{"gene":"RAB11FIP1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2001,"finding":"RAB11-FIP1 (Rab11-FIP1) was identified as a Rab11a-binding protein that associates with wild-type and dominant-active Rab11a (S20V), as well as Rab11b and Rab25, through a conserved carboxyl-terminal amphipathic alpha-helix. RAB11-FIP1 colocalizes with Rab11a in plasma membrane recycling systems in non-polarized HeLa cells and polarized MDCK cells, and co-enriches with Rab11a and H+K+-ATPase on parietal cell tubulovesicles, translocating with them upon histamine stimulation.","method":"Co-immunoprecipitation, yeast two-hybrid, colocalization by fluorescence microscopy, subcellular fractionation of parietal cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding established by multiple methods (Co-IP, colocalization, fractionation), replicated across cell types and conditions in a foundational study","pmids":["11495908"],"is_preprint":false},{"year":2001,"finding":"Binding of RAB11-FIP1 to Rab11a requires the conserved carboxyl-terminal amphipathic alpha-helix of RAB11-FIP1; this domain is necessary for Rab11 interaction.","method":"Domain deletion/mutation analysis combined with co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — domain mutagenesis with binding assay, foundational study establishing mechanism","pmids":["11495908"],"is_preprint":false},{"year":2003,"finding":"During mitosis in MDCK cells, RAB11-FIP1 dissociates from recycling system markers during late prophase and relocates to the pericentriolar material, then returns to recycling system vesicles during telophase, indicating a cell-cycle-regulated change in subcellular localization distinct from other Rab11 effectors.","method":"Live-cell and fixed fluorescence microscopy of GFP-tagged RAB11-FIP1 through cell cycle stages, western blot analysis of membrane association","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment across cell cycle with functional implication, single lab, two orthogonal methods (imaging + fractionation)","pmids":["12956871"],"is_preprint":false},{"year":2006,"finding":"The RAB11FIP1 gene encodes eight alternatively spliced transcripts (FIP1A-H); isoforms A-D contain the C-terminal Rab11-binding domain and target to Rab11a-containing recycling membranes when overexpressed in HeLa cells, while isoforms E, F, and H lack the Rab11-binding domain and do not localize to recycling system membranes. Endogenous FIP1C/RCP occupies a partially distinct subcompartment within the recycling system compared to FIP1A and FIP1B.","method":"Cloning of alternatively spliced transcripts, GFP-fusion overexpression with colocalization microscopy, isoform-specific antibody staining","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with multiple isoforms and isoform-specific antibodies, single lab","pmids":["16920206"],"is_preprint":false},{"year":2009,"finding":"Overexpression of RCP/RAB11FIP1 in MCF10A normal mammary epithelial cells induces loss of contact inhibition, growth-factor independence, and anchorage-independent growth. Knockdown of RCP in breast cancer cell lines inhibits colony formation, invasion, and migration in vitro and reduces tumor formation and metastasis in mouse xenograft models. Overexpression of RCP enhances ERK phosphorylation and increases Ras activation in vitro.","method":"Overexpression and shRNA knockdown in cell lines, mouse xenograft tumor models, ERK phosphorylation assay, Ras activation assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (in vitro proliferation, invasion, migration, in vivo xenograft) plus biochemical Ras/ERK activation, single lab","pmids":["19620787"],"is_preprint":false},{"year":2013,"finding":"RAB11-FIP1 isoforms (FIP1A, FIP1B, FIP1C) occupy spatially and temporally distinct subdomains within the Rab11a-dependent recycling system; FIP1B reaches maximal transferrin colocalization early (5 min), while FIP1A and FIP1C peak later (≥10 min). FIP1A directly associates with FIP1B and FIP1C, and also associates with FIP3-containing membranes. Rab11-FIP1 proteins form selective pairwise associations on dynamic tubular recycling compartments.","method":"Live-cell deconvolution fluorescence microscopy of GFP-tagged FIPs, transferrin pulse-chase assay, dual-expression live-cell imaging","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging with multiple orthogonal approaches, single lab","pmids":["23283983"],"is_preprint":false},{"year":2013,"finding":"RAB11-FIP1 (FIP1) overexpression decreases adiponectin secretion in HEK293 cells, and shRNA-mediated depletion of FIP1 enhances adiponectin release from 3T3-L1 adipocytes. Endogenous FIP1 co-distributes intracellularly with endogenous adiponectin. FIP1 depletion does not alter transferrin receptor recycling or insulin-mediated Glut4 trafficking.","method":"Overexpression and shRNA knockdown, adiponectin secretion ELISA, immunofluorescence colocalization, transferrin recycling assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown and overexpression with multiple readouts in two cell systems, single lab","pmids":["24040321"],"is_preprint":false},{"year":2014,"finding":"RAB11-FIP1 proteins (FIP1A, FIP1B, FIP1C) consistently colocalize with the phosphatidylserine (PS) probe LactC2 along peripheral and pericentriolar compartments. Removal of C2 domains from Rab11-FIPs causes accumulation of LactC2 probe in the pericentriolar region, suggesting that inhibition of recycling affects PS distribution.","method":"Live-cell fluorescence microscopy and structured illumination microscopy with LactC2-PS biosensor co-expressed with GFP-Rab11-FIPs","journal":"Cellular logistics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live-cell and super-resolution microscopy with domain deletion, single lab","pmids":["25210648"],"is_preprint":false},{"year":2016,"finding":"A point mutation at Threonine-197 to Alanine in Rab11-FIP1A acts as a dominant-negative that collapses the normally distributed recycling endosomes into a central membranous cisternum, sequesters endogenous Rab11a, Rab11-FIP1C, and transferrin receptor (CD71), and causes a strong block in transferrin recycling. Rab5 and EEA1 (but not Rab4) accumulate in FIP1A-positive membranes, suggesting a direct pathway from early endosomes into the Rab11a recycling system.","method":"Site-directed mutagenesis, GFP-fusion overexpression, fluorescence microscopy, transferrin recycling assay, nocodazole treatment","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis with defined functional readout (transferrin block), multiple markers assessed, single lab","pmids":["26790954"],"is_preprint":false},{"year":2017,"finding":"MARK2 kinase phosphorylates Rab11-FIP1B/C at serine 234 (in a consensus site analogous to the previously identified S227 in Rab11-FIP2). In MDCK cells during calcium-switch-induced repolarization, pS234-FIP1 phosphorylation persists through and after polarity reestablishment. Overexpression of non-phosphorylatable FIP1C(S234A) induces a lateral lumen phenotype with misorientation of apical markers (ezrin, syntaxin 3, podocalyxin), F-actin, ZO1, centrosome, and Golgi apparatus, demonstrating that FIP1 phosphorylation by MARK2 regulates epithelial polarity.","method":"Phospho-specific antibody generation, kinase assay, calcium-switch repolarization model, overexpression of phospho-mutants with immunofluorescence microscopy","journal":"Cellular logistics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — phospho-site identified by kinase assay and phospho-specific antibody, mutant phenotype with multiple orthogonal markers, single lab","pmids":["28396819"],"is_preprint":false},{"year":2019,"finding":"The ubiquitin ligase RFFL directly ubiquitylates Rab11-FIP1 in vitro, and RFFL knockout specifically reduces ubiquitylation of Rab11-FIP1 (while having minimal effect on ubiquitylation of EHD1, MICALL1, and Rab11-FIP2). RFFL interacts with class I Rab11-FIPs as identified by BioID proximity labeling. A dominant-negative RFFL mutant prolongs interaction with Rab11 effectors including FIP1, induces clustering of endocytic recycling compartments, and delays cargo recycling.","method":"BioID proximity proteomics, in vitro ubiquitylation assay, RFFL knockout cells, dominant-negative RFFL overexpression, transferrin recycling assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitylation reconstitution plus KO cells plus BioID interactome, multiple orthogonal methods establishing RFFL as E3 for Rab11-FIP1","pmids":["30659120"],"is_preprint":false},{"year":2021,"finding":"Genetic knockdown of Rab11-FIP1 in esophageal squamous cell carcinoma (ESCC) 3D organoid models increases organoid size and tumor cell invasion. Loss of Rab11-FIP1 in human ESCC cell lines decreases E-cadherin expression and increases mesenchymal markers (EMT). Rab11-FIP1 directly inhibits Zeb1, a key EMT transcription factor, thereby regulating EMT.","method":"shRNA knockdown, 3D organoid models, invasion assay, western blot for EMT markers, mouse model of ESCC","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in 3D organoids and cell lines with multiple molecular readouts and in vivo model, single lab","pmids":["33403789"],"is_preprint":false},{"year":2021,"finding":"Rab11-FIP1 and Rab11-FIP5 knockdown additively impairs pIgR/pIgA transcytosis. TRIM21 mediates K11-linked polyubiquitination of Rab11-FIP1 (and K6-linked polyubiquitination of Rab11-FIP5) to promote their 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, ubiquitin linkage-specific antibody analysis, transcytosis assay in polarized and incompletely polarized epithelial cells","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown functional assay with biochemical characterization of ubiquitination linkage, single lab","pmids":["34638806"],"is_preprint":false},{"year":2022,"finding":"Global Rab11FIP1 knockout (KO) mice develop spontaneous colonic inflammation with infiltration of macrophages and neutrophils, reduced TFF3-positive goblet cells, and abnormal accumulation of subapical vesicles in colonocytes. Rab11FIP1 loss causes mistrafficking of transmembrane mucin MUC13, which aberrantly internalizes with Rab14 instead of being properly recycled, resulting in impaired colonic mucosal integrity.","method":"Global KO mouse generation (exon 2 deletion), immunostaining, RNA-sequencing, DSS colitis model, confocal microscopy","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic KO with multiple orthogonal phenotypic readouts and specific molecular mechanism (MUC13/Rab14 mistrafficking), single lab","pmids":["35819177"],"is_preprint":false},{"year":2022,"finding":"CircRTN4 interacts with RAB11FIP1 protein to block its ubiquitination site, thereby stabilizing RAB11FIP1 and preventing its proteasomal degradation. CircRTN4 knockdown promotes RAB11FIP1 degradation by increasing its ubiquitination and decreases EMT marker expression (Slug, Snai1, Twist, Zeb1, N-cadherin) in pancreatic cancer cells.","method":"circRNA pulldown with mass spectrometry, protein stability assay, ubiquitination assay, 3D structure modeling","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulldown/MS identification plus functional ubiquitination assay, single lab, but circRNA-protein interaction is mechanistically informative for RAB11FIP1 stability","pmids":["34983537"],"is_preprint":false},{"year":2023,"finding":"HIF-1-induced upregulation of RCP/RAB11FIP1 under hypoxia promotes Rab11a-dependent recycling of internalized MSC-derived small extracellular vesicles (MSC-sEVs), reducing their intracellular cargo delivery efficiency. RAB11FIP1 enhances the interaction between Rab11a and MSC-sEVs under hypoxic conditions, and siRNA-mediated knockdown of RCP in engineered MSC-sEVs inhibits this recycling, improving cargo delivery.","method":"siRNA knockdown, co-immunoprecipitation (Rab11a-sEV interaction), rat intervertebral disk degeneration model, fluorescence microscopy of sEV trafficking","journal":"ACS nano","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with mechanistic co-IP, in vivo model validation, single lab","pmids":["36730125"],"is_preprint":false},{"year":2023,"finding":"The transcription factor Stat1 binds to the promoter of Rab11fip1 to initiate Schwann cell differentiation. Stat1 knockdown reduces Rab11fip1 expression and blocks Schwann cell differentiation, thereby inhibiting myelination.","method":"ChIP-seq, ChIP-qPCR, luciferase reporter assay, siRNA knockdown in Schwann cells, in vivo sciatic nerve model","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — ChIP-seq and luciferase assay establish direct transcriptional regulation, in vivo validation, single lab","pmids":["37365519"],"is_preprint":false},{"year":2026,"finding":"RAB11FIP5 competitively sequesters RAB11A to antagonize RAB11FIP1-mediated transferrin and transferrin receptor recycling in HNSCC cells, thereby restricting iron uptake and suppressing ferroptosis. Loss of RAB11FIP5 thus permits RAB11FIP1-mediated recycling, increasing iron uptake and ferroptosis sensitivity.","method":"RAB11FIP5 knockout cell lines, transferrin recycling assay, iron uptake measurement, ferroptosis assays, subcutaneous xenograft models","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with mechanistic epistasis between RAB11FIP5 and RAB11FIP1 in transferrin recycling, functional and in vivo data, single lab","pmids":["42207639"],"is_preprint":false}],"current_model":"RAB11FIP1 is a Rab11a effector protein that binds Rab11a (and Rab11b/Rab25) through its conserved C-terminal amphipathic alpha-helix and localizes to distinct tubular and vesicular subdomains of the slow endocytic recycling compartment, where it regulates recycling of transferrin receptor, MUC13, adiponectin, pIgR/pIgA, and extracellular vesicles; its activity is modulated by MARK2-mediated phosphorylation at S234 (regulating epithelial polarity), RFFL-mediated ubiquitylation, and TRIM21-mediated K11-linked polyubiquitination (promoting transcytosis), and its stability is controlled by ubiquitin-proteasome degradation that can be blocked by circRTN4; in cancer contexts, RAB11FIP1 activates Ras/ERK signaling, suppresses EMT through inhibition of Zeb1, and mediates transferrin receptor recycling that controls iron uptake and ferroptosis sensitivity."},"narrative":{"mechanistic_narrative":"RAB11FIP1 (Rab11-FIP1/RCP) is a Rab11a effector that organizes cargo recycling through the slow endocytic recycling compartment [PMID:11495908]. It binds active Rab11a, as well as Rab11b and Rab25, via a conserved C-terminal amphipathic alpha-helix that is required for the interaction [PMID:11495908], and is expressed as multiple alternatively spliced isoforms (FIP1A-H) of which only those retaining this domain target Rab11a-positive recycling membranes, occupying spatially and temporally distinct tubular subdomains and forming selective pairwise associations with one another [PMID:16920206, PMID:23283983]. Functionally, RAB11FIP1 channels cargo from early endosomes (Rab5/EEA1-positive) into the Rab11a recycling system, and a dominant-negative T197A mutation collapses recycling endosomes, sequesters Rab11a and transferrin receptor, and blocks transferrin recycling [PMID:26790954]; in vivo it is required for proper recycling of the transmembrane mucin MUC13, whose loss in knockout mice causes MUC13/Rab14 mistrafficking and spontaneous colonic inflammation [PMID:35819177]. RAB11FIP1 activity is set by post-translational control: MARK2 phosphorylates it at S234 to govern epithelial polarity [PMID:28396819], the E3 ligase RFFL directly ubiquitylates it [PMID:30659120], TRIM21 adds K11-linked polyubiquitin to promote pIgR/pIgA transcytosis [PMID:34638806], and its proteasomal turnover can be blocked by circRTN4 [PMID:34983537]. In cancer, RAB11FIP1 acts as an oncogenic transformer that activates Ras/ERK signaling and drives invasion and metastasis [PMID:19620787], while in epithelial contexts it suppresses EMT by inhibiting Zeb1 [PMID:33403789]; through its control of transferrin receptor recycling it governs iron uptake and ferroptosis sensitivity, a function antagonized by RAB11FIP5-mediated sequestration of Rab11a [PMID:42207639].","teleology":[{"year":2001,"claim":"Established RAB11FIP1 as a bona fide Rab11a effector and defined the structural basis of the interaction, anchoring it to the membrane recycling machinery.","evidence":"Yeast two-hybrid, Co-IP, colocalization, and parietal cell fractionation; domain deletion mapping the C-terminal amphipathic alpha-helix","pmids":["11495908"],"confidence":"High","gaps":["Did not define which cargoes traffic through FIP1-Rab11a domains","Functional consequence of binding for recycling kinetics not addressed"]},{"year":2003,"claim":"Showed RAB11FIP1 localization is cell-cycle regulated, distinguishing it from other Rab11 effectors by its mitotic relocation to pericentriolar material.","evidence":"Live and fixed fluorescence microscopy of GFP-RAB11FIP1 across cell cycle stages with membrane fractionation in MDCK cells","pmids":["12956871"],"confidence":"Medium","gaps":["Mechanism driving mitotic relocation unknown","Functional role of pericentriolar targeting not established"]},{"year":2006,"claim":"Resolved that only Rab11-binding-domain-containing isoforms target recycling membranes, and that endogenous isoforms occupy distinct subcompartments.","evidence":"Cloning of eight splice variants, GFP-fusion colocalization, isoform-specific antibody staining in HeLa","pmids":["16920206"],"confidence":"Medium","gaps":["Distinct functions of individual isoforms not defined","Regulation of splicing not addressed"]},{"year":2009,"claim":"Identified RAB11FIP1/RCP as an oncogenic driver coupling vesicle recycling to Ras/ERK signaling, transformation, and metastasis.","evidence":"Overexpression and shRNA in mammary/breast cancer lines, xenografts, ERK phosphorylation and Ras activation assays","pmids":["19620787"],"confidence":"High","gaps":["Molecular link between recycling activity and Ras activation not resolved","Relevant trafficked cargo driving transformation not identified"]},{"year":2013,"claim":"Defined the spatiotemporal organization of FIP1 isoforms within recycling tubules and their hetero-associations, plus a cargo-specific role in adiponectin secretion.","evidence":"Live-cell deconvolution imaging with transferrin pulse-chase; overexpression/knockdown with adiponectin ELISA in HEK293 and 3T3-L1","pmids":["23283983","24040321"],"confidence":"Medium","gaps":["How cargo selectivity (adiponectin vs transferrin) is achieved unclear","Basis for distinct subdomain occupancy not mechanistically defined"]},{"year":2014,"claim":"Linked FIP1-dependent recycling to phosphatidylserine distribution, implicating lipid handling in compartment organization.","evidence":"Live-cell and structured illumination microscopy with LactC2-PS biosensor and C2-domain deletion","pmids":["25210648"],"confidence":"Medium","gaps":["Whether FIP1 directly binds PS not established","Functional consequence of PS redistribution unknown"]},{"year":2016,"claim":"Demonstrated that FIP1A controls transit from early endosomes into the Rab11a recycling system, with a dominant-negative mutant blocking transferrin recycling.","evidence":"T197A site-directed mutagenesis, GFP-fusion imaging, transferrin recycling assay, marker colocalization (Rab5, EEA1)","pmids":["26790954"],"confidence":"Medium","gaps":["Molecular role of T197 not defined (not a known phospho-site here)","Direct early-endosome-to-FIP1 handoff machinery unknown"]},{"year":2017,"claim":"Identified MARK2-mediated S234 phosphorylation as a switch controlling FIP1 function in epithelial apical-basal polarity.","evidence":"Kinase assay, phospho-specific antibody, calcium-switch repolarization, phospho-mutant overexpression with polarity marker imaging in MDCK","pmids":["28396819"],"confidence":"Medium","gaps":["How S234 phosphorylation alters Rab11a binding or cargo handling not resolved","Upstream signals activating MARK2 in this context unknown"]},{"year":2019,"claim":"Established RFFL as a direct E3 ligase for FIP1, placing FIP1 activity under ubiquitin control during recycling.","evidence":"In vitro ubiquitylation reconstitution, RFFL knockout cells, BioID interactome, dominant-negative RFFL with transferrin recycling assay","pmids":["30659120"],"confidence":"High","gaps":["Ubiquitin linkage type and degradative vs non-degradative outcome not defined","Which FIP1 lysines are modified unknown"]},{"year":2021,"claim":"Revealed context-dependent roles: FIP1 suppresses EMT via Zeb1 inhibition in ESCC, and is activated by TRIM21 K11-polyubiquitination to drive pIgR/pIgA transcytosis.","evidence":"shRNA in 3D organoids and ESCC lines with EMT markers and mouse model; siRNA, Co-IP, linkage-specific ubiquitin antibodies and transcytosis assays","pmids":["33403789","34638806"],"confidence":"Medium","gaps":["Mechanism by which FIP1 inhibits Zeb1 not defined","Reconciliation of tumor-suppressive (ESCC) vs oncogenic (breast) roles unresolved"]},{"year":2022,"claim":"Defined an in vivo physiological role in colonic mucin recycling and showed circRNA-mediated stabilization of FIP1 against proteasomal degradation.","evidence":"Global KO mouse with immunostaining/RNA-seq/DSS colitis; circRTN4 pulldown-MS, protein stability and ubiquitination assays in pancreatic cancer cells","pmids":["35819177","34983537"],"confidence":"High","gaps":["How FIP1 directs MUC13 away from Rab14 not mechanistically defined","circRTN4 binding site on FIP1 vs ubiquitination site not precisely mapped"]},{"year":2023,"claim":"Extended FIP1 functions to extracellular vesicle recycling under hypoxia and to transcriptional induction during Schwann cell differentiation.","evidence":"siRNA knockdown with Rab11a-sEV Co-IP and rat IVDD model; Stat1 ChIP-seq, luciferase reporter and knockdown in Schwann cells with sciatic nerve model","pmids":["36730125","37365519"],"confidence":"Medium","gaps":["Direct role of FIP1 in sEV cargo selectivity unclear","Downstream FIP1 effectors in myelination not identified"]},{"year":2026,"claim":"Showed that FIP1-mediated transferrin receptor recycling governs iron uptake and ferroptosis, with RAB11FIP5 antagonizing FIP1 by sequestering Rab11a.","evidence":"RAB11FIP5 knockout cells, transferrin recycling and iron uptake assays, ferroptosis assays, xenografts in HNSCC","pmids":["42207639"],"confidence":"Medium","gaps":["Direct competition for Rab11a not structurally resolved","Whether other FIPs similarly modulate ferroptosis untested"]},{"year":null,"claim":"It remains unresolved how RAB11FIP1's many post-translational modifications and isoform/competition states are integrated to switch between oncogenic, tumor-suppressive, and homeostatic recycling outputs in different tissues.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking S234 phosphorylation, RFFL/TRIM21 ubiquitination, and FIP-FIP competition","Structural basis for cargo selectivity unknown","Reconciliation of opposing cancer phenotypes across tissues unaddressed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,8]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,3,5,8]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[8]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[2]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,8,13]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[8,12,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4]}],"complexes":[],"partners":["RAB11A","RAB25","RFFL","TRIM21","MARK2","RAB11FIP5","RAB11FIP3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6WKZ4","full_name":"Rab11 family-interacting protein 1","aliases":["Rab-coupling protein"],"length_aa":1283,"mass_kda":137.2,"function":"A Rab11 effector protein involved in the endosomal recycling process. Also involved in controlling membrane trafficking along the phagocytic pathway and in phagocytosis. Interaction with RAB14 may function in the process of neurite formation (PubMed:26032412)","subcellular_location":"Cytoplasmic vesicle, phagosome membrane","url":"https://www.uniprot.org/uniprotkb/Q6WKZ4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAB11FIP1","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":"RAB11A","stoichiometry":0.2},{"gene":"RAB11B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RAB11FIP1","total_profiled":1310},"omim":[{"mim_id":"611999","title":"RAB11 FAMILY-INTERACTING PROTEIN 4; RAB11FIP4","url":"https://www.omim.org/entry/611999"},{"mim_id":"608738","title":"RAB11 FAMILY-INTERACTING PROTEIN 3; RAB11FIP3","url":"https://www.omim.org/entry/608738"},{"mim_id":"608737","title":"RAB11 FAMILY-INTERACTING PROTEIN 1; RAB11FIP1","url":"https://www.omim.org/entry/608737"},{"mim_id":"608599","title":"RAB11 FAMILY-INTERACTING PROTEIN 2; RAB11FIP2","url":"https://www.omim.org/entry/608599"},{"mim_id":"605536","title":"RAB11 FAMILY-INTERACTING PROTEIN 5; RAB11FIP5","url":"https://www.omim.org/entry/605536"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Vesicles","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RAB11FIP1"},"hgnc":{"alias_symbol":["RCP","FLJ22622","FLJ22524","Rab11-FIP1"],"prev_symbol":[]},"alphafold":{"accession":"Q6WKZ4","domains":[{"cath_id":"2.60.40.150","chopping":"18-157","consensus_level":"medium","plddt":85.9538,"start":18,"end":157},{"cath_id":"1.20.5,1.20.5","chopping":"1222-1266","consensus_level":"medium","plddt":93.3884,"start":1222,"end":1266}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6WKZ4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6WKZ4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6WKZ4-F1-predicted_aligned_error_v6.png","plddt_mean":46.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAB11FIP1","jax_strain_url":"https://www.jax.org/strain/search?query=RAB11FIP1"},"sequence":{"accession":"Q6WKZ4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6WKZ4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6WKZ4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6WKZ4"}},"corpus_meta":[{"pmid":"11495908","id":"PMC_11495908","title":"Identification and characterization of a family of Rab11-interacting proteins.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11495908","citation_count":252,"is_preprint":false},{"pmid":"19620787","id":"PMC_19620787","title":"RCP is a human breast cancer-promoting gene with Ras-activating function.","date":"2009","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/19620787","citation_count":110,"is_preprint":false},{"pmid":"22724020","id":"PMC_22724020","title":"Deregulation of Rab and Rab effector genes in bladder cancer.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22724020","citation_count":100,"is_preprint":false},{"pmid":"34983537","id":"PMC_34983537","title":"CircRTN4 promotes pancreatic cancer progression through a novel CircRNA-miRNA-lncRNA pathway and stabilizing epithelial-mesenchymal transition protein.","date":"2022","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34983537","citation_count":81,"is_preprint":false},{"pmid":"23283983","id":"PMC_23283983","title":"Rab11-family interacting proteins define spatially and temporally distinct regions within the dynamic Rab11a-dependent recycling system.","date":"2013","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/23283983","citation_count":64,"is_preprint":false},{"pmid":"28123592","id":"PMC_28123592","title":"Downregulation of ARID1A, a component of the SWI/SNF chromatin remodeling complex, in breast cancer.","date":"2017","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28123592","citation_count":34,"is_preprint":false},{"pmid":"12956871","id":"PMC_12956871","title":"Dynamics of the apical plasma membrane recycling system during cell division.","date":"2003","source":"Traffic (Copenhagen, 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RAB11-FIP1 colocalizes with Rab11a in plasma membrane recycling systems in non-polarized HeLa cells and polarized MDCK cells, and co-enriches with Rab11a and H+K+-ATPase on parietal cell tubulovesicles, translocating with them upon histamine stimulation.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, colocalization by fluorescence microscopy, subcellular fractionation of parietal cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding established by multiple methods (Co-IP, colocalization, fractionation), replicated across cell types and conditions in a foundational study\",\n      \"pmids\": [\"11495908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Binding of RAB11-FIP1 to Rab11a requires the conserved carboxyl-terminal amphipathic alpha-helix of RAB11-FIP1; this domain is necessary for Rab11 interaction.\",\n      \"method\": \"Domain deletion/mutation analysis combined with co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — domain mutagenesis with binding assay, foundational study establishing mechanism\",\n      \"pmids\": [\"11495908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"During mitosis in MDCK cells, RAB11-FIP1 dissociates from recycling system markers during late prophase and relocates to the pericentriolar material, then returns to recycling system vesicles during telophase, indicating a cell-cycle-regulated change in subcellular localization distinct from other Rab11 effectors.\",\n      \"method\": \"Live-cell and fixed fluorescence microscopy of GFP-tagged RAB11-FIP1 through cell cycle stages, western blot analysis of membrane association\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment across cell cycle with functional implication, single lab, two orthogonal methods (imaging + fractionation)\",\n      \"pmids\": [\"12956871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The RAB11FIP1 gene encodes eight alternatively spliced transcripts (FIP1A-H); isoforms A-D contain the C-terminal Rab11-binding domain and target to Rab11a-containing recycling membranes when overexpressed in HeLa cells, while isoforms E, F, and H lack the Rab11-binding domain and do not localize to recycling system membranes. Endogenous FIP1C/RCP occupies a partially distinct subcompartment within the recycling system compared to FIP1A and FIP1B.\",\n      \"method\": \"Cloning of alternatively spliced transcripts, GFP-fusion overexpression with colocalization microscopy, isoform-specific antibody staining\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with multiple isoforms and isoform-specific antibodies, single lab\",\n      \"pmids\": [\"16920206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Overexpression of RCP/RAB11FIP1 in MCF10A normal mammary epithelial cells induces loss of contact inhibition, growth-factor independence, and anchorage-independent growth. Knockdown of RCP in breast cancer cell lines inhibits colony formation, invasion, and migration in vitro and reduces tumor formation and metastasis in mouse xenograft models. Overexpression of RCP enhances ERK phosphorylation and increases Ras activation in vitro.\",\n      \"method\": \"Overexpression and shRNA knockdown in cell lines, mouse xenograft tumor models, ERK phosphorylation assay, Ras activation assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (in vitro proliferation, invasion, migration, in vivo xenograft) plus biochemical Ras/ERK activation, single lab\",\n      \"pmids\": [\"19620787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RAB11-FIP1 isoforms (FIP1A, FIP1B, FIP1C) occupy spatially and temporally distinct subdomains within the Rab11a-dependent recycling system; FIP1B reaches maximal transferrin colocalization early (5 min), while FIP1A and FIP1C peak later (≥10 min). FIP1A directly associates with FIP1B and FIP1C, and also associates with FIP3-containing membranes. Rab11-FIP1 proteins form selective pairwise associations on dynamic tubular recycling compartments.\",\n      \"method\": \"Live-cell deconvolution fluorescence microscopy of GFP-tagged FIPs, transferrin pulse-chase assay, dual-expression live-cell imaging\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging with multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"23283983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RAB11-FIP1 (FIP1) overexpression decreases adiponectin secretion in HEK293 cells, and shRNA-mediated depletion of FIP1 enhances adiponectin release from 3T3-L1 adipocytes. Endogenous FIP1 co-distributes intracellularly with endogenous adiponectin. FIP1 depletion does not alter transferrin receptor recycling or insulin-mediated Glut4 trafficking.\",\n      \"method\": \"Overexpression and shRNA knockdown, adiponectin secretion ELISA, immunofluorescence colocalization, transferrin recycling assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown and overexpression with multiple readouts in two cell systems, single lab\",\n      \"pmids\": [\"24040321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RAB11-FIP1 proteins (FIP1A, FIP1B, FIP1C) consistently colocalize with the phosphatidylserine (PS) probe LactC2 along peripheral and pericentriolar compartments. Removal of C2 domains from Rab11-FIPs causes accumulation of LactC2 probe in the pericentriolar region, suggesting that inhibition of recycling affects PS distribution.\",\n      \"method\": \"Live-cell fluorescence microscopy and structured illumination microscopy with LactC2-PS biosensor co-expressed with GFP-Rab11-FIPs\",\n      \"journal\": \"Cellular logistics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-cell and super-resolution microscopy with domain deletion, single lab\",\n      \"pmids\": [\"25210648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A point mutation at Threonine-197 to Alanine in Rab11-FIP1A acts as a dominant-negative that collapses the normally distributed recycling endosomes into a central membranous cisternum, sequesters endogenous Rab11a, Rab11-FIP1C, and transferrin receptor (CD71), and causes a strong block in transferrin recycling. Rab5 and EEA1 (but not Rab4) accumulate in FIP1A-positive membranes, suggesting a direct pathway from early endosomes into the Rab11a recycling system.\",\n      \"method\": \"Site-directed mutagenesis, GFP-fusion overexpression, fluorescence microscopy, transferrin recycling assay, nocodazole treatment\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with defined functional readout (transferrin block), multiple markers assessed, single lab\",\n      \"pmids\": [\"26790954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MARK2 kinase phosphorylates Rab11-FIP1B/C at serine 234 (in a consensus site analogous to the previously identified S227 in Rab11-FIP2). In MDCK cells during calcium-switch-induced repolarization, pS234-FIP1 phosphorylation persists through and after polarity reestablishment. Overexpression of non-phosphorylatable FIP1C(S234A) induces a lateral lumen phenotype with misorientation of apical markers (ezrin, syntaxin 3, podocalyxin), F-actin, ZO1, centrosome, and Golgi apparatus, demonstrating that FIP1 phosphorylation by MARK2 regulates epithelial polarity.\",\n      \"method\": \"Phospho-specific antibody generation, kinase assay, calcium-switch repolarization model, overexpression of phospho-mutants with immunofluorescence microscopy\",\n      \"journal\": \"Cellular logistics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — phospho-site identified by kinase assay and phospho-specific antibody, mutant phenotype with multiple orthogonal markers, single lab\",\n      \"pmids\": [\"28396819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The ubiquitin ligase RFFL directly ubiquitylates Rab11-FIP1 in vitro, and RFFL knockout specifically reduces ubiquitylation of Rab11-FIP1 (while having minimal effect on ubiquitylation of EHD1, MICALL1, and Rab11-FIP2). RFFL interacts with class I Rab11-FIPs as identified by BioID proximity labeling. A dominant-negative RFFL mutant prolongs interaction with Rab11 effectors including FIP1, induces clustering of endocytic recycling compartments, and delays cargo recycling.\",\n      \"method\": \"BioID proximity proteomics, in vitro ubiquitylation assay, RFFL knockout cells, dominant-negative RFFL overexpression, transferrin recycling assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitylation reconstitution plus KO cells plus BioID interactome, multiple orthogonal methods establishing RFFL as E3 for Rab11-FIP1\",\n      \"pmids\": [\"30659120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Genetic knockdown of Rab11-FIP1 in esophageal squamous cell carcinoma (ESCC) 3D organoid models increases organoid size and tumor cell invasion. Loss of Rab11-FIP1 in human ESCC cell lines decreases E-cadherin expression and increases mesenchymal markers (EMT). Rab11-FIP1 directly inhibits Zeb1, a key EMT transcription factor, thereby regulating EMT.\",\n      \"method\": \"shRNA knockdown, 3D organoid models, invasion assay, western blot for EMT markers, mouse model of ESCC\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in 3D organoids and cell lines with multiple molecular readouts and in vivo model, single lab\",\n      \"pmids\": [\"33403789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rab11-FIP1 and Rab11-FIP5 knockdown additively impairs pIgR/pIgA transcytosis. TRIM21 mediates K11-linked polyubiquitination of Rab11-FIP1 (and K6-linked polyubiquitination of Rab11-FIP5) to promote their 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, ubiquitin linkage-specific antibody analysis, transcytosis assay in polarized and incompletely polarized epithelial cells\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown functional assay with biochemical characterization of ubiquitination linkage, single lab\",\n      \"pmids\": [\"34638806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Global Rab11FIP1 knockout (KO) mice develop spontaneous colonic inflammation with infiltration of macrophages and neutrophils, reduced TFF3-positive goblet cells, and abnormal accumulation of subapical vesicles in colonocytes. Rab11FIP1 loss causes mistrafficking of transmembrane mucin MUC13, which aberrantly internalizes with Rab14 instead of being properly recycled, resulting in impaired colonic mucosal integrity.\",\n      \"method\": \"Global KO mouse generation (exon 2 deletion), immunostaining, RNA-sequencing, DSS colitis model, confocal microscopy\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic KO with multiple orthogonal phenotypic readouts and specific molecular mechanism (MUC13/Rab14 mistrafficking), single lab\",\n      \"pmids\": [\"35819177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CircRTN4 interacts with RAB11FIP1 protein to block its ubiquitination site, thereby stabilizing RAB11FIP1 and preventing its proteasomal degradation. CircRTN4 knockdown promotes RAB11FIP1 degradation by increasing its ubiquitination and decreases EMT marker expression (Slug, Snai1, Twist, Zeb1, N-cadherin) in pancreatic cancer cells.\",\n      \"method\": \"circRNA pulldown with mass spectrometry, protein stability assay, ubiquitination assay, 3D structure modeling\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulldown/MS identification plus functional ubiquitination assay, single lab, but circRNA-protein interaction is mechanistically informative for RAB11FIP1 stability\",\n      \"pmids\": [\"34983537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HIF-1-induced upregulation of RCP/RAB11FIP1 under hypoxia promotes Rab11a-dependent recycling of internalized MSC-derived small extracellular vesicles (MSC-sEVs), reducing their intracellular cargo delivery efficiency. RAB11FIP1 enhances the interaction between Rab11a and MSC-sEVs under hypoxic conditions, and siRNA-mediated knockdown of RCP in engineered MSC-sEVs inhibits this recycling, improving cargo delivery.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation (Rab11a-sEV interaction), rat intervertebral disk degeneration model, fluorescence microscopy of sEV trafficking\",\n      \"journal\": \"ACS nano\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with mechanistic co-IP, in vivo model validation, single lab\",\n      \"pmids\": [\"36730125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The transcription factor Stat1 binds to the promoter of Rab11fip1 to initiate Schwann cell differentiation. Stat1 knockdown reduces Rab11fip1 expression and blocks Schwann cell differentiation, thereby inhibiting myelination.\",\n      \"method\": \"ChIP-seq, ChIP-qPCR, luciferase reporter assay, siRNA knockdown in Schwann cells, in vivo sciatic nerve model\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP-seq and luciferase assay establish direct transcriptional regulation, in vivo validation, single lab\",\n      \"pmids\": [\"37365519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RAB11FIP5 competitively sequesters RAB11A to antagonize RAB11FIP1-mediated transferrin and transferrin receptor recycling in HNSCC cells, thereby restricting iron uptake and suppressing ferroptosis. Loss of RAB11FIP5 thus permits RAB11FIP1-mediated recycling, increasing iron uptake and ferroptosis sensitivity.\",\n      \"method\": \"RAB11FIP5 knockout cell lines, transferrin recycling assay, iron uptake measurement, ferroptosis assays, subcutaneous xenograft models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with mechanistic epistasis between RAB11FIP5 and RAB11FIP1 in transferrin recycling, functional and in vivo data, single lab\",\n      \"pmids\": [\"42207639\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAB11FIP1 is a Rab11a effector protein that binds Rab11a (and Rab11b/Rab25) through its conserved C-terminal amphipathic alpha-helix and localizes to distinct tubular and vesicular subdomains of the slow endocytic recycling compartment, where it regulates recycling of transferrin receptor, MUC13, adiponectin, pIgR/pIgA, and extracellular vesicles; its activity is modulated by MARK2-mediated phosphorylation at S234 (regulating epithelial polarity), RFFL-mediated ubiquitylation, and TRIM21-mediated K11-linked polyubiquitination (promoting transcytosis), and its stability is controlled by ubiquitin-proteasome degradation that can be blocked by circRTN4; in cancer contexts, RAB11FIP1 activates Ras/ERK signaling, suppresses EMT through inhibition of Zeb1, and mediates transferrin receptor recycling that controls iron uptake and ferroptosis sensitivity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAB11FIP1 (Rab11-FIP1/RCP) is a Rab11a effector that organizes cargo recycling through the slow endocytic recycling compartment [#0]. It binds active Rab11a, as well as Rab11b and Rab25, via a conserved C-terminal amphipathic alpha-helix that is required for the interaction [#0, #1], and is expressed as multiple alternatively spliced isoforms (FIP1A-H) of which only those retaining this domain target Rab11a-positive recycling membranes, occupying spatially and temporally distinct tubular subdomains and forming selective pairwise associations with one another [#3, #5]. Functionally, RAB11FIP1 channels cargo from early endosomes (Rab5/EEA1-positive) into the Rab11a recycling system, and a dominant-negative T197A mutation collapses recycling endosomes, sequesters Rab11a and transferrin receptor, and blocks transferrin recycling [#8]; in vivo it is required for proper recycling of the transmembrane mucin MUC13, whose loss in knockout mice causes MUC13/Rab14 mistrafficking and spontaneous colonic inflammation [#13]. RAB11FIP1 activity is set by post-translational control: MARK2 phosphorylates it at S234 to govern epithelial polarity [#9], the E3 ligase RFFL directly ubiquitylates it [#10], TRIM21 adds K11-linked polyubiquitin to promote pIgR/pIgA transcytosis [#12], and its proteasomal turnover can be blocked by circRTN4 [#14]. In cancer, RAB11FIP1 acts as an oncogenic transformer that activates Ras/ERK signaling and drives invasion and metastasis [#4], while in epithelial contexts it suppresses EMT by inhibiting Zeb1 [#11]; through its control of transferrin receptor recycling it governs iron uptake and ferroptosis sensitivity, a function antagonized by RAB11FIP5-mediated sequestration of Rab11a [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established RAB11FIP1 as a bona fide Rab11a effector and defined the structural basis of the interaction, anchoring it to the membrane recycling machinery.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, colocalization, and parietal cell fractionation; domain deletion mapping the C-terminal amphipathic alpha-helix\",\n      \"pmids\": [\"11495908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which cargoes traffic through FIP1-Rab11a domains\", \"Functional consequence of binding for recycling kinetics not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed RAB11FIP1 localization is cell-cycle regulated, distinguishing it from other Rab11 effectors by its mitotic relocation to pericentriolar material.\",\n      \"evidence\": \"Live and fixed fluorescence microscopy of GFP-RAB11FIP1 across cell cycle stages with membrane fractionation in MDCK cells\",\n      \"pmids\": [\"12956871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism driving mitotic relocation unknown\", \"Functional role of pericentriolar targeting not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved that only Rab11-binding-domain-containing isoforms target recycling membranes, and that endogenous isoforms occupy distinct subcompartments.\",\n      \"evidence\": \"Cloning of eight splice variants, GFP-fusion colocalization, isoform-specific antibody staining in HeLa\",\n      \"pmids\": [\"16920206\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Distinct functions of individual isoforms not defined\", \"Regulation of splicing not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified RAB11FIP1/RCP as an oncogenic driver coupling vesicle recycling to Ras/ERK signaling, transformation, and metastasis.\",\n      \"evidence\": \"Overexpression and shRNA in mammary/breast cancer lines, xenografts, ERK phosphorylation and Ras activation assays\",\n      \"pmids\": [\"19620787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between recycling activity and Ras activation not resolved\", \"Relevant trafficked cargo driving transformation not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the spatiotemporal organization of FIP1 isoforms within recycling tubules and their hetero-associations, plus a cargo-specific role in adiponectin secretion.\",\n      \"evidence\": \"Live-cell deconvolution imaging with transferrin pulse-chase; overexpression/knockdown with adiponectin ELISA in HEK293 and 3T3-L1\",\n      \"pmids\": [\"23283983\", \"24040321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How cargo selectivity (adiponectin vs transferrin) is achieved unclear\", \"Basis for distinct subdomain occupancy not mechanistically defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked FIP1-dependent recycling to phosphatidylserine distribution, implicating lipid handling in compartment organization.\",\n      \"evidence\": \"Live-cell and structured illumination microscopy with LactC2-PS biosensor and C2-domain deletion\",\n      \"pmids\": [\"25210648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FIP1 directly binds PS not established\", \"Functional consequence of PS redistribution unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that FIP1A controls transit from early endosomes into the Rab11a recycling system, with a dominant-negative mutant blocking transferrin recycling.\",\n      \"evidence\": \"T197A site-directed mutagenesis, GFP-fusion imaging, transferrin recycling assay, marker colocalization (Rab5, EEA1)\",\n      \"pmids\": [\"26790954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular role of T197 not defined (not a known phospho-site here)\", \"Direct early-endosome-to-FIP1 handoff machinery unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified MARK2-mediated S234 phosphorylation as a switch controlling FIP1 function in epithelial apical-basal polarity.\",\n      \"evidence\": \"Kinase assay, phospho-specific antibody, calcium-switch repolarization, phospho-mutant overexpression with polarity marker imaging in MDCK\",\n      \"pmids\": [\"28396819\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How S234 phosphorylation alters Rab11a binding or cargo handling not resolved\", \"Upstream signals activating MARK2 in this context unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established RFFL as a direct E3 ligase for FIP1, placing FIP1 activity under ubiquitin control during recycling.\",\n      \"evidence\": \"In vitro ubiquitylation reconstitution, RFFL knockout cells, BioID interactome, dominant-negative RFFL with transferrin recycling assay\",\n      \"pmids\": [\"30659120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin linkage type and degradative vs non-degradative outcome not defined\", \"Which FIP1 lysines are modified unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed context-dependent roles: FIP1 suppresses EMT via Zeb1 inhibition in ESCC, and is activated by TRIM21 K11-polyubiquitination to drive pIgR/pIgA transcytosis.\",\n      \"evidence\": \"shRNA in 3D organoids and ESCC lines with EMT markers and mouse model; siRNA, Co-IP, linkage-specific ubiquitin antibodies and transcytosis assays\",\n      \"pmids\": [\"33403789\", \"34638806\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FIP1 inhibits Zeb1 not defined\", \"Reconciliation of tumor-suppressive (ESCC) vs oncogenic (breast) roles unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined an in vivo physiological role in colonic mucin recycling and showed circRNA-mediated stabilization of FIP1 against proteasomal degradation.\",\n      \"evidence\": \"Global KO mouse with immunostaining/RNA-seq/DSS colitis; circRTN4 pulldown-MS, protein stability and ubiquitination assays in pancreatic cancer cells\",\n      \"pmids\": [\"35819177\", \"34983537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FIP1 directs MUC13 away from Rab14 not mechanistically defined\", \"circRTN4 binding site on FIP1 vs ubiquitination site not precisely mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended FIP1 functions to extracellular vesicle recycling under hypoxia and to transcriptional induction during Schwann cell differentiation.\",\n      \"evidence\": \"siRNA knockdown with Rab11a-sEV Co-IP and rat IVDD model; Stat1 ChIP-seq, luciferase reporter and knockdown in Schwann cells with sciatic nerve model\",\n      \"pmids\": [\"36730125\", \"37365519\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct role of FIP1 in sEV cargo selectivity unclear\", \"Downstream FIP1 effectors in myelination not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed that FIP1-mediated transferrin receptor recycling governs iron uptake and ferroptosis, with RAB11FIP5 antagonizing FIP1 by sequestering Rab11a.\",\n      \"evidence\": \"RAB11FIP5 knockout cells, transferrin recycling and iron uptake assays, ferroptosis assays, xenografts in HNSCC\",\n      \"pmids\": [\"42207639\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct competition for Rab11a not structurally resolved\", \"Whether other FIPs similarly modulate ferroptosis untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how RAB11FIP1's many post-translational modifications and isoform/competition states are integrated to switch between oncogenic, tumor-suppressive, and homeostatic recycling outputs in different tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking S234 phosphorylation, RFFL/TRIM21 ubiquitination, and FIP-FIP competition\", \"Structural basis for cargo selectivity unknown\", \"Reconciliation of opposing cancer phenotypes across tissues unaddressed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 3, 5, 8]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 8, 13]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [8, 12, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAB11A\", \"RAB25\", \"RFFL\", \"TRIM21\", \"MARK2\", \"RAB11FIP5\", \"RAB11FIP3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}