{"gene":"RAB11FIP5","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2000,"finding":"Rip11 (RAB11FIP5) was identified as a novel Rab11 effector that localizes to subapical recycling endosomes (ARE) and the apical plasma membrane in polarized epithelial cells. Rip11 is recruited to ARE by binding to Rab11 and through a Mg2+-dependent interaction of its C2 domain with neutral phospholipids. The Rab11/Rip11 complex regulates vesicle targeting from ARE to the apical plasma membrane, and Rip11 membrane association is regulated by phosphorylation/dephosphorylation.","method":"Co-immunoprecipitation, subcellular fractionation, transport assays, lipid-binding assays, fluorescence/electron microscopy","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, transport assays, lipid binding, localization), foundational paper with 191 citations","pmids":["11163216"],"is_preprint":false},{"year":2008,"finding":"Rip11/FIP5 (RAB11FIP5) localizes to peripheral endosomes and regulates the sorting of internalized receptors into a slow recycling pathway through perinuclear recycling endosomes. Kinesin II was identified as a Rip11/FIP5-binding protein required for directing endocytosed proteins into the same slow recycling pathway, forming a functional Rip11/FIP5-kinesin II complex.","method":"siRNA knockdown, fluorescence and electron microscopy, co-immunoprecipitation, receptor recycling assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional siRNA knockdown with defined trafficking phenotype, 136 citations","pmids":["18957512"],"is_preprint":false},{"year":2010,"finding":"Rab11-FIP5 (RAB11FIP5) is a substrate of ERK kinase in a Yes-EGFR-ERK signaling cascade. Phosphorylation of Rab11-FIP5 by ERK controls Rab11a endosome distribution and pIgA-pIgR transcytosis. Knockdown of Rab11-FIP5 decreased pIgA transcytosis, placing Rab11-FIP5 downstream of ERK in regulating apical transcytosis.","method":"In vitro kinase assay, siRNA knockdown, phosphorylation mass spectrometry, transcytosis assays, in vivo pIgA injection in rats","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay plus in vivo validation and siRNA-mediated functional phenotype, 70 citations","pmids":["21037565"],"is_preprint":false},{"year":2007,"finding":"Rip11 (RAB11FIP5) forms a complex with AS160 (a RabGAP) in a Rab11-independent manner; insulin induces dissociation of AS160 from Rip11. siRNA-mediated knockdown of Rip11 inhibits insulin-stimulated glucose uptake, and Rip11 translocates to the plasma membrane in response to insulin (uniquely among class I Rab11-interacting proteins). Overexpression of Rip11 blocks insulin-stimulated GLUT4 vesicle insertion into the plasma membrane.","method":"siRNA knockdown, co-immunoprecipitation, 2-deoxyglucose uptake assay, immunofluorescence, subcellular fractionation","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, functional KD and OE with defined phenotypic readout, multiple orthogonal assays","pmids":["18003705"],"is_preprint":false},{"year":2009,"finding":"Rip11 (RAB11FIP5) co-localizes with insulin granules in pancreatic beta cells and is phosphorylated by PKA. Dominant-negative Rip11 mutant inhibits cAMP-potentiated insulin secretion but not glucose-induced insulin secretion, placing Rip11 as a PKA substrate that specifically regulates cAMP-potentiated exocytosis.","method":"Immunocytochemistry, subcellular fractionation, overexpression of dominant-negative mutant, insulin secretion assay, in vivo PKA phosphorylation assay","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 — functional mutant with specific phenotypic readout plus biochemical PKA phosphorylation, single lab","pmids":["19335615"],"is_preprint":false},{"year":2011,"finding":"Rip11 (RAB11FIP5) mediates acidosis-induced trafficking of V-ATPase to the plasma membrane in salivary duct cells. siRNA knockdown of Rip11 prevents acidosis-induced V-ATPase translocation, placing Rip11 downstream of Rab11b in regulating H+ transporter trafficking.","method":"siRNA knockdown, immunofluorescence co-localization, subcellular fractionation, co-immunoprecipitation","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA KD with defined trafficking phenotype plus Co-IP, single lab","pmids":["20717956"],"is_preprint":false},{"year":2015,"finding":"Knockout of Rab11Fip5 abolishes hippocampal long-term depression (LTD) measured in acute slices and cultured neurons, but does not affect basal synaptic transmission, neurotransmitter release, or postsynaptic AMPAR insertion during LTP. This places Rab11Fip5 as specifically required for LTD but not LTP.","method":"Conditional knockout mice, shRNA knockdown, electrophysiology in acute slices, chemical LTD protocol in cultured neurons, behavioral assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with specific electrophysiological phenotype confirmed by multiple approaches (acute slices + cultured neurons), in vivo behavioral validation","pmids":["25972173"],"is_preprint":false},{"year":2018,"finding":"Rab11-FIP5 (RAB11FIP5) specifically regulates recycling of α6β1 integrin but not α3β1 integrin or unrelated receptors. Its membrane-binding domain is required for α6β1 recycling. Depletion of Rab11-FIP5 results in intracellular accumulation of α6β1 in the Rab11 recycling compartment and loss of cell migration on laminin.","method":"siRNA knockdown, flow cytometry, fluorescence microscopy, cell migration assay, PDX tumor mouse model","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — KD with specific trafficking and functional phenotype, domain-deletion approach, single lab","pmids":["29759989"],"is_preprint":false},{"year":2015,"finding":"Insulin promotes Rip11 (RAB11FIP5) accumulation at the plasma membrane by inhibiting dynamin- and PI3-kinase-dependent internalization of Rip11, but not by increasing its translocation rate toward the membrane. This mechanism is independent of Akt activation.","method":"Live-cell fluorescence microscopy, pharmacological inhibition of dynamin and PI3-kinase, insulin stimulation assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional inhibitor dissection and kinetic analysis, single lab","pmids":["26515129"],"is_preprint":false},{"year":2021,"finding":"Rab11-FIP5 (RAB11FIP5) knockdown additively impairs pIgA transcytosis together with Rab11-FIP1. TRIM21 mediates K6-linked polyubiquitination of Rab11-FIP5 to promote its activation and pIgA transcytosis. In incompletely polarized cells, Rab11-FIP5 associates with pIgR/pIgA near the centrosome before transport to the apical membrane via the Golgi apparatus.","method":"siRNA knockdown, immunoprecipitation, ubiquitination assays, fluorescence microscopy, transcytosis assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical ubiquitination assay plus functional transcytosis readout, single lab","pmids":["34638806"],"is_preprint":false},{"year":2020,"finding":"RAB11FIP5 interacts with KSHV ORF45 protein in vitro and in vivo. Overexpression of RAB11FIP5 decreases ORF45 protein levels and inhibits KSHV particle release by promoting lysosomal degradation of ORF45, impairing ORF45 targeting to lipid rafts and ORF45-mediated colocalization of viral particles with the trans-Golgi network.","method":"Co-immunoprecipitation, overexpression, siRNA knockdown, viral particle quantification, lysosomal inhibition assays, immunofluorescence","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus gain/loss-of-function with defined viral release phenotype and mechanistic follow-up, single lab","pmids":["33315947"],"is_preprint":false},{"year":2021,"finding":"Rab11fip5 interacts with ephrinB1 via the PDZ binding motif of ephrinB1 and the Rab-binding domain of Rab11fip5. Loss of Rab11fip5 in Xenopus embryos reduces telencephalon size, decreases ephrinB1 expression, and reduces cell proliferation in the telencephalon. Overexpression of ephrinB1 rescues these defects, indicating that Rab11/Rab11fip5-mediated ephrinB1 recycling is required for telencephalon development.","method":"Co-immunoprecipitation, morpholino knockdown in Xenopus, rescue by ephrinB1 overexpression, cell proliferation assays, immunofluorescence","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis via rescue experiment plus domain-specific interaction mapping, single lab with Xenopus model","pmids":["33462110"],"is_preprint":false},{"year":2003,"finding":"Gaf-1/Rip11 (RAB11FIP5) interacts with both gamma-SNAP and Rab11. An alternatively spliced variant, Gaf-1b, also binds gamma-SNAP, is present in the microsomal fraction, and affects recycling endosome morphology similarly to the full-length protein.","method":"Co-immunoprecipitation, subcellular fractionation, overexpression, fluorescence microscopy","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP plus morphological observation, limited functional follow-up","pmids":["12684040"],"is_preprint":false},{"year":2025,"finding":"KLC3 co-localizes and interacts with RAB11FIP5 around the basal bodies of primary cilia. KLC3 regulates axonemal glutamylation accompanied by changes in RAB11FIP5 expression in basal bodies, suggesting RAB11FIP5 acts downstream of KLC3 to regulate tubulin post-translational modification and anterograde ciliary trafficking.","method":"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, PKD cell models","journal":"Cell communication and signaling","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP and co-localization with limited mechanistic dissection of RAB11FIP5-specific role","pmids":["41225582"],"is_preprint":false}],"current_model":"RAB11FIP5 (Rip11) is a Rab11 effector protein that localizes to recycling endosomes and is recruited to membranes via Rab11 binding and C2-domain-mediated phospholipid interaction; it forms functional complexes with kinesin II (for slow endocytic recycling), AS160 (for insulin-stimulated GLUT4 trafficking), and is phosphorylated by PKA (regulating cAMP-potentiated insulin secretion) and by ERK downstream of a Yes-EGFR-ERK cascade (regulating pIgR/pIgA transcytosis), while also being K6-polyubiquitinated by TRIM21 to promote transcytosis; it specifically mediates α6β1 integrin recycling, LTD but not LTP at hippocampal synapses, and ephrinB1 recycling during telencephalon development, and promotes lysosomal degradation of viral proteins to restrict KSHV particle release."},"narrative":{"teleology":[{"year":2000,"claim":"Identification of RAB11FIP5 as a Rab11-binding effector at the apical recycling endosome established the molecular basis by which it is recruited to membranes and participates in polarized vesicle targeting.","evidence":"Co-immunoprecipitation, lipid-binding assays, transport assays, and EM/fluorescence microscopy in polarized epithelial cells","pmids":["11163216"],"confidence":"High","gaps":["Specific cargo sorted by RAB11FIP5 was not identified","Identity of the kinase(s) regulating its phosphorylation-dependent membrane association was unknown","Whether RAB11FIP5 functions in non-epithelial contexts was untested"]},{"year":2003,"claim":"Discovery of the γ-SNAP interaction and an alternatively spliced variant suggested RAB11FIP5 may link SNARE fusion machinery to recycling endosomes, though the functional significance remained unclear.","evidence":"Co-immunoprecipitation and overexpression with morphological analysis of recycling endosomes","pmids":["12684040"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation or functional reconstitution of γ-SNAP–dependent fusion","Role of the splice variant versus full-length protein in trafficking was not dissected"]},{"year":2007,"claim":"Demonstration that RAB11FIP5 complexes with the RabGAP AS160 and is required for insulin-stimulated GLUT4 translocation placed it as a key node linking Rab11 recycling to metabolic signaling.","evidence":"Co-immunoprecipitation, siRNA knockdown, 2-deoxyglucose uptake, and subcellular fractionation in adipocytes","pmids":["18003705"],"confidence":"High","gaps":["Mechanism by which insulin dissociates the AS160–RAB11FIP5 complex was unresolved","Whether RAB11FIP5 directly contacts GLUT4 vesicles was not shown"]},{"year":2008,"claim":"Identification of kinesin II as a RAB11FIP5-binding partner that co-directs cargo into a slow recycling pathway defined the motor coupling mechanism for perinuclear endosome trafficking.","evidence":"Reciprocal Co-IP, siRNA knockdown, and receptor recycling assays with fluorescence/EM microscopy","pmids":["18957512"],"confidence":"High","gaps":["Whether RAB11FIP5 binds kinesin II directly or via an adaptor was not fully resolved","Cargo selectivity of this slow recycling route was not established"]},{"year":2009,"claim":"Showing that PKA phosphorylates RAB11FIP5 in β-cells and that a dominant-negative mutant blocks cAMP-potentiated but not basal insulin secretion established RAB11FIP5 as a regulated exocytic effector in neuroendocrine cells.","evidence":"In vivo PKA phosphorylation assay, dominant-negative mutant expression, and insulin secretion measurements in MIN6 cells","pmids":["19335615"],"confidence":"Medium","gaps":["Phosphorylation site(s) on RAB11FIP5 mediating the secretory effect were not mapped","Whether RAB11FIP5 directly regulates granule docking or fusion was not determined"]},{"year":2010,"claim":"Placing RAB11FIP5 as an ERK substrate downstream of the Yes–EGFR–ERK cascade revealed the first signal transduction pathway controlling pIgR/pIgA transcytosis through this effector.","evidence":"In vitro kinase assay, phospho-mass spectrometry, siRNA knockdown, and in vivo pIgA injection in rats","pmids":["21037565"],"confidence":"High","gaps":["How ERK-mediated phosphorylation alters RAB11FIP5 activity or binding partners was mechanistically unresolved","Whether ERK phosphorylation regulates other RAB11FIP5-dependent routes beyond transcytosis was untested"]},{"year":2011,"claim":"Demonstrating that RAB11FIP5 is required for acidosis-induced V-ATPase translocation extended its role to stimulus-responsive transporter trafficking in salivary duct cells.","evidence":"siRNA knockdown, immunofluorescence, co-immunoprecipitation, and subcellular fractionation","pmids":["20717956"],"confidence":"Medium","gaps":["The signal linking acidosis to RAB11FIP5 activation was not identified","Whether Rab11a or Rab11b preferentially partners with RAB11FIP5 in this context was not settled"]},{"year":2015,"claim":"Genetic knockout revealed that RAB11FIP5 is specifically required for hippocampal long-term depression but dispensable for LTP, uncovering a selective role in activity-dependent AMPAR removal at synapses.","evidence":"Conditional knockout mice, shRNA knockdown, electrophysiology in acute slices and cultured neurons, behavioral assays","pmids":["25972173"],"confidence":"High","gaps":["The AMPAR subtype or trafficking step controlled by RAB11FIP5 during LTD was not defined","Whether RAB11FIP5 functions at pre- or postsynaptic compartments for LTD was not resolved"]},{"year":2015,"claim":"Live-cell imaging showed that insulin increases RAB11FIP5 plasma membrane accumulation by inhibiting its dynamin- and PI3K-dependent endocytic retrieval rather than by accelerating its delivery, refining the trafficking model for its insulin-responsive behavior.","evidence":"Live-cell fluorescence microscopy with pharmacological inhibition of dynamin and PI3K","pmids":["26515129"],"confidence":"Medium","gaps":["The upstream insulin signaling intermediate that inhibits RAB11FIP5 internalization was not identified","Relevance of this mechanism to GLUT4 vesicle insertion was not directly tested"]},{"year":2018,"claim":"Selective regulation of α6β1 integrin but not α3β1 recycling by RAB11FIP5 demonstrated cargo specificity among Rab11 effectors and linked RAB11FIP5 to laminin-dependent cell migration.","evidence":"siRNA knockdown, flow cytometry, fluorescence microscopy, cell migration assay, and PDX tumor mouse model","pmids":["29759989"],"confidence":"Medium","gaps":["The recognition mechanism conferring α6β1 selectivity was not elucidated","Whether RAB11FIP5 directly contacts integrin cytoplasmic tails was unknown"]},{"year":2020,"claim":"Showing that RAB11FIP5 promotes lysosomal degradation of KSHV ORF45 and restricts viral particle release revealed an antiviral function mediated by diverting a viral protein from productive trafficking.","evidence":"Co-immunoprecipitation, overexpression/knockdown, viral particle quantification, lysosomal inhibition assays","pmids":["33315947"],"confidence":"Medium","gaps":["Whether endogenous RAB11FIP5 levels are sufficient to restrict KSHV in physiological infection was not tested","Mechanism by which RAB11FIP5 redirects ORF45 to lysosomes was not defined"]},{"year":2021,"claim":"Discovery that TRIM21-mediated K6-polyubiquitination activates RAB11FIP5 for pIgA transcytosis, and that RAB11FIP5 acts additively with FIP1, defined a non-degradative ubiquitin signal controlling transcytotic function.","evidence":"Ubiquitination assays, siRNA knockdown, immunoprecipitation, and transcytosis assays in polarized epithelial cells","pmids":["34638806"],"confidence":"Medium","gaps":["The ubiquitinated lysine residue(s) on RAB11FIP5 were not mapped","How K6-polyubiquitin alters RAB11FIP5 interactions or membrane association was not resolved"]},{"year":2021,"claim":"Demonstrating that RAB11FIP5 binds ephrinB1 and that its loss reduces telencephalon size — rescuable by ephrinB1 overexpression — established a developmental recycling pathway critical for forebrain progenitor proliferation.","evidence":"Co-immunoprecipitation, morpholino knockdown in Xenopus, rescue by ephrinB1, cell proliferation assays","pmids":["33462110"],"confidence":"Medium","gaps":["Whether this pathway operates in mammalian brain development was not tested","Whether RAB11FIP5 is recycled together with ephrinB1 or acts only as a sorting factor was not distinguished"]},{"year":null,"claim":"Key open questions include the structural basis of cargo selectivity among RAB11FIP5-dependent recycling routes, the integration of multiple post-translational modifications (ERK, PKA, TRIM21 ubiquitination) on a single effector molecule, and the mechanism by which RAB11FIP5 selectively supports LTD-associated AMPAR trafficking.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of RAB11FIP5 in complex with any cargo or regulatory partner exists","Crosstalk between phosphorylation and ubiquitination in controlling RAB11FIP5 activity has not been investigated","Identity of the specific AMPAR trafficking step dependent on RAB11FIP5 in LTD remains undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,8]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,2,3,5,7,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,4]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6]}],"complexes":[],"partners":["RAB11A","KIF3A","TBC1D4","TRIM21","EFNB1","NAPG"],"other_free_text":[]},"mechanistic_narrative":"RAB11FIP5 (also called Rip11) is a Rab11 effector protein that orchestrates membrane trafficking through recycling endosomes, controlling apical transcytosis, slow endocytic recycling, regulated exocytosis, and cargo-specific integrin and receptor recycling in diverse cell types. It is recruited to subapical recycling endosomes via direct Rab11 binding and a C2 domain that interacts with neutral phospholipids in a Mg²⁺-dependent manner, and it forms functional complexes with kinesin II to direct cargo into the slow recycling pathway and with AS160 to regulate insulin-stimulated GLUT4 trafficking [PMID:11163216, PMID:18957512, PMID:18003705]. RAB11FIP5 activity is regulated by phosphorylation — ERK phosphorylation controls pIgR/pIgA transcytosis downstream of a Yes–EGFR–ERK cascade, PKA phosphorylation regulates cAMP-potentiated insulin secretion in pancreatic β-cells, and TRIM21-mediated K6-linked polyubiquitination activates its transcytotic function [PMID:21037565, PMID:19335615, PMID:34638806]. In neurons, RAB11FIP5 is specifically required for NMDA receptor–dependent long-term depression but dispensable for long-term potentiation, and during development it mediates ephrinB1 recycling essential for telencephalon growth [PMID:25972173, PMID:33462110]."},"prefetch_data":{"uniprot":{"accession":"Q9BXF6","full_name":"Rab11 family-interacting protein 5","aliases":["Gamma-SNAP-associated factor 1","Gaf-1","Phosphoprotein pp75","Rab11-interacting protein Rip11"],"length_aa":653,"mass_kda":70.4,"function":"Rab effector involved in protein trafficking from apical recycling endosomes to the apical plasma membrane. Involved in insulin granule exocytosis. May regulate V-ATPase intracellular transport in response to extracellular acidosis","subcellular_location":"Cytoplasm; Recycling endosome membrane; Early endosome membrane; Golgi apparatus membrane; Cytoplasmic vesicle, secretory vesicle membrane; Mitochondrion membrane","url":"https://www.uniprot.org/uniprotkb/Q9BXF6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAB11FIP5","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SCAMP2","stoichiometry":10.0},{"gene":"PSME3","stoichiometry":0.2},{"gene":"RAB11A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RAB11FIP5","total_profiled":1310},"omim":[{"mim_id":"621000","title":"SORTING NEXIN 18; SNX18","url":"https://www.omim.org/entry/621000"},{"mim_id":"611999","title":"RAB11 FAMILY-INTERACTING PROTEIN 4; RAB11FIP4","url":"https://www.omim.org/entry/611999"},{"mim_id":"606540","title":"MYOSIN VB; MYO5B","url":"https://www.omim.org/entry/606540"},{"mim_id":"605536","title":"RAB11 FAMILY-INTERACTING PROTEIN 5; RAB11FIP5","url":"https://www.omim.org/entry/605536"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Centriolar satellite","reliability":"Approved"},{"location":"Basal body","reliability":"Approved"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Acrosome","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"},{"location":"Annulus","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":35.0}],"url":"https://www.proteinatlas.org/search/RAB11FIP5"},"hgnc":{"alias_symbol":["GAF1","KIAA0857","RIP11","pp75"],"prev_symbol":[]},"alphafold":{"accession":"Q9BXF6","domains":[{"cath_id":"2.60.40.150","chopping":"21-170","consensus_level":"high","plddt":84.1065,"start":21,"end":170},{"cath_id":"1.20.5","chopping":"607-641","consensus_level":"high","plddt":95.25,"start":607,"end":641}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXF6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXF6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXF6-F1-predicted_aligned_error_v6.png","plddt_mean":57.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAB11FIP5","jax_strain_url":"https://www.jax.org/strain/search?query=RAB11FIP5"},"sequence":{"accession":"Q9BXF6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BXF6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BXF6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXF6"}},"corpus_meta":[{"pmid":"11163216","id":"PMC_11163216","title":"A Rab11/Rip11 protein complex regulates apical membrane trafficking via recycling endosomes.","date":"2000","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/11163216","citation_count":191,"is_preprint":false},{"pmid":"18957512","id":"PMC_18957512","title":"The Rip11/Rab11-FIP5 and kinesin II complex regulates endocytic protein recycling.","date":"2008","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/18957512","citation_count":136,"is_preprint":false},{"pmid":"33822231","id":"PMC_33822231","title":"DELLA degradation by gibberellin promotes flowering via GAF1-TPR-dependent repression of floral repressors in Arabidopsis.","date":"2021","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/33822231","citation_count":84,"is_preprint":false},{"pmid":"30270043","id":"PMC_30270043","title":"RAB11FIP5 Expression and Altered Natural Killer Cell Function Are Associated with Induction of HIV Broadly Neutralizing Antibody Responses.","date":"2018","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/30270043","citation_count":78,"is_preprint":false},{"pmid":"21037565","id":"PMC_21037565","title":"A kinase cascade leading to Rab11-FIP5 controls transcytosis of the polymeric immunoglobulin receptor.","date":"2010","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21037565","citation_count":70,"is_preprint":false},{"pmid":"28916594","id":"PMC_28916594","title":"DELLA-GAF1 Complex Is a Main Component in Gibberellin Feedback Regulation of GA20 Oxidase 2.","date":"2017","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28916594","citation_count":69,"is_preprint":false},{"pmid":"19335615","id":"PMC_19335615","title":"Rab11 and its effector Rip11 participate in regulation of insulin granule exocytosis.","date":"2009","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/19335615","citation_count":57,"is_preprint":false},{"pmid":"18003705","id":"PMC_18003705","title":"Rip11 is a Rab11- and AS160-RabGAP-binding protein required for insulin-stimulated glucose uptake in adipocytes.","date":"2007","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/18003705","citation_count":36,"is_preprint":false},{"pmid":"32160533","id":"PMC_32160533","title":"The GATA Transcription Factor Gaf1 Represses tRNAs, Inhibits Growth, and Extends Chronological Lifespan Downstream of Fission Yeast TORC1.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32160533","citation_count":33,"is_preprint":false},{"pmid":"26152587","id":"PMC_26152587","title":"TORC1 Regulates Developmental Responses to Nitrogen Stress via Regulation of the GATA Transcription Factor 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behavior","url":"https://pubmed.ncbi.nlm.nih.gov/26237582","citation_count":17,"is_preprint":false},{"pmid":"11278501","id":"PMC_11278501","title":"Gaf-1, a gamma -SNAP-binding protein associated with the mitochondria.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11278501","citation_count":17,"is_preprint":false},{"pmid":"29759989","id":"PMC_29759989","title":"Novel Regulation of Integrin Trafficking by Rab11-FIP5 in Aggressive Prostate Cancer.","date":"2018","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/29759989","citation_count":16,"is_preprint":false},{"pmid":"18384058","id":"PMC_18384058","title":"A de novo apparently balanced translocation [46,XY,t(2;9)(p13;p24)] interrupting RAB11FIP5 identifies a potential candidate gene for autism spectrum disorder.","date":"2008","source":"American journal of medical genetics. 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/34562198","citation_count":12,"is_preprint":false},{"pmid":"34638806","id":"PMC_34638806","title":"Rab11-FIP1 and Rab11-FIP5 Regulate pIgR/pIgA Transcytosis through TRIM21-Mediated Polyubiquitination.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34638806","citation_count":9,"is_preprint":false},{"pmid":"33315947","id":"PMC_33315947","title":"Host RAB11FIP5 protein inhibits the release of Kaposi's sarcoma-associated herpesvirus particles by promoting lysosomal degradation of ORF45.","date":"2020","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/33315947","citation_count":4,"is_preprint":false},{"pmid":"10438147","id":"PMC_10438147","title":"DNA-induced conformational change of Gaf1, a novel GATA factor in Schizosaccharomyces pombe.","date":"1999","source":"Biochemistry and cell biology = Biochimie et biologie 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Rip11 is recruited to ARE by binding to Rab11 and through a Mg2+-dependent interaction of its C2 domain with neutral phospholipids. The Rab11/Rip11 complex regulates vesicle targeting from ARE to the apical plasma membrane, and Rip11 membrane association is regulated by phosphorylation/dephosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, transport assays, lipid-binding assays, fluorescence/electron microscopy\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, transport assays, lipid binding, localization), foundational paper with 191 citations\",\n      \"pmids\": [\"11163216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Rip11/FIP5 (RAB11FIP5) localizes to peripheral endosomes and regulates the sorting of internalized receptors into a slow recycling pathway through perinuclear recycling endosomes. Kinesin II was identified as a Rip11/FIP5-binding protein required for directing endocytosed proteins into the same slow recycling pathway, forming a functional Rip11/FIP5-kinesin II complex.\",\n      \"method\": \"siRNA knockdown, fluorescence and electron microscopy, co-immunoprecipitation, receptor recycling assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional siRNA knockdown with defined trafficking phenotype, 136 citations\",\n      \"pmids\": [\"18957512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Rab11-FIP5 (RAB11FIP5) is a substrate of ERK kinase in a Yes-EGFR-ERK signaling cascade. Phosphorylation of Rab11-FIP5 by ERK controls Rab11a endosome distribution and pIgA-pIgR transcytosis. Knockdown of Rab11-FIP5 decreased pIgA transcytosis, placing Rab11-FIP5 downstream of ERK in regulating apical transcytosis.\",\n      \"method\": \"In vitro kinase assay, siRNA knockdown, phosphorylation mass spectrometry, transcytosis assays, in vivo pIgA injection in rats\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay plus in vivo validation and siRNA-mediated functional phenotype, 70 citations\",\n      \"pmids\": [\"21037565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Rip11 (RAB11FIP5) forms a complex with AS160 (a RabGAP) in a Rab11-independent manner; insulin induces dissociation of AS160 from Rip11. siRNA-mediated knockdown of Rip11 inhibits insulin-stimulated glucose uptake, and Rip11 translocates to the plasma membrane in response to insulin (uniquely among class I Rab11-interacting proteins). Overexpression of Rip11 blocks insulin-stimulated GLUT4 vesicle insertion into the plasma membrane.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, 2-deoxyglucose uptake assay, immunofluorescence, subcellular fractionation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, functional KD and OE with defined phenotypic readout, multiple orthogonal assays\",\n      \"pmids\": [\"18003705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Rip11 (RAB11FIP5) co-localizes with insulin granules in pancreatic beta cells and is phosphorylated by PKA. Dominant-negative Rip11 mutant inhibits cAMP-potentiated insulin secretion but not glucose-induced insulin secretion, placing Rip11 as a PKA substrate that specifically regulates cAMP-potentiated exocytosis.\",\n      \"method\": \"Immunocytochemistry, subcellular fractionation, overexpression of dominant-negative mutant, insulin secretion assay, in vivo PKA phosphorylation assay\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional mutant with specific phenotypic readout plus biochemical PKA phosphorylation, single lab\",\n      \"pmids\": [\"19335615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rip11 (RAB11FIP5) mediates acidosis-induced trafficking of V-ATPase to the plasma membrane in salivary duct cells. siRNA knockdown of Rip11 prevents acidosis-induced V-ATPase translocation, placing Rip11 downstream of Rab11b in regulating H+ transporter trafficking.\",\n      \"method\": \"siRNA knockdown, immunofluorescence co-localization, subcellular fractionation, co-immunoprecipitation\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA KD with defined trafficking phenotype plus Co-IP, single lab\",\n      \"pmids\": [\"20717956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Knockout of Rab11Fip5 abolishes hippocampal long-term depression (LTD) measured in acute slices and cultured neurons, but does not affect basal synaptic transmission, neurotransmitter release, or postsynaptic AMPAR insertion during LTP. This places Rab11Fip5 as specifically required for LTD but not LTP.\",\n      \"method\": \"Conditional knockout mice, shRNA knockdown, electrophysiology in acute slices, chemical LTD protocol in cultured neurons, behavioral assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with specific electrophysiological phenotype confirmed by multiple approaches (acute slices + cultured neurons), in vivo behavioral validation\",\n      \"pmids\": [\"25972173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rab11-FIP5 (RAB11FIP5) specifically regulates recycling of α6β1 integrin but not α3β1 integrin or unrelated receptors. Its membrane-binding domain is required for α6β1 recycling. Depletion of Rab11-FIP5 results in intracellular accumulation of α6β1 in the Rab11 recycling compartment and loss of cell migration on laminin.\",\n      \"method\": \"siRNA knockdown, flow cytometry, fluorescence microscopy, cell migration assay, PDX tumor mouse model\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with specific trafficking and functional phenotype, domain-deletion approach, single lab\",\n      \"pmids\": [\"29759989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Insulin promotes Rip11 (RAB11FIP5) accumulation at the plasma membrane by inhibiting dynamin- and PI3-kinase-dependent internalization of Rip11, but not by increasing its translocation rate toward the membrane. This mechanism is independent of Akt activation.\",\n      \"method\": \"Live-cell fluorescence microscopy, pharmacological inhibition of dynamin and PI3-kinase, insulin stimulation assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional inhibitor dissection and kinetic analysis, single lab\",\n      \"pmids\": [\"26515129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rab11-FIP5 (RAB11FIP5) knockdown additively impairs pIgA transcytosis together with Rab11-FIP1. TRIM21 mediates K6-linked polyubiquitination of Rab11-FIP5 to promote its activation and pIgA transcytosis. In incompletely polarized cells, Rab11-FIP5 associates with pIgR/pIgA near the centrosome before transport to the apical membrane via the Golgi apparatus.\",\n      \"method\": \"siRNA knockdown, immunoprecipitation, ubiquitination assays, fluorescence microscopy, transcytosis assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical ubiquitination assay plus functional transcytosis readout, single lab\",\n      \"pmids\": [\"34638806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RAB11FIP5 interacts with KSHV ORF45 protein in vitro and in vivo. Overexpression of RAB11FIP5 decreases ORF45 protein levels and inhibits KSHV particle release by promoting lysosomal degradation of ORF45, impairing ORF45 targeting to lipid rafts and ORF45-mediated colocalization of viral particles with the trans-Golgi network.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, siRNA knockdown, viral particle quantification, lysosomal inhibition assays, immunofluorescence\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus gain/loss-of-function with defined viral release phenotype and mechanistic follow-up, single lab\",\n      \"pmids\": [\"33315947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rab11fip5 interacts with ephrinB1 via the PDZ binding motif of ephrinB1 and the Rab-binding domain of Rab11fip5. Loss of Rab11fip5 in Xenopus embryos reduces telencephalon size, decreases ephrinB1 expression, and reduces cell proliferation in the telencephalon. Overexpression of ephrinB1 rescues these defects, indicating that Rab11/Rab11fip5-mediated ephrinB1 recycling is required for telencephalon development.\",\n      \"method\": \"Co-immunoprecipitation, morpholino knockdown in Xenopus, rescue by ephrinB1 overexpression, cell proliferation assays, immunofluorescence\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via rescue experiment plus domain-specific interaction mapping, single lab with Xenopus model\",\n      \"pmids\": [\"33462110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Gaf-1/Rip11 (RAB11FIP5) interacts with both gamma-SNAP and Rab11. An alternatively spliced variant, Gaf-1b, also binds gamma-SNAP, is present in the microsomal fraction, and affects recycling endosome morphology similarly to the full-length protein.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, overexpression, fluorescence microscopy\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus morphological observation, limited functional follow-up\",\n      \"pmids\": [\"12684040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KLC3 co-localizes and interacts with RAB11FIP5 around the basal bodies of primary cilia. KLC3 regulates axonemal glutamylation accompanied by changes in RAB11FIP5 expression in basal bodies, suggesting RAB11FIP5 acts downstream of KLC3 to regulate tubulin post-translational modification and anterograde ciliary trafficking.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, PKD cell models\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP and co-localization with limited mechanistic dissection of RAB11FIP5-specific role\",\n      \"pmids\": [\"41225582\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAB11FIP5 (Rip11) is a Rab11 effector protein that localizes to recycling endosomes and is recruited to membranes via Rab11 binding and C2-domain-mediated phospholipid interaction; it forms functional complexes with kinesin II (for slow endocytic recycling), AS160 (for insulin-stimulated GLUT4 trafficking), and is phosphorylated by PKA (regulating cAMP-potentiated insulin secretion) and by ERK downstream of a Yes-EGFR-ERK cascade (regulating pIgR/pIgA transcytosis), while also being K6-polyubiquitinated by TRIM21 to promote transcytosis; it specifically mediates α6β1 integrin recycling, LTD but not LTP at hippocampal synapses, and ephrinB1 recycling during telencephalon development, and promotes lysosomal degradation of viral proteins to restrict KSHV particle release.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RAB11FIP5 (also called Rip11) is a Rab11 effector protein that orchestrates membrane trafficking through recycling endosomes, controlling apical transcytosis, slow endocytic recycling, regulated exocytosis, and cargo-specific integrin and receptor recycling in diverse cell types. It is recruited to subapical recycling endosomes via direct Rab11 binding and a C2 domain that interacts with neutral phospholipids in a Mg²⁺-dependent manner, and it forms functional complexes with kinesin II to direct cargo into the slow recycling pathway and with AS160 to regulate insulin-stimulated GLUT4 trafficking [PMID:11163216, PMID:18957512, PMID:18003705]. RAB11FIP5 activity is regulated by phosphorylation — ERK phosphorylation controls pIgR/pIgA transcytosis downstream of a Yes–EGFR–ERK cascade, PKA phosphorylation regulates cAMP-potentiated insulin secretion in pancreatic β-cells, and TRIM21-mediated K6-linked polyubiquitination activates its transcytotic function [PMID:21037565, PMID:19335615, PMID:34638806]. In neurons, RAB11FIP5 is specifically required for NMDA receptor–dependent long-term depression but dispensable for long-term potentiation, and during development it mediates ephrinB1 recycling essential for telencephalon growth [PMID:25972173, PMID:33462110].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of RAB11FIP5 as a Rab11-binding effector at the apical recycling endosome established the molecular basis by which it is recruited to membranes and participates in polarized vesicle targeting.\",\n      \"evidence\": \"Co-immunoprecipitation, lipid-binding assays, transport assays, and EM/fluorescence microscopy in polarized epithelial cells\",\n      \"pmids\": [\"11163216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific cargo sorted by RAB11FIP5 was not identified\",\n        \"Identity of the kinase(s) regulating its phosphorylation-dependent membrane association was unknown\",\n        \"Whether RAB11FIP5 functions in non-epithelial contexts was untested\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery of the γ-SNAP interaction and an alternatively spliced variant suggested RAB11FIP5 may link SNARE fusion machinery to recycling endosomes, though the functional significance remained unclear.\",\n      \"evidence\": \"Co-immunoprecipitation and overexpression with morphological analysis of recycling endosomes\",\n      \"pmids\": [\"12684040\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single Co-IP without reciprocal validation or functional reconstitution of γ-SNAP–dependent fusion\",\n        \"Role of the splice variant versus full-length protein in trafficking was not dissected\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstration that RAB11FIP5 complexes with the RabGAP AS160 and is required for insulin-stimulated GLUT4 translocation placed it as a key node linking Rab11 recycling to metabolic signaling.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, 2-deoxyglucose uptake, and subcellular fractionation in adipocytes\",\n      \"pmids\": [\"18003705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which insulin dissociates the AS160–RAB11FIP5 complex was unresolved\",\n        \"Whether RAB11FIP5 directly contacts GLUT4 vesicles was not shown\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of kinesin II as a RAB11FIP5-binding partner that co-directs cargo into a slow recycling pathway defined the motor coupling mechanism for perinuclear endosome trafficking.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown, and receptor recycling assays with fluorescence/EM microscopy\",\n      \"pmids\": [\"18957512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether RAB11FIP5 binds kinesin II directly or via an adaptor was not fully resolved\",\n        \"Cargo selectivity of this slow recycling route was not established\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showing that PKA phosphorylates RAB11FIP5 in β-cells and that a dominant-negative mutant blocks cAMP-potentiated but not basal insulin secretion established RAB11FIP5 as a regulated exocytic effector in neuroendocrine cells.\",\n      \"evidence\": \"In vivo PKA phosphorylation assay, dominant-negative mutant expression, and insulin secretion measurements in MIN6 cells\",\n      \"pmids\": [\"19335615\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Phosphorylation site(s) on RAB11FIP5 mediating the secretory effect were not mapped\",\n        \"Whether RAB11FIP5 directly regulates granule docking or fusion was not determined\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placing RAB11FIP5 as an ERK substrate downstream of the Yes–EGFR–ERK cascade revealed the first signal transduction pathway controlling pIgR/pIgA transcytosis through this effector.\",\n      \"evidence\": \"In vitro kinase assay, phospho-mass spectrometry, siRNA knockdown, and in vivo pIgA injection in rats\",\n      \"pmids\": [\"21037565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How ERK-mediated phosphorylation alters RAB11FIP5 activity or binding partners was mechanistically unresolved\",\n        \"Whether ERK phosphorylation regulates other RAB11FIP5-dependent routes beyond transcytosis was untested\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that RAB11FIP5 is required for acidosis-induced V-ATPase translocation extended its role to stimulus-responsive transporter trafficking in salivary duct cells.\",\n      \"evidence\": \"siRNA knockdown, immunofluorescence, co-immunoprecipitation, and subcellular fractionation\",\n      \"pmids\": [\"20717956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The signal linking acidosis to RAB11FIP5 activation was not identified\",\n        \"Whether Rab11a or Rab11b preferentially partners with RAB11FIP5 in this context was not settled\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Genetic knockout revealed that RAB11FIP5 is specifically required for hippocampal long-term depression but dispensable for LTP, uncovering a selective role in activity-dependent AMPAR removal at synapses.\",\n      \"evidence\": \"Conditional knockout mice, shRNA knockdown, electrophysiology in acute slices and cultured neurons, behavioral assays\",\n      \"pmids\": [\"25972173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The AMPAR subtype or trafficking step controlled by RAB11FIP5 during LTD was not defined\",\n        \"Whether RAB11FIP5 functions at pre- or postsynaptic compartments for LTD was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Live-cell imaging showed that insulin increases RAB11FIP5 plasma membrane accumulation by inhibiting its dynamin- and PI3K-dependent endocytic retrieval rather than by accelerating its delivery, refining the trafficking model for its insulin-responsive behavior.\",\n      \"evidence\": \"Live-cell fluorescence microscopy with pharmacological inhibition of dynamin and PI3K\",\n      \"pmids\": [\"26515129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The upstream insulin signaling intermediate that inhibits RAB11FIP5 internalization was not identified\",\n        \"Relevance of this mechanism to GLUT4 vesicle insertion was not directly tested\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Selective regulation of α6β1 integrin but not α3β1 recycling by RAB11FIP5 demonstrated cargo specificity among Rab11 effectors and linked RAB11FIP5 to laminin-dependent cell migration.\",\n      \"evidence\": \"siRNA knockdown, flow cytometry, fluorescence microscopy, cell migration assay, and PDX tumor mouse model\",\n      \"pmids\": [\"29759989\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The recognition mechanism conferring α6β1 selectivity was not elucidated\",\n        \"Whether RAB11FIP5 directly contacts integrin cytoplasmic tails was unknown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing that RAB11FIP5 promotes lysosomal degradation of KSHV ORF45 and restricts viral particle release revealed an antiviral function mediated by diverting a viral protein from productive trafficking.\",\n      \"evidence\": \"Co-immunoprecipitation, overexpression/knockdown, viral particle quantification, lysosomal inhibition assays\",\n      \"pmids\": [\"33315947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether endogenous RAB11FIP5 levels are sufficient to restrict KSHV in physiological infection was not tested\",\n        \"Mechanism by which RAB11FIP5 redirects ORF45 to lysosomes was not defined\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that TRIM21-mediated K6-polyubiquitination activates RAB11FIP5 for pIgA transcytosis, and that RAB11FIP5 acts additively with FIP1, defined a non-degradative ubiquitin signal controlling transcytotic function.\",\n      \"evidence\": \"Ubiquitination assays, siRNA knockdown, immunoprecipitation, and transcytosis assays in polarized epithelial cells\",\n      \"pmids\": [\"34638806\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The ubiquitinated lysine residue(s) on RAB11FIP5 were not mapped\",\n        \"How K6-polyubiquitin alters RAB11FIP5 interactions or membrane association was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that RAB11FIP5 binds ephrinB1 and that its loss reduces telencephalon size — rescuable by ephrinB1 overexpression — established a developmental recycling pathway critical for forebrain progenitor proliferation.\",\n      \"evidence\": \"Co-immunoprecipitation, morpholino knockdown in Xenopus, rescue by ephrinB1, cell proliferation assays\",\n      \"pmids\": [\"33462110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether this pathway operates in mammalian brain development was not tested\",\n        \"Whether RAB11FIP5 is recycled together with ephrinB1 or acts only as a sorting factor was not distinguished\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of cargo selectivity among RAB11FIP5-dependent recycling routes, the integration of multiple post-translational modifications (ERK, PKA, TRIM21 ubiquitination) on a single effector molecule, and the mechanism by which RAB11FIP5 selectively supports LTD-associated AMPAR trafficking.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of RAB11FIP5 in complex with any cargo or regulatory partner exists\",\n        \"Crosstalk between phosphorylation and ubiquitination in controlling RAB11FIP5 activity has not been investigated\",\n        \"Identity of the specific AMPAR trafficking step dependent on RAB11FIP5 in LTD remains undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 7, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RAB11A\",\n      \"KIF3A\",\n      \"TBC1D4\",\n      \"TRIM21\",\n      \"EFNB1\",\n      \"NAPG\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}