cells.","date":"1998","source":"Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology","url":"https://pubmed.ncbi.nlm.nih.gov/9886774","citation_count":129,"is_preprint":false},{"pmid":"22734003","id":"PMC_22734003","title":"Rab5c promotes AMAP1-PRKD2 complex formation to enhance β1 integrin recycling in EGF-induced cancer invasion.","date":"2012","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22734003","citation_count":90,"is_preprint":false},{"pmid":"10403367","id":"PMC_10403367","title":"The small GTPases Rab5a, Rab5b and Rab5c are differentially phosphorylated in vitro.","date":"1999","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/10403367","citation_count":72,"is_preprint":false},{"pmid":"15102067","id":"PMC_15102067","title":"Interphase chromosomes and the Rabl configuration: does genome size matter?","date":"2004","source":"Journal of microscopy","url":"https://pubmed.ncbi.nlm.nih.gov/15102067","citation_count":48,"is_preprint":false},{"pmid":"24587345","id":"PMC_24587345","title":"Rab5 isoforms orchestrate a \"division of labor\" in the endocytic network; Rab5C modulates Rac-mediated cell motility.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24587345","citation_count":41,"is_preprint":false},{"pmid":"35461277","id":"PMC_35461277","title":"Piezo1 promoted hepatocellular carcinoma progression and EMT through activating TGF-β signaling by recruiting Rab5c.","date":"2022","source":"Cancer cell 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Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/30968159","citation_count":23,"is_preprint":false},{"pmid":"37197899","id":"PMC_37197899","title":"Nuclear genome organization in fungi: from gene folding to Rabl chromosomes.","date":"2023","source":"FEMS microbiology reviews","url":"https://pubmed.ncbi.nlm.nih.gov/37197899","citation_count":23,"is_preprint":false},{"pmid":"32275659","id":"PMC_32275659","title":"Rab5c-mediated endocytic trafficking regulates hematopoietic stem and progenitor cell development via Notch and AKT signaling.","date":"2020","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/32275659","citation_count":21,"is_preprint":false},{"pmid":"7789185","id":"PMC_7789185","title":"Rabl orientation of CENP-B box sequences in Tupaia belangeri fibroblasts.","date":"1995","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7789185","citation_count":21,"is_preprint":false},{"pmid":"34367131","id":"PMC_34367131","title":"Novel Host Protein TBC1D16, a GTPase Activating Protein of Rab5C, Inhibits Prototype Foamy Virus Replication.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34367131","citation_count":17,"is_preprint":false},{"pmid":"32788878","id":"PMC_32788878","title":"MiR-145 functions as a tumor suppressor in Papillary Thyroid Cancer by inhibiting RAB5C.","date":"2020","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32788878","citation_count":16,"is_preprint":false},{"pmid":"24604726","id":"PMC_24604726","title":"Identification of PLP2 and RAB5C as novel TPD52 binding partners through yeast two-hybrid screening.","date":"2014","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/24604726","citation_count":12,"is_preprint":false},{"pmid":"23669133","id":"PMC_23669133","title":"Csi1 illuminates the mechanism and function of Rabl configuration.","date":"2013","source":"Nucleus (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/23669133","citation_count":12,"is_preprint":false},{"pmid":"8646882","id":"PMC_8646882","title":"Isolation and mapping of a human gene (RABL) encoding a small GTP-binding protein homologous to the Ras-related RAB gene.","date":"1996","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8646882","citation_count":9,"is_preprint":false},{"pmid":"34277811","id":"PMC_34277811","title":"RAB5C, SYNJ1, and RNF19B promote male ankylosing spondylitis by regulating immune cell infiltration.","date":"2021","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34277811","citation_count":8,"is_preprint":false},{"pmid":"33013900","id":"PMC_33013900","title":"The Small GTPase Rab5c Exerts Bi-Function in Singapore Grouper Iridovirus Infections and Cellular Responses in the Grouper, Epinephelus coioides.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33013900","citation_count":8,"is_preprint":false},{"pmid":"38242290","id":"PMC_38242290","title":"Rab5c promotes RSV and ADV replication by autophagy in respiratory epithelial cells.","date":"2024","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/38242290","citation_count":6,"is_preprint":false},{"pmid":"32014587","id":"PMC_32014587","title":"Intracellular distribution and transcriptional regulation of Atlantic salmon (Salmo salar) Rab5c, 7a and 27a homologs by immune stimuli.","date":"2020","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32014587","citation_count":6,"is_preprint":false},{"pmid":"37552066","id":"PMC_37552066","title":"Macrocephaly and developmental delay caused by missense variants in RAB5C.","date":"2023","source":"Human molecular 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virology","url":"https://pubmed.ncbi.nlm.nih.gov/29393022","citation_count":5,"is_preprint":false},{"pmid":"34013174","id":"PMC_34013174","title":"Enhancing the chondrogenic potential of chondrogenic progenitor cells by deleting RAB5C.","date":"2021","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/34013174","citation_count":5,"is_preprint":false},{"pmid":"36657426","id":"PMC_36657426","title":"Long Non-Coding RNA BCAR4 Promotes Oxaliplatin Resistance in Colorectal Cancer by Modulating miR-484-3p/RAB5C Expression.","date":"2023","source":"Chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/36657426","citation_count":4,"is_preprint":false},{"pmid":"25277538","id":"PMC_25277538","title":"Occurrence of Rabl-like telomere clustering in the holocentric chromosomes of the peach potato aphid Myzus persicae (Hemiptera; Aphididae).","date":"2014","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/25277538","citation_count":3,"is_preprint":false},{"pmid":"40196584","id":"PMC_40196584","title":"RAB5c controls the assembly of non-canonical autophagy machinery to promote phagosome maturation and microbicidal function of macrophages.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40196584","citation_count":1,"is_preprint":false},{"pmid":"40977500","id":"PMC_40977500","title":"From Rabl-like Architecture to Chromosome Territories: A Conserved Developmental Transition in Animal Genomes.","date":"2025","source":"Molecular biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/40977500","citation_count":1,"is_preprint":false},{"pmid":"41507541","id":"PMC_41507541","title":"Prolonged visual experience accelerates developmental synaptic downscaling via epigenetic regulation and Rab5c mediated AMPA receptor trafficking.","date":"2026","source":"Communications 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Parkin","date":"2024-09-15","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.14.613079","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20085,"output_tokens":5349,"usd":0.070245,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13640,"output_tokens":4675,"usd":0.092537,"stage2_stop_reason":"end_turn"},"total_usd":0.162782,"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\": 2005,\n      \"finding\": \"Wnt11 controls tissue morphogenesis during zebrafish gastrulation by modulating E-cadherin-mediated cell cohesion through Rab5c; blocking Rab5c activity phenocopied wnt11 mutants and enhancing Rab5c activity rescued the mutant phenotype, establishing Rab5c as a downstream mediator of Wnt11 signaling that regulates E-cadherin endocytosis.\",\n      \"method\": \"Genetic epistasis in zebrafish (dominant-negative/constitutively-active Rab5c injection, rescue experiments in slb/wnt11 mutants), E-cadherin endocytosis assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic epistasis (phenocopy + rescue), multiple orthogonal methods, replicated functional readouts\",\n      \"pmids\": [\"16198297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The three Rab5 isoforms (Rab5a, Rab5b, Rab5c) are differentially phosphorylated in vitro: Rab5a is efficiently phosphorylated by ERK1 but not ERK2; Rab5b is preferentially phosphorylated by Cdc2 kinase at Ser-123; Rab5c was not efficiently phosphorylated by these same kinases, establishing isoform-specific post-translational regulation.\",\n      \"method\": \"In vitro kinase phosphorylation assays with ERK1, ERK2, and Cdc2 kinase\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro kinase assay, single lab, limited follow-up on Rab5c specifically\",\n      \"pmids\": [\"10403367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GTP-Rab5c binds directly to AMAP1, and EGFR-stimulated activation of Rab5c is necessary to promote the intracellular association of AMAP1 and PRKD2, forming a complex that recycles β1 integrins (e.g., α3β1) to promote breast cancer cell invasion.\",\n      \"method\": \"Co-immunoprecipitation, direct binding assays, siRNA knockdown of Rab5c with invasion/recycling readouts\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, direct binding confirmed, functional knockdown with defined invasion phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"22734003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rab5C, but not Rab5A or Rab5B, is selectively required for EGF-stimulated Rac1 activation and cell motility; depletion of Rab5C suppressed EGF-induced Rac1 activity, reduced peripheral Rac1 localization, decreased Akt phosphorylation, reduced focal adhesion formation, and impaired directional cell migration.\",\n      \"method\": \"siRNA isoform-specific knockdown, Rac1 GTP pull-down assays, scratch wound and Transwell migration assays, micro-patterned cell imaging, phospho-Akt western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays, isoform specificity established, single lab\",\n      \"pmids\": [\"24587345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rab5C and EEA1 in the early endosomal pathway are rate-limiting regulators of antisense oligonucleotide (PS-ASO) trafficking and endosomal escape following Stabilin receptor-mediated internalization; modulating their expression altered the efficiency of ASO escape from endolysosomal compartments.\",\n      \"method\": \"Modulation of Rab5C expression (knockdown/overexpression) in cells, tracking of PS-ASO trafficking and endosomal escape\",\n      \"journal\": \"Nucleic acid therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined functional role in trafficking with loss-of-function readout, single lab, single paper\",\n      \"pmids\": [\"29437530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rab5c is a key component of the endosomal recycling machinery for CD93 in endothelial cells; Rab5c-containing endosomal compartments harbor a complex of CD93, Multimerin-2, and active β1 integrin that is recycled back to the basolaterally-polarized cell surface by clathrin-independent endocytosis, and Rab5c silencing impairs CD93 recycling and cell migration.\",\n      \"method\": \"Gene silencing (siRNA), fluorescence confocal microscopy, co-immunoprecipitation, scratch assay for migration, flow cytometry\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, confocal colocalization, functional knockdown with migration phenotype, single lab\",\n      \"pmids\": [\"31138217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rab5c modulates EGFR internalization in rectal cancer cells in response to irradiation, and this modulation affects EGFR nuclear relocalization, which in turn regulates expression of DNA repair proteins Ku70 and Ku80 to confer radiotherapy resistance.\",\n      \"method\": \"Rab5c knockdown/overexpression in irradiated rectal adenocarcinoma cell lines, EGFR internalization assays, western blot for Ku70/Ku80, radioresistance assays\",\n      \"journal\": \"Journal of molecular medicine (Berlin, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional KD with defined mechanistic pathway (EGFR internalization → nuclear EGFR → DNA repair), single lab\",\n      \"pmids\": [\"30968159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rab5c is essential for hematopoietic stem and progenitor cell (HSPC) specification in zebrafish via endocytic trafficking of Notch ligands and receptor; additionally, Rab5c interacts with Appl1 in endosomes to activate AKT signaling required for hemogenic endothelium survival, and Rab5c overactivation causes excessive endolysosomal Notch degradation and HSPC defects.\",\n      \"method\": \"Zebrafish rab5c morpholino knockdown and overexpression, co-immunoprecipitation of Rab5c with Appl1, endocytic trafficking assays of Notch components, AKT phosphorylation readouts\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP (Rab5c-Appl1), genetic loss-of-function with defined molecular pathway, bidirectional perturbation (KD and overactivation), multiple signaling readouts\",\n      \"pmids\": [\"32275659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RAB5C is a direct target of miR-509; enforced miR-509 expression reduced RAB5C mRNA and protein in B-ALL cells, and knockdown of RAB5C alone recapitulated the growth-inhibitory and pro-apoptotic effects of miR-509; co-expression of RAB5C ORF (without 3'UTR) blocked miR-509-mediated growth inhibition.\",\n      \"method\": \"miR-509 overexpression, RAB5C shRNA knockdown, rescue by RAB5C ORF re-expression, luciferase reporter assay for direct targeting, flow cytometry for proliferation/apoptosis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct miRNA target validated by 3'UTR reporter + rescue experiment, functional knockdown with cellular phenotype, single lab\",\n      \"pmids\": [\"25368993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RAB5C physically interacts with TPD52 (Tumor Protein D52); this interaction was identified by yeast two-hybrid screening and confirmed by pull-down assays, with domain mapping identifying a novel binding region on TPD52.\",\n      \"method\": \"Yeast two-hybrid screening, pull-down assays, interaction domain mapping\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pulldown confirmation of two-hybrid hit, no functional consequence established for RAB5C specifically\",\n      \"pmids\": [\"24604726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TBC1D16, a TBC domain-containing GAP protein, targets Rab5C to suppress prototype foamy virus (PFV) replication; the conserved arginine finger and glutamine residues R494 and Q531 in the TBC domain are essential for this inhibitory function, and TBC1D16 promotes IFN-β production.\",\n      \"method\": \"TBC1D16 overexpression/silencing in PFV-infected cells, mutagenesis of TBC domain catalytic residues (R494A, Q531A), IFN-β reporter assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — active-site mutagenesis of the GAP + functional assays for viral replication and IFN-β, identifies Rab5C as the substrate, single lab\",\n      \"pmids\": [\"34367131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Piezo1 recruits and physically interacts with Rab5c to activate TGF-β signaling, thereby promoting HCC progression and EMT; knockdown of Piezo1 impaired this complex formation and reduced TGF-β pathway activation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, Piezo1 knockdown with TGF-β signaling readouts, in vitro and in vivo tumor models\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP showing Piezo1-Rab5c interaction, functional KD with defined pathway readout, single lab\",\n      \"pmids\": [\"35461277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HuR RNA-binding protein binds the 3'UTR of RAB5C mRNA to stabilize it, maintaining RAB5C protein levels; HuR shRNA knockdown decreased RAB5C mRNA and protein, and suppression of RAB5C reduced breast cancer cell proliferation.\",\n      \"method\": \"RNA immunoprecipitation (RIP) of HuR-RAB5C mRNA, shRNA knockdown of HuR, mRNA stability assays, colony formation and MTT assays\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RIP confirmed direct HuR-RAB5C mRNA binding, functional KD phenotype, single lab\",\n      \"pmids\": [\"36480789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Heterozygous de novo missense variants in RAB5C cause macrocephaly and developmental delay; biochemical studies showed the variants increased nucleotide exchange rate, attenuated responsivity to guanine exchange factors, and had heterogeneous effects on effector protein interactions; two variants acted through a dominant-negative mechanism; C. elegans and zebrafish models confirmed in vivo disruption of the endocytic pathway.\",\n      \"method\": \"In vitro nucleotide exchange assays, GEF responsivity assays, effector binding assays, C. elegans in vivo endocytic pathway assays, zebrafish embryo expression studies\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical assays (nucleotide exchange, GEF responsivity, effector binding) plus two independent in vivo model systems (C. elegans and zebrafish)\",\n      \"pmids\": [\"37552066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Rab5c promotes RSV and ADV replication via autophagy rather than endocytosis; activated Rab5c upregulates LC3-II protein expression by interacting with Beclin1, inducing autophagy that facilitates viral replication in respiratory epithelial cells and in Rab5c-overexpressing mice.\",\n      \"method\": \"Rab5c overexpression/knockdown in A549 cells and transgenic mice, co-immunoprecipitation of Rab5c with Beclin1, LC3-II western blot, viral replication assays\",\n      \"journal\": \"Virus research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying Rab5c-Beclin1 interaction, in vitro and in vivo functional assays, mechanism distinguished from endocytosis by pharmacological inhibitors, single lab\",\n      \"pmids\": [\"38242290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RAB5c regulates phagosome recruitment of complexes required for PI(3)P and ROS generation during LC3-associated phagocytosis (LAP); specifically, RAB5c facilitates phagosome translocation of the V-ATPase transmembrane core, which enables ATG16L1 binding and consequent LC3 conjugation to phagosomes; RAB5c depletion impaired macrophage elimination of Aspergillus fumigatus and disruption of the V-ATPase-ATG16L1 axis increased susceptibility in vivo.\",\n      \"method\": \"RAB5c knockdown/depletion in macrophages, phagosome fractionation, V-ATPase and ATG16L1 recruitment assays, LC3 conjugation assays, in vivo Aspergillus fumigatus infection model\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal mechanistic assays (phagosome fractionation, recruitment of V-ATPase/ATG16L1, LC3 conjugation), in vivo validation, peer-reviewed publication\",\n      \"pmids\": [\"42102192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Parkin E3 ubiquitin ligase ubiquitinates RAB5C (along with other Rab GTPases); this was identified by orthogonal ubiquitin transfer (OUT) proteomics and confirmed by reconstituted in vitro ubiquitination reactions, and Parkin-mediated ubiquitination of Rab proteins was enhanced upon mitophagy stimulation.\",\n      \"method\": \"Orthogonal ubiquitin transfer (OUT) cascade proteomics, in vitro reconstituted ubiquitination assay, mitophagy stimulation experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstituted ubiquitination confirmed by OUT screen, preprint, RAB5C is one of many substrates identified\",\n      \"pmids\": [\"bio_10.1101_2024.09.14.613079\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RAB5C regulates VWF exocytosis from endothelial cells; RAB5C silencing decreased VWF release after histamine stimulation whereas constitutively active RAB5C increased it; proximity labeling and mass spectrometry identified SNAP29 (a SNARE-associated protein) as a key RAB5C interactor mediating this effect on vesicle fusion and VWF secretion.\",\n      \"method\": \"RAB5C silencing/overexpression in HUVECs, ELISA for VWF release, proximity labeling (BioID) + mass spectrometry for interactome, constitutively active and dominant negative RAB5C constructs\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional perturbation (KD and CA/DN OE), proximity proteomics identifying SNAP29 as interactor, functional VWF secretion assay, multiple orthogonal methods\",\n      \"pmids\": [\"41537263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Rab5c-dependent endocytosis of AMPA receptor subunits GluA1 and GluA2 mediates developmental synaptic downscaling in Xenopus tadpoles; prolonged visual experience accelerated this Rab5c-dependent AMPAR endocytosis, reducing mEPSC amplitudes, and the effect was reversible.\",\n      \"method\": \"Rab5c manipulation in Xenopus laevis tadpoles, electrophysiology (mEPSC recordings), AMPAR subunit trafficking assays, pharmacological and genetic inhibition of Rab5c\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined role for Rab5c in AMPAR endocytosis with electrophysiological readout, single lab, single paper\",\n      \"pmids\": [\"41507541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The human RABL gene (now RAB5C) encodes a 216 amino acid small GTP-binding protein with 86% amino acid identity to the RAB5 subfamily; it is expressed ubiquitously in all human tissues examined and maps to chromosome band 17q21.2 by FISH.\",\n      \"method\": \"cDNA cloning from human fetal lung library, sequence analysis, fluorescence in situ hybridization (FISH) for chromosomal mapping, northern blot for tissue expression\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct cloning and chromosomal mapping by FISH, establishes identity and ubiquitous expression, single lab\",\n      \"pmids\": [\"8646882\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAB5C (also known as RABL) is a member of the RAB5 subfamily of small GTPases that acts as a master regulator of early endocytic trafficking, with isoform-specific functions including: regulating E-cadherin endocytosis downstream of Wnt11 signaling during gastrulation; promoting Rac1 activation and focal adhesion-dependent cell motility; forming a complex with AMAP1 and PRKD2 to recycle β1 integrins upon EGFR stimulation; directing Notch and AKT signaling via endocytic trafficking in hematopoietic progenitor development; facilitating LC3-associated phagocytosis by recruiting V-ATPase to phagosomes to enable ATG16L1-dependent LC3 conjugation; promoting VWF exocytosis through SNAP29-mediated vesicle fusion in endothelial cells; and interacting with Beclin1 to induce autophagy during viral infection; it is differentially phosphorylated by ERK1 and Cdc2 compared to the other Rab5 isoforms, ubiquitinated by Parkin, and its activity is regulated by the GAP TBC1D16; de novo missense variants in RAB5C cause a neurodevelopmental disorder by increasing nucleotide exchange rate and disrupting effector interactions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAB5C is a member of the RAB5 subfamily of small GTP-binding proteins that functions as a master regulator of early endocytic trafficking, cycling between GTP- and GDP-bound states to control cargo internalization, sorting, and recycling [#19, #13]. Its GTPase activity is governed by nucleotide exchange and by the TBC-domain GAP TBC1D16, whose conserved catalytic arginine and glutamine residues are required to turn RAB5C off [#10, #13]. RAB5C engages effectors and adaptors in a GTP-dependent manner: active RAB5C binds AMAP1 to nucleate an AMAP1–PRKD2 complex that recycles \\u03b21 integrins upon EGFR stimulation, and it associates with Appl1 on endosomes to drive AKT signaling, illustrating how its endosomal output is coupled to growth-factor and survival pathways [#2, #7]. Through control of receptor and ligand trafficking, RAB5C is selectively required—relative to other RAB5 isoforms—for EGF-stimulated Rac1 activation, focal adhesion formation, and directional cell migration, and it mediates endocytic regulation of E-cadherin downstream of Wnt11 during gastrulation and Notch ligand/receptor trafficking during hematopoietic progenitor specification [#3, #0, #7]. Beyond classical endocytosis, RAB5C facilitates LC3-associated phagocytosis by promoting phagosomal recruitment of the V-ATPase core to enable ATG16L1-dependent LC3 conjugation, and it controls regulated secretion by promoting SNAP29-mediated VWF exocytosis in endothelial cells [#15, #17]. Heterozygous de novo missense variants in RAB5C cause a neurodevelopmental disorder with macrocephaly and developmental delay by increasing nucleotide exchange rate, attenuating GEF responsivity, and disrupting effector interactions, with some variants acting dominant-negatively [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the molecular identity of RAB5C, defining it as a ubiquitously expressed small GTPase closely related to the RAB5 subfamily before any function was known.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, FISH mapping, and northern blot in human tissues\",\n      \"pmids\": [\"8646882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or trafficking role assigned\", \"Isoform-specific behavior versus RAB5A/RAB5B not addressed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Asked whether the three RAB5 isoforms are post-translationally regulated differently, revealing isoform-selective phosphorylation as a basis for functional divergence.\",\n      \"evidence\": \"In vitro kinase assays with ERK1, ERK2, and Cdc2\",\n      \"pmids\": [\"10403367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RAB5C was not efficiently phosphorylated, leaving its specific regulatory inputs unresolved\", \"In vitro only; no cellular validation\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Placed RAB5C in a developmental signaling pathway by showing it mediates Wnt11 control of E-cadherin endocytosis during morphogenesis.\",\n      \"evidence\": \"Reciprocal genetic epistasis (dominant-negative/constitutively-active Rab5c, rescue) in zebrafish slb/wnt11 mutants with E-cadherin endocytosis assays\",\n      \"pmids\": [\"16198297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between Wnt11 and RAB5C activation not defined\", \"Effectors mediating E-cadherin endocytosis unidentified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined a direct GTP-dependent effector interaction, showing active RAB5C nucleates an AMAP1-PRKD2 complex for integrin recycling downstream of EGFR.\",\n      \"evidence\": \"Co-IP, direct binding assays, and siRNA knockdown with invasion/recycling readouts in breast cancer cells\",\n      \"pmids\": [\"22734003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GEF activating RAB5C downstream of EGFR not identified\", \"Structural basis of AMAP1 binding unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established functional isoform specificity, demonstrating RAB5C (not RAB5A/B) is required for EGF-driven Rac1 activation and cell motility.\",\n      \"evidence\": \"Isoform-specific siRNA, Rac1 GTP pull-downs, migration assays, and phospho-Akt blots\",\n      \"pmids\": [\"24587345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking RAB5C endosomes to Rac1 activation not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified upstream and physical regulators of RAB5C abundance and interaction, including miR-509 targeting and a TPD52 interaction.\",\n      \"evidence\": \"miR-509 overexpression with RAB5C ORF rescue and luciferase reporter (B-ALL); yeast two-hybrid and pull-down for TPD52\",\n      \"pmids\": [\"25368993\", \"24604726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the TPD52 interaction for RAB5C not established\", \"TPD52 interaction rests on a single Y2H/pull-down without reciprocal validation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended RAB5C into endosomal recycling of cell-surface receptors and into a receptor-internalization-to-nuclear-signaling axis affecting DNA repair.\",\n      \"evidence\": \"siRNA, confocal colocalization, and Co-IP for CD93/Multimerin-2/\\u03b21-integrin recycling; knockdown/overexpression with EGFR internalization and Ku70/Ku80 readouts in irradiated rectal cancer cells\",\n      \"pmids\": [\"31138217\", \"30968159\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effectors mediating CD93 recycling not defined\", \"Causal chain from EGFR internalization to nuclear EGFR not fully reconstituted\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated RAB5C couples endocytic trafficking to two signaling outputs (Notch and AKT) in vivo, with both loss and overactivation disrupting hematopoietic specification.\",\n      \"evidence\": \"Zebrafish morpholino knockdown and overexpression, Rab5c-Appl1 Co-IP, Notch trafficking and AKT phosphorylation readouts\",\n      \"pmids\": [\"32275659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism balancing Notch recycling versus degradation unresolved\", \"GEF/GAP setting RAB5C activity level in HSPCs unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified TBC1D16 as a GAP for RAB5C, linking RAB5C inactivation to antiviral restriction and IFN-\\u03b2 induction.\",\n      \"evidence\": \"TBC1D16 overexpression/silencing and catalytic-residue mutagenesis (R494A, Q531A) in PFV-infected cells with IFN-\\u03b2 reporters\",\n      \"pmids\": [\"34367131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GAP activity on RAB5C not measured biochemically\", \"Other GAPs/GEFs for RAB5C remain unidentified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Added mechanosensory and RNA-stability inputs to RAB5C, via a Piezo1 interaction promoting TGF-\\u03b2 signaling and HuR-mediated mRNA stabilization.\",\n      \"evidence\": \"Co-IP and knockdown for Piezo1-RAB5C/TGF-\\u03b2 in HCC; RIP and mRNA stability assays for HuR-RAB5C in breast cancer\",\n      \"pmids\": [\"35461277\", \"36480789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Piezo1 modulates RAB5C nucleotide state is unknown\", \"Both rest on single-lab Co-IP/RIP evidence\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided the causal disease mechanism, showing de novo RAB5C missense variants drive a neurodevelopmental disorder by altering nucleotide cycling and effector binding.\",\n      \"evidence\": \"In vitro nucleotide exchange, GEF responsivity, and effector binding assays plus C. elegans and zebrafish in vivo endocytic models\",\n      \"pmids\": [\"37552066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific consequences in human neurons not defined\", \"Which effector disruptions drive macrocephaly versus developmental delay unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected RAB5C to autophagy and to ubiquitin-mediated regulation, via a Beclin1 interaction promoting viral replication and Parkin-dependent ubiquitination.\",\n      \"evidence\": \"Rab5c-Beclin1 Co-IP, LC3-II blots, and viral replication assays in A549/mice; OUT proteomics and reconstituted in vitro ubiquitination by Parkin (preprint)\",\n      \"pmids\": [\"38242290\", \"bio_10.1101_2024.09.14.613079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Parkin ubiquitination of RAB5C not established\", \"RAB5C is one of many Parkin substrates; specificity unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a non-canonical role in LC3-associated phagocytosis, with RAB5C driving phagosomal V-ATPase recruitment to license ATG16L1-dependent LC3 conjugation and antifungal defense.\",\n      \"evidence\": \"RAB5C depletion, phagosome fractionation, V-ATPase/ATG16L1 recruitment and LC3 conjugation assays, in vivo Aspergillus fumigatus model\",\n      \"pmids\": [\"42102192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RAB5C selects V-ATPase as effector versus canonical endosome fusion machinery is unclear\", \"Nucleotide-state requirement for LAP not dissected\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended RAB5C to regulated secretion and neuronal plasticity, identifying SNAP29-mediated VWF exocytosis and Rab5c-dependent AMPAR endocytosis in synaptic downscaling.\",\n      \"evidence\": \"BioID/MS interactome and bidirectional perturbation with VWF release ELISA in HUVECs; Rab5c manipulation with mEPSC recordings in Xenopus tadpoles\",\n      \"pmids\": [\"41537263\", \"41507541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How an endocytic GTPase promotes SNAP29-dependent fusion mechanistically is unresolved\", \"Synaptic AMPAR role rests on a single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RAB5C achieves its distinct, isoform-specific outputs across endocytosis, recycling, LC3-associated phagocytosis, and regulated exocytosis from a shared RAB5 GTPase scaffold remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural basis for effector selectivity between RAB5 isoforms\", \"Full GEF/GAP regulatory network beyond TBC1D16 undefined\", \"Connection between nucleotide-cycling defects and specific tissue phenotypes not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [13, 10, 19]},\n      {\"term_id\": \"GO:0005525\", \"supporting_discovery_ids\": [19, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5, 7, 2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [15, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 5, 3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [15, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 2, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AMAP1\", \"PRKD2\", \"Appl1\", \"TBC1D16\", \"Beclin1\", \"SNAP29\", \"Piezo1\", \"TPD52\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}