{"gene":"RAB6B","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2000,"finding":"RAB6B localizes to the Golgi apparatus and ERGIC-53-positive vesicles. Unlike the ubiquitously expressed RAB6A, RAB6B shows cell-type-specific expression predominantly in brain (microglia, pericytes, Purkinje cells) and neuroblastoma cells. RAB6B displays lower GTP-binding activities than RAB6A and in overexpression distributes over both Golgi and ER membranes, whereas RAB6A is more restricted to Golgi. The GTP-bound form (Q72L mutant) interacts with all known RAB6A effectors including Rabkinesin-6, suggesting a cell-type-specific role in retrograde membrane traffic at the Golgi complex.","method":"Subcellular fractionation, immunofluorescence, northern blot, immunohistochemistry, overexpression of GTP-locked mutant (Q72L), co-immunoprecipitation with effectors","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (localization, biochemistry, mutant analysis), foundational characterization paper replicated in subsequent studies","pmids":["10893188"],"is_preprint":false},{"year":2007,"finding":"RAB6B interacts with Bicaudal-D1 (BICD1) in its GTP-bound (active) form. RAB6B and BICD1 co-localize at the Golgi and on vesicles aligning along microtubules, and both co-localize with dynein in neurites of SK-N-SH neuronal cells. Live cell imaging revealed bi-directional movement of EGFP-RAB6B structures in neurites. This places RAB6B, via BICD1, in the dynein/dynactin retrograde transport complex in neuronal cells.","method":"Yeast two-hybrid screen, co-immunoprecipitation, pull-down assays, confocal co-localization, live cell imaging (EGFP-RAB6B)","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and pull-down confirmed interaction, live imaging and co-localization provide functional context, multiple orthogonal methods in one study","pmids":["17707369"],"is_preprint":false},{"year":2008,"finding":"RAB6B directly interacts with the dynein light chain DYNLRB1. Pull-down experiments showed a preferred association of DYNLRB1 with GDP-bound RAB6B (and GDP-bound RAB6A'), in contrast to GTP-bound RAB6A. DYNLRB1 co-localizes with all three RAB6 isoforms at the Golgi. In vitro GTPase activity assays showed DYNLRB1 does NOT stimulate RAB6 GTPase activity.","method":"Yeast two-hybrid, co-immunoprecipitation, pull-down assays, immunofluorescence co-localization, in vitro GTPase activity assay","journal":"Cell motility and the cytoskeleton","confidence":"High","confidence_rationale":"Tier 2 / Strong — three orthogonal binding methods plus functional in vitro assay; negative GTPase result explicitly established","pmids":["18044744"],"is_preprint":false},{"year":2006,"finding":"Crystal structures of human neuronal RAB6B were solved in the GDP-bound ('inactive', 2.3 Å) and GTPγS-bound ('active', 1.8 Å) forms. Conformational changes between states are concentrated in the switch I and switch II regions. Additional changes were observed in the RAB6 subfamily-specific RabSF3 region, potentially contributing to effector specificity of RAB6 isoforms.","method":"X-ray crystallography (space group P2₁2₁2₁; 2.3 Å GDP-bound and 1.8 Å GTPγS-bound structures)","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution crystal structures of both nucleotide states solved; single lab but direct structural evidence","pmids":["16790928"],"is_preprint":false},{"year":2013,"finding":"RAB6B physically interacts with GDAP1 (an outer mitochondrial membrane protein implicated in Charcot-Marie-Tooth disease) and with caytaxin, suggesting RAB6B participates in mitochondrial movement within the cell.","method":"Co-immunoprecipitation (interaction between GDAP1 and RAB6B/caytaxin in SH-SY5Y cells)","journal":"Neurobiology of disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP in one cell line; no direct functional follow-up specific to RAB6B mechanism","pmids":["23542510"],"is_preprint":false},{"year":2021,"finding":"RAB6B is expressed in primary mouse macrophages and localizes to the Golgi complex. Mycobacterium bovis BCG infection dynamically alters RAB6B expression in macrophages in vitro and in vivo. RAB6B knockdown reduces TNF secretion from BCG-infected macrophages without affecting Tnf mRNA levels or intracellular TNF protein abundance, establishing RAB6B as a positive regulator of TNF vesicle trafficking and secretion in macrophages.","method":"Immunofluorescence localization, siRNA knockdown, ELISA (TNF secretion), qRT-PCR (Tnf mRNA), intracellular flow cytometry (TNF protein), in vivo infection model","journal":"Immunology and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined secretion phenotype and multiple orthogonal readouts (RNA, protein, secretion), single lab","pmids":["34555867"],"is_preprint":false},{"year":2022,"finding":"Double knockout of RAB6A/A' and RAB6B in radial glial (aRG) neural progenitors impairs apical localization of the polarity determinant CRB3 (Crumbs3) and induces retraction of the aRG apical process, leading to delamination and ectopic division. Live imaging showed RAB6+ post-Golgi vesicles move toward microtubule minus ends in a dynein-dependent manner. RAB6-dynein-LIS1 constitute a complex required for Golgi-to-apical-surface transport in aRG cells.","method":"In situ subcellular live imaging, RAB6A/A' and RAB6B double knockout (conditional KO mice/organoids), immunofluorescence for CRB3 apical localization, LIS1 knockout phenocopy, co-localization studies","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic double KO with specific cellular phenotype, live imaging of vesicle transport, LIS1 KO phenocopy, multiple orthogonal methods across labs","pmids":["35979738"],"is_preprint":false},{"year":2023,"finding":"ELKS1 binds RAB6B through a C-terminal helical hairpin segment that engages RAB6B via a unique binding mode (co-crystal structure solved). Liquid-liquid phase separation (LLPS) of ELKS1 allows it to compete with other RAB6 effectors for RAB6B binding and accumulate RAB6B-coated liposomes into ELKS1 condensates. ELKS1 condensates recruit RAB6B-coated vesicles to vesicle-releasing sites and promote vesicle exocytosis.","method":"X-ray co-crystal structure of RAB6B–ELKS1 Rab6-binding domain complex, in vitro LLPS assay, liposome-condensate co-sedimentation, live cell vesicle exocytosis assay, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — co-crystal structure plus in vitro reconstitution of LLPS, liposome capture, and cellular exocytosis assay; multiple orthogonal methods in one study","pmids":["37172719"],"is_preprint":false},{"year":2024,"finding":"CNS-specific Rab6a/b double knockout (DKO) mice exhibit severe dysplasia of the neocortex and cerebellum. In Rab6 DKO neurons, synaptic vesicle precursors (SVPs) abnormally accumulate adjacent to the Golgi apparatus, causing defects in axonal extension and loss of axon-dendrite polarity. RAB6 DKO also causes significant lysosomal expansion in the soma. This establishes Rab6 (including Rab6b) as required for polarized anterograde transport of SVPs from the Golgi to the axon during neuronal polarity establishment.","method":"CNS-specific conditional Rab6a/b double KO mice (both sexes), in vitro primary neuron culture with Rab6a/b deletion, immunofluorescence for SVP markers and polarity markers, electron microscopy (lysosome expansion)","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo DKO with defined brain phenotype plus in vitro neuronal assays; both sexes examined; multiple orthogonal readouts","pmids":["38830762"],"is_preprint":false},{"year":2023,"finding":"Statin treatment (HMGCR inhibition) reduces RAB6B prenylation, which decreases RAB6B membrane association and affects integrin localization and downstream FAK signaling required for cell growth in PGC1α-suppressed BRAF-inhibitor-resistant melanoma cells. Combined re-expression of RAB6B and RAB27A reverses statin vulnerability in these cells.","method":"Pharmacological statin treatment, membrane fractionation (prenylation/membrane association), rescue by RAB6B+RAB27A re-expression, integrin localization immunofluorescence, FAK signaling western blot","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — membrane fractionation and rescue experiments establish mechanistic link between prenylation and membrane function; single lab, two orthogonal approaches","pmids":["37277330"],"is_preprint":false},{"year":2019,"finding":"RAB6B silencing in gastric cancer cells inhibits cell proliferation and G1/S transition through suppression of AKT/JNK signaling pathways, leading to reduced Cyclin D1 and CDK4 levels. miR-4268 directly targets RAB6B mRNA and phenocopies RAB6B silencing.","method":"siRNA-mediated RAB6B knockdown, luciferase reporter assay (miR-4268 targeting), cell cycle analysis, western blot (AKT/JNK/p38 pathway, Cyclin D1, CDK4), proliferation assays","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct KD with defined proliferative phenotype and pathway readouts; single lab but multiple orthogonal methods","pmids":["31303644"],"is_preprint":false},{"year":2023,"finding":"miR-6216 directly targets and negatively regulates RAB6B expression in neural stem cells (NSCs). Overexpression of RAB6B promotes NSC proliferation, whereas forced overexpression of miR-6216 inhibits NSC proliferation.","method":"Luciferase reporter assay (miR-6216 targeting of RAB6B 3'UTR), RAB6B overexpression, miR-6216 overexpression, NSC proliferation assays","journal":"Neuroscience research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct luciferase validation of miRNA-target relationship plus gain-of-function proliferation phenotype; single lab, two methods","pmids":["37059126"],"is_preprint":false},{"year":2017,"finding":"RAB6B was identified as a protein that co-immunoprecipitates with CEA (carcinoembryonic antigen) in LoVo colon cancer cells. RAB6B expression was down-regulated in LoVo cells in a radiation dose-dependent manner.","method":"Anti-CEA immunoprecipitation followed by LC-MS/MS mass spectrometry; western blot post-irradiation","journal":"Radiation oncology journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/MS identification in one cell line; no mechanistic follow-up of the RAB6B–CEA interaction","pmids":["28881503"],"is_preprint":false}],"current_model":"RAB6B is a brain-enriched small GTPase that localizes to the Golgi apparatus and post-Golgi vesicles, where it functions in retrograde Golgi-to-ER membrane traffic and anterograde polarized vesicle transport; it does so by engaging effectors including Bicaudal-D1, DYNLRB1, and ELKS1 to link vesicles to the dynein/dynactin motor complex, and in neurons its combined activity with RAB6A is required for polarized axonal transport of synaptic vesicle precursors, neuronal polarity establishment, and proper neocortical development; outside the brain, RAB6B also regulates TNF secretion in macrophages and cell proliferation via AKT/JNK signaling, and its membrane association depends on prenylation."},"narrative":{"mechanistic_narrative":"RAB6B is a brain-enriched small GTPase of the Golgi apparatus and post-Golgi vesicles that cycles between GDP- and GTP-bound conformations, with switch I/II and the RAB6 subfamily-specific RabSF3 region governing effector engagement and isoform specificity [PMID:10893188, PMID:16790928]. In its active GTP-bound state it recruits effectors that couple vesicles to the dynein/dynactin retrograde motor machinery, binding Bicaudal-D1 (BICD1) at the Golgi and along microtubules and engaging the dynein light chain DYNLRB1, thereby directing bi-directional vesicle movement in neurites [PMID:17707369, PMID:18044744]. RAB6B-coated vesicles move toward microtubule minus ends in a dynein-dependent manner, and ELKS1 captures these vesicles into liquid-liquid phase-separated condensates—via a unique C-terminal helical-hairpin binding mode—to deliver them to release sites and promote exocytosis [PMID:35979738, PMID:37172719]. In the developing nervous system RAB6B acts redundantly with RAB6A/A': combined loss disrupts apical CRB3 localization and the RAB6–dynein–LIS1-dependent Golgi-to-apical-surface transport that maintains radial glial progenitors, and causes accumulation of synaptic vesicle precursors at the Golgi with failure of polarized axonal transport, producing neocortical and cerebellar dysplasia and loss of axon–dendrite polarity [PMID:35979738, PMID:38830762]. Outside the brain, RAB6B positively regulates TNF vesicle trafficking and secretion in infected macrophages without altering Tnf transcription [PMID:34555867], and its membrane association requires prenylation, linking it to integrin localization and FAK signaling [PMID:37277330]. RAB6B expression is repressed by miR-4268 and miR-6216, and modulating its levels alters cell proliferation through AKT/JNK signaling and Cyclin D1/CDK4 [PMID:31303644, PMID:37059126].","teleology":[{"year":2000,"claim":"Established RAB6B as a brain-restricted RAB6 paralog distinct from ubiquitous RAB6A, defining its Golgi/ER localization, weaker GTP-binding, and capacity to share RAB6A effectors—framing a cell-type-specific role in Golgi membrane traffic.","evidence":"Subcellular fractionation, immunofluorescence, immunohistochemistry, and GTP-locked Q72L mutant co-IP with effectors","pmids":["10893188"],"confidence":"High","gaps":["Did not resolve which effectors are functionally relevant in neurons","No in vivo functional consequence tested"]},{"year":2006,"claim":"Solved the structural basis of RAB6B nucleotide switching, localizing conformational change to switch I/II and identifying the RabSF3 region as a candidate determinant of RAB6 isoform effector specificity.","evidence":"X-ray crystallography of GDP-bound (2.3 Å) and GTPγS-bound (1.8 Å) RAB6B","pmids":["16790928"],"confidence":"High","gaps":["RabSF3 contribution to specificity inferred from structure, not validated by effector-binding mutagenesis","No effector co-structure in this study"]},{"year":2007,"claim":"Connected active RAB6B to the dynein retrograde transport machinery in neuronal cells by identifying GTP-dependent binding to BICD1 and co-localization with dynein in neurites.","evidence":"Yeast two-hybrid, reciprocal Co-IP, pull-down, confocal co-localization, and live imaging of EGFP-RAB6B in SK-N-SH cells","pmids":["17707369"],"confidence":"High","gaps":["Cargo transported via RAB6B-BICD1 not defined","Functional requirement of the interaction not tested by loss-of-function"]},{"year":2008,"claim":"Refined the motor coupling by showing RAB6B binds the dynein light chain DYNLRB1 preferentially in the GDP state and that DYNLRB1 is not a GAP, distinguishing structural motor association from nucleotide regulation.","evidence":"Yeast two-hybrid, Co-IP, pull-down, co-localization, and in vitro GTPase assay","pmids":["18044744"],"confidence":"High","gaps":["Physiological role of nucleotide-state-dependent DYNLRB1 binding unresolved","GDP-preference versus GTP-dependent BICD1 binding not mechanistically reconciled"]},{"year":2021,"claim":"Extended RAB6B function beyond the nervous system by establishing it as a positive regulator of TNF vesicle secretion in macrophages, acting at the trafficking step rather than transcription.","evidence":"siRNA knockdown with ELISA, qRT-PCR, and intracellular flow cytometry in BCG-infected primary mouse macrophages","pmids":["34555867"],"confidence":"Medium","gaps":["Effectors mediating TNF vesicle transport not identified","Single lab; specific Golgi-to-surface route not mapped"]},{"year":2022,"claim":"Demonstrated in vivo that RAB6A/B redundantly drive dynein-dependent minus-end-directed transport of post-Golgi vesicles delivering polarity determinant CRB3 to the apical surface, integrating RAB6 into a RAB6–dynein–LIS1 complex maintaining radial glial progenitors.","evidence":"Conditional Rab6a/a' and Rab6b double knockout, in situ live imaging, CRB3 immunofluorescence, and LIS1-KO phenocopy","pmids":["35979738"],"confidence":"High","gaps":["Individual contribution of RAB6B versus RAB6A not separated","Direct biochemical link of RAB6 to LIS1 not shown"]},{"year":2023,"claim":"Provided the structural and biophysical mechanism by which ELKS1 captures RAB6B vesicles, showing a unique helical-hairpin binding mode and phase-separation-driven competition that concentrates RAB6B-coated vesicles at release sites for exocytosis.","evidence":"X-ray co-crystal structure, in vitro LLPS and liposome-condensate co-sedimentation, mutagenesis, and live-cell exocytosis assay","pmids":["37172719"],"confidence":"High","gaps":["In vivo requirement of ELKS1-RAB6B condensates not tested","Competition hierarchy among RAB6 effectors in cells not quantified"]},{"year":2024,"claim":"Established the in vivo neurodevelopmental requirement: RAB6 (including RAB6B) is needed for polarized anterograde Golgi-to-axon transport of synaptic vesicle precursors, with loss causing SVP accumulation, axon-dendrite polarity failure, and neocortical/cerebellar dysplasia.","evidence":"CNS-specific conditional Rab6a/b double KO mice, primary neuron deletion, polarity/SVP marker immunofluorescence, and EM of lysosomal expansion","pmids":["38830762"],"confidence":"High","gaps":["RAB6B-specific role versus RAB6A redundancy not dissected","Mechanism linking transport block to lysosomal expansion unresolved"]},{"year":2023,"claim":"Linked RAB6B membrane targeting to prenylation, showing statin-mediated loss of prenylation reduces membrane association and affects integrin localization and FAK signaling in drug-resistant melanoma.","evidence":"Statin treatment, membrane fractionation, and RAB6B+RAB27A re-expression rescue with integrin/FAK readouts","pmids":["37277330"],"confidence":"Medium","gaps":["Direct enzymology of RAB6B prenylation not characterized","RAB6B-specific contribution separable from RAB27A only partially resolved"]},{"year":2019,"claim":"Implicated RAB6B in proliferative control, showing its silencing suppresses AKT/JNK signaling and G1/S transition and that miR-4268 directly targets it.","evidence":"siRNA knockdown, luciferase reporter, cell cycle analysis, and pathway western blots in gastric cancer cells","pmids":["31303644"],"confidence":"Medium","gaps":["Mechanistic link between a trafficking GTPase and AKT/JNK signaling not defined","Single cancer cell context"]},{"year":2023,"claim":"Added a second regulatory miRNA, showing miR-6216 directly represses RAB6B and that RAB6B levels bidirectionally control neural stem cell proliferation.","evidence":"Luciferase 3'UTR reporter, RAB6B and miR-6216 overexpression, and NSC proliferation assays","pmids":["37059126"],"confidence":"Medium","gaps":["Downstream pathway from RAB6B to NSC proliferation not mapped","Single lab; in vivo relevance untested"]},{"year":null,"claim":"Whether RAB6B has non-redundant, isoform-specific functions distinct from RAB6A in neurons and other tissues, and how its distinct effectors (BICD1, DYNLRB1, ELKS1) are coordinated on individual vesicles, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No RAB6B-single-knockout phenotype reported in the corpus","Spatiotemporal hierarchy of effector recruitment per vesicle not defined","Mechanism connecting RAB6B trafficking to AKT/JNK proliferative signaling unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,6,7]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[6,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,8]}],"complexes":["RAB6-dynein-LIS1 complex"],"partners":["BICD1","DYNLRB1","ELKS1","GDAP1","RAB27A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NRW1","full_name":"Ras-related protein Rab-6B","aliases":[],"length_aa":208,"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 active GTP-bound and inactive GDP-bound states. In their active state, drive transport of vesicular carriers from donor organelles to acceptor organelles to regulate the membrane traffic that maintains organelle identity and morphology (By similarity). Recruits VPS13B to the Golgi membrane (PubMed:25492866). Regulates the compacted morphology of the Golgi (PubMed:26209634). Seems to have a role in retrograde membrane traffic at the level of the Golgi complex. May function in retrograde transport in neuronal cells (PubMed:17707369). Plays a role in neuron projection development (PubMed:25492866)","subcellular_location":"Golgi apparatus membrane; Endoplasmic reticulum-Golgi intermediate compartment; Cytoplasmic vesicle","url":"https://www.uniprot.org/uniprotkb/Q9NRW1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAB6B","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000154917","cell_line_id":"CID000440","localizations":[{"compartment":"golgi","grade":3},{"compartment":"vesicles","grade":2},{"compartment":"er","grade":1}],"interactors":[{"gene":"GDI1","stoichiometry":0.2},{"gene":"GDI2","stoichiometry":0.2},{"gene":"SPCS3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000440","total_profiled":1310},"omim":[{"mim_id":"617002","title":"BICD FAMILY-LIKE CARGO ADAPTOR 1; BICDL1","url":"https://www.omim.org/entry/617002"},{"mim_id":"615852","title":"RAS-ASSOCIATED PROTEIN RAB6B; RAB6B","url":"https://www.omim.org/entry/615852"},{"mim_id":"615850","title":"VPS53 SUBUNIT OF GARP COMPLEX; VPS53","url":"https://www.omim.org/entry/615850"},{"mim_id":"614633","title":"VPS54 SUBUNIT OF GARP COMPLEX; VPS54","url":"https://www.omim.org/entry/614633"},{"mim_id":"603443","title":"VPS52 SUBUNIT OF GARP COMPLEX; VPS52","url":"https://www.omim.org/entry/603443"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":131.0}],"url":"https://www.proteinatlas.org/search/RAB6B"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9NRW1","domains":[{"cath_id":"3.40.50.300","chopping":"12-172","consensus_level":"high","plddt":95.4375,"start":12,"end":172}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRW1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRW1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRW1-F1-predicted_aligned_error_v6.png","plddt_mean":85.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAB6B","jax_strain_url":"https://www.jax.org/strain/search?query=RAB6B"},"sequence":{"accession":"Q9NRW1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NRW1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NRW1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRW1"}},"corpus_meta":[{"pmid":"10893188","id":"PMC_10893188","title":"The small 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ERGIC-53-positive vesicles. Unlike the ubiquitously expressed RAB6A, RAB6B shows cell-type-specific expression predominantly in brain (microglia, pericytes, Purkinje cells) and neuroblastoma cells. RAB6B displays lower GTP-binding activities than RAB6A and in overexpression distributes over both Golgi and ER membranes, whereas RAB6A is more restricted to Golgi. The GTP-bound form (Q72L mutant) interacts with all known RAB6A effectors including Rabkinesin-6, suggesting a cell-type-specific role in retrograde membrane traffic at the Golgi complex.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence, northern blot, immunohistochemistry, overexpression of GTP-locked mutant (Q72L), co-immunoprecipitation with effectors\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (localization, biochemistry, mutant analysis), foundational characterization paper replicated in subsequent studies\",\n      \"pmids\": [\"10893188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RAB6B interacts with Bicaudal-D1 (BICD1) in its GTP-bound (active) form. RAB6B and BICD1 co-localize at the Golgi and on vesicles aligning along microtubules, and both co-localize with dynein in neurites of SK-N-SH neuronal cells. Live cell imaging revealed bi-directional movement of EGFP-RAB6B structures in neurites. This places RAB6B, via BICD1, in the dynein/dynactin retrograde transport complex in neuronal cells.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, pull-down assays, confocal co-localization, live cell imaging (EGFP-RAB6B)\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and pull-down confirmed interaction, live imaging and co-localization provide functional context, multiple orthogonal methods in one study\",\n      \"pmids\": [\"17707369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RAB6B directly interacts with the dynein light chain DYNLRB1. Pull-down experiments showed a preferred association of DYNLRB1 with GDP-bound RAB6B (and GDP-bound RAB6A'), in contrast to GTP-bound RAB6A. DYNLRB1 co-localizes with all three RAB6 isoforms at the Golgi. In vitro GTPase activity assays showed DYNLRB1 does NOT stimulate RAB6 GTPase activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, pull-down assays, immunofluorescence co-localization, in vitro GTPase activity assay\",\n      \"journal\": \"Cell motility and the cytoskeleton\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three orthogonal binding methods plus functional in vitro assay; negative GTPase result explicitly established\",\n      \"pmids\": [\"18044744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structures of human neuronal RAB6B were solved in the GDP-bound ('inactive', 2.3 Å) and GTPγS-bound ('active', 1.8 Å) forms. Conformational changes between states are concentrated in the switch I and switch II regions. Additional changes were observed in the RAB6 subfamily-specific RabSF3 region, potentially contributing to effector specificity of RAB6 isoforms.\",\n      \"method\": \"X-ray crystallography (space group P2₁2₁2₁; 2.3 Å GDP-bound and 1.8 Å GTPγS-bound structures)\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution crystal structures of both nucleotide states solved; single lab but direct structural evidence\",\n      \"pmids\": [\"16790928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RAB6B physically interacts with GDAP1 (an outer mitochondrial membrane protein implicated in Charcot-Marie-Tooth disease) and with caytaxin, suggesting RAB6B participates in mitochondrial movement within the cell.\",\n      \"method\": \"Co-immunoprecipitation (interaction between GDAP1 and RAB6B/caytaxin in SH-SY5Y cells)\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP in one cell line; no direct functional follow-up specific to RAB6B mechanism\",\n      \"pmids\": [\"23542510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RAB6B is expressed in primary mouse macrophages and localizes to the Golgi complex. Mycobacterium bovis BCG infection dynamically alters RAB6B expression in macrophages in vitro and in vivo. RAB6B knockdown reduces TNF secretion from BCG-infected macrophages without affecting Tnf mRNA levels or intracellular TNF protein abundance, establishing RAB6B as a positive regulator of TNF vesicle trafficking and secretion in macrophages.\",\n      \"method\": \"Immunofluorescence localization, siRNA knockdown, ELISA (TNF secretion), qRT-PCR (Tnf mRNA), intracellular flow cytometry (TNF protein), in vivo infection model\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined secretion phenotype and multiple orthogonal readouts (RNA, protein, secretion), single lab\",\n      \"pmids\": [\"34555867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Double knockout of RAB6A/A' and RAB6B in radial glial (aRG) neural progenitors impairs apical localization of the polarity determinant CRB3 (Crumbs3) and induces retraction of the aRG apical process, leading to delamination and ectopic division. Live imaging showed RAB6+ post-Golgi vesicles move toward microtubule minus ends in a dynein-dependent manner. RAB6-dynein-LIS1 constitute a complex required for Golgi-to-apical-surface transport in aRG cells.\",\n      \"method\": \"In situ subcellular live imaging, RAB6A/A' and RAB6B double knockout (conditional KO mice/organoids), immunofluorescence for CRB3 apical localization, LIS1 knockout phenocopy, co-localization studies\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic double KO with specific cellular phenotype, live imaging of vesicle transport, LIS1 KO phenocopy, multiple orthogonal methods across labs\",\n      \"pmids\": [\"35979738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ELKS1 binds RAB6B through a C-terminal helical hairpin segment that engages RAB6B via a unique binding mode (co-crystal structure solved). Liquid-liquid phase separation (LLPS) of ELKS1 allows it to compete with other RAB6 effectors for RAB6B binding and accumulate RAB6B-coated liposomes into ELKS1 condensates. ELKS1 condensates recruit RAB6B-coated vesicles to vesicle-releasing sites and promote vesicle exocytosis.\",\n      \"method\": \"X-ray co-crystal structure of RAB6B–ELKS1 Rab6-binding domain complex, in vitro LLPS assay, liposome-condensate co-sedimentation, live cell vesicle exocytosis assay, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — co-crystal structure plus in vitro reconstitution of LLPS, liposome capture, and cellular exocytosis assay; multiple orthogonal methods in one study\",\n      \"pmids\": [\"37172719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CNS-specific Rab6a/b double knockout (DKO) mice exhibit severe dysplasia of the neocortex and cerebellum. In Rab6 DKO neurons, synaptic vesicle precursors (SVPs) abnormally accumulate adjacent to the Golgi apparatus, causing defects in axonal extension and loss of axon-dendrite polarity. RAB6 DKO also causes significant lysosomal expansion in the soma. This establishes Rab6 (including Rab6b) as required for polarized anterograde transport of SVPs from the Golgi to the axon during neuronal polarity establishment.\",\n      \"method\": \"CNS-specific conditional Rab6a/b double KO mice (both sexes), in vitro primary neuron culture with Rab6a/b deletion, immunofluorescence for SVP markers and polarity markers, electron microscopy (lysosome expansion)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo DKO with defined brain phenotype plus in vitro neuronal assays; both sexes examined; multiple orthogonal readouts\",\n      \"pmids\": [\"38830762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Statin treatment (HMGCR inhibition) reduces RAB6B prenylation, which decreases RAB6B membrane association and affects integrin localization and downstream FAK signaling required for cell growth in PGC1α-suppressed BRAF-inhibitor-resistant melanoma cells. Combined re-expression of RAB6B and RAB27A reverses statin vulnerability in these cells.\",\n      \"method\": \"Pharmacological statin treatment, membrane fractionation (prenylation/membrane association), rescue by RAB6B+RAB27A re-expression, integrin localization immunofluorescence, FAK signaling western blot\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — membrane fractionation and rescue experiments establish mechanistic link between prenylation and membrane function; single lab, two orthogonal approaches\",\n      \"pmids\": [\"37277330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RAB6B silencing in gastric cancer cells inhibits cell proliferation and G1/S transition through suppression of AKT/JNK signaling pathways, leading to reduced Cyclin D1 and CDK4 levels. miR-4268 directly targets RAB6B mRNA and phenocopies RAB6B silencing.\",\n      \"method\": \"siRNA-mediated RAB6B knockdown, luciferase reporter assay (miR-4268 targeting), cell cycle analysis, western blot (AKT/JNK/p38 pathway, Cyclin D1, CDK4), proliferation assays\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct KD with defined proliferative phenotype and pathway readouts; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"31303644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-6216 directly targets and negatively regulates RAB6B expression in neural stem cells (NSCs). Overexpression of RAB6B promotes NSC proliferation, whereas forced overexpression of miR-6216 inhibits NSC proliferation.\",\n      \"method\": \"Luciferase reporter assay (miR-6216 targeting of RAB6B 3'UTR), RAB6B overexpression, miR-6216 overexpression, NSC proliferation assays\",\n      \"journal\": \"Neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct luciferase validation of miRNA-target relationship plus gain-of-function proliferation phenotype; single lab, two methods\",\n      \"pmids\": [\"37059126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RAB6B was identified as a protein that co-immunoprecipitates with CEA (carcinoembryonic antigen) in LoVo colon cancer cells. RAB6B expression was down-regulated in LoVo cells in a radiation dose-dependent manner.\",\n      \"method\": \"Anti-CEA immunoprecipitation followed by LC-MS/MS mass spectrometry; western blot post-irradiation\",\n      \"journal\": \"Radiation oncology journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/MS identification in one cell line; no mechanistic follow-up of the RAB6B–CEA interaction\",\n      \"pmids\": [\"28881503\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAB6B is a brain-enriched small GTPase that localizes to the Golgi apparatus and post-Golgi vesicles, where it functions in retrograde Golgi-to-ER membrane traffic and anterograde polarized vesicle transport; it does so by engaging effectors including Bicaudal-D1, DYNLRB1, and ELKS1 to link vesicles to the dynein/dynactin motor complex, and in neurons its combined activity with RAB6A is required for polarized axonal transport of synaptic vesicle precursors, neuronal polarity establishment, and proper neocortical development; outside the brain, RAB6B also regulates TNF secretion in macrophages and cell proliferation via AKT/JNK signaling, and its membrane association depends on prenylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAB6B is a brain-enriched small GTPase of the Golgi apparatus and post-Golgi vesicles that cycles between GDP- and GTP-bound conformations, with switch I/II and the RAB6 subfamily-specific RabSF3 region governing effector engagement and isoform specificity [#0, #3]. In its active GTP-bound state it recruits effectors that couple vesicles to the dynein/dynactin retrograde motor machinery, binding Bicaudal-D1 (BICD1) at the Golgi and along microtubules and engaging the dynein light chain DYNLRB1, thereby directing bi-directional vesicle movement in neurites [#1, #2]. RAB6B-coated vesicles move toward microtubule minus ends in a dynein-dependent manner, and ELKS1 captures these vesicles into liquid-liquid phase-separated condensates—via a unique C-terminal helical-hairpin binding mode—to deliver them to release sites and promote exocytosis [#6, #7]. In the developing nervous system RAB6B acts redundantly with RAB6A/A': combined loss disrupts apical CRB3 localization and the RAB6–dynein–LIS1-dependent Golgi-to-apical-surface transport that maintains radial glial progenitors, and causes accumulation of synaptic vesicle precursors at the Golgi with failure of polarized axonal transport, producing neocortical and cerebellar dysplasia and loss of axon–dendrite polarity [#6, #8]. Outside the brain, RAB6B positively regulates TNF vesicle trafficking and secretion in infected macrophages without altering Tnf transcription [#5], and its membrane association requires prenylation, linking it to integrin localization and FAK signaling [#9]. RAB6B expression is repressed by miR-4268 and miR-6216, and modulating its levels alters cell proliferation through AKT/JNK signaling and Cyclin D1/CDK4 [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established RAB6B as a brain-restricted RAB6 paralog distinct from ubiquitous RAB6A, defining its Golgi/ER localization, weaker GTP-binding, and capacity to share RAB6A effectors—framing a cell-type-specific role in Golgi membrane traffic.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence, immunohistochemistry, and GTP-locked Q72L mutant co-IP with effectors\",\n      \"pmids\": [\"10893188\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which effectors are functionally relevant in neurons\", \"No in vivo functional consequence tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Solved the structural basis of RAB6B nucleotide switching, localizing conformational change to switch I/II and identifying the RabSF3 region as a candidate determinant of RAB6 isoform effector specificity.\",\n      \"evidence\": \"X-ray crystallography of GDP-bound (2.3 Å) and GTPγS-bound (1.8 Å) RAB6B\",\n      \"pmids\": [\"16790928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RabSF3 contribution to specificity inferred from structure, not validated by effector-binding mutagenesis\", \"No effector co-structure in this study\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Connected active RAB6B to the dynein retrograde transport machinery in neuronal cells by identifying GTP-dependent binding to BICD1 and co-localization with dynein in neurites.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, pull-down, confocal co-localization, and live imaging of EGFP-RAB6B in SK-N-SH cells\",\n      \"pmids\": [\"17707369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo transported via RAB6B-BICD1 not defined\", \"Functional requirement of the interaction not tested by loss-of-function\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Refined the motor coupling by showing RAB6B binds the dynein light chain DYNLRB1 preferentially in the GDP state and that DYNLRB1 is not a GAP, distinguishing structural motor association from nucleotide regulation.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, pull-down, co-localization, and in vitro GTPase assay\",\n      \"pmids\": [\"18044744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological role of nucleotide-state-dependent DYNLRB1 binding unresolved\", \"GDP-preference versus GTP-dependent BICD1 binding not mechanistically reconciled\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended RAB6B function beyond the nervous system by establishing it as a positive regulator of TNF vesicle secretion in macrophages, acting at the trafficking step rather than transcription.\",\n      \"evidence\": \"siRNA knockdown with ELISA, qRT-PCR, and intracellular flow cytometry in BCG-infected primary mouse macrophages\",\n      \"pmids\": [\"34555867\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effectors mediating TNF vesicle transport not identified\", \"Single lab; specific Golgi-to-surface route not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated in vivo that RAB6A/B redundantly drive dynein-dependent minus-end-directed transport of post-Golgi vesicles delivering polarity determinant CRB3 to the apical surface, integrating RAB6 into a RAB6–dynein–LIS1 complex maintaining radial glial progenitors.\",\n      \"evidence\": \"Conditional Rab6a/a' and Rab6b double knockout, in situ live imaging, CRB3 immunofluorescence, and LIS1-KO phenocopy\",\n      \"pmids\": [\"35979738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contribution of RAB6B versus RAB6A not separated\", \"Direct biochemical link of RAB6 to LIS1 not shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided the structural and biophysical mechanism by which ELKS1 captures RAB6B vesicles, showing a unique helical-hairpin binding mode and phase-separation-driven competition that concentrates RAB6B-coated vesicles at release sites for exocytosis.\",\n      \"evidence\": \"X-ray co-crystal structure, in vitro LLPS and liposome-condensate co-sedimentation, mutagenesis, and live-cell exocytosis assay\",\n      \"pmids\": [\"37172719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo requirement of ELKS1-RAB6B condensates not tested\", \"Competition hierarchy among RAB6 effectors in cells not quantified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established the in vivo neurodevelopmental requirement: RAB6 (including RAB6B) is needed for polarized anterograde Golgi-to-axon transport of synaptic vesicle precursors, with loss causing SVP accumulation, axon-dendrite polarity failure, and neocortical/cerebellar dysplasia.\",\n      \"evidence\": \"CNS-specific conditional Rab6a/b double KO mice, primary neuron deletion, polarity/SVP marker immunofluorescence, and EM of lysosomal expansion\",\n      \"pmids\": [\"38830762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RAB6B-specific role versus RAB6A redundancy not dissected\", \"Mechanism linking transport block to lysosomal expansion unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked RAB6B membrane targeting to prenylation, showing statin-mediated loss of prenylation reduces membrane association and affects integrin localization and FAK signaling in drug-resistant melanoma.\",\n      \"evidence\": \"Statin treatment, membrane fractionation, and RAB6B+RAB27A re-expression rescue with integrin/FAK readouts\",\n      \"pmids\": [\"37277330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymology of RAB6B prenylation not characterized\", \"RAB6B-specific contribution separable from RAB27A only partially resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Implicated RAB6B in proliferative control, showing its silencing suppresses AKT/JNK signaling and G1/S transition and that miR-4268 directly targets it.\",\n      \"evidence\": \"siRNA knockdown, luciferase reporter, cell cycle analysis, and pathway western blots in gastric cancer cells\",\n      \"pmids\": [\"31303644\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between a trafficking GTPase and AKT/JNK signaling not defined\", \"Single cancer cell context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Added a second regulatory miRNA, showing miR-6216 directly represses RAB6B and that RAB6B levels bidirectionally control neural stem cell proliferation.\",\n      \"evidence\": \"Luciferase 3'UTR reporter, RAB6B and miR-6216 overexpression, and NSC proliferation assays\",\n      \"pmids\": [\"37059126\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream pathway from RAB6B to NSC proliferation not mapped\", \"Single lab; in vivo relevance untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether RAB6B has non-redundant, isoform-specific functions distinct from RAB6A in neurons and other tissues, and how its distinct effectors (BICD1, DYNLRB1, ELKS1) are coordinated on individual vesicles, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No RAB6B-single-knockout phenotype reported in the corpus\", \"Spatiotemporal hierarchy of effector recruitment per vesicle not defined\", \"Mechanism connecting RAB6B trafficking to AKT/JNK proliferative signaling unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 6, 7]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"complexes\": [\"RAB6-dynein-LIS1 complex\"],\n    \"partners\": [\"BICD1\", \"DYNLRB1\", \"ELKS1\", \"GDAP1\", \"RAB27A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}