{"gene":"RAB11FIP5","run_date":"2026-06-10T06:43:36","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, where it is required for protein trafficking from ARE to the apical plasma membrane. Rip11 is recruited to ARE by direct binding to Rab11 and through a Mg2+-dependent interaction of its C2 domain with neutral phospholipids. The association of Rip11 with membranes is regulated by a phosphorylation/dephosphorylation cycle.","method":"Co-immunoprecipitation, transport assays, subcellular localization (fluorescence/EM), lipid-binding assays, phosphorylation analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, transport assays, lipid binding, localization), foundational study replicated by many subsequent papers","pmids":["11163216"],"is_preprint":false},{"year":2001,"finding":"Gaf-1 (RAB11FIP5) specifically binds gamma-SNAP but not alpha-SNAP, as shown by two-hybrid screen and co-precipitation. Gaf-1 is stoichiometrically associated with gamma-SNAP in cellular extracts and is peripherally associated with the outer mitochondrial membrane, with a reticular distribution colocalizing with microtubules.","method":"Yeast two-hybrid, co-precipitation, subcellular fractionation, immunofluorescence, GFP imaging","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-precipitation and localization by multiple methods in single lab; functional consequence of gamma-SNAP binding not fully defined","pmids":["11278501"],"is_preprint":false},{"year":2003,"finding":"Gaf-1b, an alternative splice variant of Gaf-1/Rip11 (RAB11FIP5), also interacts with gamma-SNAP and is present in the microsomal fraction. Overexpression of Gaf-1b, like Gaf-1/Rip11, affects the morphology of recycling endosomes.","method":"Co-immunoprecipitation, subcellular fractionation, overexpression with morphological readout","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP plus fractionation and morphological assay, single lab","pmids":["12684040"],"is_preprint":false},{"year":2007,"finding":"Rip11 (RAB11FIP5) translocates to the plasma membrane of 3T3-L1 adipocytes in response to insulin. siRNA-mediated knockdown of Rip11 inhibits insulin-stimulated 2-deoxyglucose uptake. Rip11 forms a complex with the Rab-GAP AS160 in a Rab11-independent manner, and insulin induces dissociation of AS160 from Rip11. Overexpression of Rip11 blocks insulin-stimulated insertion of GLUT4 vesicles into the plasma membrane.","method":"siRNA knockdown with glucose uptake assay, co-immunoprecipitation, fluorescence microscopy, overexpression","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KD with functional readout, Co-IP, localization), single lab","pmids":["18003705"],"is_preprint":false},{"year":2007,"finding":"Knockdown of Rip11 (RAB11FIP5) in H9c2-hIR cells increases FAT/CD36 abundance at the plasma membrane, while knockdown of Rab11a increases both GLUT4 and FAT/CD36 at the surface. FIP2 knockdown selectively increases GLUT4 surface abundance. These data show Rab11a-mediated trafficking of GLUT4 and FAT/CD36 is regulated differently by Rip11 versus FIP2.","method":"siRNA knockdown, cell surface abundance assay (GLUT4myc and FAT/CD36)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA knockdown with surface abundance readout, single lab, no binding assay for this study","pmids":["17854769"],"is_preprint":false},{"year":2008,"finding":"Rip11/FIP5 (RAB11FIP5) is present at peripheral endosomes and regulates the sorting of internalized receptors to a slow recycling pathway via perinuclear recycling endosomes. Kinesin II was identified as a Rip11/FIP5-binding protein and is required for directing endocytosed proteins into the same slow recycling pathway. Thus, the Rip11/FIP5-kinesin II complex routes internalized receptors through perinuclear recycling endosomes.","method":"siRNA knockdown, electron microscopy, fluorescence microscopy, co-immunoprecipitation (identifying kinesin II as binding partner)","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (EM, fluorescence microscopy, Co-IP, siRNA KD with trafficking readout), single lab","pmids":["18957512"],"is_preprint":false},{"year":2009,"finding":"Rip11 (RAB11FIP5) co-localizes with insulin granules in pancreatic beta-cells and is involved in cAMP-potentiated insulin secretion but not glucose-induced secretion. Rip11 is phosphorylated by PKA in MIN6 cells, and its inhibitory mutant effect on secretion was independent of Epac2, placing Rip11 downstream of PKA in the cAMP/insulin secretion pathway.","method":"Immunocytochemistry, subcellular fractionation, overexpression of dominant-negative mutants, insulin secretion assay, PKA phosphorylation assay","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (localization, functional secretion assay, phosphorylation assay, epistasis with Epac2 KO), single lab","pmids":["19335615"],"is_preprint":false},{"year":2010,"finding":"Rab11-FIP5 (RAB11FIP5) is a substrate of ERK kinase in a Yes-EGFR-ERK signaling cascade. pIgA binding to pIgR activates Yes, which phosphorylates EGFR on liver endosomes, activating ERK, which then phosphorylates Rab11-FIP5. Phosphorylation of Rab11-FIP5 by ERK controls Rab11a endosome distribution and pIgA-pIgR transcytosis. Knockdown of Rab11-FIP5 or inhibition of the Yes-EGFR-ERK cascade decreased transcytosis.","method":"In vitro kinase assay, mass spectrometry, siRNA knockdown, pharmacological inhibition, in vivo rat pIgA injection with EGFR phosphorylation measurement","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay identifying FIP5 as ERK substrate, MS, siRNA KD with functional readout, in vivo validation, multiple orthogonal methods","pmids":["21037565"],"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 from intracellular pools to the plasma membrane, downstream of Rab11b.","method":"siRNA knockdown, immunofluorescence, subcellular fractionation, co-localization analysis","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with specific trafficking readout plus co-localization, single lab","pmids":["20717956"],"is_preprint":false},{"year":2015,"finding":"Knockout of Rab11Fip5 (RAB11FIP5) in mice specifically abolishes hippocampal long-term depression (LTD), measured in acute slices and with chemical LTD protocol, but does not affect hippocampal LTP or basic parameters of synaptic transmission including postsynaptic AMPAR insertion. KO mice show enhanced contextual fear extinction.","method":"Conditional knockout mice, electrophysiology (LTP/LTD in acute hippocampal slices), chemical LTD in cultured neurons, shRNA knockdown with rescue by cDNA","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple rigorous electrophysiological readouts, shRNA rescue experiment, behavioral assays","pmids":["25972173"],"is_preprint":false},{"year":2015,"finding":"Insulin promotes accumulation of Rip11 (RAB11FIP5) at the plasma membrane by inhibiting its internalisation rather than increasing its outward transport rate. This inhibition of Rip11 endocytosis requires dynamin and class I PI3-kinases but is independent of Akt activation.","method":"Live-cell fluorescence microscopy of Rip11 dynamics, pharmacological inhibitors (dynamin, PI3-kinase, Akt), quantitative surface accumulation assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging with kinetic analysis plus pharmacological dissection, single lab","pmids":["26515129"],"is_preprint":false},{"year":2016,"finding":"In Drosophila epithelia, Rip11 (ortholog of RAB11FIP5) contributes to maintenance of apico-basal polarity via Rab11-recycling endosomes. Nuf (nuclear fallout) and Rip11 have distinct contributions: aPKC is recycled via Rab11-Nuf-recycling endosomes, and phosphorylation of Nuf by aPKC controls Nuf sub-cellular localization and aPKC membrane accumulation.","method":"Genetic analysis in Drosophila, fluorescence imaging of polarity determinants, phosphorylation assay","journal":"Small GTPases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Drosophila genetic and imaging analysis with defined phenotypic readout, single lab","pmids":["27687567"],"is_preprint":false},{"year":2018,"finding":"Rab11-FIP5 (RAB11FIP5) specifically mediates recycling of integrin α6β1 (but not α3β1, CD44, transferrin receptor, or E-cadherin) in prostate cancer cells. Depletion of Rab11-FIP5 results in intracellular accumulation of α6β1 in the Rab11 recycling compartment and loss of cell migration on laminin. The membrane-binding domain of Rab11-FIP5 is required for α6β1 recycling.","method":"siRNA knockdown, fluorescence microscopy, integrin recycling assay, cell migration assay, PDX mouse tumor model","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with multiple functional readouts (recycling assay, migration, localization), single lab","pmids":["29759989"],"is_preprint":false},{"year":2020,"finding":"RAB11FIP5 interacts with KSHV ORF45 in vitro and in vivo. Overexpression of RAB11FIP5 decreases ORF45 levels and inhibits release of KSHV particles by promoting lysosomal degradation of ORF45, thereby impairing ORF45 targeting to lipid rafts in the Golgi and inhibiting co-localization of viral particles with the trans-Golgi network. Silencing RAB11FIP5 increases ORF45 expression and promotes virion release.","method":"Co-immunoprecipitation (in vitro and in vivo), overexpression/knockdown with virion release assay, lysosomal inhibition assay, fluorescence microscopy","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, gain/loss-of-function with functional readout, lysosomal pathway assay, single lab","pmids":["33315947"],"is_preprint":false},{"year":2021,"finding":"Rab11-FIP5 (RAB11FIP5) and Rab11-FIP1 knockdown additively impair pIgA transcytosis. TRIM21 mediates K6-linked polyubiquitination of Rab11-FIP5 to promote its activation and facilitate pIgA transcytosis. In incompletely polarized cells, Rab11a-positive endosomes containing pIgR/pIgA, Rab11-FIP1, and Rab11-FIP5 are transported to the apical membrane via the Golgi apparatus.","method":"siRNA knockdown, co-immunoprecipitation, ubiquitination assays (identifying K6-linked chains and specific lysine residues), transcytosis assays in polarized and incompletely polarized cells","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods including ubiquitination mapping, functional transcytosis assay, KD studies; single lab","pmids":["34638806"],"is_preprint":false},{"year":2021,"finding":"Rab11fip5 (RAB11FIP5) interacts with ephrinB1 via the PDZ binding motif of ephrinB1 and the Rab-binding domain of Rab11fip5. Loss of Rab11fip5 function in Xenopus reduces telencephalon size, decreases ephrinB1 expression, and impairs cell proliferation in the telencephalon. Overexpression of ephrinB1 rescues these defects, indicating that ephrinB1 recycling by the Rab11/Rab11fip5 complex is required for proper telencephalon development.","method":"Co-immunoprecipitation (domain mapping), morpholino knockdown in Xenopus, overexpression rescue, immunofluorescence, cell proliferation assay","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, morpholino KD with rescue experiment, in vivo Xenopus model; single lab","pmids":["33462110"],"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, which may be involved in anterograde ciliary trafficking. Increased RAB11FIP5 and axonemal glutamylation are observed in cyst-lining cells of polycystic kidney disease.","method":"Co-localization microscopy, co-immunoprecipitation, siRNA knockdown of KLC3 with RAB11FIP5 expression readout, PKD patient-derived cells","journal":"Cell communication and signaling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, co-localization and Co-IP with limited functional mechanistic follow-up for RAB11FIP5 specifically","pmids":["41225582"],"is_preprint":false},{"year":2026,"finding":"RAB11FIP5 competitively sequesters RAB11A to antagonize RAB11FIP1-mediated transferrin receptor recycling, thereby restricting iron uptake and suppressing ferroptosis in HNSCC cells. The deubiquitinase USP52 stabilizes RAB11FIP5 by cleaving K48-linked ubiquitin chains specifically at lysine residues 583 and 586. RAB11FIP5 deletion impairs long-term proliferative capacity and suppresses tumor growth in xenografts through both ferroptosis-dependent and -independent mechanisms.","method":"Co-immunoprecipitation, transferrin receptor recycling assay, iron uptake assay, ferroptosis assays, ubiquitination mapping (K583/K586 site mutagenesis), USP52 knockdown/overexpression, xenograft tumor model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods including site-specific mutagenesis, recycling assays, in vivo xenograft, single lab","pmids":["42207639"],"is_preprint":false}],"current_model":"RAB11FIP5 (Rip11) is a Rab11 effector protein that localizes to recycling endosomes and regulates cargo trafficking to the apical plasma membrane; it binds Rab11 via its Rab-binding domain and membranes via its C2 domain in a phosphorylation-regulated manner, forms complexes with kinesin II (for slow endocytic recycling), gamma-SNAP (mitochondria-associated), AS160 (insulin/GLUT4 pathway), and ephrinB1 (telencephalon development); it is phosphorylated by PKA (regulating cAMP-potentiated insulin secretion) and by ERK downstream of a Yes-EGFR-ERK cascade (controlling pIgA-pIgR transcytosis); it is polyubiquitinated by TRIM21 (K6-linked, activating pIgA transcytosis) and stabilized by USP52 (cleaving K48-linked chains at K583/K586); it specifically recycles integrin α6β1 and, by competitively sequestering RAB11A, suppresses RAB11FIP1-mediated transferrin receptor recycling to restrict iron uptake and ferroptosis; and in neurons it is selectively required for hippocampal long-term depression but not LTP."},"narrative":{"mechanistic_narrative":"RAB11FIP5 (Rip11/Gaf-1) is a Rab11 effector that organizes cargo trafficking through recycling endosomes, directing internalized receptors and other cargo toward the apical/plasma membrane in polarized epithelia [PMID:11163216, PMID:18957512]. It is recruited to subapical recycling endosomes through direct binding to Rab11 and a Mg2+-dependent interaction of its C2 domain with neutral phospholipids, an association governed by a phosphorylation/dephosphorylation cycle [PMID:11163216]. Through its membrane-binding domain it routes internalized receptors into a slow recycling pathway in complex with kinesin II, linking recycling endosomes to microtubule-based transport [PMID:18957512]. RAB11FIP5 controls specific cargoes rather than bulk recycling: it mediates insulin-stimulated GLUT4 and FAT/CD36 surface delivery in adipocytes via a Rab11a-dependent route while forming a Rab11-independent complex with the Rab-GAP AS160 that dissociates upon insulin stimulation [PMID:18003705, PMID:17854769], and it selectively recycles integrin α6β1 to support cell migration on laminin [PMID:29759989]. Its activity is regulated by signal-driven phosphorylation and ubiquitination: ERK phosphorylates RAB11FIP5 downstream of a Yes-EGFR cascade to drive pIgA-pIgR transcytosis [PMID:21037565], PKA phosphorylates it during cAMP-potentiated insulin secretion [PMID:19335615], TRIM21 attaches activating K6-linked polyubiquitin chains that promote transcytosis [PMID:34638806], and the deubiquitinase USP52 stabilizes the protein by removing K48-linked chains at K583/K586 [PMID:42207639]. By competitively sequestering RAB11A away from RAB11FIP1, RAB11FIP5 restrains transferrin receptor recycling and iron uptake, thereby suppressing ferroptosis and supporting tumor growth in HNSCC [PMID:42207639]. RAB11FIP5 also interacts with γ-SNAP at the outer mitochondrial membrane [PMID:11278501] and with ephrinB1 to enable its recycling during telencephalon development [PMID:33462110], and in mice it is selectively required for hippocampal long-term depression but not LTP [PMID:25972173].","teleology":[{"year":2000,"claim":"Established RAB11FIP5 as a Rab11 effector that physically links recycling endosomes to the apical membrane trafficking route, answering what molecular machinery drives apical cargo delivery.","evidence":"Co-IP, transport assays, lipid-binding and localization in polarized epithelial cells","pmids":["11163216"],"confidence":"High","gaps":["The kinase/phosphatase pair controlling the membrane-association cycle was not identified","Specific apical cargoes not defined at this stage"]},{"year":2001,"claim":"Identified γ-SNAP and the outer mitochondrial membrane as a binding partner and localization distinct from recycling endosomes, raising the question of a non-canonical role.","evidence":"Yeast two-hybrid, reciprocal co-precipitation, fractionation and imaging","pmids":["11278501"],"confidence":"Medium","gaps":["Functional consequence of γ-SNAP binding undefined","Relationship between mitochondrial and endosomal pools unresolved"]},{"year":2007,"claim":"Placed RAB11FIP5 in insulin-regulated cargo trafficking, distinguishing it from FIP2 in routing GLUT4 versus FAT/CD36 and revealing a Rab11-independent AS160 complex.","evidence":"siRNA knockdown with glucose-uptake and surface-abundance assays, Co-IP, microscopy in adipocyte/cardiomyocyte lines","pmids":["18003705","17854769"],"confidence":"High","gaps":["Mechanism by which insulin triggers AS160 dissociation not defined","How cargo selectivity between FIP isoforms is encoded unclear"]},{"year":2008,"claim":"Defined the RAB11FIP5-kinesin II complex as the route channeling internalized receptors into a slow perinuclear recycling pathway, connecting endosome sorting to microtubule motors.","evidence":"siRNA knockdown, EM, fluorescence microscopy, Co-IP identifying kinesin II","pmids":["18957512"],"confidence":"High","gaps":["Direct vs. indirect nature of kinesin II binding not resolved","Cargo selectivity of the slow pathway not mapped"]},{"year":2009,"claim":"Positioned RAB11FIP5 downstream of PKA in cAMP-potentiated insulin secretion, identifying it as a phosphorylation target in regulated secretion.","evidence":"Localization, secretion assays, PKA phosphorylation assay, epistasis with Epac2 in beta-cells","pmids":["19335615"],"confidence":"Medium","gaps":["PKA phosphosites on RAB11FIP5 not mapped","Effect of phosphorylation on Rab11 binding not tested"]},{"year":2010,"claim":"Identified RAB11FIP5 as an ERK substrate within a Yes-EGFR-ERK cascade that controls Rab11a endosome distribution and pIgA-pIgR transcytosis, linking receptor signaling to recycling.","evidence":"In vitro kinase assay, mass spectrometry, siRNA KD, pharmacological inhibition, in vivo rat pIgA injection","pmids":["21037565"],"confidence":"High","gaps":["How phosphorylation alters FIP5 membrane/Rab11 interactions mechanistically not resolved"]},{"year":2011,"claim":"Extended RAB11FIP5 function to acidosis-induced V-ATPase delivery to the plasma membrane downstream of Rab11b, broadening its cargo repertoire.","evidence":"siRNA knockdown, immunofluorescence, fractionation in salivary duct cells","pmids":["20717956"],"confidence":"Medium","gaps":["Direct interaction with V-ATPase not shown","Single cell-type context"]},{"year":2015,"claim":"Genetic knockout revealed a selective requirement for RAB11FIP5 in hippocampal LTD but not LTP, implicating endosomal recycling specifically in synaptic depression.","evidence":"Conditional KO mice, hippocampal slice and chemical LTD electrophysiology, shRNA rescue, behavior","pmids":["25972173"],"confidence":"High","gaps":["Synaptic cargo recycled by RAB11FIP5 during LTD not identified","Molecular partners in neurons not defined"]},{"year":2015,"claim":"Defined the kinetic basis of insulin-driven plasma-membrane accumulation as inhibition of RAB11FIP5 endocytosis requiring dynamin and PI3-kinase but not Akt.","evidence":"Live-cell imaging with kinetic analysis and pharmacological dissection","pmids":["26515129"],"confidence":"Medium","gaps":["The signaling effector downstream of PI3-kinase not identified","Link to AS160 dissociation not established"]},{"year":2018,"claim":"Demonstrated cargo-specific recycling of integrin α6β1 by RAB11FIP5, requiring its membrane-binding domain and driving cancer cell migration on laminin.","evidence":"siRNA KD, recycling and migration assays, PDX tumor model in prostate cancer cells","pmids":["29759989"],"confidence":"Medium","gaps":["Determinant of α6β1 selectivity over other integrins not defined","Single tumor context"]},{"year":2020,"claim":"Identified an antiviral role in which RAB11FIP5 binds KSHV ORF45 and routes it to lysosomal degradation, restricting virion release.","evidence":"Reciprocal Co-IP, gain/loss-of-function with virion release and lysosomal inhibition assays","pmids":["33315947"],"confidence":"Medium","gaps":["Mechanism directing ORF45 to lysosomes vs. recycling unclear","Physiological relevance during natural infection not addressed"]},{"year":2021,"claim":"Showed that TRIM21-mediated K6-linked polyubiquitination activates RAB11FIP5 to facilitate pIgA transcytosis, and that FIP5 and FIP1 act additively, revealing ubiquitin control of effector activity.","evidence":"siRNA KD, Co-IP, ubiquitination mapping, transcytosis assays in polarized/incompletely polarized cells","pmids":["34638806"],"confidence":"Medium","gaps":["Structural effect of K6 ubiquitination on FIP5 activity unknown","Ubiquitinated lysines not fully mapped here"]},{"year":2021,"claim":"Linked RAB11FIP5 to development by mapping a Rab-binding-domain interaction with ephrinB1 whose recycling is required for telencephalon growth and proliferation.","evidence":"Co-IP domain mapping, morpholino KD with overexpression rescue in Xenopus","pmids":["33462110"],"confidence":"Medium","gaps":["Conservation of the ephrinB1 interaction in mammals not shown","Downstream signaling of recycled ephrinB1 not dissected"]},{"year":2025,"claim":"Associated RAB11FIP5 with primary cilia via KLC3 interaction at basal bodies and with axonemal glutamylation changes in polycystic kidney disease.","evidence":"Co-localization, Co-IP, siRNA KD of KLC3, PKD patient-derived cells","pmids":["41225582"],"confidence":"Low","gaps":["Functional role of RAB11FIP5 in ciliary trafficking not directly tested","Direct vs. indirect KLC3 binding unresolved","Causal contribution to PKD not established"]},{"year":2026,"claim":"Defined a competitive sequestration mechanism in which RAB11FIP5 traps RAB11A from RAB11FIP1 to limit transferrin receptor recycling, iron uptake and ferroptosis, with USP52 stabilizing it by removing K48 chains at K583/K586.","evidence":"Co-IP, recycling/iron-uptake/ferroptosis assays, site-specific mutagenesis, USP52 perturbation, xenografts in HNSCC","pmids":["42207639"],"confidence":"High","gaps":["Stoichiometry of RAB11A competition between FIP5 and FIP1 not quantified","Ferroptosis-independent tumor mechanism not defined"]},{"year":null,"claim":"How RAB11FIP5 integrates its multiple post-translational modifications (PKA/ERK phosphorylation, K6 vs. K48 ubiquitination) to select among its many cargoes in a given cell type remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking modification state to cargo selectivity","Tissue-specific partner usage not systematically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,17]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[17]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,5,14]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,8,10]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[13,14]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,5,7,12]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,3,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,7,6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[17]}],"complexes":[],"partners":["RAB11A","AS160 (TBC1D4)","KIF3 (KINESIN II)","EFNB1","RAB11FIP1","USP52","TRIM21","NAPG (GAMMA-SNAP)"],"other_free_text":[]}},"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":192,"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":137,"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":80,"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 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Rip11 is recruited to ARE by direct binding to Rab11 and through a Mg2+-dependent interaction of its C2 domain with neutral phospholipids. The association of Rip11 with membranes is regulated by a phosphorylation/dephosphorylation cycle.\",\n      \"method\": \"Co-immunoprecipitation, transport assays, subcellular localization (fluorescence/EM), lipid-binding assays, phosphorylation analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, transport assays, lipid binding, localization), foundational study replicated by many subsequent papers\",\n      \"pmids\": [\"11163216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Gaf-1 (RAB11FIP5) specifically binds gamma-SNAP but not alpha-SNAP, as shown by two-hybrid screen and co-precipitation. Gaf-1 is stoichiometrically associated with gamma-SNAP in cellular extracts and is peripherally associated with the outer mitochondrial membrane, with a reticular distribution colocalizing with microtubules.\",\n      \"method\": \"Yeast two-hybrid, co-precipitation, subcellular fractionation, immunofluorescence, GFP imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-precipitation and localization by multiple methods in single lab; functional consequence of gamma-SNAP binding not fully defined\",\n      \"pmids\": [\"11278501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Gaf-1b, an alternative splice variant of Gaf-1/Rip11 (RAB11FIP5), also interacts with gamma-SNAP and is present in the microsomal fraction. Overexpression of Gaf-1b, like Gaf-1/Rip11, affects the morphology of recycling endosomes.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, overexpression with morphological readout\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP plus fractionation and morphological assay, single lab\",\n      \"pmids\": [\"12684040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Rip11 (RAB11FIP5) translocates to the plasma membrane of 3T3-L1 adipocytes in response to insulin. siRNA-mediated knockdown of Rip11 inhibits insulin-stimulated 2-deoxyglucose uptake. Rip11 forms a complex with the Rab-GAP AS160 in a Rab11-independent manner, and insulin induces dissociation of AS160 from Rip11. Overexpression of Rip11 blocks insulin-stimulated insertion of GLUT4 vesicles into the plasma membrane.\",\n      \"method\": \"siRNA knockdown with glucose uptake assay, co-immunoprecipitation, fluorescence microscopy, overexpression\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KD with functional readout, Co-IP, localization), single lab\",\n      \"pmids\": [\"18003705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Knockdown of Rip11 (RAB11FIP5) in H9c2-hIR cells increases FAT/CD36 abundance at the plasma membrane, while knockdown of Rab11a increases both GLUT4 and FAT/CD36 at the surface. FIP2 knockdown selectively increases GLUT4 surface abundance. These data show Rab11a-mediated trafficking of GLUT4 and FAT/CD36 is regulated differently by Rip11 versus FIP2.\",\n      \"method\": \"siRNA knockdown, cell surface abundance assay (GLUT4myc and FAT/CD36)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA knockdown with surface abundance readout, single lab, no binding assay for this study\",\n      \"pmids\": [\"17854769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Rip11/FIP5 (RAB11FIP5) is present at peripheral endosomes and regulates the sorting of internalized receptors to a slow recycling pathway via perinuclear recycling endosomes. Kinesin II was identified as a Rip11/FIP5-binding protein and is required for directing endocytosed proteins into the same slow recycling pathway. Thus, the Rip11/FIP5-kinesin II complex routes internalized receptors through perinuclear recycling endosomes.\",\n      \"method\": \"siRNA knockdown, electron microscopy, fluorescence microscopy, co-immunoprecipitation (identifying kinesin II as binding partner)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (EM, fluorescence microscopy, Co-IP, siRNA KD with trafficking readout), single lab\",\n      \"pmids\": [\"18957512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Rip11 (RAB11FIP5) co-localizes with insulin granules in pancreatic beta-cells and is involved in cAMP-potentiated insulin secretion but not glucose-induced secretion. Rip11 is phosphorylated by PKA in MIN6 cells, and its inhibitory mutant effect on secretion was independent of Epac2, placing Rip11 downstream of PKA in the cAMP/insulin secretion pathway.\",\n      \"method\": \"Immunocytochemistry, subcellular fractionation, overexpression of dominant-negative mutants, insulin secretion assay, PKA phosphorylation assay\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (localization, functional secretion assay, phosphorylation assay, epistasis with Epac2 KO), single lab\",\n      \"pmids\": [\"19335615\"],\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. pIgA binding to pIgR activates Yes, which phosphorylates EGFR on liver endosomes, activating ERK, which then phosphorylates Rab11-FIP5. Phosphorylation of Rab11-FIP5 by ERK controls Rab11a endosome distribution and pIgA-pIgR transcytosis. Knockdown of Rab11-FIP5 or inhibition of the Yes-EGFR-ERK cascade decreased transcytosis.\",\n      \"method\": \"In vitro kinase assay, mass spectrometry, siRNA knockdown, pharmacological inhibition, in vivo rat pIgA injection with EGFR phosphorylation measurement\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay identifying FIP5 as ERK substrate, MS, siRNA KD with functional readout, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"21037565\"],\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 from intracellular pools to the plasma membrane, downstream of Rab11b.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, subcellular fractionation, co-localization analysis\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with specific trafficking readout plus co-localization, single lab\",\n      \"pmids\": [\"20717956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Knockout of Rab11Fip5 (RAB11FIP5) in mice specifically abolishes hippocampal long-term depression (LTD), measured in acute slices and with chemical LTD protocol, but does not affect hippocampal LTP or basic parameters of synaptic transmission including postsynaptic AMPAR insertion. KO mice show enhanced contextual fear extinction.\",\n      \"method\": \"Conditional knockout mice, electrophysiology (LTP/LTD in acute hippocampal slices), chemical LTD in cultured neurons, shRNA knockdown with rescue by cDNA\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple rigorous electrophysiological readouts, shRNA rescue experiment, behavioral assays\",\n      \"pmids\": [\"25972173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Insulin promotes accumulation of Rip11 (RAB11FIP5) at the plasma membrane by inhibiting its internalisation rather than increasing its outward transport rate. This inhibition of Rip11 endocytosis requires dynamin and class I PI3-kinases but is independent of Akt activation.\",\n      \"method\": \"Live-cell fluorescence microscopy of Rip11 dynamics, pharmacological inhibitors (dynamin, PI3-kinase, Akt), quantitative surface accumulation assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging with kinetic analysis plus pharmacological dissection, single lab\",\n      \"pmids\": [\"26515129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Drosophila epithelia, Rip11 (ortholog of RAB11FIP5) contributes to maintenance of apico-basal polarity via Rab11-recycling endosomes. Nuf (nuclear fallout) and Rip11 have distinct contributions: aPKC is recycled via Rab11-Nuf-recycling endosomes, and phosphorylation of Nuf by aPKC controls Nuf sub-cellular localization and aPKC membrane accumulation.\",\n      \"method\": \"Genetic analysis in Drosophila, fluorescence imaging of polarity determinants, phosphorylation assay\",\n      \"journal\": \"Small GTPases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Drosophila genetic and imaging analysis with defined phenotypic readout, single lab\",\n      \"pmids\": [\"27687567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rab11-FIP5 (RAB11FIP5) specifically mediates recycling of integrin α6β1 (but not α3β1, CD44, transferrin receptor, or E-cadherin) in prostate cancer cells. Depletion of Rab11-FIP5 results in intracellular accumulation of α6β1 in the Rab11 recycling compartment and loss of cell migration on laminin. The membrane-binding domain of Rab11-FIP5 is required for α6β1 recycling.\",\n      \"method\": \"siRNA knockdown, fluorescence microscopy, integrin recycling assay, cell migration assay, PDX mouse tumor model\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with multiple functional readouts (recycling assay, migration, localization), single lab\",\n      \"pmids\": [\"29759989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RAB11FIP5 interacts with KSHV ORF45 in vitro and in vivo. Overexpression of RAB11FIP5 decreases ORF45 levels and inhibits release of KSHV particles by promoting lysosomal degradation of ORF45, thereby impairing ORF45 targeting to lipid rafts in the Golgi and inhibiting co-localization of viral particles with the trans-Golgi network. Silencing RAB11FIP5 increases ORF45 expression and promotes virion release.\",\n      \"method\": \"Co-immunoprecipitation (in vitro and in vivo), overexpression/knockdown with virion release assay, lysosomal inhibition assay, fluorescence microscopy\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, gain/loss-of-function with functional readout, lysosomal pathway assay, single lab\",\n      \"pmids\": [\"33315947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rab11-FIP5 (RAB11FIP5) and Rab11-FIP1 knockdown additively impair pIgA transcytosis. TRIM21 mediates K6-linked polyubiquitination of Rab11-FIP5 to promote its activation and facilitate pIgA transcytosis. In incompletely polarized cells, Rab11a-positive endosomes containing pIgR/pIgA, Rab11-FIP1, and Rab11-FIP5 are transported to the apical membrane via the Golgi apparatus.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, ubiquitination assays (identifying K6-linked chains and specific lysine residues), transcytosis assays in polarized and incompletely polarized cells\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods including ubiquitination mapping, functional transcytosis assay, KD studies; single lab\",\n      \"pmids\": [\"34638806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rab11fip5 (RAB11FIP5) interacts with ephrinB1 via the PDZ binding motif of ephrinB1 and the Rab-binding domain of Rab11fip5. Loss of Rab11fip5 function in Xenopus reduces telencephalon size, decreases ephrinB1 expression, and impairs cell proliferation in the telencephalon. Overexpression of ephrinB1 rescues these defects, indicating that ephrinB1 recycling by the Rab11/Rab11fip5 complex is required for proper telencephalon development.\",\n      \"method\": \"Co-immunoprecipitation (domain mapping), morpholino knockdown in Xenopus, overexpression rescue, immunofluorescence, cell proliferation assay\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, morpholino KD with rescue experiment, in vivo Xenopus model; single lab\",\n      \"pmids\": [\"33462110\"],\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, which may be involved in anterograde ciliary trafficking. Increased RAB11FIP5 and axonemal glutamylation are observed in cyst-lining cells of polycystic kidney disease.\",\n      \"method\": \"Co-localization microscopy, co-immunoprecipitation, siRNA knockdown of KLC3 with RAB11FIP5 expression readout, PKD patient-derived cells\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, co-localization and Co-IP with limited functional mechanistic follow-up for RAB11FIP5 specifically\",\n      \"pmids\": [\"41225582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RAB11FIP5 competitively sequesters RAB11A to antagonize RAB11FIP1-mediated transferrin receptor recycling, thereby restricting iron uptake and suppressing ferroptosis in HNSCC cells. The deubiquitinase USP52 stabilizes RAB11FIP5 by cleaving K48-linked ubiquitin chains specifically at lysine residues 583 and 586. RAB11FIP5 deletion impairs long-term proliferative capacity and suppresses tumor growth in xenografts through both ferroptosis-dependent and -independent mechanisms.\",\n      \"method\": \"Co-immunoprecipitation, transferrin receptor recycling assay, iron uptake assay, ferroptosis assays, ubiquitination mapping (K583/K586 site mutagenesis), USP52 knockdown/overexpression, xenograft tumor model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods including site-specific mutagenesis, recycling assays, in vivo xenograft, single lab\",\n      \"pmids\": [\"42207639\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAB11FIP5 (Rip11) is a Rab11 effector protein that localizes to recycling endosomes and regulates cargo trafficking to the apical plasma membrane; it binds Rab11 via its Rab-binding domain and membranes via its C2 domain in a phosphorylation-regulated manner, forms complexes with kinesin II (for slow endocytic recycling), gamma-SNAP (mitochondria-associated), AS160 (insulin/GLUT4 pathway), and ephrinB1 (telencephalon development); it is phosphorylated by PKA (regulating cAMP-potentiated insulin secretion) and by ERK downstream of a Yes-EGFR-ERK cascade (controlling pIgA-pIgR transcytosis); it is polyubiquitinated by TRIM21 (K6-linked, activating pIgA transcytosis) and stabilized by USP52 (cleaving K48-linked chains at K583/K586); it specifically recycles integrin α6β1 and, by competitively sequestering RAB11A, suppresses RAB11FIP1-mediated transferrin receptor recycling to restrict iron uptake and ferroptosis; and in neurons it is selectively required for hippocampal long-term depression but not LTP.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAB11FIP5 (Rip11/Gaf-1) is a Rab11 effector that organizes cargo trafficking through recycling endosomes, directing internalized receptors and other cargo toward the apical/plasma membrane in polarized epithelia [#0, #5]. It is recruited to subapical recycling endosomes through direct binding to Rab11 and a Mg2+-dependent interaction of its C2 domain with neutral phospholipids, an association governed by a phosphorylation/dephosphorylation cycle [#0]. Through its membrane-binding domain it routes internalized receptors into a slow recycling pathway in complex with kinesin II, linking recycling endosomes to microtubule-based transport [#5]. RAB11FIP5 controls specific cargoes rather than bulk recycling: it mediates insulin-stimulated GLUT4 and FAT/CD36 surface delivery in adipocytes via a Rab11a-dependent route while forming a Rab11-independent complex with the Rab-GAP AS160 that dissociates upon insulin stimulation [#3, #4], and it selectively recycles integrin \\u03b16\\u03b21 to support cell migration on laminin [#12]. Its activity is regulated by signal-driven phosphorylation and ubiquitination: ERK phosphorylates RAB11FIP5 downstream of a Yes-EGFR cascade to drive pIgA-pIgR transcytosis [#7], PKA phosphorylates it during cAMP-potentiated insulin secretion [#6], TRIM21 attaches activating K6-linked polyubiquitin chains that promote transcytosis [#14], and the deubiquitinase USP52 stabilizes the protein by removing K48-linked chains at K583/K586 [#17]. By competitively sequestering RAB11A away from RAB11FIP1, RAB11FIP5 restrains transferrin receptor recycling and iron uptake, thereby suppressing ferroptosis and supporting tumor growth in HNSCC [#17]. RAB11FIP5 also interacts with \\u03b3-SNAP at the outer mitochondrial membrane [#1] and with ephrinB1 to enable its recycling during telencephalon development [#15], and in mice it is selectively required for hippocampal long-term depression but not LTP [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established RAB11FIP5 as a Rab11 effector that physically links recycling endosomes to the apical membrane trafficking route, answering what molecular machinery drives apical cargo delivery.\",\n      \"evidence\": \"Co-IP, transport assays, lipid-binding and localization in polarized epithelial cells\",\n      \"pmids\": [\"11163216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The kinase/phosphatase pair controlling the membrane-association cycle was not identified\", \"Specific apical cargoes not defined at this stage\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified \\u03b3-SNAP and the outer mitochondrial membrane as a binding partner and localization distinct from recycling endosomes, raising the question of a non-canonical role.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-precipitation, fractionation and imaging\",\n      \"pmids\": [\"11278501\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of \\u03b3-SNAP binding undefined\", \"Relationship between mitochondrial and endosomal pools unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Placed RAB11FIP5 in insulin-regulated cargo trafficking, distinguishing it from FIP2 in routing GLUT4 versus FAT/CD36 and revealing a Rab11-independent AS160 complex.\",\n      \"evidence\": \"siRNA knockdown with glucose-uptake and surface-abundance assays, Co-IP, microscopy in adipocyte/cardiomyocyte lines\",\n      \"pmids\": [\"18003705\", \"17854769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which insulin triggers AS160 dissociation not defined\", \"How cargo selectivity between FIP isoforms is encoded unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the RAB11FIP5-kinesin II complex as the route channeling internalized receptors into a slow perinuclear recycling pathway, connecting endosome sorting to microtubule motors.\",\n      \"evidence\": \"siRNA knockdown, EM, fluorescence microscopy, Co-IP identifying kinesin II\",\n      \"pmids\": [\"18957512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect nature of kinesin II binding not resolved\", \"Cargo selectivity of the slow pathway not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Positioned RAB11FIP5 downstream of PKA in cAMP-potentiated insulin secretion, identifying it as a phosphorylation target in regulated secretion.\",\n      \"evidence\": \"Localization, secretion assays, PKA phosphorylation assay, epistasis with Epac2 in beta-cells\",\n      \"pmids\": [\"19335615\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PKA phosphosites on RAB11FIP5 not mapped\", \"Effect of phosphorylation on Rab11 binding not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified RAB11FIP5 as an ERK substrate within a Yes-EGFR-ERK cascade that controls Rab11a endosome distribution and pIgA-pIgR transcytosis, linking receptor signaling to recycling.\",\n      \"evidence\": \"In vitro kinase assay, mass spectrometry, siRNA KD, pharmacological inhibition, in vivo rat pIgA injection\",\n      \"pmids\": [\"21037565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation alters FIP5 membrane/Rab11 interactions mechanistically not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended RAB11FIP5 function to acidosis-induced V-ATPase delivery to the plasma membrane downstream of Rab11b, broadening its cargo repertoire.\",\n      \"evidence\": \"siRNA knockdown, immunofluorescence, fractionation in salivary duct cells\",\n      \"pmids\": [\"20717956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction with V-ATPase not shown\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Genetic knockout revealed a selective requirement for RAB11FIP5 in hippocampal LTD but not LTP, implicating endosomal recycling specifically in synaptic depression.\",\n      \"evidence\": \"Conditional KO mice, hippocampal slice and chemical LTD electrophysiology, shRNA rescue, behavior\",\n      \"pmids\": [\"25972173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Synaptic cargo recycled by RAB11FIP5 during LTD not identified\", \"Molecular partners in neurons not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the kinetic basis of insulin-driven plasma-membrane accumulation as inhibition of RAB11FIP5 endocytosis requiring dynamin and PI3-kinase but not Akt.\",\n      \"evidence\": \"Live-cell imaging with kinetic analysis and pharmacological dissection\",\n      \"pmids\": [\"26515129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The signaling effector downstream of PI3-kinase not identified\", \"Link to AS160 dissociation not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated cargo-specific recycling of integrin \\u03b16\\u03b21 by RAB11FIP5, requiring its membrane-binding domain and driving cancer cell migration on laminin.\",\n      \"evidence\": \"siRNA KD, recycling and migration assays, PDX tumor model in prostate cancer cells\",\n      \"pmids\": [\"29759989\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinant of \\u03b16\\u03b21 selectivity over other integrins not defined\", \"Single tumor context\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified an antiviral role in which RAB11FIP5 binds KSHV ORF45 and routes it to lysosomal degradation, restricting virion release.\",\n      \"evidence\": \"Reciprocal Co-IP, gain/loss-of-function with virion release and lysosomal inhibition assays\",\n      \"pmids\": [\"33315947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism directing ORF45 to lysosomes vs. recycling unclear\", \"Physiological relevance during natural infection not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed that TRIM21-mediated K6-linked polyubiquitination activates RAB11FIP5 to facilitate pIgA transcytosis, and that FIP5 and FIP1 act additively, revealing ubiquitin control of effector activity.\",\n      \"evidence\": \"siRNA KD, Co-IP, ubiquitination mapping, transcytosis assays in polarized/incompletely polarized cells\",\n      \"pmids\": [\"34638806\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural effect of K6 ubiquitination on FIP5 activity unknown\", \"Ubiquitinated lysines not fully mapped here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked RAB11FIP5 to development by mapping a Rab-binding-domain interaction with ephrinB1 whose recycling is required for telencephalon growth and proliferation.\",\n      \"evidence\": \"Co-IP domain mapping, morpholino KD with overexpression rescue in Xenopus\",\n      \"pmids\": [\"33462110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of the ephrinB1 interaction in mammals not shown\", \"Downstream signaling of recycled ephrinB1 not dissected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Associated RAB11FIP5 with primary cilia via KLC3 interaction at basal bodies and with axonemal glutamylation changes in polycystic kidney disease.\",\n      \"evidence\": \"Co-localization, Co-IP, siRNA KD of KLC3, PKD patient-derived cells\",\n      \"pmids\": [\"41225582\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Functional role of RAB11FIP5 in ciliary trafficking not directly tested\", \"Direct vs. indirect KLC3 binding unresolved\", \"Causal contribution to PKD not established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a competitive sequestration mechanism in which RAB11FIP5 traps RAB11A from RAB11FIP1 to limit transferrin receptor recycling, iron uptake and ferroptosis, with USP52 stabilizing it by removing K48 chains at K583/K586.\",\n      \"evidence\": \"Co-IP, recycling/iron-uptake/ferroptosis assays, site-specific mutagenesis, USP52 perturbation, xenografts in HNSCC\",\n      \"pmids\": [\"42207639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of RAB11A competition between FIP5 and FIP1 not quantified\", \"Ferroptosis-independent tumor mechanism not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RAB11FIP5 integrates its multiple post-translational modifications (PKA/ERK phosphorylation, K6 vs. K48 ubiquitination) to select among its many cargoes in a given cell type remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking modification state to cargo selectivity\", \"Tissue-specific partner usage not systematically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 17]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 5, 14]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 8, 10]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [13, 14]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 5, 7, 12]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 7, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAB11A\", \"AS160 (TBC1D4)\", \"KIF3 (kinesin II)\", \"EFNB1\", \"RAB11FIP1\", \"USP52\", \"TRIM21\", \"NAPG (gamma-SNAP)\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}