{"gene":"RAB11A","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1999,"finding":"RAB11A localizes to an apical pericentriolar endosomal compartment in MDCK epithelial cells that is dependent on intact microtubules for its integrity; this compartment is accessible to membrane-bound markers internalized from either apical or basolateral poles, functionally defining it as the apical recycling endosome.","method":"Immunofluorescence, nocodazole treatment, dimeric IgA trafficking assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (immunofluorescence, microtubule disruption, functional endocytic tracking), replicated across subsequent studies","pmids":["9880326"],"is_preprint":false},{"year":2000,"finding":"A dominant-negative GTP-binding-deficient RAB11A mutant (Rab11aS25N) potently inhibits both transcytosis and apical recycling of IgA but not basolateral transferrin recycling in polarized MDCK cells; conversely, GTPase-deficient RAB11A (S20V) inhibits basolateral-to-apical transcytosis but not recycling. This defines RAB11A's GTPase cycle as essential specifically for apical recycling and transcytotic pathways.","method":"Inducible expression of dominant-negative and constitutively active RAB11A mutants, IgA transcytosis assay, transferrin recycling assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple gain/loss-of-function mutants, multiple cargo assays, replicates prior morphological findings","pmids":["10869360"],"is_preprint":false},{"year":1999,"finding":"RAB11A is associated with H+/K+-ATPase-enriched gastric microsomes at a stoichiometry of approximately one RAB11A per six H+/K+-ATPase copies; expression of dominant-negative RAB11A N124I in primary parietal cells inhibits histamine-stimulated recruitment of H+/K+-ATPase to the apical membrane.","method":"Mass spectrometry co-fractionation, adenoviral dominant-negative expression, aminopyrine uptake assay, immunocytochemistry","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — stoichiometry established by MS, functional inhibition confirmed by two independent readouts (aminopyrine uptake and immunocytochemistry), controlled with tetracycline-regulated expression","pmids":["10484323"],"is_preprint":false},{"year":1998,"finding":"RAB11A redistributes to the apical secretory canaliculus during histamine stimulation of gastric parietal cells but does not dissociate into soluble fractions during vesicle fusion, indicating it remains membrane-associated through the tubulovesicle–canaliculus fusion cycle.","method":"Subcellular fractionation, immunofluorescence of resting vs. stimulated parietal cells","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (fractionation + imaging), single lab","pmids":["9688847"],"is_preprint":false},{"year":2002,"finding":"After agonist-induced internalization, the M4 muscarinic acetylcholine receptor (M4 mAChR) traffics to transferrin receptor- and RAB11A-positive perinuclear recycling endosomes; dominant-negative RAB11A (S25N) inhibits M4 recycling to the cell surface, and expression of the myosin Vb C-terminal tail (a RAB11A effector) enhances M4 accumulation in perinuclear endosomes and impairs recycling.","method":"Fluorescence co-localization, dominant-negative RAB11A expression, myosin Vb tail overexpression, receptor recycling assay","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent dominant-negative approaches, single lab","pmids":["12427833"],"is_preprint":false},{"year":2005,"finding":"RAB11A and myosin Vb are required for bile canalicular formation in polarized hepatic WIF-B9 cells; knockdown of RAB11A or expression of GDP-locked RAB11A prevents canalicular formation, as does overexpression of the myosin Vb motorless tail domain.","method":"siRNA knockdown, dominant-negative overexpression, confocal imaging, polarized hepatic cell model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent approaches (KD and dominant-negative) give same phenotype; myosin Vb identified as effector, replicated by subsequent studies","pmids":["16214890"],"is_preprint":false},{"year":2006,"finding":"RAB11A directly interacts with TRPV5 and TRPV6 Ca2+ channels in the GDP-bound conformation, co-localizing in vesicular structures beneath the apical plasma membrane; co-expression of GDP-locked RAB11A reduces cell surface expression and Ca2+ uptake of these channels.","method":"Co-immunoprecipitation, yeast-two-hybrid, Ca2+ uptake assay, dominant-negative RAB11A co-expression","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction demonstrated, functional consequence shown, single lab","pmids":["16354700"],"is_preprint":false},{"year":2007,"finding":"RAB11A co-localizes with CFTR in apical recycling endosomes in polarized human airway epithelial cells; endogenous CFTR forms a complex with endogenous myosin Vb and RAB11A; myosin Vb silencing or expression of a dominant myosin Vb tail fragment (which requires RAB11A interaction to exert its effect) decreases CFTR apical membrane expression and reduces Cl− secretion.","method":"Co-immunoprecipitation of endogenous proteins, siRNA knockdown of myosin Vb, dominant-negative myosin Vb tail fragment expression, electrophysiology (Cl− secretion assay), surface biotinylation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — endogenous complex confirmed, multiple orthogonal functional assays, mechanistic dependency on RAB11A-myosin Vb interaction established","pmids":["17462998"],"is_preprint":false},{"year":2007,"finding":"RAB11A controls biogenesis of Birbeck granules in Langerhans cells by regulating Langerin trafficking and stability; dominant-negative RAB11A or RAB11A depletion causes missorting of Langerin to lysosomes and abolishes Birbeck granule formation; loss of the RAB11A effector RCP (but not Rip11) also modestly impairs this process, suggesting RAB11A-RCP complexes mediate Langerin recycling.","method":"Dominant-negative RAB11A overexpression, siRNA depletion of RAB11A and Rab11-FIPs, electron microscopy, fluorescence microscopy","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent loss-of-function approaches, effector specificity determined, single lab","pmids":["17538027"],"is_preprint":false},{"year":2008,"finding":"RAB11A directly interacts with the C-terminal tail of the human prostacyclin receptor (hIP) via a defined 22-amino-acid sequence (Val299-Gln320); this interaction is augmented by agonist stimulation; overexpression of RAB11A increases hIP recycling to the plasma membrane, whereas dominant-negative RAB11A (S25N) impairs recycling.","method":"Yeast-two-hybrid screen, co-immunoprecipitation in HEK293 cells, dominant-negative RAB11A overexpression, fluorescence co-localization, deletion mapping","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction confirmed by two methods and domain mapped; functional recycling assay performed; single lab","pmids":["18832025"],"is_preprint":false},{"year":2008,"finding":"Gβγ subunits interact with RAB11A and co-localize at early and recycling endosomes upon LPA receptor activation; this RAB11A-dependent association promotes PI3K recruitment and AKT phosphorylation at endosomal compartments; dominant-negative RAB11A or RAB11A depletion attenuates LPA-dependent AKT activation and cell survival.","method":"Co-immunoprecipitation, co-localization, dominant-negative RAB11A expression, siRNA knockdown, AKT phosphorylation assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction and pathway position established by multiple methods, single lab","pmids":["18701709"],"is_preprint":false},{"year":2008,"finding":"RAB11A is expressed in bladder umbrella cells where it associates with discoidal/fusiform vesicles (DFV); dominant-active RAB11A stimulates apical surface area increase and hGH secretion in the absence of stretch, while dominant-negative RAB11A inhibits stretch-induced exocytosis; endocytosed fluid and membrane markers have little access to RAB11A-positive DFV, suggesting DFV are biosynthetic.","method":"Adenovirus-mediated dominant-active/dominant-negative RAB11A expression in situ, surface area measurement, secretory marker (hGH) packaging/release assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in native tissue, multiple readouts, single lab","pmids":["18843107"],"is_preprint":false},{"year":2009,"finding":"RAB11A is required for completion of cytokinesis in Toxoplasma gondii-related apicomplexan parasites; RAB11A associates with Myosin-Tail-Interacting-Protein (MTIP/MLC1), a component of the glideosome motor complex; ablation of RAB11A function results in an incompletely formed Inner Membrane Complex and a block at a late stage of cell division.","method":"Co-immunoprecipitation (RAB11A-MTIP interaction), dominant-negative RAB11A expression, electron microscopy of IMC formation, conditional knockout","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction and functional consequence established in parasite model; multiple phenotypic readouts; single lab","pmids":["19165333"],"is_preprint":false},{"year":2009,"finding":"RAB11A regulates recycling of extracellular alpha-synuclein from neurons; proteomic analysis of RAB11A-associated proteins identified HSP90, which was validated as a RAB11A-interacting protein; HSP90 inhibition with geldanamycin prevents re-secretion of alpha-synuclein.","method":"Quantitative proteomics of RAB11A-associated proteins, co-immunoprecipitation of RAB11A-HSP90, alpha-synuclein secretion assay, pharmacological inhibition","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by Co-IP, functional consequence shown with pharmacological inhibition, single lab","pmids":["19193894"],"is_preprint":false},{"year":2009,"finding":"Myosin Vb, RAB11A, and Rab11-FIP2 form a required triple complex for cholesterol-depletion-induced transport of NPC1L1 from the endocytic recycling compartment to the plasma membrane; inactivation of any component of this complex inhibits NPC1L1 export and reduces cellular cholesterol uptake.","method":"Dominant-negative mutant expression of myosin Vb, RAB11A, and Rab11-FIP2; fluorescence microscopy; cholesterol uptake assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three-component complex required; multiple independent dominant-negative experiments; single lab","pmids":["19542231"],"is_preprint":false},{"year":2010,"finding":"RAB11A controls TLR4 trafficking from the endocytic recycling compartment to E. coli phagosomes; suppression of RAB11A reduces TLR4 and TRAM on phagosomes, inhibiting the IRF3 signaling pathway (IFN-β induction) while NF-κB activation is unaffected.","method":"siRNA knockdown, co-localization studies, interferon-β reporter assay, NF-κB activity assay","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — pathway position defined (RAB11A→TRAM/TLR4 phagosomal delivery→IRF3, not NF-κB), multiple readouts, mechanistically dissected with siRNA","pmids":["20933442"],"is_preprint":false},{"year":2011,"finding":"RAB11A is indispensable for transport of influenza A vRNPs to the plasma membrane; RAB11A associates with vRNPs at all stages of cytoplasmic transport; siRNA knockdown or expression of dominant-negative/constitutively active RAB11A mutants causes aberrant vRNP perinuclear retention and prevents plasma membrane accumulation; RAB11A-vRNP complex formation was confirmed biochemically.","method":"siRNA knockdown, dominant-negative/constitutively active RAB11A expression, immunofluorescence, biochemical co-precipitation of RAB11A-vRNP complex","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (KD, dominant-negative, constitutively active, biochemical complex), replicated by multiple subsequent studies","pmids":["21525351"],"is_preprint":false},{"year":2012,"finding":"A RAB11A/Myosin Vb/Rab11-FIP2 platform regulates langerin recycling at two distinct intracellular sites: first at the sorting site in the endosomal recycling compartment (ERC) where transport vesicles are formed, and subsequently at the docking/tethering and fusion step at the plasma membrane.","method":"Live-FRET, fast FRAP, fast confocal, TIRF microscopy in live cells expressing tagged langerin, RAB11A, Myosin Vb, FIP2","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple live-cell imaging modalities define spatiotemporal sequence; single lab","pmids":["22420646"],"is_preprint":false},{"year":2013,"finding":"RAB11A functions upstream of RAB8A to promote regulated exocytosis of discoidal/fusiform vesicles in bladder umbrella cells; myosin 5B cooperates with the RAB11A-RAB8A module, possibly by facilitating transit through the cortical actin cytoskeleton; Rabin8 (a RAB11A effector and RAB8 GEF) stimulates exocytosis independently of its GEF catalytic activity.","method":"Dominant-active/dominant-negative RAB11A and RAB8A expression, myosin 5B dominant-negative, catalytically inactive Rabin8 expression, stretch-induced exocytosis assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis between RAB11A and RAB8A established, mechanistic role of Rabin8 GEF activity excluded experimentally; single lab","pmids":["23389633"],"is_preprint":false},{"year":2013,"finding":"Reggie-1 directly interacts with RAB11A and SNX4; reggie-1 knockdown reduces association of RAB11A with tubular structures and impairs transferrin receptor and E-cadherin recycling to the plasma membrane; these defects are rescued by overexpression of constitutively active RAB11A.","method":"siRNA knockdown, fluorescence microscopy, co-immunoprecipitation of reggie-1 and RAB11A, transferrin recycling assay, Ca2+-switch E-cadherin recycling assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction and epistatic rescue established; multiple cargos tested; single lab","pmids":["23825023"],"is_preprint":false},{"year":2013,"finding":"Rab11-FIPs define spatially and temporally distinct regions within the RAB11A-dependent recycling system; internalized transferrin enters different Rab11-FIP-containing compartments with distinct kinetics (FIP1B/FIP2 early; FIP1A/FIP1C/FIP3/FIP5 delayed), indicating temporal ordering of cargo passage through RAB11A recycling subdomains.","method":"Live-cell deconvolution microscopy, fluorescent transferrin kinetics in HeLa cells expressing chimeric fluorescent Rab11-FIPs","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic live-cell kinetic analysis, single lab, multiple FIPs compared","pmids":["23283983"],"is_preprint":false},{"year":2013,"finding":"RAB11A mediates intracellular transport of measles virus RNP complexes in Rab11A-containing recycling endosomes in a microtubule-dependent manner; dominant-negative RAB11A severely impairs RNP apical accumulation and infectious virion shedding from polarized epithelial cells.","method":"Live-cell imaging with fluorescent protein-tagged L protein, dominant-negative RAB11A expression, nocodazole treatment, viral titer assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging plus dominant-negative functional data; single lab","pmids":["23408617"],"is_preprint":false},{"year":2014,"finding":"TBC1D9B acts as a GAP for RAB11A in polarized MDCK cells; TBC1D9B interacts with RAB11A in a nucleotide-dependent manner via its TBC domain and specifically stimulates GTP hydrolysis on RAB11A (but not other Rabs tested at physiological Mg2+); TBC1D9B overexpression decreases active RAB11A, disrupts the RAB11A-Sec15A interaction, and slows IgA transcytosis, while TBC1D9B knockdown accelerates it.","method":"GTPase activity assay in vitro, co-immunoprecipitation, overexpression and shRNA knockdown of TBC1D9B, IgA transcytosis assay, active RAB11A pull-down","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro GAP activity assay plus multiple cellular functional assays; gain and loss-of-function both tested; substrate specificity determined","pmids":["25232007"],"is_preprint":false},{"year":2014,"finding":"Rab11-FIP2 interacts with MYO5B via residues S229 and G233; mutations disrupting this interaction increase speed and track length of RAB11A-containing vesicle movement, consistent with impaired MYO5B-mediated tethering; Rab11-FIP2 knockdown phenocopies this.","method":"Random mutagenesis, yeast two-hybrid, HeLa cell expression assays, live-cell fluorescence microscopy of RAB11A vesicle dynamics","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction domain mapped by mutagenesis, vesicle dynamics quantified; single lab","pmids":["24372966"],"is_preprint":false},{"year":2014,"finding":"RAB11A is required for apical protein localization in mouse intestinal epithelial cells in vivo; intestine-specific RAB11A knockout mice show apical protein mislocalization to the basolateral membrane, shortened microvilli, and microvillus inclusion bodies; RAB8A mislocalizes in RAB11A knockout intestine, and RAB11A mislocalizes in RAB8A knockout intestine, indicating a functional relationship between RAB11A, RAB8A, and myosin Vb.","method":"Conditional knockout mouse, immunofluorescence, electron microscopy, epistasis analysis with RAB8A knockout","journal":"Biology open","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with defined polarity phenotype, epistasis between RAB11A and RAB8A established by double-KO comparison","pmids":["25527643"],"is_preprint":false},{"year":2014,"finding":"Loss of RAB11A in mouse embryonic fibroblasts impairs secretion of multiple soluble matrix metalloproteinases (MMPs); global RAB11A knockout embryos form normal blastocysts but die at peri-implantation stages.","method":"Global RAB11A knockout mouse, multiple trafficking assays, MMP secretion assays, complementation analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO phenotype established, cargo specificity (soluble MMPs) identified by multiple assays; single lab","pmids":["25271168"],"is_preprint":false},{"year":2014,"finding":"RAB11A deficiency in enterocytes alters apical localization of syntaxin 3 and impairs microvillus assembly; conditional RAB11A knockout mice and stable RAB11A-knockdown CaCo2-BBE cells both show shortened or displaced microvilli, affirming RAB11A's role in apical membrane trafficking in intestinal cells.","method":"Conditional knockout mouse, stable shRNA knockdown, immunofluorescence, electron microscopy","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro loss-of-function with defined cargo (syntaxin 3); single lab","pmids":["25673875"],"is_preprint":false},{"year":2014,"finding":"Myosin Vb and RAB11A control phosphorylation of ezrin at T567 in enterocytes; dominant-negative RAB11A or myosin Vb depletion prevents subapical enrichment of RAB11A and ezrin kinases and reduces ezrin phosphorylation and microvilli development; similar loss occurs in microvillus inclusion disease (MYO5B mutations).","method":"Dominant-negative RAB11A expression, myosin Vb knockdown, phospho-specific ezrin western blot, immunofluorescence","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanism linking RAB11A/Myo5B to kinase localization and ezrin phosphorylation established; replicated in patient tissue; single lab","pmids":["24413175"],"is_preprint":false},{"year":2014,"finding":"MYO5B uncoupling from RAB11A induces microvillus inclusions in enterocytes; the MVID-associated MYO5B-P660L mutation loses interaction with RAB11A and causes microvillus inclusion formation; microvilli restoration requires RAB8A-MYO5B interaction, while microvillus inclusions are driven by loss of RAB11A-MYO5B interaction; early inclusions are SNX18-positive and derived from apical membrane internalization.","method":"Stable MYO5B knockdown in CaCo2-BBE cells, expression of WT and mutant MYO5B, surface biotinylation, immunofluorescence, co-immunoprecipitation","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection using patient mutation, multiple orthogonal methods, epistasis between RAB8A-MYO5B and RAB11A-MYO5B interactions defined","pmids":["24892806"],"is_preprint":false},{"year":2015,"finding":"RAB11A and Rab11-FIP2 mediate VE-cadherin recycling and vascular barrier integrity; VE-cadherin directly interacts with Rab11-FIP2 (at aa 453-484), forming a ternary complex with RAB11A; silencing RAB11A or Rab11-FIP2 prevents VE-cadherin recycling and junctional reannealing; selective pulmonary microvessel RAB11A knockdown increases vascular leakage in sepsis models.","method":"Yeast two-hybrid, co-immunoprecipitation, Ca2+-switch recycling assay, confocal imaging, siRNA knockdown, in vivo intratracheal siRNA, permeability assay","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction mapped, multiple in vitro and in vivo functional assays; single lab with multiple orthogonal methods","pmids":["26663395"],"is_preprint":false},{"year":2015,"finding":"RAB11A inactivation in macrophages facilitates efferocytosis of apoptotic neutrophils via modulation of ADAM17-mediated CD36 surface expression; apoptotic cell feeding induces rapid loss of RAB11A activity; RAB11A knockdown increases surface CD36 by reducing ADAM17 surface levels; blockade of CD36 abolishes the augmented phagocytosis.","method":"siRNA knockdown, wild-type and dominant-negative RAB11A overexpression, flow cytometry for surface CD36/ADAM17, efferocytosis assay, in vivo instillation of RAB11A-depleted macrophages","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway dissected with multiple genetic tools; ADAM17-CD36 axis identified; single lab","pmids":["28053235"],"is_preprint":false},{"year":2015,"finding":"Huntingtin (HTT) forms a complex with PAR3, aPKC, and RAB11A, and ensures microtubule-dependent apical vesicular translocation of PAR3-aPKC through RAB11A; HTT depletion disrupts apical localization of PAR3-aPKC during mammary epithelial morphogenesis.","method":"Co-immunoprecipitation (HTT-PAR3-aPKC-RAB11A complex), conditional HTT depletion in vivo, immunofluorescence, mouse mammary epithelium model","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complex formation confirmed, in vivo phenotype established; single lab","pmids":["25942483"],"is_preprint":false},{"year":2015,"finding":"RAB11A is essential for lamellar body biogenesis in human epidermis; RAB11A silencing in 3D reconstructed human epidermis reduces lamellar body density and secretion, misdirects lamellar body cargoes to lysosomes, decreases stratum corneum lipid content, and causes epidermal barrier defects.","method":"siRNA knockdown in 3D reconstructed human epidermis, electron microscopy, immunofluorescence, epidermal barrier function assay","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in physiologically relevant 3D model; multiple readouts; single lab","pmids":["26872604"],"is_preprint":false},{"year":2016,"finding":"RAB11A regulates ezrin phosphorylation and microvilli-associated membrane supply in neurons via LMTK1; LMTK1 knockout increases prevalence, velocity, and run length of anterograde RAB11A-positive endosome movement; a non-phosphorylatable LMTK1 mutant at Ser34 (Cdk5 phosphorylation site) dramatically promotes dendrite growth; Cdk5-LMTK1 axis negatively controls dendritic formation through regulation of RAB11A-positive endosomal trafficking.","method":"LMTK1 knockout mice, live-cell imaging of RAB11A-positive endosome dynamics, dominant-negative and constitutively active RAB11A expression, in vitro and in vivo cortical neuron cultures","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout plus live-imaging quantitation; Cdk5-LMTK1 pathway placement established; single lab","pmids":["24672056"],"is_preprint":false},{"year":2017,"finding":"ET-1 activates PKC, which phosphorylates RAB11A at serine 177, inhibiting RAB11A activity and reducing surface trafficking of BK channel β1 subunits in arterial smooth muscle cells; expression of phosphorylation-incapable RAB11A S177A blocks ET-1-induced effects; NO-induced RAB11A activation and vasodilation do not involve S177.","method":"PKC inhibitor, RAB11A S177A phosphorylation-incapable mutant expression, RAB11A activity assay, surface protein quantitation, patch-clamp electrophysiology, ex vivo vasoconstriction assay","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — PTM site identified and functionally validated with phosphorylation-incapable mutant; multiple orthogonal assays (activity, surface protein, electrophysiology, contractility); single lab","pmids":["28696251"],"is_preprint":false},{"year":2017,"finding":"RAB11A promotes proliferation and invasion in non-small cell lung cancer via interaction with and upregulation of YAP protein; co-immunoprecipitation shows RAB11A-YAP interaction in lung cancer cells; YAP depletion abolishes RAB11A-induced cell cycle protein changes and proliferation.","method":"Co-immunoprecipitation, RAB11A overexpression/knockdown, YAP siRNA epistasis, cell proliferation and invasion assays","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, mechanistic link between RAB11A-YAP interaction and trafficking not established; single lab, cancer cell-line only","pmids":["28468127"],"is_preprint":false},{"year":2018,"finding":"RAB11A-positive recycling endosomes serve as a primary platform for autophagosome biogenesis; WIPI2 is recruited to RAB11A-positive membranes by binding RAB11A, and PI3P is generated on these membranes upon starvation; loss of RAB11A impairs recruitment and assembly of the autophagic machinery including WIPI2, ATG16L1, and LC3.","method":"RAB11A knockout/knockdown, confocal and live-cell imaging, WIPI2-RAB11A binding assay, PI3P detection on RAB11A membranes, LC3 lipidation assay, mitophagy and transferrin receptor autophagy assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods defining RAB11A as a primary autophagosome biogenesis platform; WIPI2-RAB11A interaction and PI3P generation on RAB11A membranes both established; single rigorous study","pmids":["29634932"],"is_preprint":false},{"year":2018,"finding":"Rab11a and Rab8a act in a cascade (RAB11A upstream of RAB8A, independent of Rabin8 GEF activity) to regulate tunneling nanotube (TNT) formation; overexpression of both increases TNT-connected cells and intercellular vesicle propagation; VAMP3 acts downstream of RAB8A in this pathway.","method":"RAB11A and RAB8A overexpression/dominant-negative expression, Rabin8 catalytic mutant, live-cell imaging, TNT quantification, VAMP3 interference","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established between RAB11A, RAB8A, and VAMP3; GEF-independent mechanism confirmed; single lab","pmids":["30209134"],"is_preprint":false},{"year":2019,"finding":"The LMTK1A-TBC1D9B-RAB11A cascade regulates dendritic spine formation; LMTK1 binds and controls the GAP activity of TBC1D9B on RAB11A; TBC1D9B inactivates RAB11A under LMTK1A control; depletion of LMTK1 or TBC1D9B increases spine formation and density in neurons in vitro and in vivo.","method":"Co-immunoprecipitation (LMTK1-TBC1D9B), in vitro GAP assay, siRNA/shRNA knockdown in primary neurons and in vivo mouse brain, spine density analysis by confocal microscopy","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro GAP activity assay establishes TBC1D9B as RAB11A GAP; cascade order confirmed by epistasis; in vivo validation; single rigorous study with multiple methods","pmids":["31628178"],"is_preprint":false},{"year":2019,"finding":"Myosin-5b motor function is activated by RAB11A binding to its globular tail domain (GTD), which abolishes the autoinhibitory head-GTD interaction; FIP2 bridges MYO5B and RAB11A on vesicles without directly activating the motor; RAB11A has higher affinity for FIP2 than for MYO5B, suggesting FIP2-mediated vesicle tethering with RAB11A-dependent motor activation.","method":"In vitro binding assays (RAB11A-MYO5B GTD interaction), ATPase/motor activity assay, affinity measurements","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution of motor activation mechanism; affinity measurements; single lab, single study","pmids":["30545898"],"is_preprint":false},{"year":2020,"finding":"The C9ORF72-SMCR8-WDR41 complex has GAP activity toward RAB11A and RAB8A; cryo-EM structure at 3.2 Å reveals that Arg147 of SMCR8 acts as the arginine finger critical for stimulating GTP hydrolysis by RAB11A; biochemical mutagenesis of R147 eliminates this GAP activity.","method":"Cryo-EM structure determination, in vitro GTPase activity assay with SMCR8 R147 mutant, biochemical analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic structure plus in vitro mutagenesis of catalytic residue confirm GAP mechanism; multiple methods in single study","pmids":["32303654"],"is_preprint":false},{"year":2020,"finding":"RAB11A is directly activated (GTP-loaded) by the insulin signaling cascade in a PI3K- and Akt-dependent manner; GTP loading of RAB11A peaks ~4 min after insulin stimulation and is required for GLUT4 and FAT/CD36 trafficking in cardiomyocytes.","method":"Biotinylated GTP analog loading assay, PI3K/Akt inhibitor pharmacology, siRNA knockdown in H9c2-hIR cells","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel GTP-loading assay, pathway placement established with inhibitors; single lab","pmids":["17158030"],"is_preprint":false},{"year":2020,"finding":"RAB11A Rab11A-positive vesicles serve as hubs for congregation of influenza vRNP complexes, enabling vRNP:vRNP interactions required for specific genome assembly; RAB11A-deficient cells produce smaller vRNP bundles with reduced co-localization between distinct vRNA segments and generate non-infectious particles with high RNA copy-to-PFU ratios.","method":"Tetracysteine-tagged NP reporter virus, siRNA RAB11A depletion, fluorescence microscopy of vRNP dynamics, RNA copy number/PFU ratio assay","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional genome assembly role defined; multiple readouts; single lab","pmids":["33970958"],"is_preprint":false},{"year":2020,"finding":"IAV infection decreases speed and increases arrest of RAB11A-positive recycling endosomes through a mechanism involving reduced dynein motor association with RAB11A vesicles; co-transport of RAB11A and vRNA was directly demonstrated in infected cells by two-color live imaging.","method":"High-spatiotemporal-resolution light-sheet microscopy, two-color live imaging, quantitative motion analysis, proteomic analysis of dynein association","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative live imaging plus proteomic evidence; mechanism (reduced dynein) proposed but not fully validated by mutagenesis; single lab","pmids":["31911620"],"is_preprint":false},{"year":2021,"finding":"RAB11A mediates cell-cell spread of influenza A vRNPs via tunneling nanotubes (TNTs); in a system where conventional virion-mediated spread was blocked, vRNP transfer to neighboring cells was dependent on both actin and RAB11A; genome mixing and reassortment via TNT transfer was demonstrated.","method":"HA-deficient reporter virus system, actin disruption, RAB11A knockdown/dominant-negative, fluorescence microscopy of TNTs, infectious virus reassortment assay","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel TNT transport function established with two independent inhibitors; single lab","pmids":["34473799"],"is_preprint":false},{"year":2021,"finding":"RAB11A controls YAP localization to adherens and tight junctions in colonic epithelium; loss of RAB11A reduces YAP association with α-catenin, β-catenin, and Merlin, and causes nuclear YAP accumulation and increased β-catenin-YAP complex formation; RAB11A-deficient mice show reduced colonic epithelial integrity and impaired repair after chemical injury.","method":"Conditional RAB11A knockout mice, co-immunoprecipitation (YAP with junctional components), immunofluorescence, epithelial injury assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout plus biochemical complex characterization; Hippo-YAP pathway placement; single lab","pmids":["34058200"],"is_preprint":false},{"year":2022,"finding":"The C-terminal two-thirds of the influenza A virus PB2 polymerase subunit (PB2-C, comprising cap-binding, mid-link, 627, and NLS domains) directly interact with RAB11A; SAXS confirms a compact 1:1 stoichiometric complex in solution; the switch I region of RAB11A (used for Rab11-FIP binding) mediates PB2-C binding, indicating competition between viral polymerase and Rab11-FIPs for the same RAB11A site.","method":"Pulldown assays, mass spectrometry, small-angle X-ray scattering (SAXS), domain deletion mapping","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct interaction structurally validated by SAXS with 1:1 stoichiometry; binding domain mapped biochemically; competitive mechanism with Rab11-FIPs established","pmids":["35019720"],"is_preprint":false},{"year":2023,"finding":"RAB11A and RAB11B redundantly control mitotic spindle function in intestinal epithelial progenitor cells; compound RAB11A/RAB11B double-knockout causes mitotic spindle defects, cell cycle arrest, and apoptosis leading to lethality within 3 days; unbiased proteomics of RAB11A and RAB11B immunoprecipitates identified shared mitotic spindle microtubule regulators; disrupting RAB11 impairs KIF11 (kinesin motor) function and bipolar spindle formation.","method":"Double-knockout mouse model, enteroid culture, proteomic immunoprecipitation, KIF11 functional analysis, mitotic spindle imaging","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo double knockout with penetrant phenotype, unbiased proteomics identifies interactome, specific mechanism (KIF11/bipolar spindle) established; single lab with multiple orthogonal approaches","pmids":["37424454"],"is_preprint":false},{"year":2023,"finding":"Accessory ESCRT-III proteins CHMP1A, CHMP1B, CHMP5, and IST1 are selectively required for ILV formation in RAB11A-positive recycling endosomes but not in late endosomes; CHMP5 knockdown in HCT116 cells selectively inhibits RAB11A-exosome production without affecting late-endosome-derived exosomes.","method":"Comparative proteomics, Drosophila secondary cell knockdown, human HCT116 cell siRNA knockdown, electron microscopy of ILVs, exosome secretion assay","journal":"Journal of extracellular vesicles","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ortholog-validated mechanism across two species; selective CHMP5 role in RAB11A-exosome production established; single lab","pmids":["36872252"],"is_preprint":false},{"year":2018,"finding":"FLCN (folliculin, Birt-Hogg-Dubé protein) binds RAB11A via its C-terminal DENN-like domain; suppression of either RAB11A or FLCN redirects overexpressed PAT1 (amino acid transporter) to lysosomes and reduces its plasma membrane targeting; FLCN promotes loading of PAT1 onto RAB11A vesicles; FLCN does not have direct GEF activity on RAB11A in vitro.","method":"Co-immunoprecipitation of FLCN-RAB11A, in vitro GEF activity assay (negative result for FLCN), siRNA knockdown, PAT1 trafficking assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction and cargo-loading function defined; GEF activity explicitly excluded by in vitro assay; single lab","pmids":["30446510"],"is_preprint":false},{"year":2014,"finding":"Rab11a-Rab8a double-knockout in neonatal enterocytes causes basolateral microvilli formation and more severe enteropathy than either single knockout; inducible Rab11a deletion alone from neonatal enterocytes induces basolateral microvilli within 3 days; distinct cargo sets depend individually on Rab8a or Rab11a, while some basolateral cargos are redundantly transported by both.","method":"Enterocyte-specific single and double conditional knockout mice, inducible Rab11a deletion, immunofluorescence, electron microscopy","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic genetic epistasis in vivo with single and double KOs; phenotypic hierarchy established; cargo specificity defined","pmids":["28596241"],"is_preprint":false}],"current_model":"RAB11A is a GTPase that cycles between GDP- and GTP-bound states (regulated by GAPs including TBC1D9B, C9ORF72-SMCR8, and the Cdk5-LMTK1-TBC1D9B cascade, and activated downstream of insulin/PI3K-Akt signaling) and, in its GTP-bound form, organizes an apical recycling endosome (ARE) compartment dependent on microtubules; from this compartment RAB11A—acting as a scaffold for the myosin Vb/Rab11-FIP2/FIP effector complex—drives slow recycling and transcytosis of diverse membrane cargoes (CFTR, TRPV5/6, EGFR, VE-cadherin, syntaxin 3, PAR3-aPKC, TLR4, GPCR substrates, H+/K+-ATPase, NPC1L1, BK channel β1) to the correct plasma-membrane domain; RAB11A-positive membranes also serve as the primary site for autophagosome nucleation through WIPI2 binding and PI3P generation, for ILV biogenesis to produce a distinct class of exosomes via accessory ESCRT-III proteins, for mitotic spindle regulation via interaction with KIF11 kinesin, and for intercellular cargo transfer via tunneling nanotubes; RAB11A is additionally hijacked by multiple RNA viruses (influenza A, measles, parainfluenza) to transport viral ribonucleoprotein complexes to the plasma membrane, with influenza PB2 directly binding the switch I region of RAB11A to compete with Rab11-FIPs."},"narrative":{"mechanistic_narrative":"RAB11A is a small GTPase that organizes a microtubule-dependent apical/endocytic recycling endosome compartment and, in its GTP-bound state, directs the slow recycling and transcytosis of membrane cargoes to the correct plasma-membrane domain [PMID:9880326, PMID:10869360]. Its central effector module is the myosin Vb/Rab11-FIP2 complex: RAB11A binding to the myosin Vb globular tail relieves motor autoinhibition while FIP2 bridges the motor to RAB11A on vesicles, with the FIPs further subdividing the recycling system into kinetically distinct subdomains [PMID:30545898, PMID:23283983, PMID:24372966]. Through this machinery RAB11A controls polarized delivery of a broad cargo set—H+/K+-ATPase, CFTR, TRPV5/6, NPC1L1, VE-cadherin, syntaxin 3, GPCRs, and the PAR3-aPKC polarity complex—and is required in vivo for apical membrane identity, microvillus assembly, and ezrin phosphorylation in intestinal epithelium [PMID:10484323, PMID:17462998, PMID:16354700, PMID:19542231, PMID:26663395, PMID:25673875, PMID:25942483, PMID:24413175]. RAB11A acts upstream of RAB8A in a cascade governing regulated exocytosis, apical polarity, and tunneling-nanotube formation, and the two paralogs redundantly support mitotic spindle bipolarity via KIF11 [PMID:23389633, PMID:25527643, PMID:28596241, PMID:30209134]. Beyond recycling, RAB11A-positive membranes nucleate autophagosome biogenesis by recruiting WIPI2 and generating PI3P, and support a distinct class of exosomes formed by accessory ESCRT-III proteins [PMID:29634932, PMID:36872252]. The GTPase cycle is set by GAPs—TBC1D9B (acting downstream of an LMTK1 cascade) and the C9ORF72-SMCR8-WDR41 complex whose SMCR8 Arg147 arginine finger drives hydrolysis—and by activating insulin/PI3K-Akt signaling and inhibitory PKC phosphorylation at Ser177 [PMID:25232007, PMID:31628178, PMID:32303654, PMID:17158030, PMID:28696251]. Multiple RNA viruses including influenza A and measles hijack RAB11A to transport viral ribonucleoproteins to the plasma membrane, with influenza PB2 binding the RAB11A switch I region to compete directly with Rab11-FIPs [PMID:21525351, PMID:23408617, PMID:35019720].","teleology":[{"year":1999,"claim":"Defined RAB11A's compartment: established that RAB11A marks a microtubule-dependent apical recycling endosome accessible to cargo from both poles, giving the protein a physical address.","evidence":"Immunofluorescence, nocodazole microtubule disruption, and IgA trafficking in polarized MDCK cells","pmids":["9880326"],"confidence":"High","gaps":["Did not define which cargoes obligately pass through this compartment","GTPase cycle requirements not yet dissected"]},{"year":2000,"claim":"Linked the GTPase cycle to pathway specificity: showed nucleotide-state mutants selectively block apical recycling and transcytosis but not basolateral recycling, defining RAB11A as a pathway-specific regulator.","evidence":"Inducible dominant-negative (S25N) and constitutively active (S20V) mutants with IgA transcytosis and transferrin recycling assays","pmids":["10869360"],"confidence":"High","gaps":["Effectors mediating apical specificity not identified","Molecular basis of cargo discrimination unknown"]},{"year":2007,"claim":"Identified the core effector module and demonstrated cargo control: established that an endogenous RAB11A/myosin Vb/Rab11-FIP complex recycles physiological cargoes (H+/K+-ATPase, CFTR, TRPV5/6, GPCRs) to the apical surface with functional output.","evidence":"Co-IP of endogenous complexes, dominant-negative and effector-tail mutants, surface biotinylation, Ca2+ uptake and Cl- secretion electrophysiology across parietal, airway, and renal cell models","pmids":["10484323","17462998","16354700","12427833","18832025"],"confidence":"High","gaps":["Mechanism of cargo selection by individual FIPs not resolved","Single-cell-type studies for several cargoes"]},{"year":2014,"claim":"Resolved the recycling machinery into subdomains and a tethering/motor mechanism: showed FIPs partition the system temporally and that FIP2 tethers MYO5B to RAB11A vesicles, controlling vesicle dynamics.","evidence":"Live-cell deconvolution kinetics of FIP compartments and mutagenesis mapping FIP2-MYO5B interaction with vesicle tracking","pmids":["23283983","24372966"],"confidence":"Medium","gaps":["How FIPs achieve cargo specificity within subdomains unresolved","In vivo relevance of subdomain ordering untested"]},{"year":2014,"claim":"Established RAB11A's in vivo requirement for epithelial polarity and the RAB11A-RAB8A-MYO5B axis: conditional and global knockouts revealed apical cargo mislocalization, microvillus inclusion disease-like phenotypes, and reciprocal RAB11A-RAB8A dependence.","evidence":"Intestine-specific and global RAB11A knockout mice, single/double RAB11A-RAB8A knockouts, MYO5B patient mutation analysis, MMP secretion and ezrin phosphorylation assays","pmids":["25527643","25271168","25673875","24892806","28596241","24413175"],"confidence":"High","gaps":["Precise cargo sets uniquely versus redundantly handled by RAB8A still being delineated","Mechanism coupling trafficking to microvillus inclusion formation incompletely defined"]},{"year":2017,"claim":"Defined the regulatory inputs controlling RAB11A activity: identified TBC1D9B and the C9ORF72-SMCR8-WDR41 complex as GAPs, the LMTK1 cascade as their controller, insulin/PI3K-Akt as an activating input, and PKC-Ser177 phosphorylation as an inhibitory PTM.","evidence":"In vitro GAP assays, cryo-EM of SMCR8 with Arg147 arginine-finger mutagenesis, GTP-loading assays under insulin/PI3K-Akt inhibition, and a phosphorylation-incapable S177A mutant with electrophysiology and vasoreactivity readouts","pmids":["25232007","31628178","32303654","17158030","28696251"],"confidence":"High","gaps":["GEF(s) that load GTP onto RAB11A not definitively identified (FLCN explicitly lacks GEF activity)","Crosstalk between phosphorylation and GAP regulation unmapped"]},{"year":2018,"claim":"Expanded RAB11A's role beyond recycling to autophagosome and exosome biogenesis: showed RAB11A membranes recruit WIPI2 and generate PI3P to nucleate autophagy and use accessory ESCRT-III for a distinct exosome class.","evidence":"RAB11A knockout/knockdown with WIPI2 binding, PI3P detection, LC3 lipidation assays, and comparative proteomics plus CHMP5 knockdown ILV/exosome assays","pmids":["29634932","36872252"],"confidence":"High","gaps":["How RAB11A membranes are selected as autophagy platforms versus recycling carriers unclear","Cargo selectivity of RAB11A-derived exosomes unknown"]},{"year":2022,"claim":"Established the structural basis of viral hijacking: showed influenza PB2 binds the RAB11A switch I region in a 1:1 complex, directly competing with Rab11-FIPs to commandeer the recycling machinery for vRNP transport and genome assembly.","evidence":"Pulldown, SAXS solution structure, domain mapping, and live-imaging/siRNA studies of vRNP transport, TNT spread, and genome bundling across influenza and measles models","pmids":["35019720","21525351","23408617","33970958","31911620","34473799"],"confidence":"High","gaps":["Whether host motor/adaptor swapping is general across viruses untested","Therapeutic exploitation of the PB2-switch I interface unexplored"]},{"year":2023,"claim":"Revealed a recycling-independent mitotic function and paralog redundancy: RAB11A/RAB11B double-knockout disrupts bipolar spindle formation via KIF11, with lethal cell-cycle arrest.","evidence":"Double-knockout mice, enteroid culture, unbiased IP proteomics, and KIF11 functional/spindle imaging analysis","pmids":["37424454"],"confidence":"High","gaps":["Whether RAB11A acts as a vesicular platform or directly on spindle microtubules unresolved","Functional non-redundancy of RAB11A versus RAB11B for spindle role undefined"]},{"year":null,"claim":"The GEF(s) responsible for physiological GTP-loading of RAB11A and the structural rules by which a single GTPase compartment is partitioned among recycling, autophagy, exosome, and spindle functions remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No validated RAB11A GEF identified in the corpus (FLCN lacks GEF activity)","Molecular switch directing RAB11A membranes to distinct downstream fates unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[1,22,40]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[39,36]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[29,14,31]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,4,20]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[11,16,32]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,7,29]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,7]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[24,26,50]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[36]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[47]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,46,21]}],"complexes":["RAB11A/myosin Vb/Rab11-FIP2 recycling complex","C9ORF72-SMCR8-WDR41 GAP complex"],"partners":["MYO5B","RAB11FIP2","TBC1D9B","SMCR8","RAB8A","WIPI2","KIF11","PB2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P62491","full_name":"Ras-related protein Rab-11A","aliases":["YL8"],"length_aa":216,"mass_kda":24.4,"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 set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion (PubMed:15601896, PubMed:15689490, PubMed:17462998, PubMed:19542231, PubMed:20026645, PubMed:20890297, PubMed:21282656, PubMed:26032412). RAB11A regulates endocytic recycling (PubMed:20026645). Forms a functional Rab11/RAB11FIP3/dynein complex that regulates the movement of peripheral sorting endosomes (SE) along microtubule tracks toward the microtubule organizing center/centrosome, generating the endosomal recycling compartment (ERC) (PubMed:20026645). Acts as a major regulator of membrane delivery during cytokinesis (PubMed:15601896). Together with MYO5B and RAB8A participates in epithelial cell polarization (PubMed:21282656). Together with Rabin8/RAB3IP, RAB8A, the exocyst complex, PARD3, PRKCI, ANXA2, CDC42 and DNMBP promotes transcytosis of PODXL to the apical membrane initiation sites (AMIS), apical surface formation and lumenogenesis (PubMed:20890297). Together with MYO5B participates in CFTR trafficking to the plasma membrane and TF (Transferrin) recycling in nonpolarized cells (PubMed:17462998). Required in a complex with MYO5B and RAB11FIP2 for the transport of NPC1L1 to the plasma membrane (PubMed:19542231). Participates in the sorting and basolateral transport of CDH1 from the Golgi apparatus to the plasma membrane (PubMed:15689490). Regulates the recycling of FCGRT (receptor of Fc region of monomeric IgG) to basolateral membranes (By similarity). May also play a role in melanosome transport and release from melanocytes (By similarity). Promotes Rabin8/RAB3IP preciliary vesicular trafficking to mother centriole by forming a ciliary targeting complex containing Rab11, ASAP1, Rabin8/RAB3IP, RAB11FIP3 and ARF4, thereby regulating ciliogenesis initiation (PubMed:25673879, PubMed:31204173). On the contrary, upon LPAR1 receptor signaling pathway activation, interaction with phosphorylated WDR44 prevents Rab11-RAB3IP-RAB11FIP3 complex formation and cilia growth (PubMed:31204173). Participates in the export of a subset of neosynthesized proteins through a Rab8-Rab10-Rab11-endososomal dependent export route via interaction with WDR44 (PubMed:32344433). Also interacts with RABL3 to promote ciliary vesicle formation (PubMed:36052645)","subcellular_location":"Cell membrane; Endosome membrane; Recycling endosome membrane; Cleavage furrow; Cytoplasmic vesicle, phagosome membrane; Golgi apparatus membrane; Golgi apparatus, trans-Golgi network; Cytoplasmic vesicle membrane; Cell projection, cilium","url":"https://www.uniprot.org/uniprotkb/P62491/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAB11A","classification":"Not Classified","n_dependent_lines":298,"n_total_lines":1208,"dependency_fraction":0.24668874172185432},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000103769","cell_line_id":"CID000416","localizations":[{"compartment":"golgi","grade":3},{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"VAMP3;VAMP2","stoichiometry":10.0},{"gene":"RAB11B","stoichiometry":10.0},{"gene":"UBL4A","stoichiometry":10.0},{"gene":"VAMP8","stoichiometry":10.0},{"gene":"VIM","stoichiometry":10.0},{"gene":"GDI2","stoichiometry":10.0},{"gene":"SCAMP3","stoichiometry":10.0},{"gene":"NOP56","stoichiometry":10.0},{"gene":"TFRC","stoichiometry":10.0},{"gene":"ATP6V1G1;ATP6V1G2-DDX39B;ATP6V1G2","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000416","total_profiled":1310},"omim":[{"mim_id":"621025","title":"RAB3A-INTERACTING PROTEIN-LIKE 1; RAB3IL1","url":"https://www.omim.org/entry/621025"},{"mim_id":"620949","title":"TOG ARRAY REGULATOR OF AXONEMAL MICROTUBULES 2; TOGARAM2","url":"https://www.omim.org/entry/620949"},{"mim_id":"620667","title":"CENTROSOMAL PROTEIN, 128-KD; CEP128","url":"https://www.omim.org/entry/620667"},{"mim_id":"620652","title":"SH3 DOMAIN-BINDING PROTEIN 5-LIKE; SH3BP5L","url":"https://www.omim.org/entry/620652"},{"mim_id":"620003","title":"TBC1 DOMAIN FAMILY, MEMBER 12; TBC1D12","url":"https://www.omim.org/entry/620003"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Centriolar satellite","reliability":"Supported"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"},{"location":"Equatorial segment","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RAB11A"},"hgnc":{"alias_symbol":["YL8"],"prev_symbol":[]},"alphafold":{"accession":"P62491","domains":[{"cath_id":"3.40.50.300","chopping":"7-183","consensus_level":"high","plddt":94.2292,"start":7,"end":183}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62491","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62491-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62491-F1-predicted_aligned_error_v6.png","plddt_mean":87.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAB11A","jax_strain_url":"https://www.jax.org/strain/search?query=RAB11A"},"sequence":{"accession":"P62491","fasta_url":"https://rest.uniprot.org/uniprotkb/P62491.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62491/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62491"}},"corpus_meta":[{"pmid":"9880326","id":"PMC_9880326","title":"Association of Rab25 and Rab11a with the apical recycling system of polarized Madin-Darby canine kidney cells.","date":"1999","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/9880326","citation_count":345,"is_preprint":false},{"pmid":"10869360","id":"PMC_10869360","title":"Regulation of vesicle trafficking in madin-darby canine kidney cells by Rab11a and Rab25.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10869360","citation_count":195,"is_preprint":false},{"pmid":"29634932","id":"PMC_29634932","title":"The RAB11A-Positive Compartment Is a Primary Platform for Autophagosome Assembly Mediated by WIPI2 Recognition of PI3P-RAB11A.","date":"2018","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/29634932","citation_count":180,"is_preprint":false},{"pmid":"20933442","id":"PMC_20933442","title":"The Rab11a GTPase controls Toll-like receptor 4-induced activation of interferon regulatory factor-3 on phagosomes.","date":"2010","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/20933442","citation_count":175,"is_preprint":false},{"pmid":"21525351","id":"PMC_21525351","title":"RAB11A is essential for transport of the influenza virus genome to the plasma membrane.","date":"2011","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/21525351","citation_count":154,"is_preprint":false},{"pmid":"16214890","id":"PMC_16214890","title":"Rab11a and myosin Vb are required for bile canalicular formation in WIF-B9 cells.","date":"2005","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16214890","citation_count":129,"is_preprint":false},{"pmid":"19193894","id":"PMC_19193894","title":"Rab11a and HSP90 regulate recycling of extracellular alpha-synuclein.","date":"2009","source":"The Journal of neuroscience : the official journal of the Society for 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PI3K/AKT pathways.","date":"2024","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/38806000","citation_count":11,"is_preprint":false},{"pmid":"20727405","id":"PMC_20727405","title":"Rab11a and its binding partners regulate the recycling of the ß1-adrenergic receptor.","date":"2010","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/20727405","citation_count":11,"is_preprint":false},{"pmid":"36125654","id":"PMC_36125654","title":"Rab11a promotes the malignant progression of ovarian cancer by inducing autophagy.","date":"2022","source":"Genes & genomics","url":"https://pubmed.ncbi.nlm.nih.gov/36125654","citation_count":10,"is_preprint":false},{"pmid":"8536309","id":"PMC_8536309","title":"The evolutionary relationships between homologs of ribosomal YL8 protein and YL8-like proteins.","date":"1995","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8536309","citation_count":9,"is_preprint":false},{"pmid":"35789415","id":"PMC_35789415","title":"RAB11A aggravates PDGF-BB-stimulated proliferation, migration, and inflammation of airway smooth muscle cells via affecting the NF-κB and PI3K/AKT pathways.","date":"2022","source":"Allergologia et immunopathologia","url":"https://pubmed.ncbi.nlm.nih.gov/35789415","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52536,"output_tokens":13059,"usd":0.176747,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":24682,"output_tokens":4228,"usd":0.114555,"stage2_stop_reason":"end_turn"},"total_usd":0.291302,"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\": 1999,\n      \"finding\": \"RAB11A localizes to an apical pericentriolar endosomal compartment in MDCK epithelial cells that is dependent on intact microtubules for its integrity; this compartment is accessible to membrane-bound markers internalized from either apical or basolateral poles, functionally defining it as the apical recycling endosome.\",\n      \"method\": \"Immunofluorescence, nocodazole treatment, dimeric IgA trafficking assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (immunofluorescence, microtubule disruption, functional endocytic tracking), replicated across subsequent studies\",\n      \"pmids\": [\"9880326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A dominant-negative GTP-binding-deficient RAB11A mutant (Rab11aS25N) potently inhibits both transcytosis and apical recycling of IgA but not basolateral transferrin recycling in polarized MDCK cells; conversely, GTPase-deficient RAB11A (S20V) inhibits basolateral-to-apical transcytosis but not recycling. This defines RAB11A's GTPase cycle as essential specifically for apical recycling and transcytotic pathways.\",\n      \"method\": \"Inducible expression of dominant-negative and constitutively active RAB11A mutants, IgA transcytosis assay, transferrin recycling assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple gain/loss-of-function mutants, multiple cargo assays, replicates prior morphological findings\",\n      \"pmids\": [\"10869360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RAB11A is associated with H+/K+-ATPase-enriched gastric microsomes at a stoichiometry of approximately one RAB11A per six H+/K+-ATPase copies; expression of dominant-negative RAB11A N124I in primary parietal cells inhibits histamine-stimulated recruitment of H+/K+-ATPase to the apical membrane.\",\n      \"method\": \"Mass spectrometry co-fractionation, adenoviral dominant-negative expression, aminopyrine uptake assay, immunocytochemistry\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — stoichiometry established by MS, functional inhibition confirmed by two independent readouts (aminopyrine uptake and immunocytochemistry), controlled with tetracycline-regulated expression\",\n      \"pmids\": [\"10484323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"RAB11A redistributes to the apical secretory canaliculus during histamine stimulation of gastric parietal cells but does not dissociate into soluble fractions during vesicle fusion, indicating it remains membrane-associated through the tubulovesicle–canaliculus fusion cycle.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence of resting vs. stimulated parietal cells\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (fractionation + imaging), single lab\",\n      \"pmids\": [\"9688847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"After agonist-induced internalization, the M4 muscarinic acetylcholine receptor (M4 mAChR) traffics to transferrin receptor- and RAB11A-positive perinuclear recycling endosomes; dominant-negative RAB11A (S25N) inhibits M4 recycling to the cell surface, and expression of the myosin Vb C-terminal tail (a RAB11A effector) enhances M4 accumulation in perinuclear endosomes and impairs recycling.\",\n      \"method\": \"Fluorescence co-localization, dominant-negative RAB11A expression, myosin Vb tail overexpression, receptor recycling assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent dominant-negative approaches, single lab\",\n      \"pmids\": [\"12427833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RAB11A and myosin Vb are required for bile canalicular formation in polarized hepatic WIF-B9 cells; knockdown of RAB11A or expression of GDP-locked RAB11A prevents canalicular formation, as does overexpression of the myosin Vb motorless tail domain.\",\n      \"method\": \"siRNA knockdown, dominant-negative overexpression, confocal imaging, polarized hepatic cell model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent approaches (KD and dominant-negative) give same phenotype; myosin Vb identified as effector, replicated by subsequent studies\",\n      \"pmids\": [\"16214890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RAB11A directly interacts with TRPV5 and TRPV6 Ca2+ channels in the GDP-bound conformation, co-localizing in vesicular structures beneath the apical plasma membrane; co-expression of GDP-locked RAB11A reduces cell surface expression and Ca2+ uptake of these channels.\",\n      \"method\": \"Co-immunoprecipitation, yeast-two-hybrid, Ca2+ uptake assay, dominant-negative RAB11A co-expression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction demonstrated, functional consequence shown, single lab\",\n      \"pmids\": [\"16354700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RAB11A co-localizes with CFTR in apical recycling endosomes in polarized human airway epithelial cells; endogenous CFTR forms a complex with endogenous myosin Vb and RAB11A; myosin Vb silencing or expression of a dominant myosin Vb tail fragment (which requires RAB11A interaction to exert its effect) decreases CFTR apical membrane expression and reduces Cl− secretion.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins, siRNA knockdown of myosin Vb, dominant-negative myosin Vb tail fragment expression, electrophysiology (Cl− secretion assay), surface biotinylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endogenous complex confirmed, multiple orthogonal functional assays, mechanistic dependency on RAB11A-myosin Vb interaction established\",\n      \"pmids\": [\"17462998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RAB11A controls biogenesis of Birbeck granules in Langerhans cells by regulating Langerin trafficking and stability; dominant-negative RAB11A or RAB11A depletion causes missorting of Langerin to lysosomes and abolishes Birbeck granule formation; loss of the RAB11A effector RCP (but not Rip11) also modestly impairs this process, suggesting RAB11A-RCP complexes mediate Langerin recycling.\",\n      \"method\": \"Dominant-negative RAB11A overexpression, siRNA depletion of RAB11A and Rab11-FIPs, electron microscopy, fluorescence microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent loss-of-function approaches, effector specificity determined, single lab\",\n      \"pmids\": [\"17538027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RAB11A directly interacts with the C-terminal tail of the human prostacyclin receptor (hIP) via a defined 22-amino-acid sequence (Val299-Gln320); this interaction is augmented by agonist stimulation; overexpression of RAB11A increases hIP recycling to the plasma membrane, whereas dominant-negative RAB11A (S25N) impairs recycling.\",\n      \"method\": \"Yeast-two-hybrid screen, co-immunoprecipitation in HEK293 cells, dominant-negative RAB11A overexpression, fluorescence co-localization, deletion mapping\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction confirmed by two methods and domain mapped; functional recycling assay performed; single lab\",\n      \"pmids\": [\"18832025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Gβγ subunits interact with RAB11A and co-localize at early and recycling endosomes upon LPA receptor activation; this RAB11A-dependent association promotes PI3K recruitment and AKT phosphorylation at endosomal compartments; dominant-negative RAB11A or RAB11A depletion attenuates LPA-dependent AKT activation and cell survival.\",\n      \"method\": \"Co-immunoprecipitation, co-localization, dominant-negative RAB11A expression, siRNA knockdown, AKT phosphorylation assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction and pathway position established by multiple methods, single lab\",\n      \"pmids\": [\"18701709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RAB11A is expressed in bladder umbrella cells where it associates with discoidal/fusiform vesicles (DFV); dominant-active RAB11A stimulates apical surface area increase and hGH secretion in the absence of stretch, while dominant-negative RAB11A inhibits stretch-induced exocytosis; endocytosed fluid and membrane markers have little access to RAB11A-positive DFV, suggesting DFV are biosynthetic.\",\n      \"method\": \"Adenovirus-mediated dominant-active/dominant-negative RAB11A expression in situ, surface area measurement, secretory marker (hGH) packaging/release assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in native tissue, multiple readouts, single lab\",\n      \"pmids\": [\"18843107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RAB11A is required for completion of cytokinesis in Toxoplasma gondii-related apicomplexan parasites; RAB11A associates with Myosin-Tail-Interacting-Protein (MTIP/MLC1), a component of the glideosome motor complex; ablation of RAB11A function results in an incompletely formed Inner Membrane Complex and a block at a late stage of cell division.\",\n      \"method\": \"Co-immunoprecipitation (RAB11A-MTIP interaction), dominant-negative RAB11A expression, electron microscopy of IMC formation, conditional knockout\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction and functional consequence established in parasite model; multiple phenotypic readouts; single lab\",\n      \"pmids\": [\"19165333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RAB11A regulates recycling of extracellular alpha-synuclein from neurons; proteomic analysis of RAB11A-associated proteins identified HSP90, which was validated as a RAB11A-interacting protein; HSP90 inhibition with geldanamycin prevents re-secretion of alpha-synuclein.\",\n      \"method\": \"Quantitative proteomics of RAB11A-associated proteins, co-immunoprecipitation of RAB11A-HSP90, alpha-synuclein secretion assay, pharmacological inhibition\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by Co-IP, functional consequence shown with pharmacological inhibition, single lab\",\n      \"pmids\": [\"19193894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Myosin Vb, RAB11A, and Rab11-FIP2 form a required triple complex for cholesterol-depletion-induced transport of NPC1L1 from the endocytic recycling compartment to the plasma membrane; inactivation of any component of this complex inhibits NPC1L1 export and reduces cellular cholesterol uptake.\",\n      \"method\": \"Dominant-negative mutant expression of myosin Vb, RAB11A, and Rab11-FIP2; fluorescence microscopy; cholesterol uptake assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three-component complex required; multiple independent dominant-negative experiments; single lab\",\n      \"pmids\": [\"19542231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RAB11A controls TLR4 trafficking from the endocytic recycling compartment to E. coli phagosomes; suppression of RAB11A reduces TLR4 and TRAM on phagosomes, inhibiting the IRF3 signaling pathway (IFN-β induction) while NF-κB activation is unaffected.\",\n      \"method\": \"siRNA knockdown, co-localization studies, interferon-β reporter assay, NF-κB activity assay\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pathway position defined (RAB11A→TRAM/TLR4 phagosomal delivery→IRF3, not NF-κB), multiple readouts, mechanistically dissected with siRNA\",\n      \"pmids\": [\"20933442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RAB11A is indispensable for transport of influenza A vRNPs to the plasma membrane; RAB11A associates with vRNPs at all stages of cytoplasmic transport; siRNA knockdown or expression of dominant-negative/constitutively active RAB11A mutants causes aberrant vRNP perinuclear retention and prevents plasma membrane accumulation; RAB11A-vRNP complex formation was confirmed biochemically.\",\n      \"method\": \"siRNA knockdown, dominant-negative/constitutively active RAB11A expression, immunofluorescence, biochemical co-precipitation of RAB11A-vRNP complex\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (KD, dominant-negative, constitutively active, biochemical complex), replicated by multiple subsequent studies\",\n      \"pmids\": [\"21525351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A RAB11A/Myosin Vb/Rab11-FIP2 platform regulates langerin recycling at two distinct intracellular sites: first at the sorting site in the endosomal recycling compartment (ERC) where transport vesicles are formed, and subsequently at the docking/tethering and fusion step at the plasma membrane.\",\n      \"method\": \"Live-FRET, fast FRAP, fast confocal, TIRF microscopy in live cells expressing tagged langerin, RAB11A, Myosin Vb, FIP2\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple live-cell imaging modalities define spatiotemporal sequence; single lab\",\n      \"pmids\": [\"22420646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RAB11A functions upstream of RAB8A to promote regulated exocytosis of discoidal/fusiform vesicles in bladder umbrella cells; myosin 5B cooperates with the RAB11A-RAB8A module, possibly by facilitating transit through the cortical actin cytoskeleton; Rabin8 (a RAB11A effector and RAB8 GEF) stimulates exocytosis independently of its GEF catalytic activity.\",\n      \"method\": \"Dominant-active/dominant-negative RAB11A and RAB8A expression, myosin 5B dominant-negative, catalytically inactive Rabin8 expression, stretch-induced exocytosis assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis between RAB11A and RAB8A established, mechanistic role of Rabin8 GEF activity excluded experimentally; single lab\",\n      \"pmids\": [\"23389633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Reggie-1 directly interacts with RAB11A and SNX4; reggie-1 knockdown reduces association of RAB11A with tubular structures and impairs transferrin receptor and E-cadherin recycling to the plasma membrane; these defects are rescued by overexpression of constitutively active RAB11A.\",\n      \"method\": \"siRNA knockdown, fluorescence microscopy, co-immunoprecipitation of reggie-1 and RAB11A, transferrin recycling assay, Ca2+-switch E-cadherin recycling assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction and epistatic rescue established; multiple cargos tested; single lab\",\n      \"pmids\": [\"23825023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rab11-FIPs define spatially and temporally distinct regions within the RAB11A-dependent recycling system; internalized transferrin enters different Rab11-FIP-containing compartments with distinct kinetics (FIP1B/FIP2 early; FIP1A/FIP1C/FIP3/FIP5 delayed), indicating temporal ordering of cargo passage through RAB11A recycling subdomains.\",\n      \"method\": \"Live-cell deconvolution microscopy, fluorescent transferrin kinetics in HeLa cells expressing chimeric fluorescent Rab11-FIPs\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic live-cell kinetic analysis, single lab, multiple FIPs compared\",\n      \"pmids\": [\"23283983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RAB11A mediates intracellular transport of measles virus RNP complexes in Rab11A-containing recycling endosomes in a microtubule-dependent manner; dominant-negative RAB11A severely impairs RNP apical accumulation and infectious virion shedding from polarized epithelial cells.\",\n      \"method\": \"Live-cell imaging with fluorescent protein-tagged L protein, dominant-negative RAB11A expression, nocodazole treatment, viral titer assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging plus dominant-negative functional data; single lab\",\n      \"pmids\": [\"23408617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TBC1D9B acts as a GAP for RAB11A in polarized MDCK cells; TBC1D9B interacts with RAB11A in a nucleotide-dependent manner via its TBC domain and specifically stimulates GTP hydrolysis on RAB11A (but not other Rabs tested at physiological Mg2+); TBC1D9B overexpression decreases active RAB11A, disrupts the RAB11A-Sec15A interaction, and slows IgA transcytosis, while TBC1D9B knockdown accelerates it.\",\n      \"method\": \"GTPase activity assay in vitro, co-immunoprecipitation, overexpression and shRNA knockdown of TBC1D9B, IgA transcytosis assay, active RAB11A pull-down\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro GAP activity assay plus multiple cellular functional assays; gain and loss-of-function both tested; substrate specificity determined\",\n      \"pmids\": [\"25232007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rab11-FIP2 interacts with MYO5B via residues S229 and G233; mutations disrupting this interaction increase speed and track length of RAB11A-containing vesicle movement, consistent with impaired MYO5B-mediated tethering; Rab11-FIP2 knockdown phenocopies this.\",\n      \"method\": \"Random mutagenesis, yeast two-hybrid, HeLa cell expression assays, live-cell fluorescence microscopy of RAB11A vesicle dynamics\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction domain mapped by mutagenesis, vesicle dynamics quantified; single lab\",\n      \"pmids\": [\"24372966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RAB11A is required for apical protein localization in mouse intestinal epithelial cells in vivo; intestine-specific RAB11A knockout mice show apical protein mislocalization to the basolateral membrane, shortened microvilli, and microvillus inclusion bodies; RAB8A mislocalizes in RAB11A knockout intestine, and RAB11A mislocalizes in RAB8A knockout intestine, indicating a functional relationship between RAB11A, RAB8A, and myosin Vb.\",\n      \"method\": \"Conditional knockout mouse, immunofluorescence, electron microscopy, epistasis analysis with RAB8A knockout\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with defined polarity phenotype, epistasis between RAB11A and RAB8A established by double-KO comparison\",\n      \"pmids\": [\"25527643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of RAB11A in mouse embryonic fibroblasts impairs secretion of multiple soluble matrix metalloproteinases (MMPs); global RAB11A knockout embryos form normal blastocysts but die at peri-implantation stages.\",\n      \"method\": \"Global RAB11A knockout mouse, multiple trafficking assays, MMP secretion assays, complementation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO phenotype established, cargo specificity (soluble MMPs) identified by multiple assays; single lab\",\n      \"pmids\": [\"25271168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RAB11A deficiency in enterocytes alters apical localization of syntaxin 3 and impairs microvillus assembly; conditional RAB11A knockout mice and stable RAB11A-knockdown CaCo2-BBE cells both show shortened or displaced microvilli, affirming RAB11A's role in apical membrane trafficking in intestinal cells.\",\n      \"method\": \"Conditional knockout mouse, stable shRNA knockdown, immunofluorescence, electron microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro loss-of-function with defined cargo (syntaxin 3); single lab\",\n      \"pmids\": [\"25673875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Myosin Vb and RAB11A control phosphorylation of ezrin at T567 in enterocytes; dominant-negative RAB11A or myosin Vb depletion prevents subapical enrichment of RAB11A and ezrin kinases and reduces ezrin phosphorylation and microvilli development; similar loss occurs in microvillus inclusion disease (MYO5B mutations).\",\n      \"method\": \"Dominant-negative RAB11A expression, myosin Vb knockdown, phospho-specific ezrin western blot, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanism linking RAB11A/Myo5B to kinase localization and ezrin phosphorylation established; replicated in patient tissue; single lab\",\n      \"pmids\": [\"24413175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MYO5B uncoupling from RAB11A induces microvillus inclusions in enterocytes; the MVID-associated MYO5B-P660L mutation loses interaction with RAB11A and causes microvillus inclusion formation; microvilli restoration requires RAB8A-MYO5B interaction, while microvillus inclusions are driven by loss of RAB11A-MYO5B interaction; early inclusions are SNX18-positive and derived from apical membrane internalization.\",\n      \"method\": \"Stable MYO5B knockdown in CaCo2-BBE cells, expression of WT and mutant MYO5B, surface biotinylation, immunofluorescence, co-immunoprecipitation\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection using patient mutation, multiple orthogonal methods, epistasis between RAB8A-MYO5B and RAB11A-MYO5B interactions defined\",\n      \"pmids\": [\"24892806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RAB11A and Rab11-FIP2 mediate VE-cadherin recycling and vascular barrier integrity; VE-cadherin directly interacts with Rab11-FIP2 (at aa 453-484), forming a ternary complex with RAB11A; silencing RAB11A or Rab11-FIP2 prevents VE-cadherin recycling and junctional reannealing; selective pulmonary microvessel RAB11A knockdown increases vascular leakage in sepsis models.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, Ca2+-switch recycling assay, confocal imaging, siRNA knockdown, in vivo intratracheal siRNA, permeability assay\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction mapped, multiple in vitro and in vivo functional assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26663395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RAB11A inactivation in macrophages facilitates efferocytosis of apoptotic neutrophils via modulation of ADAM17-mediated CD36 surface expression; apoptotic cell feeding induces rapid loss of RAB11A activity; RAB11A knockdown increases surface CD36 by reducing ADAM17 surface levels; blockade of CD36 abolishes the augmented phagocytosis.\",\n      \"method\": \"siRNA knockdown, wild-type and dominant-negative RAB11A overexpression, flow cytometry for surface CD36/ADAM17, efferocytosis assay, in vivo instillation of RAB11A-depleted macrophages\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway dissected with multiple genetic tools; ADAM17-CD36 axis identified; single lab\",\n      \"pmids\": [\"28053235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Huntingtin (HTT) forms a complex with PAR3, aPKC, and RAB11A, and ensures microtubule-dependent apical vesicular translocation of PAR3-aPKC through RAB11A; HTT depletion disrupts apical localization of PAR3-aPKC during mammary epithelial morphogenesis.\",\n      \"method\": \"Co-immunoprecipitation (HTT-PAR3-aPKC-RAB11A complex), conditional HTT depletion in vivo, immunofluorescence, mouse mammary epithelium model\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complex formation confirmed, in vivo phenotype established; single lab\",\n      \"pmids\": [\"25942483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RAB11A is essential for lamellar body biogenesis in human epidermis; RAB11A silencing in 3D reconstructed human epidermis reduces lamellar body density and secretion, misdirects lamellar body cargoes to lysosomes, decreases stratum corneum lipid content, and causes epidermal barrier defects.\",\n      \"method\": \"siRNA knockdown in 3D reconstructed human epidermis, electron microscopy, immunofluorescence, epidermal barrier function assay\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in physiologically relevant 3D model; multiple readouts; single lab\",\n      \"pmids\": [\"26872604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RAB11A regulates ezrin phosphorylation and microvilli-associated membrane supply in neurons via LMTK1; LMTK1 knockout increases prevalence, velocity, and run length of anterograde RAB11A-positive endosome movement; a non-phosphorylatable LMTK1 mutant at Ser34 (Cdk5 phosphorylation site) dramatically promotes dendrite growth; Cdk5-LMTK1 axis negatively controls dendritic formation through regulation of RAB11A-positive endosomal trafficking.\",\n      \"method\": \"LMTK1 knockout mice, live-cell imaging of RAB11A-positive endosome dynamics, dominant-negative and constitutively active RAB11A expression, in vitro and in vivo cortical neuron cultures\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout plus live-imaging quantitation; Cdk5-LMTK1 pathway placement established; single lab\",\n      \"pmids\": [\"24672056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ET-1 activates PKC, which phosphorylates RAB11A at serine 177, inhibiting RAB11A activity and reducing surface trafficking of BK channel β1 subunits in arterial smooth muscle cells; expression of phosphorylation-incapable RAB11A S177A blocks ET-1-induced effects; NO-induced RAB11A activation and vasodilation do not involve S177.\",\n      \"method\": \"PKC inhibitor, RAB11A S177A phosphorylation-incapable mutant expression, RAB11A activity assay, surface protein quantitation, patch-clamp electrophysiology, ex vivo vasoconstriction assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — PTM site identified and functionally validated with phosphorylation-incapable mutant; multiple orthogonal assays (activity, surface protein, electrophysiology, contractility); single lab\",\n      \"pmids\": [\"28696251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RAB11A promotes proliferation and invasion in non-small cell lung cancer via interaction with and upregulation of YAP protein; co-immunoprecipitation shows RAB11A-YAP interaction in lung cancer cells; YAP depletion abolishes RAB11A-induced cell cycle protein changes and proliferation.\",\n      \"method\": \"Co-immunoprecipitation, RAB11A overexpression/knockdown, YAP siRNA epistasis, cell proliferation and invasion assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, mechanistic link between RAB11A-YAP interaction and trafficking not established; single lab, cancer cell-line only\",\n      \"pmids\": [\"28468127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RAB11A-positive recycling endosomes serve as a primary platform for autophagosome biogenesis; WIPI2 is recruited to RAB11A-positive membranes by binding RAB11A, and PI3P is generated on these membranes upon starvation; loss of RAB11A impairs recruitment and assembly of the autophagic machinery including WIPI2, ATG16L1, and LC3.\",\n      \"method\": \"RAB11A knockout/knockdown, confocal and live-cell imaging, WIPI2-RAB11A binding assay, PI3P detection on RAB11A membranes, LC3 lipidation assay, mitophagy and transferrin receptor autophagy assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods defining RAB11A as a primary autophagosome biogenesis platform; WIPI2-RAB11A interaction and PI3P generation on RAB11A membranes both established; single rigorous study\",\n      \"pmids\": [\"29634932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rab11a and Rab8a act in a cascade (RAB11A upstream of RAB8A, independent of Rabin8 GEF activity) to regulate tunneling nanotube (TNT) formation; overexpression of both increases TNT-connected cells and intercellular vesicle propagation; VAMP3 acts downstream of RAB8A in this pathway.\",\n      \"method\": \"RAB11A and RAB8A overexpression/dominant-negative expression, Rabin8 catalytic mutant, live-cell imaging, TNT quantification, VAMP3 interference\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established between RAB11A, RAB8A, and VAMP3; GEF-independent mechanism confirmed; single lab\",\n      \"pmids\": [\"30209134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The LMTK1A-TBC1D9B-RAB11A cascade regulates dendritic spine formation; LMTK1 binds and controls the GAP activity of TBC1D9B on RAB11A; TBC1D9B inactivates RAB11A under LMTK1A control; depletion of LMTK1 or TBC1D9B increases spine formation and density in neurons in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation (LMTK1-TBC1D9B), in vitro GAP assay, siRNA/shRNA knockdown in primary neurons and in vivo mouse brain, spine density analysis by confocal microscopy\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro GAP activity assay establishes TBC1D9B as RAB11A GAP; cascade order confirmed by epistasis; in vivo validation; single rigorous study with multiple methods\",\n      \"pmids\": [\"31628178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Myosin-5b motor function is activated by RAB11A binding to its globular tail domain (GTD), which abolishes the autoinhibitory head-GTD interaction; FIP2 bridges MYO5B and RAB11A on vesicles without directly activating the motor; RAB11A has higher affinity for FIP2 than for MYO5B, suggesting FIP2-mediated vesicle tethering with RAB11A-dependent motor activation.\",\n      \"method\": \"In vitro binding assays (RAB11A-MYO5B GTD interaction), ATPase/motor activity assay, affinity measurements\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution of motor activation mechanism; affinity measurements; single lab, single study\",\n      \"pmids\": [\"30545898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The C9ORF72-SMCR8-WDR41 complex has GAP activity toward RAB11A and RAB8A; cryo-EM structure at 3.2 Å reveals that Arg147 of SMCR8 acts as the arginine finger critical for stimulating GTP hydrolysis by RAB11A; biochemical mutagenesis of R147 eliminates this GAP activity.\",\n      \"method\": \"Cryo-EM structure determination, in vitro GTPase activity assay with SMCR8 R147 mutant, biochemical analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic structure plus in vitro mutagenesis of catalytic residue confirm GAP mechanism; multiple methods in single study\",\n      \"pmids\": [\"32303654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RAB11A is directly activated (GTP-loaded) by the insulin signaling cascade in a PI3K- and Akt-dependent manner; GTP loading of RAB11A peaks ~4 min after insulin stimulation and is required for GLUT4 and FAT/CD36 trafficking in cardiomyocytes.\",\n      \"method\": \"Biotinylated GTP analog loading assay, PI3K/Akt inhibitor pharmacology, siRNA knockdown in H9c2-hIR cells\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel GTP-loading assay, pathway placement established with inhibitors; single lab\",\n      \"pmids\": [\"17158030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RAB11A Rab11A-positive vesicles serve as hubs for congregation of influenza vRNP complexes, enabling vRNP:vRNP interactions required for specific genome assembly; RAB11A-deficient cells produce smaller vRNP bundles with reduced co-localization between distinct vRNA segments and generate non-infectious particles with high RNA copy-to-PFU ratios.\",\n      \"method\": \"Tetracysteine-tagged NP reporter virus, siRNA RAB11A depletion, fluorescence microscopy of vRNP dynamics, RNA copy number/PFU ratio assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional genome assembly role defined; multiple readouts; single lab\",\n      \"pmids\": [\"33970958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IAV infection decreases speed and increases arrest of RAB11A-positive recycling endosomes through a mechanism involving reduced dynein motor association with RAB11A vesicles; co-transport of RAB11A and vRNA was directly demonstrated in infected cells by two-color live imaging.\",\n      \"method\": \"High-spatiotemporal-resolution light-sheet microscopy, two-color live imaging, quantitative motion analysis, proteomic analysis of dynein association\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative live imaging plus proteomic evidence; mechanism (reduced dynein) proposed but not fully validated by mutagenesis; single lab\",\n      \"pmids\": [\"31911620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RAB11A mediates cell-cell spread of influenza A vRNPs via tunneling nanotubes (TNTs); in a system where conventional virion-mediated spread was blocked, vRNP transfer to neighboring cells was dependent on both actin and RAB11A; genome mixing and reassortment via TNT transfer was demonstrated.\",\n      \"method\": \"HA-deficient reporter virus system, actin disruption, RAB11A knockdown/dominant-negative, fluorescence microscopy of TNTs, infectious virus reassortment assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel TNT transport function established with two independent inhibitors; single lab\",\n      \"pmids\": [\"34473799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RAB11A controls YAP localization to adherens and tight junctions in colonic epithelium; loss of RAB11A reduces YAP association with α-catenin, β-catenin, and Merlin, and causes nuclear YAP accumulation and increased β-catenin-YAP complex formation; RAB11A-deficient mice show reduced colonic epithelial integrity and impaired repair after chemical injury.\",\n      \"method\": \"Conditional RAB11A knockout mice, co-immunoprecipitation (YAP with junctional components), immunofluorescence, epithelial injury assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout plus biochemical complex characterization; Hippo-YAP pathway placement; single lab\",\n      \"pmids\": [\"34058200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The C-terminal two-thirds of the influenza A virus PB2 polymerase subunit (PB2-C, comprising cap-binding, mid-link, 627, and NLS domains) directly interact with RAB11A; SAXS confirms a compact 1:1 stoichiometric complex in solution; the switch I region of RAB11A (used for Rab11-FIP binding) mediates PB2-C binding, indicating competition between viral polymerase and Rab11-FIPs for the same RAB11A site.\",\n      \"method\": \"Pulldown assays, mass spectrometry, small-angle X-ray scattering (SAXS), domain deletion mapping\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct interaction structurally validated by SAXS with 1:1 stoichiometry; binding domain mapped biochemically; competitive mechanism with Rab11-FIPs established\",\n      \"pmids\": [\"35019720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RAB11A and RAB11B redundantly control mitotic spindle function in intestinal epithelial progenitor cells; compound RAB11A/RAB11B double-knockout causes mitotic spindle defects, cell cycle arrest, and apoptosis leading to lethality within 3 days; unbiased proteomics of RAB11A and RAB11B immunoprecipitates identified shared mitotic spindle microtubule regulators; disrupting RAB11 impairs KIF11 (kinesin motor) function and bipolar spindle formation.\",\n      \"method\": \"Double-knockout mouse model, enteroid culture, proteomic immunoprecipitation, KIF11 functional analysis, mitotic spindle imaging\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo double knockout with penetrant phenotype, unbiased proteomics identifies interactome, specific mechanism (KIF11/bipolar spindle) established; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"37424454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Accessory ESCRT-III proteins CHMP1A, CHMP1B, CHMP5, and IST1 are selectively required for ILV formation in RAB11A-positive recycling endosomes but not in late endosomes; CHMP5 knockdown in HCT116 cells selectively inhibits RAB11A-exosome production without affecting late-endosome-derived exosomes.\",\n      \"method\": \"Comparative proteomics, Drosophila secondary cell knockdown, human HCT116 cell siRNA knockdown, electron microscopy of ILVs, exosome secretion assay\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ortholog-validated mechanism across two species; selective CHMP5 role in RAB11A-exosome production established; single lab\",\n      \"pmids\": [\"36872252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FLCN (folliculin, Birt-Hogg-Dubé protein) binds RAB11A via its C-terminal DENN-like domain; suppression of either RAB11A or FLCN redirects overexpressed PAT1 (amino acid transporter) to lysosomes and reduces its plasma membrane targeting; FLCN promotes loading of PAT1 onto RAB11A vesicles; FLCN does not have direct GEF activity on RAB11A in vitro.\",\n      \"method\": \"Co-immunoprecipitation of FLCN-RAB11A, in vitro GEF activity assay (negative result for FLCN), siRNA knockdown, PAT1 trafficking assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction and cargo-loading function defined; GEF activity explicitly excluded by in vitro assay; single lab\",\n      \"pmids\": [\"30446510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rab11a-Rab8a double-knockout in neonatal enterocytes causes basolateral microvilli formation and more severe enteropathy than either single knockout; inducible Rab11a deletion alone from neonatal enterocytes induces basolateral microvilli within 3 days; distinct cargo sets depend individually on Rab8a or Rab11a, while some basolateral cargos are redundantly transported by both.\",\n      \"method\": \"Enterocyte-specific single and double conditional knockout mice, inducible Rab11a deletion, immunofluorescence, electron microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic genetic epistasis in vivo with single and double KOs; phenotypic hierarchy established; cargo specificity defined\",\n      \"pmids\": [\"28596241\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAB11A is a GTPase that cycles between GDP- and GTP-bound states (regulated by GAPs including TBC1D9B, C9ORF72-SMCR8, and the Cdk5-LMTK1-TBC1D9B cascade, and activated downstream of insulin/PI3K-Akt signaling) and, in its GTP-bound form, organizes an apical recycling endosome (ARE) compartment dependent on microtubules; from this compartment RAB11A—acting as a scaffold for the myosin Vb/Rab11-FIP2/FIP effector complex—drives slow recycling and transcytosis of diverse membrane cargoes (CFTR, TRPV5/6, EGFR, VE-cadherin, syntaxin 3, PAR3-aPKC, TLR4, GPCR substrates, H+/K+-ATPase, NPC1L1, BK channel β1) to the correct plasma-membrane domain; RAB11A-positive membranes also serve as the primary site for autophagosome nucleation through WIPI2 binding and PI3P generation, for ILV biogenesis to produce a distinct class of exosomes via accessory ESCRT-III proteins, for mitotic spindle regulation via interaction with KIF11 kinesin, and for intercellular cargo transfer via tunneling nanotubes; RAB11A is additionally hijacked by multiple RNA viruses (influenza A, measles, parainfluenza) to transport viral ribonucleoprotein complexes to the plasma membrane, with influenza PB2 directly binding the switch I region of RAB11A to compete with Rab11-FIPs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAB11A is a small GTPase that organizes a microtubule-dependent apical/endocytic recycling endosome compartment and, in its GTP-bound state, directs the slow recycling and transcytosis of membrane cargoes to the correct plasma-membrane domain [#0, #1]. Its central effector module is the myosin Vb/Rab11-FIP2 complex: RAB11A binding to the myosin Vb globular tail relieves motor autoinhibition while FIP2 bridges the motor to RAB11A on vesicles, with the FIPs further subdividing the recycling system into kinetically distinct subdomains [#39, #20, #23]. Through this machinery RAB11A controls polarized delivery of a broad cargo set—H+/K+-ATPase, CFTR, TRPV5/6, NPC1L1, VE-cadherin, syntaxin 3, GPCRs, and the PAR3-aPKC polarity complex—and is required in vivo for apical membrane identity, microvillus assembly, and ezrin phosphorylation in intestinal epithelium [#2, #7, #6, #14, #29, #26, #31, #27]. RAB11A acts upstream of RAB8A in a cascade governing regulated exocytosis, apical polarity, and tunneling-nanotube formation, and the two paralogs redundantly support mitotic spindle bipolarity via KIF11 [#18, #24, #50, #37]. Beyond recycling, RAB11A-positive membranes nucleate autophagosome biogenesis by recruiting WIPI2 and generating PI3P, and support a distinct class of exosomes formed by accessory ESCRT-III proteins [#36, #48]. The GTPase cycle is set by GAPs—TBC1D9B (acting downstream of an LMTK1 cascade) and the C9ORF72-SMCR8-WDR41 complex whose SMCR8 Arg147 arginine finger drives hydrolysis—and by activating insulin/PI3K-Akt signaling and inhibitory PKC phosphorylation at Ser177 [#22, #38, #40, #41, #34]. Multiple RNA viruses including influenza A and measles hijack RAB11A to transport viral ribonucleoproteins to the plasma membrane, with influenza PB2 binding the RAB11A switch I region to compete directly with Rab11-FIPs [#16, #21, #46].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined RAB11A's compartment: established that RAB11A marks a microtubule-dependent apical recycling endosome accessible to cargo from both poles, giving the protein a physical address.\",\n      \"evidence\": \"Immunofluorescence, nocodazole microtubule disruption, and IgA trafficking in polarized MDCK cells\",\n      \"pmids\": [\"9880326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which cargoes obligately pass through this compartment\", \"GTPase cycle requirements not yet dissected\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Linked the GTPase cycle to pathway specificity: showed nucleotide-state mutants selectively block apical recycling and transcytosis but not basolateral recycling, defining RAB11A as a pathway-specific regulator.\",\n      \"evidence\": \"Inducible dominant-negative (S25N) and constitutively active (S20V) mutants with IgA transcytosis and transferrin recycling assays\",\n      \"pmids\": [\"10869360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effectors mediating apical specificity not identified\", \"Molecular basis of cargo discrimination unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified the core effector module and demonstrated cargo control: established that an endogenous RAB11A/myosin Vb/Rab11-FIP complex recycles physiological cargoes (H+/K+-ATPase, CFTR, TRPV5/6, GPCRs) to the apical surface with functional output.\",\n      \"evidence\": \"Co-IP of endogenous complexes, dominant-negative and effector-tail mutants, surface biotinylation, Ca2+ uptake and Cl- secretion electrophysiology across parietal, airway, and renal cell models\",\n      \"pmids\": [\"10484323\", \"17462998\", \"16354700\", \"12427833\", \"18832025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of cargo selection by individual FIPs not resolved\", \"Single-cell-type studies for several cargoes\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the recycling machinery into subdomains and a tethering/motor mechanism: showed FIPs partition the system temporally and that FIP2 tethers MYO5B to RAB11A vesicles, controlling vesicle dynamics.\",\n      \"evidence\": \"Live-cell deconvolution kinetics of FIP compartments and mutagenesis mapping FIP2-MYO5B interaction with vesicle tracking\",\n      \"pmids\": [\"23283983\", \"24372966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How FIPs achieve cargo specificity within subdomains unresolved\", \"In vivo relevance of subdomain ordering untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established RAB11A's in vivo requirement for epithelial polarity and the RAB11A-RAB8A-MYO5B axis: conditional and global knockouts revealed apical cargo mislocalization, microvillus inclusion disease-like phenotypes, and reciprocal RAB11A-RAB8A dependence.\",\n      \"evidence\": \"Intestine-specific and global RAB11A knockout mice, single/double RAB11A-RAB8A knockouts, MYO5B patient mutation analysis, MMP secretion and ezrin phosphorylation assays\",\n      \"pmids\": [\"25527643\", \"25271168\", \"25673875\", \"24892806\", \"28596241\", \"24413175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise cargo sets uniquely versus redundantly handled by RAB8A still being delineated\", \"Mechanism coupling trafficking to microvillus inclusion formation incompletely defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the regulatory inputs controlling RAB11A activity: identified TBC1D9B and the C9ORF72-SMCR8-WDR41 complex as GAPs, the LMTK1 cascade as their controller, insulin/PI3K-Akt as an activating input, and PKC-Ser177 phosphorylation as an inhibitory PTM.\",\n      \"evidence\": \"In vitro GAP assays, cryo-EM of SMCR8 with Arg147 arginine-finger mutagenesis, GTP-loading assays under insulin/PI3K-Akt inhibition, and a phosphorylation-incapable S177A mutant with electrophysiology and vasoreactivity readouts\",\n      \"pmids\": [\"25232007\", \"31628178\", \"32303654\", \"17158030\", \"28696251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GEF(s) that load GTP onto RAB11A not definitively identified (FLCN explicitly lacks GEF activity)\", \"Crosstalk between phosphorylation and GAP regulation unmapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded RAB11A's role beyond recycling to autophagosome and exosome biogenesis: showed RAB11A membranes recruit WIPI2 and generate PI3P to nucleate autophagy and use accessory ESCRT-III for a distinct exosome class.\",\n      \"evidence\": \"RAB11A knockout/knockdown with WIPI2 binding, PI3P detection, LC3 lipidation assays, and comparative proteomics plus CHMP5 knockdown ILV/exosome assays\",\n      \"pmids\": [\"29634932\", \"36872252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RAB11A membranes are selected as autophagy platforms versus recycling carriers unclear\", \"Cargo selectivity of RAB11A-derived exosomes unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established the structural basis of viral hijacking: showed influenza PB2 binds the RAB11A switch I region in a 1:1 complex, directly competing with Rab11-FIPs to commandeer the recycling machinery for vRNP transport and genome assembly.\",\n      \"evidence\": \"Pulldown, SAXS solution structure, domain mapping, and live-imaging/siRNA studies of vRNP transport, TNT spread, and genome bundling across influenza and measles models\",\n      \"pmids\": [\"35019720\", \"21525351\", \"23408617\", \"33970958\", \"31911620\", \"34473799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether host motor/adaptor swapping is general across viruses untested\", \"Therapeutic exploitation of the PB2-switch I interface unexplored\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a recycling-independent mitotic function and paralog redundancy: RAB11A/RAB11B double-knockout disrupts bipolar spindle formation via KIF11, with lethal cell-cycle arrest.\",\n      \"evidence\": \"Double-knockout mice, enteroid culture, unbiased IP proteomics, and KIF11 functional/spindle imaging analysis\",\n      \"pmids\": [\"37424454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RAB11A acts as a vesicular platform or directly on spindle microtubules unresolved\", \"Functional non-redundancy of RAB11A versus RAB11B for spindle role undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The GEF(s) responsible for physiological GTP-loading of RAB11A and the structural rules by which a single GTPase compartment is partitioned among recycling, autophagy, exosome, and spindle functions remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No validated RAB11A GEF identified in the corpus (FLCN lacks GEF activity)\", \"Molecular switch directing RAB11A membranes to distinct downstream fates unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [1, 22, 40]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [39, 36]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [29, 14, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 4, 20]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [11, 16, 32]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 7, 29]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [24, 26, 50]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [36]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [47]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 46, 21]}\n    ],\n    \"complexes\": [\n      \"RAB11A/myosin Vb/Rab11-FIP2 recycling complex\",\n      \"C9ORF72-SMCR8-WDR41 GAP complex\"\n    ],\n    \"partners\": [\n      \"MYO5B\",\n      \"RAB11FIP2\",\n      \"TBC1D9B\",\n      \"SMCR8\",\n      \"RAB8A\",\n      \"WIPI2\",\n      \"KIF11\",\n      \"PB2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}