{"gene":"RAB14","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2004,"finding":"Rab14 localizes to biosynthetic compartments (rough ER, Golgi, TGN) and early endosomal vacuoles/vesicles. Constitutively active Rab14Q70L shifts distribution toward early endosome-associated vesicles, while dominant-negative S25N and N124I mutants shift distribution toward the Golgi. These manipulations partially redistribute the transferrin receptor but do not affect transferrin uptake or recycling kinetics, suggesting Rab14 functions in the biosynthetic/recycling pathway between the Golgi and endosomal compartments.","method":"Immunofluorescence, immunoelectron microscopy, overexpression of dominant-active and dominant-negative Rab14 mutants, transferrin uptake/recycling assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (IF, immunoEM, functional mutant analysis) in foundational paper; findings replicated across subsequent studies","pmids":["15004230"],"is_preprint":false},{"year":2006,"finding":"Rab14 is recruited to phagosomes containing live Mycobacterium tuberculosis following phagocytosis. Knockdown of Rab14 by siRNA or overexpression of dominant-negative mutants (Rab14S25N, Rab14N125I) releases the phagosomal maturation block, allowing phagosomes to progress to phagolysosomes. Conversely, overexpression of wild-type or constitutively active Rab14Q70L prevents dead mycobacterial phagosomes from undergoing normal maturation. Mechanistically, Rab14 stimulates organellar fusion between phagosomes and early endosomes but not late endosomes.","method":"4D live-cell microscopy, siRNA knockdown, overexpression of dominant-negative and constitutively active mutants, phagosomal fusion assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (live imaging, siRNA, dominant mutants, fusion assays) with clear mechanistic readout; replicated concept in subsequent pathogen studies","pmids":["17082769"],"is_preprint":false},{"year":2006,"finding":"Rab14 is part of the early endosomal AP-1 clathrin-coated microdomain at the TGN. Overexpression of a dominant-negative GTP-binding mutant that localizes exclusively to the Golgi accelerates EGF degradation, suggesting Rab14 vesicles cycle between early endosomes and Golgi cisternae within this AP-1 microdomain.","method":"Structural modeling, quantitative confocal microscopy, density centrifugation, dominant-negative overexpression, EGF degradation assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (confocal, fractionation, functional assay) in single lab","pmids":["16962593"],"is_preprint":false},{"year":2008,"finding":"Rab14 interacts with apical membrane proteins and localizes to the TGN and apical endosomes in polarized epithelial cells. Expression of the GDP-locked Rab14-S25N induces TGN enlargement and vesicle accumulation around Golgi membranes, and causes mislocalization of the apical raft-associated protein VIP/MAL to the basolateral domain without disrupting basolateral targeting or recycling, indicating Rab14 specifically regulates cargo delivery from the TGN to the apical domain.","method":"Yeast two-hybrid, GST pulldown, immunofluorescence, overexpression of dominant-negative Rab14-S25N, polarity assays in epithelial cells","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus GST pulldown plus functional imaging; single lab","pmids":["18429929"],"is_preprint":false},{"year":2008,"finding":"Rab14 co-immunoprecipitates with Annexin A2 in alveolar type II cells, co-localizes with Annexin A2 and lamellar bodies, and siRNA-mediated knockdown of Rab14 decreases lung surfactant secretion.","method":"Co-immunoprecipitation, co-localization by immunofluorescence, siRNA knockdown, surfactant secretion assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional knockdown readout; single lab","pmids":["18332131"],"is_preprint":false},{"year":2009,"finding":"Class I Rab11-family interacting proteins (FIP2, RCP/Rab-coupling protein, Rip11) bind Rab14 in a GTP-dependent manner via their C-terminal Rab-binding domain (RBD), making them the first identified effectors of Rab14. Rab14Q70L co-localizes with Rab11a and class I FIPs at the endosomal recycling compartment during interphase. During cytokinesis, Rab14 localizes to the cleavage furrow/midbody.","method":"Co-immunoprecipitation, co-localization by confocal microscopy, GTP-dependency binding assays","journal":"Biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GTP-dependent Co-IP plus co-localization; single lab, two methods","pmids":["19702578"],"is_preprint":false},{"year":2010,"finding":"Rab14 facilitates the delivery of sphingolipids from the Golgi to Chlamydia trachomatis-containing inclusions. Dominant-negative Rab14 mutants delayed inclusion enlargement and impaired bacterial replication; siRNA silencing of Rab14 decreased bacterial multiplication and infectivity; electron microscopy showed aberrant bacteria after dominant-negative expression. Rab14 recruitment to inclusions was dependent on bacterial protein synthesis but independent of microtubules and Golgi integrity.","method":"Overexpression of dominant-negative mutants, siRNA knockdown, immunofluorescence, electron microscopy, bacterial infectivity assays (IFU), sphingolipid delivery assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA, dominant-negative, EM, lipid trafficking assay, infectivity); replicated in subsequent studies","pmids":["21124879"],"is_preprint":false},{"year":2011,"finding":"KIF16B (kinesin-3 motor) directly associates with GTP-bound Rab14 on FGFR-containing vesicles and transports them toward the plasma membrane in a Golgi-to-endosome biosynthetic pathway. Kif16b knockout mouse embryos die at peri-implantation stage, phenocopying FGFR2 knockout. Dominant-negative Rab14-GDP overexpression recapitulates defects in FGFR transport, FGF signaling, basement membrane assembly, and epiblast development.","method":"Kif16b knockout mouse model, co-immunoprecipitation, dominant-negative Rab14-GDP overexpression, embryonic phenotype analysis, FGF signaling assays, basement membrane immunostaining","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo genetic knockout combined with biochemical interaction (Co-IP) and dominant-negative rescue; multiple orthogonal methods","pmids":["21238925"],"is_preprint":false},{"year":2012,"finding":"Rab14 and its GDP-GTP exchange factor FAM116A define an intermediate recycling compartment in the transferrin-recycling pathway, positioned after Rab5/Rab4 and before Rab11. Rab14-depleted cells accumulate ADAM10 in a transferrin-positive endocytic compartment, reduce ADAM10 cell-surface levels, decrease ADAM10-mediated shedding of N-cadherin, and consequently cannot resolve cell-cell junctions, impairing cell migration.","method":"siRNA depletion, confocal microscopy, transferrin recycling assays, cell surface ADAM10 measurements, N-cadherin shedding assays, migration assays, identification of FAM116A as GEF by yeast two-hybrid/functional assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA, trafficking assays, surface protein quantitation, functional migration assay) establishing pathway position and molecular mechanism","pmids":["22595670"],"is_preprint":false},{"year":2012,"finding":"Rab14 co-localizes with IRAP and syntaxin 6 in regulated endosomal storage compartments in conventional dendritic cells (cDCs). Increased recruitment of an IRAP+/Rab14+ compartment to antigen-containing vesicles correlates with superior cross-presentation efficacy of CD8+ cDCs.","method":"Immunofluorescence co-localization, IRAP-deficient DC analysis, cross-presentation assays","journal":"Journal of immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-localization study without direct mechanistic manipulation of Rab14","pmids":["22238454"],"is_preprint":false},{"year":2013,"finding":"Rab14 binds to the C-terminus of the UT-A1 urea transporter preferentially in the GDP-bound inactive form (identified by yeast two-hybrid). Co-injection of Rab14 in Xenopus oocytes decreases UT-A1 urea transport activity by reducing cell membrane expression of UT-A1 via clathrin-mediated endocytosis (blocked by chlorpromazine but not filipin). Rab14 co-distributes with Rab5 in non-lipid raft microdomains in kidney inner medullary cells.","method":"Yeast two-hybrid, Xenopus oocyte co-injection/transport assay, cell surface biotinylation, pharmacological inhibition (chlorpromazine/filipin), co-localization with Rab5 marker","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reconstitution in Xenopus oocytes (functional transport assay), yeast two-hybrid interaction, and pharmacological dissection of endocytic pathway; multiple orthogonal methods in single paper","pmids":["23796783"],"is_preprint":false},{"year":2013,"finding":"Rab11a-FIP1C/RCP is required for HIV-1 envelope glycoprotein (Env) incorporation onto particles in a cytoplasmic tail-dependent manner. Rab14 is required for HIV-1 Env incorporation; FIP1C mutants unable to bind Rab14 fail to rescue Env incorporation. FIP1C is redistributed by wild-type Env CT to the plasma membrane. This defines a Rab14-FIP1C endocytic recycling pathway mediating Env targeting to the assembly microdomain.","method":"siRNA depletion, dominant-negative and rescue experiments, FIP1C Rab14-binding mutants, viral particle assembly assays, Western blotting","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal siRNA knockdown, Rab14-binding mutant rescue experiments, and functional viral incorporation assay; multiple orthogonal methods","pmids":["23592992"],"is_preprint":false},{"year":2013,"finding":"Rab14 controls transit of internalized GLUT4 through early endosomal compartments toward the perinuclear region in 3T3-L1 adipocytes. Constitutively active Rab14Q70L reduces basal and insulin-stimulated cell-surface GLUT4 by retaining GLUT4 in an insulin-insensitive early endosomal compartment. shRNA-mediated Rab14 depletion inhibits GLUT4 transit from early endosomes to perinuclear vesicles/tubules. Overexpressed Rab14/Rab14Q70L creates enlarged ring-like early endosomal structures (~1.3 µm) that rapidly accumulate GLUT4 and transferrin by endocytosis.","method":"Confocal microscopy, shRNA knockdown, overexpression of WT and Q70L/S25N mutants, cell-surface GLUT4 quantification","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (shRNA, constitutively active/dominant-negative mutants, surface quantitation, live imaging) in same study","pmids":["23444368"],"is_preprint":false},{"year":2014,"finding":"Rab14 knockdown in MDCK cells increases transepithelial resistance and substantially depletes claudin-2 (a leaky claudin), without affecting claudin-1, ZO-1, or occludin. Claudin-2 loss is rescued by lysosomal inhibition, indicating Rab14 sorts claudin-2 away from the lysosomal degradation pathway. Rab14 knockdown in 3D culture causes failure to form normal single-lumen cysts. MDCK I cells lacking claudin-2 endogenously show no change in TER upon Rab14 knockdown, confirming specificity.","method":"siRNA knockdown, transepithelial resistance measurement, immunofluorescence, lysosomal inhibition rescue, 3D culture lumen morphogenesis assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA, TER, rescue with lysosomal inhibitor, 3D culture) with rigorous specificity controls","pmids":["24694596"],"is_preprint":false},{"year":2015,"finding":"PKCι directly interacts with Rab14 (shown by ELISA and co-immunoprecipitation). PKCι and Rab14 co-localize in intracellular puncta and at the plasma membrane. PKCι knockdown decreases claudin-2 levels; Rab14 expression is required for normal PKCι distribution in 3D cysts. The data indicate PKCι and Rab14 interact to regulate claudin-2 trafficking out of the lysosome-directed pathway.","method":"Co-immunoprecipitation, ELISA, immunofluorescence co-localization, siRNA knockdown, 3D cyst culture","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP/ELISA plus functional knockdown evidence; single lab","pmids":["25694446"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of Rab14 in complex with the Rab-binding domain of RCP (Rab-coupling protein/FIP1C) reveals Rab14 binds RCP with reduced affinity compared to Rab11/25 and with a noncanonical 1:2 stoichiometry (Rab14:RCP) in dilute solution. In vivo, Rab11 (not Rab14) recruits RCP onto biological membranes. Both RCP and Rab14 function in neuritogenesis.","method":"X-ray crystallography, isothermal titration calorimetry, yeast two-hybrid, co-localization, neuritogenesis functional assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus thermodynamic measurements plus functional cellular assay; multiple rigorous methods in single paper","pmids":["26032412"],"is_preprint":false},{"year":2016,"finding":"Rab14 knockdown disrupts polarized lipid domains and prevents the Par/aPKC/Cdc42 polarity complex from localizing to the apical membrane during de novo polarity establishment. These effects are mediated through lipid localization, as overexpression of PtdIns(4)P5K activator Arf6, PtdIns(4)P5K alone, or PI3K inhibition (wortmannin) rescues the multi-apical phenotype. Rab14 co-immunoprecipitates and co-localizes with Cdc42; Rab14 knockdown increases Cdc42 activity. Rab14 also regulates mitotic spindle orientation and midbody position.","method":"siRNA knockdown, overexpression of Arf6/PtdIns(4)P5K, pharmacological rescue (wortmannin), co-immunoprecipitation, Cdc42 activity assay, 3D MDCK culture, confocal microscopy","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (siRNA, genetic rescue, pharmacological rescue, Co-IP, activity assay) with rigorous controls","pmids":["27901125"],"is_preprint":false},{"year":2016,"finding":"Rab14 limits sorting of Glut4 from sorting endosomes into the specialized insulin-regulated GSV (Glut4 storage vesicle) pathway in adipocytes. Both overexpression and knockdown of Rab14 decrease Glut4 plasma membrane translocation. Kinetic analysis supports that Rab14 controls sorting at the early/sorting endosome step, consistent with AS160 (a Rab GAP) regulating both Rab14 and Rab10 sequentially to control GSV entry and exocytosis.","method":"Rab14 knockdown, kinetic trafficking assays measuring Glut4 vs transferrin receptor vs LRP1, mathematical modeling of trafficking kinetics","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative kinetic trafficking measurements with knockdown; single lab, single approach","pmids":["26936971"],"is_preprint":false},{"year":2016,"finding":"Rab14 depletion in Drosophila fat body cells causes abnormal clustering of autophagosomes and lysosomes and reduces autophagosome-lysosome fusion. The kinesin Klp98A (ortholog of KIF16B) interacts with and co-localizes with Rab14, and requires Rab14 for normal localization. Rab14 is required for Klp98A-mediated autophagosome-lysosome fusion but not for vesicle positioning, indicating fusion and localization are separable events.","method":"Genetic depletion (Drosophila), co-immunoprecipitation/co-localization of Klp98A and Rab14, autophagy flux assays, autophagosome-lysosome fusion quantification","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Drosophila genetic model with Co-IP interaction and functional fusion assay; single lab","pmids":["26763909"],"is_preprint":false},{"year":2017,"finding":"Phosphorylation of RCP (Rab-coupling protein) at Ser435 by LMTK3 and of EphA2 at Ser897 by Akt together promote Rab14-dependent (and Rab11-independent) trafficking of EphA2 to drive cell-cell repulsion and metastasis in vivo. Genetic disruption of RCP or EphA2 opposes cell-cell repulsion and metastasis in an autochthonous mouse model of pancreatic adenocarcinoma.","method":"Phospho-specific mutants, kinase assays, RCP/EphA2 conditional knockout mouse model, cell repulsion assays, in vivo metastasis quantification","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo genetic mouse model combined with biochemical phosphorylation analysis and mechanistic mutants; multiple orthogonal approaches","pmids":["28294115"],"is_preprint":false},{"year":2017,"finding":"Electrical pulse stimulation (EPS)-induced GLUT4 translocation in C2C12 myotubes requires Rab8a, Rab13, and Rab14 (siRNA knockdown of each partially reduces GLUT4 translocation), while AICAR (AMPK-mediated) GLUT4 translocation requires Rab8a and Rab14 but not Rab13 or Rab10.","method":"siRNA knockdown of individual Rabs, HA-GLUT4 surface quantitation, EPS contraction model, AMPK/CaMKII phosphorylation assays","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic siRNA knockdown of multiple Rabs with quantitative surface GLUT4 readout; single lab","pmids":["29089333"],"is_preprint":false},{"year":2019,"finding":"CHML (choroideremia-like) promotes HCC cell metastasis by facilitating Rab14 recycling to the membrane. CHML escorts Rab14 to the membrane, enabling constant Rab14 recycling. Metastasis-promoting cargoes on Rab14-positive vesicles include Mucin13 and CD44. CHML-mediated migration, invasion, and metastasis require Rab14.","method":"Co-immunoprecipitation, Rab14 knockdown, overexpression, vesicle cargo identification, in vivo metastasis assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional knockdown, and in vivo assays; single lab","pmids":["31175290"],"is_preprint":false},{"year":2019,"finding":"C. trachomatis activates the Akt/AS160 signaling pathway to promote Rab14-controlled sphingolipid delivery to chlamydial inclusions. C. trachomatis induces Akt phosphorylation and recruits phospho-Akt to the inclusion membrane, inactivating the Rab14-GAP AS160/TBC1D4 by phosphorylation, thereby maintaining Rab14 in the GTP-bound active state. Akt inhibition prevents AS160 phosphorylation, reduces Rab14 recruitment to inclusions, impairs sphingolipid acquisition, and decreases bacterial multiplication.","method":"Akt inhibitor (iAkt), siRNA knockdown of AS160, phospho-Western blotting, Rab14 recruitment quantification, sphingolipid trafficking assay, bacterial infectivity (IFU), electron microscopy","journal":"Frontiers in microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological inhibition, genetic siRNA knockdown, biochemical phosphorylation analysis, lipid trafficking assay, and EM; multiple orthogonal methods","pmids":["31001235"],"is_preprint":false},{"year":2020,"finding":"Rab14 functions in the trafficking of Ebola virus matrix protein VP40. Proximity proteomics (BioID) identified Rab14 as a VP40-proximal protein at late stages of VP40 expression. VP40 and Rab14 substantially co-localize in HeLa cells. Overexpression of dominant-negative Rab14(S25N) diminishes VP40 plasma membrane localization. Secreted VP40 can be endocytosed into Rab14-positive compartments.","method":"BioID proximity proteomics, co-localization imaging, dominant-negative Rab14(S25N) overexpression, plasma membrane localization assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — BioID screen plus imaging plus dominant-negative functional assay; single lab","pmids":["32327259"],"is_preprint":false},{"year":2021,"finding":"RAB14 is required for actin-based asymmetric division during mouse oocyte meiotic maturation. RAB14 localizes in the cytoplasm and accumulates at the cortex and spindle periphery during maturation. RAB14 depletion (siRNA) causes spindle migration defects and large polar bodies (failure of asymmetric division) without affecting spindle organization, mediated through the ROCK-cofilin signaling pathway for cytoplasmic actin assembly. RAB14 depletion also causes aberrant Golgi distribution. Rescue by exogenous Myc-Rab14 mRNA confirms specificity.","method":"Microinjection of siRNA and rescue mRNA, immunofluorescence for spindle/actin/Golgi, ROCK-cofilin pathway analysis (Western blot), polar body extrusion assay","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with mRNA rescue plus pathway analysis; single lab","pmids":["34323331"],"is_preprint":false},{"year":2021,"finding":"Rab14 defines a novel endocytic pathway for cationic substances (cell-penetrating peptides, polyamines, homeodomains) that is fully independent of Rab5 and Rab7, leading to non-acidic LAMP1-positive late endosomes. The pathway diverges from conventional clathrin-mediated endocytosis and macropinocytosis at the vesicle formation stage.","method":"siRNA knockdown of Rab14, Rab5, and Rab7, pharmacological inhibitors of clathrin-mediated endocytosis and macropinocytosis, live-cell imaging with fluorescent CPPs, LAMP1 co-localization","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic siRNA knockdown of multiple Rab GTPases plus pharmacological dissection plus multiple cargo types; multiple orthogonal methods","pmids":["34731620"],"is_preprint":false},{"year":2022,"finding":"Endocytosed HIV-1 envelope glycoprotein (Env) traffics to Rab14-positive compartments that possess hallmarks of late endosomes and lysosomes in infected CD4+ T-cell lines, where it can be recycled back to the plasma membrane. This defines a T-cell-specific late-endosomal/lysosomal Rab14-positive pathway for Env trafficking.","method":"Pulse-labeling with monovalent anti-Env Fab probe, CRISPR/Cas9 endogenous tagging of Rab GTPases, confocal microscopy, recycling assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR endogenous tagging combined with pulse-chase tracking; single lab","pmids":["35770989"],"is_preprint":false},{"year":2022,"finding":"Geranylgeranylation of RAB14 (catalyzed by GGTase II) is required for phosphorylation of AKT at Ser473 and normal hepatic insulin signaling and glucose metabolism. Geranylgeranylation-deficient RAB14 inhibits mTORC2 complex assembly, disrupting AKT phosphorylation. Geranylgeranyl pyrophosphate supplementation rescues simvastatin-caused disruption of hepatic insulin signaling in vitro, and geranylgeraniol (GGOH) ameliorates statin-induced systemic glucose disorders in vivo.","method":"siRNA screen (small-scale), GGTase II inhibition/RABGGTA knockdown (AAV8 in vivo), GGPP/GGOH supplementation, AKT phosphorylation assays (Western blot), mTORC2 complex assembly assay, in vivo glucose metabolism tests","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV8 knockdown plus in vitro mechanistic studies; single lab but multiple methods","pmids":["34995578"],"is_preprint":false},{"year":2023,"finding":"CSFV NS5A recruits Rab14 to the ER, followed by Rab14-dependent ceramide transport to the Golgi apparatus where sphingomyelin is synthesized. The PI3K/AKT/AS160 signaling pathway regulates this Rab14-controlled ceramide transport; blocking this pathway reduces sphingomyelin content at the Golgi and impairs viral particle assembly.","method":"Rab14 knockdown/overexpression, co-localization and interaction assays, small-molecule PI3K/AKT/AS160 inhibitors, lipid quantification, viral assembly assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional approaches (knockdown, pharmacological, lipid assay, viral assembly); single lab","pmids":["37255314"],"is_preprint":false},{"year":2023,"finding":"AMPK activation promotes Rab14-dependent ADAM10 cell-surface translocation in human aortic endothelial cells. Rab14 siRNA knockdown prevents AICAR-induced ADAM10 surface translocation and RAGE ectodomain shedding, placing Rab14 downstream of AMPK in the ADAM10 trafficking pathway.","method":"AICAR treatment, AMPK inhibitor (Compound C), AMPKα1-siRNA, Rab14-siRNA, ADAM10 cell-surface ELISA, RAGE shedding assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological plus genetic siRNA evidence with functional shedding assay; single lab","pmids":["37451218"],"is_preprint":false},{"year":2020,"finding":"CCN2 interacts with Rab14 through its IGFBP-like domain. Co-expression of CCN2 and Rab14 in COS7 cells redistributes Rab14 from diffuse cytosolic to dot-like vesicular structures that co-localize with CCN2. Dominant-negative Rab14DN reduces extracellular proteoglycan accumulation in chondrocytes. siRNA knockdown of Rab14 or CCN2 induces ER/Golgi stress markers (BIP, CHOP), suggesting they cooperate in proteoglycan-containing vesicle transport from the Golgi to endosomes.","method":"Yeast two-hybrid, in situ proximity ligation assay, overexpression of WT/CA/DN Rab14, proteoglycan secretion assay, siRNA knockdown, qRT-PCR for ER stress markers","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus PLA plus functional mutant analysis; single lab","pmids":["32316324"],"is_preprint":false},{"year":2024,"finding":"RAB14 is a regulator of autophagosome maturation. In rab14-KO MDCK cells, LC3-II levels are altered, indicating autophagy defect specifically at the autophagosome maturation step. Double KO of rab2 and rab14 causes a severer autophagy defect than either single KO, demonstrating overlapping roles. RAB14 localizes to autophagosomes and interacts with the HOPS complex subunits VPS39 and VPS41 (confirmed by co-immunoprecipitation), similar to RAB2.","method":"Comprehensive rab-KO library in MDCK cells, LC3-II level quantification, basal and starvation-induced autophagy assays, co-immunoprecipitation of HOPS subunits, autophagosome localization imaging","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic knockout library with double KO epistasis, Co-IP of HOPS subunits, and autophagosome localization; multiple orthogonal methods","pmids":["38953305"],"is_preprint":false},{"year":2024,"finding":"A complex of SHIP164, RhoBTB3 (ATPase), and Vps26B (retromer subunit) promotes formation of early endosome buds at Golgi-EE contact sites. Vps26B acts as a novel Rab14 effector; Rab14 activity regulates SHIP164 association with early endosomes. Depletion of SHIP164 causes enlarged Rab14+ EEs without buds, rescued by WT SHIP164 but not lipid-transfer-defective mutants. Suppression of RhoBTB3 or Vps26B mirrors SHIP164 depletion effects.","method":"Co-immunoprecipitation, siRNA depletion, overexpression of lipid-transfer-defective SHIP164 mutants, live imaging of EE bud formation, Golgi-EE contact site analysis","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple components of a defined complex characterized by Co-IP and functional mutant rescue; multiple orthogonal methods in single rigorous study","pmids":["38565878"],"is_preprint":false},{"year":2025,"finding":"AKT activation (via SC79) translocates ADAM10 to the cell surface in human aortic endothelial cells through Rab14. Rab14 co-immunoprecipitates with ADAM10; after AKT activation Rab14 moves to the cell surface. siRNA-mediated Rab14 knockdown prevents AKT-induced ADAM10 surface translocation and RAGE ectodomain shedding, and abolishes AKT's ability to inhibit AGE-BSA-induced ICAM-1 expression.","method":"Co-immunoprecipitation of Rab14 with ADAM10, siRNA knockdown of Rab14 and AKT isoforms, surface ADAM10 quantification, RAGE shedding assay, ICAM-1 expression assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional siRNA knockdown with multiple downstream readouts; single lab","pmids":["40032916"],"is_preprint":false},{"year":2025,"finding":"Rab14 promotes Parkin-dependent mitophagy. Rab14 knockdown causes mitochondrial elongation and accumulation of mitochondrial proteins; Rab14 overexpression increases mitophagy (mito-Keima assay) in a Parkin-, TBK1-, and PI3K-dependent manner. 3D reconstruction reveals Rab14-mitochondria contact sites; PI(4)KIIIβ inhibition (TGN kinase) decreases these contacts and prevents Rab14-mediated mitophagy, suggesting TGN-derived Rab14 vesicles mediate the mitophagic process.","method":"siRNA knockdown, Rab14 overexpression, mito-Keima mitophagy assay, PI(4)KIIIβ inhibitor, Parkin/TBK1 dependency experiments, 3D reconstruction of contact sites","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression/knockdown plus pathway epistasis (Parkin, TBK1, PI3K, PI(4)KIIIβ) plus 3D contact site imaging; single lab","pmids":["40737294"],"is_preprint":false},{"year":2026,"finding":"GTP-bound Rab14 acts as a broad-spectrum restriction factor against multiple bacteria and viruses by promoting V-ATPase delivery to lysosomes and lysosomal acidification. Mechanistically, active Rab14 binds CAMK2D and suppresses CAMK2D-mediated phosphorylation of V0a1 (the V-ATPase subunit determining lysosomal localization), thereby promoting V0a1 interaction with the COPII complex and facilitating V-ATPase trafficking from the ER to lysosomes.","method":"Screen for lysosomal acidification factors, Co-immunoprecipitation (Rab14-CAMK2D interaction), CAMK2D kinase assay (V0a1 phosphorylation), COPII complex binding assay, lysosomal acidification assays, pathogen clearance experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection using Co-IP, kinase assay, trafficking experiments, and functional pathogen clearance; multiple orthogonal methods in single study","pmids":["41771894"],"is_preprint":false},{"year":2026,"finding":"Rab14 is required for human papillomavirus (HPV) transport to the trans-Golgi network (TGN) for infectious cell entry. Rab14 KO cells resist HPV pseudovirion (PsV) infection; wild-type Rab14 re-expression restores infection. Neither GDP-locked (S25N) nor GTP-locked (Q70L) mutants rescue infection, indicating that Rab14 GTPase cycling (not just one nucleotide state) is required. GDP-bound Rab14(S25N) preferentially localizes to the TGN while GTP-bound Rab14(Q70L) co-localizes with both early endosomes and TGN.","method":"Rab14 KO (CRISPR), wild-type and nucleotide-state mutant rescue, confocal microscopy tracking of PsV and Rab14 localization, infectivity assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO plus nucleotide-state mutant rescue with functional infectivity readout; single lab","pmids":["42186738"],"is_preprint":false},{"year":2025,"finding":"The RCP-RAB14 axis mediates surface delivery of MET receptor tyrosine kinase through tubulovesicular carriers to invadopodia in TNBC cells, with KIF16B promoting formation of vesicular tubules on RAB14-positive endosomes. HGF stimulation enhances MET recycling to invadopodia via this pathway, driving MT1-MMP delivery and matrix degradation.","method":"Degradation-defective MET mutant, KIF16B manipulation, RCP knockdown, RAB14-positive endosome imaging, invadopodium functional assays, MET surface delivery tracking","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, imaging-dominant with limited biochemical validation of the Rab14-specific interactions","pmids":[],"is_preprint":true}],"current_model":"RAB14 is a GTP-cycling small GTPase that operates at early endosomes and the trans-Golgi network to regulate bidirectional membrane trafficking: it facilitates Golgi-to-endosome and endosome-to-plasma-membrane transport of diverse cargoes (GLUT4, ADAM10/N-cadherin, EphA2, FGFR, claudin-2, HIV Env, UT-A1, MET, ceramide/sphingolipids) via its class I Rab11-FIP effectors (RCP/FIP1C, FIP2, Rip11); its activity is controlled by the GAP AS160/TBC1D4 (regulated by Akt/AMPK signaling) and the GEF FAM116A; it is geranylgeranylated by GGTase II for membrane attachment; it interacts with CAMK2D to promote V-ATPase lysosomal delivery and acidification for pathogen clearance; and it plays defined roles in phagosomal maturation, autophagosome maturation (via HOPS complex recruitment in concert with RAB2), Parkin-dependent mitophagy (via TGN contact sites), apical membrane specification, epithelial polarity (via Arf6/Cdc42), cytokinesis, and oocyte asymmetric division through ROCK-cofilin-regulated actin dynamics."},"narrative":{"mechanistic_narrative":"RAB14 is a GTP-cycling small GTPase that operates between the trans-Golgi network and the endosomal system to direct bidirectional membrane trafficking of diverse cargoes, occupying an intermediate recycling compartment positioned after Rab5/Rab4 and before Rab11 [PMID:15004230, PMID:22595670]. Its activity depends on a nucleotide cycle—both GDP- and GTP-locked mutants fail to support its functions—and on geranylgeranylation by GGTase II for membrane attachment [PMID:34995578, PMID:42186738]. Cargo routing through RAB14 governs surface delivery and post-endocytic sorting of ADAM10 (controlling N-cadherin and RAGE shedding) [PMID:22595670, PMID:37451218, PMID:40032916], the leaky tight-junction protein claudin-2 (which it diverts from lysosomal degradation) [PMID:24694596], GLUT4 in adipocytes and myotubes downstream of insulin/AMPK signaling via the GAP AS160/TBC1D4 [PMID:23444368, PMID:26936971, PMID:29089333], the urea transporter UT-A1 [PMID:23796783], and FGFR via the kinesin-3 motor KIF16B [PMID:21238925]. RAB14 acts through class I Rab11-FIP effectors (FIP2, RCP/FIP1C, Rip11) bound in a GTP-dependent manner, and structurally engages the RCP Rab-binding domain with noncanonical stoichiometry and lower affinity than Rab11 [PMID:19702578, PMID:26032412]. Beyond constitutive transport, RAB14 controls phagosomal and autophagosome maturation—the latter via direct interaction with HOPS subunits VPS39/VPS41 in overlapping roles with RAB2 [PMID:17082769, PMID:38953305]—drives lysosomal acidification by binding CAMK2D to promote V-ATPase delivery as a broad-spectrum antimicrobial restriction factor [PMID:41771894], and mediates epithelial apical polarity and lumen morphogenesis through lipid-dependent recruitment of the Par/aPKC/Cdc42 complex [PMID:18429929, PMID:27901125]. Numerous pathogens co-opt RAB14, including Chlamydia and CSFV (Golgi-derived sphingolipid/ceramide delivery, sustained by Akt-mediated AS160 inactivation) [PMID:21124879, PMID:31001235, PMID:37255314] and HIV-1 Env incorporation via the RCP/FIP1C pathway [PMID:23592992].","teleology":[{"year":2004,"claim":"Established RAB14's basic residence and itinerary—whether it acts in the biosynthetic versus endocytic system—by mapping its localization and the effect of nucleotide-state mutants.","evidence":"Immunofluorescence, immunoEM, and dominant-active/negative mutant analysis with transferrin assays","pmids":["15004230"],"confidence":"High","gaps":["No effectors or cargo identified","Did not establish how Rab14 selects between Golgi and endosomal compartments"]},{"year":2006,"claim":"Defined RAB14's first physiological role: it arrests phagosome maturation by promoting phagosome–early endosome fusion, a process exploited by intracellular mycobacteria.","evidence":"Live-cell imaging, siRNA, dominant mutants, and phagosomal fusion assays in M. tuberculosis infection","pmids":["17082769","16962593"],"confidence":"High","gaps":["Effectors mediating fusion not identified","Link to AP-1 microdomain partner only Medium-confidence"]},{"year":2008,"claim":"Extended RAB14 into polarized epithelial and secretory trafficking, showing it directs cargo from the TGN to the apical domain and supports lamellar-body surfactant secretion.","evidence":"Yeast two-hybrid, GST pulldown, dominant-negative imaging in epithelia; Co-IP/knockdown with Annexin A2 in alveolar cells","pmids":["18429929","18332131"],"confidence":"Medium","gaps":["Apical cargo receptor mechanism undefined","Annexin A2 interaction not placed in a defined pathway step"]},{"year":2009,"claim":"Identified the first RAB14 effectors—class I Rab11-FIPs—establishing how RAB14 connects to the recycling machinery and to cytokinesis.","evidence":"GTP-dependent Co-IP and confocal co-localization of FIP2/RCP/Rip11 with Rab14","pmids":["19702578"],"confidence":"Medium","gaps":["Functional consequence of each FIP interaction not dissected","Shared use of FIPs with Rab11 not resolved"]},{"year":2011,"claim":"Linked RAB14 to a motor and a developmental program, showing KIF16B transports GTP-Rab14/FGFR vesicles in a Golgi-to-surface biosynthetic route essential for embryogenesis.","evidence":"Kif16b knockout mouse, Co-IP, dominant-negative Rab14 rescue, FGF signaling and basement membrane analysis","pmids":["21238925"],"confidence":"High","gaps":["Rab14 GEF/GAP regulating this route not identified at the time","Did not address other KIF16B cargoes"]},{"year":2012,"claim":"Positioned RAB14 precisely within the recycling cascade and identified its GEF FAM116A, defining ADAM10 trafficking and N-cadherin shedding as a downstream output controlling cell migration.","evidence":"siRNA, transferrin recycling kinetics, surface ADAM10 and N-cadherin shedding/migration assays; GEF identification by yeast two-hybrid","pmids":["22595670"],"confidence":"High","gaps":["Structural basis of FAM116A activation not defined","ADAM10 sorting determinant on Rab14 vesicles unknown"]},{"year":2013,"claim":"Generalized RAB14 as a cargo-sorting hub, showing it routes GLUT4 through early endosomes, recycles UT-A1, and—via RCP/FIP1C—delivers HIV-1 Env to the assembly site.","evidence":"shRNA/mutant GLUT4 surface assays in adipocytes; Xenopus oocyte UT-A1 transport; FIP1C Rab14-binding mutant rescue of HIV Env incorporation","pmids":["23444368","23796783","23592992"],"confidence":"High","gaps":["How a single Rab14 compartment discriminates among GLUT4, UT-A1, and Env unclear","Insulin-regulated GAP linkage to GLUT4 not yet established here"]},{"year":2015,"claim":"Provided the structural and thermodynamic basis of the RAB14–RCP interaction, revealing noncanonical 1:2 binding and lower affinity than Rab11, clarifying effector sharing.","evidence":"X-ray crystallography, ITC, yeast two-hybrid, neuritogenesis assays","pmids":["26032412"],"confidence":"High","gaps":["In vivo significance of the 1:2 stoichiometry not resolved","Membrane recruitment shown to depend on Rab11 rather than Rab14"]},{"year":2016,"claim":"Defined RAB14's role in de novo epithelial polarity and lumen morphogenesis through lipid-dependent recruitment of the Par/aPKC/Cdc42 complex, and its sorting of claudin-2 away from lysosomes (with PKCι).","evidence":"siRNA, Arf6/PI5K and wortmannin rescue, Cdc42 activity and Co-IP assays; TER and 3D cyst assays with lysosomal-inhibition rescue","pmids":["27901125","24694596","25694446","26936971"],"confidence":"High","gaps":["Direct lipid species regulated by Rab14 not defined","Mechanism coupling Rab14 to Cdc42 activity state unresolved"]},{"year":2017,"claim":"Demonstrated regulated, signaling-driven RAB14 trafficking in disease, with kinase phosphorylation of RCP and EphA2 routing EphA2 through a Rab14-dependent pathway to drive metastasis.","evidence":"Phospho-mutants, kinase assays, RCP/EphA2 conditional knockout mouse, repulsion and metastasis assays","pmids":["28294115"],"confidence":"High","gaps":["How phosphorylation switches cargo from Rab11 to Rab14 route mechanistically unclear","Generality beyond pancreatic adenocarcinoma not tested"]},{"year":2019,"claim":"Identified the prenyl escort CHML as enabling continuous RAB14 membrane recycling and linked Rab14 cargo (Mucin13, CD44) to metastatic invasion.","evidence":"Co-IP, Rab14 knockdown/overexpression, cargo identification, in vivo metastasis assays in HCC","pmids":["31175290"],"confidence":"Medium","gaps":["CHML escort mechanism not biochemically reconstituted","Single tumor context"]},{"year":2024,"claim":"Placed RAB14 in autophagosome maturation, showing it binds HOPS subunits VPS39/VPS41 and acts in overlapping fashion with RAB2 at the fusion step.","evidence":"Comprehensive rab-KO MDCK library, LC3-II quantitation, rab2/rab14 double-KO epistasis, HOPS Co-IP","pmids":["38953305","26763909"],"confidence":"High","gaps":["Direct contribution of Rab14 versus Rab2 to HOPS tethering not separated","Nucleotide regulation at autophagosomes undefined"]},{"year":2024,"claim":"Revealed a RAB14 effector–machinery (SHIP164/RhoBTB3/Vps26B) that forms early-endosome buds at Golgi-EE contact sites, with Vps26B as a novel effector.","evidence":"Co-IP, siRNA, lipid-transfer-defective mutant rescue, live imaging of EE bud formation","pmids":["38565878"],"confidence":"High","gaps":["How Rab14 activity gates SHIP164 recruitment mechanistically unresolved","Cargo carried by these buds not defined"]},{"year":2026,"claim":"Established a non-trafficking signaling output: GTP-RAB14 binds CAMK2D to suppress V0a1 phosphorylation, promoting V-ATPase delivery and lysosomal acidification as broad antimicrobial restriction.","evidence":"Acidification screen, Rab14-CAMK2D Co-IP, V0a1 kinase assay, COPII binding, pathogen clearance assays","pmids":["41771894"],"confidence":"High","gaps":["How active Rab14 inhibits CAMK2D catalysis structurally undefined","Relationship between this role and its endosomal trafficking role unclear"]},{"year":2025,"claim":"Connected RAB14 to organelle quality control, showing TGN-derived Rab14 vesicles support Parkin-dependent mitophagy through mitochondria contact sites.","evidence":"siRNA/overexpression, mito-Keima assay, Parkin/TBK1/PI3K dependency, PI(4)KIIIβ inhibition, 3D contact-site imaging","pmids":["40737294"],"confidence":"Medium","gaps":["Molecular tether at Rab14-mitochondria contacts unidentified","Effector linking Rab14 to Parkin pathway unknown"]},{"year":null,"claim":"It remains unresolved how a single Rab14 compartment achieves cargo-selective sorting across its many itineraries, and what GEF/GAP/effector combinations specify each route.","evidence":"Open question synthesized across the timeline","pmids":[],"confidence":"Low","gaps":["No unified model of cargo discrimination","Effector repertoire for many cargoes (UT-A1, claudin-2, mitophagy) incompletely defined","In vivo loss-of-function phenotypes outside development largely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,5,36]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,31,35]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,3,6,28]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,8,12,32]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[13,25,35]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,33]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,28]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,8,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[18,31,34]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,6,35]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,22,27]}],"complexes":[],"partners":["RCP/FIP1C","FIP2","KIF16B","CAMK2D","CDC42","VPS39","VPS41","ADAM10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P61106","full_name":"Ras-related protein Rab-14","aliases":[],"length_aa":215,"mass_kda":23.9,"function":"The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion (PubMed:22595670). RAB14 is involved in membrane trafficking between the Golgi complex and endosomes during early embryonic development (By similarity). Regulates the Golgi to endosome transport of FGFR-containing vesicles during early development, a key process for developing basement membrane and epiblast and primitive endoderm lineages during early postimplantation development. May act by modulating the kinesin KIF16B-cargo association to endosomes (By similarity). Regulates, together with its guanine nucleotide exchange factor DENND6A, the specific endocytic transport of ADAM10, N-cadherin/CDH2 shedding and cell-cell adhesion (PubMed:22595670). Mediates endosomal tethering and fusion through the interaction with RUFY1 and RAB4B (PubMed:20534812). Interaction with RAB11FIP1 may function in the process of neurite formation (PubMed:26032412)","subcellular_location":"Recycling endosome; Early endosome membrane; Golgi apparatus membrane; Golgi apparatus, trans-Golgi network membrane; Cytoplasmic vesicle, phagosome; Cytoplasmic vesicle","url":"https://www.uniprot.org/uniprotkb/P61106/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAB14","classification":"Not Classified","n_dependent_lines":59,"n_total_lines":1208,"dependency_fraction":0.048841059602649006},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000119396","cell_line_id":"CID000420","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"GDI2","stoichiometry":10.0},{"gene":"GDI1","stoichiometry":4.0},{"gene":"SCAMP4","stoichiometry":4.0},{"gene":"CHM","stoichiometry":0.2},{"gene":"LAMP1","stoichiometry":0.2},{"gene":"LAMTOR2","stoichiometry":0.2},{"gene":"TOMM40","stoichiometry":0.2},{"gene":"TFRC","stoichiometry":0.2},{"gene":"TSPAN6","stoichiometry":0.2},{"gene":"NSF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000420","total_profiled":1310},"omim":[{"mim_id":"620562","title":"DENN DOMAIN-CONTAINING PROTEIN 6B; DENND6B","url":"https://www.omim.org/entry/620562"},{"mim_id":"620561","title":"DENN DOMAIN-CONTAINING PROTEIN 6A; DENND6A","url":"https://www.omim.org/entry/620561"},{"mim_id":"612673","title":"RAS-ASSOCIATED PROTEIN RAB14; RAB14","url":"https://www.omim.org/entry/612673"},{"mim_id":"612672","title":"RAS-ASSOCIATED PROTEIN RAB10; RAB10","url":"https://www.omim.org/entry/612672"},{"mim_id":"612465","title":"TBC1 DOMAIN FAMILY, MEMBER 4; TBC1D4","url":"https://www.omim.org/entry/612465"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RAB14"},"hgnc":{"alias_symbol":["FBP","RAB-14"],"prev_symbol":[]},"alphafold":{"accession":"P61106","domains":[{"cath_id":"3.40.50.300","chopping":"9-191","consensus_level":"high","plddt":91.3125,"start":9,"end":191}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P61106","model_url":"https://alphafold.ebi.ac.uk/files/AF-P61106-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P61106-F1-predicted_aligned_error_v6.png","plddt_mean":84.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAB14","jax_strain_url":"https://www.jax.org/strain/search?query=RAB14"},"sequence":{"accession":"P61106","fasta_url":"https://rest.uniprot.org/uniprotkb/P61106.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P61106/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P61106"}},"corpus_meta":[{"pmid":"21358675","id":"PMC_21358675","title":"MicroRNA-451 functions as a 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Constitutively active Rab14Q70L shifts distribution toward early endosome-associated vesicles, while dominant-negative S25N and N124I mutants shift distribution toward the Golgi. These manipulations partially redistribute the transferrin receptor but do not affect transferrin uptake or recycling kinetics, suggesting Rab14 functions in the biosynthetic/recycling pathway between the Golgi and endosomal compartments.\",\n      \"method\": \"Immunofluorescence, immunoelectron microscopy, overexpression of dominant-active and dominant-negative Rab14 mutants, transferrin uptake/recycling assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (IF, immunoEM, functional mutant analysis) in foundational paper; findings replicated across subsequent studies\",\n      \"pmids\": [\"15004230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Rab14 is recruited to phagosomes containing live Mycobacterium tuberculosis following phagocytosis. Knockdown of Rab14 by siRNA or overexpression of dominant-negative mutants (Rab14S25N, Rab14N125I) releases the phagosomal maturation block, allowing phagosomes to progress to phagolysosomes. Conversely, overexpression of wild-type or constitutively active Rab14Q70L prevents dead mycobacterial phagosomes from undergoing normal maturation. Mechanistically, Rab14 stimulates organellar fusion between phagosomes and early endosomes but not late endosomes.\",\n      \"method\": \"4D live-cell microscopy, siRNA knockdown, overexpression of dominant-negative and constitutively active mutants, phagosomal fusion assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (live imaging, siRNA, dominant mutants, fusion assays) with clear mechanistic readout; replicated concept in subsequent pathogen studies\",\n      \"pmids\": [\"17082769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Rab14 is part of the early endosomal AP-1 clathrin-coated microdomain at the TGN. Overexpression of a dominant-negative GTP-binding mutant that localizes exclusively to the Golgi accelerates EGF degradation, suggesting Rab14 vesicles cycle between early endosomes and Golgi cisternae within this AP-1 microdomain.\",\n      \"method\": \"Structural modeling, quantitative confocal microscopy, density centrifugation, dominant-negative overexpression, EGF degradation assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (confocal, fractionation, functional assay) in single lab\",\n      \"pmids\": [\"16962593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Rab14 interacts with apical membrane proteins and localizes to the TGN and apical endosomes in polarized epithelial cells. Expression of the GDP-locked Rab14-S25N induces TGN enlargement and vesicle accumulation around Golgi membranes, and causes mislocalization of the apical raft-associated protein VIP/MAL to the basolateral domain without disrupting basolateral targeting or recycling, indicating Rab14 specifically regulates cargo delivery from the TGN to the apical domain.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, immunofluorescence, overexpression of dominant-negative Rab14-S25N, polarity assays in epithelial cells\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus GST pulldown plus functional imaging; single lab\",\n      \"pmids\": [\"18429929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Rab14 co-immunoprecipitates with Annexin A2 in alveolar type II cells, co-localizes with Annexin A2 and lamellar bodies, and siRNA-mediated knockdown of Rab14 decreases lung surfactant secretion.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by immunofluorescence, siRNA knockdown, surfactant secretion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional knockdown readout; single lab\",\n      \"pmids\": [\"18332131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Class I Rab11-family interacting proteins (FIP2, RCP/Rab-coupling protein, Rip11) bind Rab14 in a GTP-dependent manner via their C-terminal Rab-binding domain (RBD), making them the first identified effectors of Rab14. Rab14Q70L co-localizes with Rab11a and class I FIPs at the endosomal recycling compartment during interphase. During cytokinesis, Rab14 localizes to the cleavage furrow/midbody.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by confocal microscopy, GTP-dependency binding assays\",\n      \"journal\": \"Biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GTP-dependent Co-IP plus co-localization; single lab, two methods\",\n      \"pmids\": [\"19702578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Rab14 facilitates the delivery of sphingolipids from the Golgi to Chlamydia trachomatis-containing inclusions. Dominant-negative Rab14 mutants delayed inclusion enlargement and impaired bacterial replication; siRNA silencing of Rab14 decreased bacterial multiplication and infectivity; electron microscopy showed aberrant bacteria after dominant-negative expression. Rab14 recruitment to inclusions was dependent on bacterial protein synthesis but independent of microtubules and Golgi integrity.\",\n      \"method\": \"Overexpression of dominant-negative mutants, siRNA knockdown, immunofluorescence, electron microscopy, bacterial infectivity assays (IFU), sphingolipid delivery assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA, dominant-negative, EM, lipid trafficking assay, infectivity); replicated in subsequent studies\",\n      \"pmids\": [\"21124879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KIF16B (kinesin-3 motor) directly associates with GTP-bound Rab14 on FGFR-containing vesicles and transports them toward the plasma membrane in a Golgi-to-endosome biosynthetic pathway. Kif16b knockout mouse embryos die at peri-implantation stage, phenocopying FGFR2 knockout. Dominant-negative Rab14-GDP overexpression recapitulates defects in FGFR transport, FGF signaling, basement membrane assembly, and epiblast development.\",\n      \"method\": \"Kif16b knockout mouse model, co-immunoprecipitation, dominant-negative Rab14-GDP overexpression, embryonic phenotype analysis, FGF signaling assays, basement membrane immunostaining\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo genetic knockout combined with biochemical interaction (Co-IP) and dominant-negative rescue; multiple orthogonal methods\",\n      \"pmids\": [\"21238925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Rab14 and its GDP-GTP exchange factor FAM116A define an intermediate recycling compartment in the transferrin-recycling pathway, positioned after Rab5/Rab4 and before Rab11. Rab14-depleted cells accumulate ADAM10 in a transferrin-positive endocytic compartment, reduce ADAM10 cell-surface levels, decrease ADAM10-mediated shedding of N-cadherin, and consequently cannot resolve cell-cell junctions, impairing cell migration.\",\n      \"method\": \"siRNA depletion, confocal microscopy, transferrin recycling assays, cell surface ADAM10 measurements, N-cadherin shedding assays, migration assays, identification of FAM116A as GEF by yeast two-hybrid/functional assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA, trafficking assays, surface protein quantitation, functional migration assay) establishing pathway position and molecular mechanism\",\n      \"pmids\": [\"22595670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Rab14 co-localizes with IRAP and syntaxin 6 in regulated endosomal storage compartments in conventional dendritic cells (cDCs). Increased recruitment of an IRAP+/Rab14+ compartment to antigen-containing vesicles correlates with superior cross-presentation efficacy of CD8+ cDCs.\",\n      \"method\": \"Immunofluorescence co-localization, IRAP-deficient DC analysis, cross-presentation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-localization study without direct mechanistic manipulation of Rab14\",\n      \"pmids\": [\"22238454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rab14 binds to the C-terminus of the UT-A1 urea transporter preferentially in the GDP-bound inactive form (identified by yeast two-hybrid). Co-injection of Rab14 in Xenopus oocytes decreases UT-A1 urea transport activity by reducing cell membrane expression of UT-A1 via clathrin-mediated endocytosis (blocked by chlorpromazine but not filipin). Rab14 co-distributes with Rab5 in non-lipid raft microdomains in kidney inner medullary cells.\",\n      \"method\": \"Yeast two-hybrid, Xenopus oocyte co-injection/transport assay, cell surface biotinylation, pharmacological inhibition (chlorpromazine/filipin), co-localization with Rab5 marker\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reconstitution in Xenopus oocytes (functional transport assay), yeast two-hybrid interaction, and pharmacological dissection of endocytic pathway; multiple orthogonal methods in single paper\",\n      \"pmids\": [\"23796783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rab11a-FIP1C/RCP is required for HIV-1 envelope glycoprotein (Env) incorporation onto particles in a cytoplasmic tail-dependent manner. Rab14 is required for HIV-1 Env incorporation; FIP1C mutants unable to bind Rab14 fail to rescue Env incorporation. FIP1C is redistributed by wild-type Env CT to the plasma membrane. This defines a Rab14-FIP1C endocytic recycling pathway mediating Env targeting to the assembly microdomain.\",\n      \"method\": \"siRNA depletion, dominant-negative and rescue experiments, FIP1C Rab14-binding mutants, viral particle assembly assays, Western blotting\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal siRNA knockdown, Rab14-binding mutant rescue experiments, and functional viral incorporation assay; multiple orthogonal methods\",\n      \"pmids\": [\"23592992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rab14 controls transit of internalized GLUT4 through early endosomal compartments toward the perinuclear region in 3T3-L1 adipocytes. Constitutively active Rab14Q70L reduces basal and insulin-stimulated cell-surface GLUT4 by retaining GLUT4 in an insulin-insensitive early endosomal compartment. shRNA-mediated Rab14 depletion inhibits GLUT4 transit from early endosomes to perinuclear vesicles/tubules. Overexpressed Rab14/Rab14Q70L creates enlarged ring-like early endosomal structures (~1.3 µm) that rapidly accumulate GLUT4 and transferrin by endocytosis.\",\n      \"method\": \"Confocal microscopy, shRNA knockdown, overexpression of WT and Q70L/S25N mutants, cell-surface GLUT4 quantification\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (shRNA, constitutively active/dominant-negative mutants, surface quantitation, live imaging) in same study\",\n      \"pmids\": [\"23444368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rab14 knockdown in MDCK cells increases transepithelial resistance and substantially depletes claudin-2 (a leaky claudin), without affecting claudin-1, ZO-1, or occludin. Claudin-2 loss is rescued by lysosomal inhibition, indicating Rab14 sorts claudin-2 away from the lysosomal degradation pathway. Rab14 knockdown in 3D culture causes failure to form normal single-lumen cysts. MDCK I cells lacking claudin-2 endogenously show no change in TER upon Rab14 knockdown, confirming specificity.\",\n      \"method\": \"siRNA knockdown, transepithelial resistance measurement, immunofluorescence, lysosomal inhibition rescue, 3D culture lumen morphogenesis assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA, TER, rescue with lysosomal inhibitor, 3D culture) with rigorous specificity controls\",\n      \"pmids\": [\"24694596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PKCι directly interacts with Rab14 (shown by ELISA and co-immunoprecipitation). PKCι and Rab14 co-localize in intracellular puncta and at the plasma membrane. PKCι knockdown decreases claudin-2 levels; Rab14 expression is required for normal PKCι distribution in 3D cysts. The data indicate PKCι and Rab14 interact to regulate claudin-2 trafficking out of the lysosome-directed pathway.\",\n      \"method\": \"Co-immunoprecipitation, ELISA, immunofluorescence co-localization, siRNA knockdown, 3D cyst culture\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP/ELISA plus functional knockdown evidence; single lab\",\n      \"pmids\": [\"25694446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of Rab14 in complex with the Rab-binding domain of RCP (Rab-coupling protein/FIP1C) reveals Rab14 binds RCP with reduced affinity compared to Rab11/25 and with a noncanonical 1:2 stoichiometry (Rab14:RCP) in dilute solution. In vivo, Rab11 (not Rab14) recruits RCP onto biological membranes. Both RCP and Rab14 function in neuritogenesis.\",\n      \"method\": \"X-ray crystallography, isothermal titration calorimetry, yeast two-hybrid, co-localization, neuritogenesis functional assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus thermodynamic measurements plus functional cellular assay; multiple rigorous methods in single paper\",\n      \"pmids\": [\"26032412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rab14 knockdown disrupts polarized lipid domains and prevents the Par/aPKC/Cdc42 polarity complex from localizing to the apical membrane during de novo polarity establishment. These effects are mediated through lipid localization, as overexpression of PtdIns(4)P5K activator Arf6, PtdIns(4)P5K alone, or PI3K inhibition (wortmannin) rescues the multi-apical phenotype. Rab14 co-immunoprecipitates and co-localizes with Cdc42; Rab14 knockdown increases Cdc42 activity. Rab14 also regulates mitotic spindle orientation and midbody position.\",\n      \"method\": \"siRNA knockdown, overexpression of Arf6/PtdIns(4)P5K, pharmacological rescue (wortmannin), co-immunoprecipitation, Cdc42 activity assay, 3D MDCK culture, confocal microscopy\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (siRNA, genetic rescue, pharmacological rescue, Co-IP, activity assay) with rigorous controls\",\n      \"pmids\": [\"27901125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rab14 limits sorting of Glut4 from sorting endosomes into the specialized insulin-regulated GSV (Glut4 storage vesicle) pathway in adipocytes. Both overexpression and knockdown of Rab14 decrease Glut4 plasma membrane translocation. Kinetic analysis supports that Rab14 controls sorting at the early/sorting endosome step, consistent with AS160 (a Rab GAP) regulating both Rab14 and Rab10 sequentially to control GSV entry and exocytosis.\",\n      \"method\": \"Rab14 knockdown, kinetic trafficking assays measuring Glut4 vs transferrin receptor vs LRP1, mathematical modeling of trafficking kinetics\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative kinetic trafficking measurements with knockdown; single lab, single approach\",\n      \"pmids\": [\"26936971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rab14 depletion in Drosophila fat body cells causes abnormal clustering of autophagosomes and lysosomes and reduces autophagosome-lysosome fusion. The kinesin Klp98A (ortholog of KIF16B) interacts with and co-localizes with Rab14, and requires Rab14 for normal localization. Rab14 is required for Klp98A-mediated autophagosome-lysosome fusion but not for vesicle positioning, indicating fusion and localization are separable events.\",\n      \"method\": \"Genetic depletion (Drosophila), co-immunoprecipitation/co-localization of Klp98A and Rab14, autophagy flux assays, autophagosome-lysosome fusion quantification\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Drosophila genetic model with Co-IP interaction and functional fusion assay; single lab\",\n      \"pmids\": [\"26763909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Phosphorylation of RCP (Rab-coupling protein) at Ser435 by LMTK3 and of EphA2 at Ser897 by Akt together promote Rab14-dependent (and Rab11-independent) trafficking of EphA2 to drive cell-cell repulsion and metastasis in vivo. Genetic disruption of RCP or EphA2 opposes cell-cell repulsion and metastasis in an autochthonous mouse model of pancreatic adenocarcinoma.\",\n      \"method\": \"Phospho-specific mutants, kinase assays, RCP/EphA2 conditional knockout mouse model, cell repulsion assays, in vivo metastasis quantification\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo genetic mouse model combined with biochemical phosphorylation analysis and mechanistic mutants; multiple orthogonal approaches\",\n      \"pmids\": [\"28294115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Electrical pulse stimulation (EPS)-induced GLUT4 translocation in C2C12 myotubes requires Rab8a, Rab13, and Rab14 (siRNA knockdown of each partially reduces GLUT4 translocation), while AICAR (AMPK-mediated) GLUT4 translocation requires Rab8a and Rab14 but not Rab13 or Rab10.\",\n      \"method\": \"siRNA knockdown of individual Rabs, HA-GLUT4 surface quantitation, EPS contraction model, AMPK/CaMKII phosphorylation assays\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic siRNA knockdown of multiple Rabs with quantitative surface GLUT4 readout; single lab\",\n      \"pmids\": [\"29089333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CHML (choroideremia-like) promotes HCC cell metastasis by facilitating Rab14 recycling to the membrane. CHML escorts Rab14 to the membrane, enabling constant Rab14 recycling. Metastasis-promoting cargoes on Rab14-positive vesicles include Mucin13 and CD44. CHML-mediated migration, invasion, and metastasis require Rab14.\",\n      \"method\": \"Co-immunoprecipitation, Rab14 knockdown, overexpression, vesicle cargo identification, in vivo metastasis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional knockdown, and in vivo assays; single lab\",\n      \"pmids\": [\"31175290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"C. trachomatis activates the Akt/AS160 signaling pathway to promote Rab14-controlled sphingolipid delivery to chlamydial inclusions. C. trachomatis induces Akt phosphorylation and recruits phospho-Akt to the inclusion membrane, inactivating the Rab14-GAP AS160/TBC1D4 by phosphorylation, thereby maintaining Rab14 in the GTP-bound active state. Akt inhibition prevents AS160 phosphorylation, reduces Rab14 recruitment to inclusions, impairs sphingolipid acquisition, and decreases bacterial multiplication.\",\n      \"method\": \"Akt inhibitor (iAkt), siRNA knockdown of AS160, phospho-Western blotting, Rab14 recruitment quantification, sphingolipid trafficking assay, bacterial infectivity (IFU), electron microscopy\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological inhibition, genetic siRNA knockdown, biochemical phosphorylation analysis, lipid trafficking assay, and EM; multiple orthogonal methods\",\n      \"pmids\": [\"31001235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rab14 functions in the trafficking of Ebola virus matrix protein VP40. Proximity proteomics (BioID) identified Rab14 as a VP40-proximal protein at late stages of VP40 expression. VP40 and Rab14 substantially co-localize in HeLa cells. Overexpression of dominant-negative Rab14(S25N) diminishes VP40 plasma membrane localization. Secreted VP40 can be endocytosed into Rab14-positive compartments.\",\n      \"method\": \"BioID proximity proteomics, co-localization imaging, dominant-negative Rab14(S25N) overexpression, plasma membrane localization assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — BioID screen plus imaging plus dominant-negative functional assay; single lab\",\n      \"pmids\": [\"32327259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RAB14 is required for actin-based asymmetric division during mouse oocyte meiotic maturation. RAB14 localizes in the cytoplasm and accumulates at the cortex and spindle periphery during maturation. RAB14 depletion (siRNA) causes spindle migration defects and large polar bodies (failure of asymmetric division) without affecting spindle organization, mediated through the ROCK-cofilin signaling pathway for cytoplasmic actin assembly. RAB14 depletion also causes aberrant Golgi distribution. Rescue by exogenous Myc-Rab14 mRNA confirms specificity.\",\n      \"method\": \"Microinjection of siRNA and rescue mRNA, immunofluorescence for spindle/actin/Golgi, ROCK-cofilin pathway analysis (Western blot), polar body extrusion assay\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with mRNA rescue plus pathway analysis; single lab\",\n      \"pmids\": [\"34323331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rab14 defines a novel endocytic pathway for cationic substances (cell-penetrating peptides, polyamines, homeodomains) that is fully independent of Rab5 and Rab7, leading to non-acidic LAMP1-positive late endosomes. The pathway diverges from conventional clathrin-mediated endocytosis and macropinocytosis at the vesicle formation stage.\",\n      \"method\": \"siRNA knockdown of Rab14, Rab5, and Rab7, pharmacological inhibitors of clathrin-mediated endocytosis and macropinocytosis, live-cell imaging with fluorescent CPPs, LAMP1 co-localization\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic siRNA knockdown of multiple Rab GTPases plus pharmacological dissection plus multiple cargo types; multiple orthogonal methods\",\n      \"pmids\": [\"34731620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Endocytosed HIV-1 envelope glycoprotein (Env) traffics to Rab14-positive compartments that possess hallmarks of late endosomes and lysosomes in infected CD4+ T-cell lines, where it can be recycled back to the plasma membrane. This defines a T-cell-specific late-endosomal/lysosomal Rab14-positive pathway for Env trafficking.\",\n      \"method\": \"Pulse-labeling with monovalent anti-Env Fab probe, CRISPR/Cas9 endogenous tagging of Rab GTPases, confocal microscopy, recycling assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR endogenous tagging combined with pulse-chase tracking; single lab\",\n      \"pmids\": [\"35770989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Geranylgeranylation of RAB14 (catalyzed by GGTase II) is required for phosphorylation of AKT at Ser473 and normal hepatic insulin signaling and glucose metabolism. Geranylgeranylation-deficient RAB14 inhibits mTORC2 complex assembly, disrupting AKT phosphorylation. Geranylgeranyl pyrophosphate supplementation rescues simvastatin-caused disruption of hepatic insulin signaling in vitro, and geranylgeraniol (GGOH) ameliorates statin-induced systemic glucose disorders in vivo.\",\n      \"method\": \"siRNA screen (small-scale), GGTase II inhibition/RABGGTA knockdown (AAV8 in vivo), GGPP/GGOH supplementation, AKT phosphorylation assays (Western blot), mTORC2 complex assembly assay, in vivo glucose metabolism tests\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV8 knockdown plus in vitro mechanistic studies; single lab but multiple methods\",\n      \"pmids\": [\"34995578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CSFV NS5A recruits Rab14 to the ER, followed by Rab14-dependent ceramide transport to the Golgi apparatus where sphingomyelin is synthesized. The PI3K/AKT/AS160 signaling pathway regulates this Rab14-controlled ceramide transport; blocking this pathway reduces sphingomyelin content at the Golgi and impairs viral particle assembly.\",\n      \"method\": \"Rab14 knockdown/overexpression, co-localization and interaction assays, small-molecule PI3K/AKT/AS160 inhibitors, lipid quantification, viral assembly assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional approaches (knockdown, pharmacological, lipid assay, viral assembly); single lab\",\n      \"pmids\": [\"37255314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AMPK activation promotes Rab14-dependent ADAM10 cell-surface translocation in human aortic endothelial cells. Rab14 siRNA knockdown prevents AICAR-induced ADAM10 surface translocation and RAGE ectodomain shedding, placing Rab14 downstream of AMPK in the ADAM10 trafficking pathway.\",\n      \"method\": \"AICAR treatment, AMPK inhibitor (Compound C), AMPKα1-siRNA, Rab14-siRNA, ADAM10 cell-surface ELISA, RAGE shedding assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological plus genetic siRNA evidence with functional shedding assay; single lab\",\n      \"pmids\": [\"37451218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCN2 interacts with Rab14 through its IGFBP-like domain. Co-expression of CCN2 and Rab14 in COS7 cells redistributes Rab14 from diffuse cytosolic to dot-like vesicular structures that co-localize with CCN2. Dominant-negative Rab14DN reduces extracellular proteoglycan accumulation in chondrocytes. siRNA knockdown of Rab14 or CCN2 induces ER/Golgi stress markers (BIP, CHOP), suggesting they cooperate in proteoglycan-containing vesicle transport from the Golgi to endosomes.\",\n      \"method\": \"Yeast two-hybrid, in situ proximity ligation assay, overexpression of WT/CA/DN Rab14, proteoglycan secretion assay, siRNA knockdown, qRT-PCR for ER stress markers\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus PLA plus functional mutant analysis; single lab\",\n      \"pmids\": [\"32316324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RAB14 is a regulator of autophagosome maturation. In rab14-KO MDCK cells, LC3-II levels are altered, indicating autophagy defect specifically at the autophagosome maturation step. Double KO of rab2 and rab14 causes a severer autophagy defect than either single KO, demonstrating overlapping roles. RAB14 localizes to autophagosomes and interacts with the HOPS complex subunits VPS39 and VPS41 (confirmed by co-immunoprecipitation), similar to RAB2.\",\n      \"method\": \"Comprehensive rab-KO library in MDCK cells, LC3-II level quantification, basal and starvation-induced autophagy assays, co-immunoprecipitation of HOPS subunits, autophagosome localization imaging\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic knockout library with double KO epistasis, Co-IP of HOPS subunits, and autophagosome localization; multiple orthogonal methods\",\n      \"pmids\": [\"38953305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A complex of SHIP164, RhoBTB3 (ATPase), and Vps26B (retromer subunit) promotes formation of early endosome buds at Golgi-EE contact sites. Vps26B acts as a novel Rab14 effector; Rab14 activity regulates SHIP164 association with early endosomes. Depletion of SHIP164 causes enlarged Rab14+ EEs without buds, rescued by WT SHIP164 but not lipid-transfer-defective mutants. Suppression of RhoBTB3 or Vps26B mirrors SHIP164 depletion effects.\",\n      \"method\": \"Co-immunoprecipitation, siRNA depletion, overexpression of lipid-transfer-defective SHIP164 mutants, live imaging of EE bud formation, Golgi-EE contact site analysis\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple components of a defined complex characterized by Co-IP and functional mutant rescue; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"38565878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AKT activation (via SC79) translocates ADAM10 to the cell surface in human aortic endothelial cells through Rab14. Rab14 co-immunoprecipitates with ADAM10; after AKT activation Rab14 moves to the cell surface. siRNA-mediated Rab14 knockdown prevents AKT-induced ADAM10 surface translocation and RAGE ectodomain shedding, and abolishes AKT's ability to inhibit AGE-BSA-induced ICAM-1 expression.\",\n      \"method\": \"Co-immunoprecipitation of Rab14 with ADAM10, siRNA knockdown of Rab14 and AKT isoforms, surface ADAM10 quantification, RAGE shedding assay, ICAM-1 expression assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional siRNA knockdown with multiple downstream readouts; single lab\",\n      \"pmids\": [\"40032916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Rab14 promotes Parkin-dependent mitophagy. Rab14 knockdown causes mitochondrial elongation and accumulation of mitochondrial proteins; Rab14 overexpression increases mitophagy (mito-Keima assay) in a Parkin-, TBK1-, and PI3K-dependent manner. 3D reconstruction reveals Rab14-mitochondria contact sites; PI(4)KIIIβ inhibition (TGN kinase) decreases these contacts and prevents Rab14-mediated mitophagy, suggesting TGN-derived Rab14 vesicles mediate the mitophagic process.\",\n      \"method\": \"siRNA knockdown, Rab14 overexpression, mito-Keima mitophagy assay, PI(4)KIIIβ inhibitor, Parkin/TBK1 dependency experiments, 3D reconstruction of contact sites\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression/knockdown plus pathway epistasis (Parkin, TBK1, PI3K, PI(4)KIIIβ) plus 3D contact site imaging; single lab\",\n      \"pmids\": [\"40737294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"GTP-bound Rab14 acts as a broad-spectrum restriction factor against multiple bacteria and viruses by promoting V-ATPase delivery to lysosomes and lysosomal acidification. Mechanistically, active Rab14 binds CAMK2D and suppresses CAMK2D-mediated phosphorylation of V0a1 (the V-ATPase subunit determining lysosomal localization), thereby promoting V0a1 interaction with the COPII complex and facilitating V-ATPase trafficking from the ER to lysosomes.\",\n      \"method\": \"Screen for lysosomal acidification factors, Co-immunoprecipitation (Rab14-CAMK2D interaction), CAMK2D kinase assay (V0a1 phosphorylation), COPII complex binding assay, lysosomal acidification assays, pathogen clearance experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection using Co-IP, kinase assay, trafficking experiments, and functional pathogen clearance; multiple orthogonal methods in single study\",\n      \"pmids\": [\"41771894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Rab14 is required for human papillomavirus (HPV) transport to the trans-Golgi network (TGN) for infectious cell entry. Rab14 KO cells resist HPV pseudovirion (PsV) infection; wild-type Rab14 re-expression restores infection. Neither GDP-locked (S25N) nor GTP-locked (Q70L) mutants rescue infection, indicating that Rab14 GTPase cycling (not just one nucleotide state) is required. GDP-bound Rab14(S25N) preferentially localizes to the TGN while GTP-bound Rab14(Q70L) co-localizes with both early endosomes and TGN.\",\n      \"method\": \"Rab14 KO (CRISPR), wild-type and nucleotide-state mutant rescue, confocal microscopy tracking of PsV and Rab14 localization, infectivity assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO plus nucleotide-state mutant rescue with functional infectivity readout; single lab\",\n      \"pmids\": [\"42186738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The RCP-RAB14 axis mediates surface delivery of MET receptor tyrosine kinase through tubulovesicular carriers to invadopodia in TNBC cells, with KIF16B promoting formation of vesicular tubules on RAB14-positive endosomes. HGF stimulation enhances MET recycling to invadopodia via this pathway, driving MT1-MMP delivery and matrix degradation.\",\n      \"method\": \"Degradation-defective MET mutant, KIF16B manipulation, RCP knockdown, RAB14-positive endosome imaging, invadopodium functional assays, MET surface delivery tracking\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, imaging-dominant with limited biochemical validation of the Rab14-specific interactions\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RAB14 is a GTP-cycling small GTPase that operates at early endosomes and the trans-Golgi network to regulate bidirectional membrane trafficking: it facilitates Golgi-to-endosome and endosome-to-plasma-membrane transport of diverse cargoes (GLUT4, ADAM10/N-cadherin, EphA2, FGFR, claudin-2, HIV Env, UT-A1, MET, ceramide/sphingolipids) via its class I Rab11-FIP effectors (RCP/FIP1C, FIP2, Rip11); its activity is controlled by the GAP AS160/TBC1D4 (regulated by Akt/AMPK signaling) and the GEF FAM116A; it is geranylgeranylated by GGTase II for membrane attachment; it interacts with CAMK2D to promote V-ATPase lysosomal delivery and acidification for pathogen clearance; and it plays defined roles in phagosomal maturation, autophagosome maturation (via HOPS complex recruitment in concert with RAB2), Parkin-dependent mitophagy (via TGN contact sites), apical membrane specification, epithelial polarity (via Arf6/Cdc42), cytokinesis, and oocyte asymmetric division through ROCK-cofilin-regulated actin dynamics.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAB14 is a GTP-cycling small GTPase that operates between the trans-Golgi network and the endosomal system to direct bidirectional membrane trafficking of diverse cargoes, occupying an intermediate recycling compartment positioned after Rab5/Rab4 and before Rab11 [#0, #8]. Its activity depends on a nucleotide cycle—both GDP- and GTP-locked mutants fail to support its functions—and on geranylgeranylation by GGTase II for membrane attachment [#27, #36]. Cargo routing through RAB14 governs surface delivery and post-endocytic sorting of ADAM10 (controlling N-cadherin and RAGE shedding) [#8, #29, #33], the leaky tight-junction protein claudin-2 (which it diverts from lysosomal degradation) [#13], GLUT4 in adipocytes and myotubes downstream of insulin/AMPK signaling via the GAP AS160/TBC1D4 [#12, #17, #20], the urea transporter UT-A1 [#10], and FGFR via the kinesin-3 motor KIF16B [#7]. RAB14 acts through class I Rab11-FIP effectors (FIP2, RCP/FIP1C, Rip11) bound in a GTP-dependent manner, and structurally engages the RCP Rab-binding domain with noncanonical stoichiometry and lower affinity than Rab11 [#5, #15]. Beyond constitutive transport, RAB14 controls phagosomal and autophagosome maturation—the latter via direct interaction with HOPS subunits VPS39/VPS41 in overlapping roles with RAB2 [#1, #31]—drives lysosomal acidification by binding CAMK2D to promote V-ATPase delivery as a broad-spectrum antimicrobial restriction factor [#35], and mediates epithelial apical polarity and lumen morphogenesis through lipid-dependent recruitment of the Par/aPKC/Cdc42 complex [#3, #16]. Numerous pathogens co-opt RAB14, including Chlamydia and CSFV (Golgi-derived sphingolipid/ceramide delivery, sustained by Akt-mediated AS160 inactivation) [#6, #22, #28] and HIV-1 Env incorporation via the RCP/FIP1C pathway [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established RAB14's basic residence and itinerary—whether it acts in the biosynthetic versus endocytic system—by mapping its localization and the effect of nucleotide-state mutants.\",\n      \"evidence\": \"Immunofluorescence, immunoEM, and dominant-active/negative mutant analysis with transferrin assays\",\n      \"pmids\": [\"15004230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No effectors or cargo identified\", \"Did not establish how Rab14 selects between Golgi and endosomal compartments\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined RAB14's first physiological role: it arrests phagosome maturation by promoting phagosome–early endosome fusion, a process exploited by intracellular mycobacteria.\",\n      \"evidence\": \"Live-cell imaging, siRNA, dominant mutants, and phagosomal fusion assays in M. tuberculosis infection\",\n      \"pmids\": [\"17082769\", \"16962593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effectors mediating fusion not identified\", \"Link to AP-1 microdomain partner only Medium-confidence\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended RAB14 into polarized epithelial and secretory trafficking, showing it directs cargo from the TGN to the apical domain and supports lamellar-body surfactant secretion.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, dominant-negative imaging in epithelia; Co-IP/knockdown with Annexin A2 in alveolar cells\",\n      \"pmids\": [\"18429929\", \"18332131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apical cargo receptor mechanism undefined\", \"Annexin A2 interaction not placed in a defined pathway step\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified the first RAB14 effectors—class I Rab11-FIPs—establishing how RAB14 connects to the recycling machinery and to cytokinesis.\",\n      \"evidence\": \"GTP-dependent Co-IP and confocal co-localization of FIP2/RCP/Rip11 with Rab14\",\n      \"pmids\": [\"19702578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of each FIP interaction not dissected\", \"Shared use of FIPs with Rab11 not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked RAB14 to a motor and a developmental program, showing KIF16B transports GTP-Rab14/FGFR vesicles in a Golgi-to-surface biosynthetic route essential for embryogenesis.\",\n      \"evidence\": \"Kif16b knockout mouse, Co-IP, dominant-negative Rab14 rescue, FGF signaling and basement membrane analysis\",\n      \"pmids\": [\"21238925\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Rab14 GEF/GAP regulating this route not identified at the time\", \"Did not address other KIF16B cargoes\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Positioned RAB14 precisely within the recycling cascade and identified its GEF FAM116A, defining ADAM10 trafficking and N-cadherin shedding as a downstream output controlling cell migration.\",\n      \"evidence\": \"siRNA, transferrin recycling kinetics, surface ADAM10 and N-cadherin shedding/migration assays; GEF identification by yeast two-hybrid\",\n      \"pmids\": [\"22595670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FAM116A activation not defined\", \"ADAM10 sorting determinant on Rab14 vesicles unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Generalized RAB14 as a cargo-sorting hub, showing it routes GLUT4 through early endosomes, recycles UT-A1, and—via RCP/FIP1C—delivers HIV-1 Env to the assembly site.\",\n      \"evidence\": \"shRNA/mutant GLUT4 surface assays in adipocytes; Xenopus oocyte UT-A1 transport; FIP1C Rab14-binding mutant rescue of HIV Env incorporation\",\n      \"pmids\": [\"23444368\", \"23796783\", \"23592992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single Rab14 compartment discriminates among GLUT4, UT-A1, and Env unclear\", \"Insulin-regulated GAP linkage to GLUT4 not yet established here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided the structural and thermodynamic basis of the RAB14–RCP interaction, revealing noncanonical 1:2 binding and lower affinity than Rab11, clarifying effector sharing.\",\n      \"evidence\": \"X-ray crystallography, ITC, yeast two-hybrid, neuritogenesis assays\",\n      \"pmids\": [\"26032412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of the 1:2 stoichiometry not resolved\", \"Membrane recruitment shown to depend on Rab11 rather than Rab14\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined RAB14's role in de novo epithelial polarity and lumen morphogenesis through lipid-dependent recruitment of the Par/aPKC/Cdc42 complex, and its sorting of claudin-2 away from lysosomes (with PKCι).\",\n      \"evidence\": \"siRNA, Arf6/PI5K and wortmannin rescue, Cdc42 activity and Co-IP assays; TER and 3D cyst assays with lysosomal-inhibition rescue\",\n      \"pmids\": [\"27901125\", \"24694596\", \"25694446\", \"26936971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct lipid species regulated by Rab14 not defined\", \"Mechanism coupling Rab14 to Cdc42 activity state unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated regulated, signaling-driven RAB14 trafficking in disease, with kinase phosphorylation of RCP and EphA2 routing EphA2 through a Rab14-dependent pathway to drive metastasis.\",\n      \"evidence\": \"Phospho-mutants, kinase assays, RCP/EphA2 conditional knockout mouse, repulsion and metastasis assays\",\n      \"pmids\": [\"28294115\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation switches cargo from Rab11 to Rab14 route mechanistically unclear\", \"Generality beyond pancreatic adenocarcinoma not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the prenyl escort CHML as enabling continuous RAB14 membrane recycling and linked Rab14 cargo (Mucin13, CD44) to metastatic invasion.\",\n      \"evidence\": \"Co-IP, Rab14 knockdown/overexpression, cargo identification, in vivo metastasis assays in HCC\",\n      \"pmids\": [\"31175290\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CHML escort mechanism not biochemically reconstituted\", \"Single tumor context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed RAB14 in autophagosome maturation, showing it binds HOPS subunits VPS39/VPS41 and acts in overlapping fashion with RAB2 at the fusion step.\",\n      \"evidence\": \"Comprehensive rab-KO MDCK library, LC3-II quantitation, rab2/rab14 double-KO epistasis, HOPS Co-IP\",\n      \"pmids\": [\"38953305\", \"26763909\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct contribution of Rab14 versus Rab2 to HOPS tethering not separated\", \"Nucleotide regulation at autophagosomes undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a RAB14 effector–machinery (SHIP164/RhoBTB3/Vps26B) that forms early-endosome buds at Golgi-EE contact sites, with Vps26B as a novel effector.\",\n      \"evidence\": \"Co-IP, siRNA, lipid-transfer-defective mutant rescue, live imaging of EE bud formation\",\n      \"pmids\": [\"38565878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Rab14 activity gates SHIP164 recruitment mechanistically unresolved\", \"Cargo carried by these buds not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established a non-trafficking signaling output: GTP-RAB14 binds CAMK2D to suppress V0a1 phosphorylation, promoting V-ATPase delivery and lysosomal acidification as broad antimicrobial restriction.\",\n      \"evidence\": \"Acidification screen, Rab14-CAMK2D Co-IP, V0a1 kinase assay, COPII binding, pathogen clearance assays\",\n      \"pmids\": [\"41771894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How active Rab14 inhibits CAMK2D catalysis structurally undefined\", \"Relationship between this role and its endosomal trafficking role unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected RAB14 to organelle quality control, showing TGN-derived Rab14 vesicles support Parkin-dependent mitophagy through mitochondria contact sites.\",\n      \"evidence\": \"siRNA/overexpression, mito-Keima assay, Parkin/TBK1/PI3K dependency, PI(4)KIIIβ inhibition, 3D contact-site imaging\",\n      \"pmids\": [\"40737294\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular tether at Rab14-mitochondria contacts unidentified\", \"Effector linking Rab14 to Parkin pathway unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single Rab14 compartment achieves cargo-selective sorting across its many itineraries, and what GEF/GAP/effector combinations specify each route.\",\n      \"evidence\": \"Open question synthesized across the timeline\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model of cargo discrimination\", \"Effector repertoire for many cargoes (UT-A1, claudin-2, mitophagy) incompletely defined\", \"In vivo loss-of-function phenotypes outside development largely uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 5, 36]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 31, 35]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 3, 6, 28]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 8, 12, 32]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [13, 25, 35]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 33]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 8, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [18, 31, 34]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 6, 35]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 22, 27]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RCP/FIP1C\", \"FIP2\", \"KIF16B\", \"CAMK2D\", \"CDC42\", \"VPS39\", \"VPS41\", \"ADAM10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}