{"gene":"EXOC6","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1989,"finding":"Sec15 (yeast ortholog of EXOC6) functions at a late stage of the secretory pathway and responds to the Sec4 GTP-binding protein to control vesicular traffic; overproduction of Sec15 leads to accumulation of secretory vesicles, and sec4-8 and sec2-41 mutations prevent Sec15 protein patch formation","method":"Genetic suppression analysis, immunofluorescence, overexpression phenotype in yeast","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple mutant backgrounds, replicated functional readouts","pmids":["2504727"],"is_preprint":false},{"year":1991,"finding":"Yeast Sec15p (EXOC6 ortholog) associates with the plasma membrane (23% of total) and with a soluble 19.5S particle; its membrane attachment is regulated by Sec8 and Sec10, as sec8-9 and sec10-2 mutations shift Sec15p to the plasma membrane","method":"Subcellular fractionation, sucrose gradient sedimentation, genetic analysis with sec mutants","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — biochemical fractionation combined with genetic analysis across multiple mutant backgrounds","pmids":["1900300"],"is_preprint":false},{"year":1995,"finding":"Sec6 (yeast EXOC6 ortholog) is a stable component of the Sec6/8/15 multisubunit exocyst complex (~1-2 MDa); co-fractionates with Sec8 and Sec15 by affinity chromatography, gel filtration, and sucrose velocity centrifugation, and the complex localizes to small bud tips (sites of exocytosis)","method":"Immobilized metal affinity chromatography, co-immunoprecipitation, gel filtration, sucrose gradient centrifugation, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical methods establishing complex composition and localization; foundational paper with 257 citations","pmids":["7615633"],"is_preprint":false},{"year":2001,"finding":"The mammalian exocyst complex (including rSec6 and rSec8, EXOC6 orthologs) interacts with RalA in a GTP-dependent manner in brain nerve terminals, placing the exocyst as an effector for activated RalA in directing sites of exocytosis","method":"GTP-dependent pulldown from brain lysates, MALDI-TOF MS identification, Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — GTP-dependent binding demonstrated by pulldown with MS confirmation; replicated with Western blot for specific subunits","pmids":["11406615"],"is_preprint":false},{"year":2004,"finding":"Mammalian Sec15 (EXOC6) localizes to Rab11-positive recycling endosomal tubular/vesicular clusters in the perinuclear region and exhibits GTP-dependent interaction with Rab11, but not Rab4, Rab6, or Rab7, establishing the exocyst as a Rab11 effector complex in mammalian cells","method":"Colocalization by immunofluorescence, co-immunoprecipitation with GTP/GDP-locked Rab11 mutants, transferrin endocytosis assay, nocodazole treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — GTP-dependent interaction specificity demonstrated with multiple Rab GTPases, supported by colocalization and trafficking assay","pmids":["15292201"],"is_preprint":false},{"year":2005,"finding":"Drosophila Sec15 (EXOC6 ortholog) regulates DE-Cadherin trafficking from Rab11 recycling endosomes to the plasma membrane; loss of sec5, sec6, or sec15 causes accumulation of DE-Cad in enlarged Rab11 compartments and inhibits DE-Cad membrane delivery","method":"Loss-of-function genetics in Drosophila epithelial cells, immunofluorescence, co-immunoprecipitation (Rab11-Sec15, Armadillo-Sec10)","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function combined with molecular interaction data; 231 citations","pmids":["16224820"],"is_preprint":false},{"year":2005,"finding":"Drosophila Sec15 (EXOC6 ortholog) is required for Delta recycling to ensure proper Notch signaling during asymmetric SOP division; sec15 mutants accumulate Notch/Sanpodo/Delta in basal vesicles, and Sec15 colocalizes with Rab11 recycling endosomes","method":"Genetic screen, loss-of-function clonal analysis, immunofluorescence colocalization with Rab11 and trafficking markers","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function with defined cell fate phenotype and molecular colocalization evidence; 161 citations","pmids":["16137928"],"is_preprint":false},{"year":2005,"finding":"Drosophila Sec15 (EXOC6 ortholog) is required for neuronal targeting of photoreceptors and localization of specific cell adhesion/signaling molecules; loss of sec15 causes mislocalization of Sec5 and Sec8 but not Sec6 at neuronal terminals, suggesting Sec15 participates in an exocyst subcomplex with separable functions","method":"Genetic loss-of-function screen, immunofluorescence of exocyst subunit localization in sec15 mutant neurons","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis establishing differential subunit dependencies; 119 citations","pmids":["15848801"],"is_preprint":false},{"year":2010,"finding":"Anthrax toxins EF and LF convergently inhibit the Rab11/Sec15 exocyst at the last step of endocytic recycling: EF reduces Rab11 levels and indirectly blocks Sec15-GFP vesicle formation, while LF more directly reduces Sec15-GFP vesicles, inhibiting Notch/Delta signaling and cadherin expression in both Drosophila and human endothelial cells","method":"Drosophila genetics, live imaging of Sec15-GFP vesicles, human endothelial cell experiments with toxin treatment, immunofluorescence","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — mechanistic perturbation with defined molecular readouts validated in two species; published in Nature with 87 citations","pmids":["20944747"],"is_preprint":false},{"year":2013,"finding":"NDR2-phosphorylated Rabin8 (at Ser-272) switches binding specificity from phosphatidylserine to Sec15 (EXOC6), promoting ciliogenesis; the phospho-mimetic S272E Rabin8 mutation increases affinity for Sec15 and decreases PS affinity, driving Rab8 activation and ciliary membrane assembly","method":"In vitro phosphorylation assay, GST pulldown, colocalization, ciliogenesis rescue assay with phospho-mimetic/dead mutants","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro phosphorylation combined with binding assays and mutational analysis establishing mechanistic switch","pmids":["23435566"],"is_preprint":false},{"year":2015,"finding":"Rab10-GTP binds directly to Exoc6 (EXOC6) and Exoc6b; both isoforms are present in 3T3-L1 adipocytes, and knockdown of Exoc6, Exoc6b, or both inhibits insulin-stimulated GLUT4 translocation, establishing Exoc6 as a molecular link between Rab10-GTP signaling and exocytic tethering of GLUT4 vesicles","method":"Co-immunoprecipitation with GTP/GDP Rab10 mutants, siRNA knockdown, GLUT4 translocation assay in 3T3-L1 adipocytes","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — GTP-dependent interaction combined with loss-of-function phenotype in relevant cell type","pmids":["26299925"],"is_preprint":false},{"year":2021,"finding":"Sec15 (EXOC6), acting as a Rab11 effector, is required for Ca2+-induced lysosome exocytosis; silencing of Sec15 impairs lysosome exocytosis, and Rab11-positive vesicles transiently interact with lysosomes at the cell periphery in a Rab11-Sec15-Rab3a cascade","method":"siRNA knockdown, live-cell imaging, lysosome exocytosis assay (plasma membrane repair), co-immunoprecipitation","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined functional readout and molecular interaction data from single study","pmids":["34100549"],"is_preprint":false},{"year":2022,"finding":"EXOC6 (and EXOC6B) are required for insulin secretion and exocytosis machinery in pancreatic β-cells; siRNA silencing of Exoc6/6b in INS1-832/13 cells impairs insulin secretion, insulin content, and exocytosis, with decreased expression of Ins1, Pdx1, Glut2, and Vamp2","method":"siRNA knockdown in rat β-cell line, insulin secretion assay, RT-PCR and Western blot for exocytosis machinery components","journal":"Biology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with functional secretion readout, but single lab and limited mechanistic depth","pmids":["35336762"],"is_preprint":false},{"year":2023,"finding":"Presynaptic knockdown of Sec15 (EXOC6 ortholog) in Drosophila NMJ causes active zone defects devoid of essential presynaptic proteins, increased branching, decreased postsynaptic current amplitude, reduced spontaneous vesicle release frequency, and diminished extracellular vesicle release; these phenotypes are partially mediated by enhanced BMP signaling (elevated pMad), and are mimicked by Rab11 knockdown","method":"Transgenic RNAi in Drosophila NMJ, electrophysiology (mEJC, EJC recordings), immunofluorescence, extracellular vesicle assay, BMP signaling pathway epistasis","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with multiple orthogonal phenotypic readouts and pathway epistasis, single study","pmids":["38086519"],"is_preprint":false}],"current_model":"EXOC6 (Sec15) is a core subunit of the octameric exocyst complex that functions as a GTP-dependent effector for Rab11 (and Rab10) GTPases, tethering recycling endosomal vesicles to the plasma membrane to mediate polarized exocytosis of cargo including E-Cadherin, GLUT4, Delta/Notch ligands, and lysosomal content, with its interaction with Rabin8 regulated by NDR2 phosphorylation to couple vesicle tethering to ciliogenesis."},"narrative":{"teleology":[{"year":1989,"claim":"Establishing that Sec15 acts downstream of the Sec4 GTPase at a late secretory step resolved where in the exocytic pathway this protein functions, showing it responds to Rab-family signaling to control vesicle delivery.","evidence":"Genetic suppression analysis and overexpression phenotyping in yeast sec4 and sec2 mutant backgrounds","pmids":["2504727"],"confidence":"High","gaps":["Mechanism of Sec4-Sec15 coupling unknown","No direct binding demonstrated","Mammalian relevance not tested"]},{"year":1991,"claim":"Demonstrating that Sec15p partitions between the plasma membrane and a soluble 19.5S particle—regulated by Sec8 and Sec10—established that Sec15 cycles between a soluble complex and the membrane, defining the biophysical basis of exocyst dynamics.","evidence":"Subcellular fractionation and sucrose gradient sedimentation in sec8 and sec10 mutant yeast","pmids":["1900300"],"confidence":"High","gaps":["Identity of 19.5S particle subunits incomplete","Membrane attachment mechanism unknown"]},{"year":1995,"claim":"Biochemical isolation of a stable multisubunit exocyst complex containing Sec15, Sec8, and Sec6 at sites of active exocytosis established EXOC6 as an integral subunit of the exocyst tethering machinery.","evidence":"Affinity chromatography, gel filtration, sucrose gradient centrifugation, and immunofluorescence in yeast","pmids":["7615633"],"confidence":"High","gaps":["Full octameric composition not yet defined","Subunit–subunit interaction hierarchy unclear"]},{"year":2001,"claim":"Identifying the mammalian exocyst as a GTP-dependent effector of RalA in brain tissue extended the exocyst's regulatory logic beyond yeast Sec4 to a mammalian GTPase, positioning the complex in Ral-dependent signaling.","evidence":"GTP-dependent pulldown from rat brain lysates with MALDI-TOF MS identification","pmids":["11406615"],"confidence":"High","gaps":["Direct EXOC6–RalA contact not resolved","Functional consequence of RalA–exocyst interaction not tested in vivo"]},{"year":2004,"claim":"Showing that mammalian Sec15 (EXOC6) directly and specifically binds Rab11-GTP on recycling endosomes identified EXOC6 as the Rab11 effector subunit, establishing the molecular bridge between recycling vesicles and the exocyst.","evidence":"Co-immunoprecipitation with GTP/GDP-locked Rab11 mutants and colocalization in mammalian cells","pmids":["15292201"],"confidence":"High","gaps":["Structural basis of Rab11–Sec15 interaction unknown","Which exocyst subunits are co-recruited unclear"]},{"year":2005,"claim":"Genetic studies in Drosophila revealed that EXOC6 is required for recycling of DE-Cadherin and Delta from Rab11 endosomes to the plasma membrane, establishing its essential role in polarized cargo delivery for cell adhesion and Notch signaling.","evidence":"Loss-of-function clonal analysis in Drosophila epithelial cells and sensory organ precursors with immunofluorescence for cargo trafficking","pmids":["16224820","16137928","15848801"],"confidence":"High","gaps":["Cargo selectivity mechanism unknown","Whether Sec15 recognizes cargo adaptors or acts generically unresolved"]},{"year":2010,"claim":"Demonstrating that anthrax toxins EF and LF convergently target the Rab11–Sec15 axis to block endocytic recycling and Notch/cadherin signaling validated this pathway as a critical node exploited by pathogens, and confirmed its conservation between Drosophila and human endothelial cells.","evidence":"Live imaging of Sec15-GFP vesicles under toxin treatment in Drosophila and human endothelial cells","pmids":["20944747"],"confidence":"High","gaps":["Direct molecular target of LF on the Sec15 pathway not identified","Extent to which other exocyst subunits are affected unclear"]},{"year":2013,"claim":"Revealing that NDR2 phosphorylation of Rabin8 switches its binding from phosphatidylserine to Sec15, coupling vesicle tethering to Rab8 activation and ciliogenesis, uncovered a phospho-regulated mechanism that redirects exocyst function toward ciliary membrane assembly.","evidence":"In vitro phosphorylation, GST pulldown with phospho-mimetic mutants, and ciliogenesis rescue assays","pmids":["23435566"],"confidence":"High","gaps":["Structural basis of the phospho-switch on Rabin8–Sec15 interface unknown","Whether this mechanism operates in all ciliated cell types not tested"]},{"year":2015,"claim":"Identifying Rab10-GTP as a second direct Rab binding partner of EXOC6, and showing that EXOC6 knockdown blocks insulin-stimulated GLUT4 translocation, established EXOC6 as a shared effector for multiple Rab GTPases with tissue-specific trafficking functions.","evidence":"Co-immunoprecipitation with GTP/GDP Rab10 mutants and siRNA knockdown with GLUT4 translocation assay in 3T3-L1 adipocytes","pmids":["26299925"],"confidence":"High","gaps":["Whether Rab10 and Rab11 compete for the same binding site on EXOC6 unknown","Relative contributions of EXOC6 vs EXOC6B in adipocytes not resolved"]},{"year":2021,"claim":"Demonstrating that EXOC6, as a Rab11 effector, is required for Ca²⁺-triggered lysosome exocytosis via a Rab11–Sec15–Rab3a cascade extended the exocyst's role beyond conventional secretion to lysosomal fusion with the plasma membrane.","evidence":"siRNA knockdown, live-cell imaging of Rab11-positive vesicle–lysosome interactions, and lysosome exocytosis/plasma membrane repair assays","pmids":["34100549"],"confidence":"Medium","gaps":["How Sec15 hands off vesicles to Rab3a mechanistically undefined","Single study; independent replication needed"]},{"year":2022,"claim":"Showing that EXOC6 silencing impairs insulin secretion and reduces expression of key β-cell genes (Ins1, Pdx1, Glut2, Vamp2) revealed its importance in pancreatic β-cell exocytosis beyond GLUT4 trafficking.","evidence":"siRNA knockdown in INS1-832/13 rat β-cell line with insulin secretion assay and expression analysis","pmids":["35336762"],"confidence":"Medium","gaps":["Whether gene expression changes are direct or secondary to trafficking defects unknown","Not validated in primary human β-cells"]},{"year":2023,"claim":"Presynaptic knockdown of Sec15 at Drosophila NMJs revealed its requirement for active zone integrity, synaptic vesicle release, and extracellular vesicle secretion, with phenotypes partly driven by aberrant BMP signaling, extending EXOC6's role to synapse organization.","evidence":"Transgenic RNAi in Drosophila NMJ with electrophysiology, immunofluorescence, extracellular vesicle assays, and BMP pathway epistasis","pmids":["38086519"],"confidence":"Medium","gaps":["Mechanism by which Sec15 loss enhances BMP signaling unclear","Whether mammalian synapses show analogous phenotypes not tested"]},{"year":null,"claim":"A structural understanding of how EXOC6 simultaneously or sequentially engages Rab11, Rab10, and Rabin8—and how cargo selectivity is achieved—remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of EXOC6 in complex with Rab partners","Cargo adaptor recognition mechanism unknown","How EXOC6 vs EXOC6B isoforms are differentially regulated in vivo unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,5,9,10]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4,5,6]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[4,5,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,2,4,5,10,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,6,9,13]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[7,13]}],"complexes":["Exocyst complex"],"partners":["RAB11","RAB10","RALA","RABIN8","EXOC3","EXOC4","EXOC6B"],"other_free_text":[]},"mechanistic_narrative":"EXOC6 (Sec15) is a core subunit of the octameric exocyst complex that couples Rab GTPase signaling to vesicle tethering at the plasma membrane, mediating polarized exocytosis and endocytic recycling across diverse cell types. EXOC6 functions as a direct GTP-dependent effector of Rab11 and Rab10, linking recycling endosomal vesicles to membrane fusion sites to deliver cargoes including E-Cadherin, Delta/Notch ligands, GLUT4, and lysosomal contents [PMID:15292201, PMID:16224820, PMID:26299925, PMID:34100549]. Its interaction with Rabin8, regulated by NDR2 phosphorylation, switches Rabin8 from lipid binding to exocyst engagement, coupling vesicle tethering to Rab8 activation and ciliogenesis [PMID:23435566]. Loss of EXOC6 disrupts active zone assembly and synaptic transmission at neuromuscular junctions, impairs insulin secretion in pancreatic β-cells, and blocks Notch signaling during asymmetric cell division, underscoring its role as a central node integrating vesicle trafficking with cell polarity, signaling, and secretion [PMID:38086519, PMID:35336762, PMID:16137928]."},"prefetch_data":{"uniprot":{"accession":"Q8TAG9","full_name":"Exocyst complex component 6","aliases":["Exocyst complex component Sec15A","SEC15-like protein 1"],"length_aa":804,"mass_kda":93.7,"function":"Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane. Together with RAB11A, RAB3IP, RAB8A, PARD3, PRKCI, ANXA2, CDC42 and DNMBP promotes transcytosis of PODXL to the apical membrane initiation sites (AMIS), apical surface formation and lumenogenesis (By similarity)","subcellular_location":"Cytoplasm; Cytoplasm, perinuclear region; Cell projection, growth cone; Midbody, Midbody ring","url":"https://www.uniprot.org/uniprotkb/Q8TAG9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EXOC6","classification":"Not Classified","n_dependent_lines":19,"n_total_lines":1208,"dependency_fraction":0.015728476821192054},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EXOC6","total_profiled":1310},"omim":[{"mim_id":"621025","title":"RAB3A-INTERACTING PROTEIN-LIKE 1; RAB3IL1","url":"https://www.omim.org/entry/621025"},{"mim_id":"609672","title":"EXOCYST COMPLEX COMPONENT 6; EXOC6","url":"https://www.omim.org/entry/609672"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Centrosome","reliability":"Uncertain"},{"location":"Basal body","reliability":"Uncertain"},{"location":"Cytosol","reliability":"Uncertain"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"retina","ntpm":152.0}],"url":"https://www.proteinatlas.org/search/EXOC6"},"hgnc":{"alias_symbol":["SEC15L","FLJ1125","DKFZp761I2124","MGC33397","Sec15","EXOC6A"],"prev_symbol":["SEC15L1"]},"alphafold":{"accession":"Q8TAG9","domains":[{"cath_id":"1.20.1310","chopping":"279-409","consensus_level":"high","plddt":89.6519,"start":279,"end":409},{"cath_id":"1.10.357.30","chopping":"429-447_483-600","consensus_level":"high","plddt":87.3356,"start":429,"end":600},{"cath_id":"1.20.58.670","chopping":"620-803","consensus_level":"high","plddt":84.8598,"start":620,"end":803}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TAG9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TAG9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TAG9-F1-predicted_aligned_error_v6.png","plddt_mean":82.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EXOC6","jax_strain_url":"https://www.jax.org/strain/search?query=EXOC6"},"sequence":{"accession":"Q8TAG9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TAG9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TAG9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TAG9"}},"corpus_meta":[{"pmid":"7615633","id":"PMC_7615633","title":"Sec6, Sec8, and Sec15 are components of a multisubunit complex which localizes to small bud tips in Saccharomyces cerevisiae.","date":"1995","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/7615633","citation_count":257,"is_preprint":false},{"pmid":"16224820","id":"PMC_16224820","title":"Drosophila exocyst components Sec5, Sec6, and Sec15 regulate DE-Cadherin trafficking from recycling endosomes to the plasma membrane.","date":"2005","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/16224820","citation_count":231,"is_preprint":false},{"pmid":"15292201","id":"PMC_15292201","title":"Sec15 is an effector for the Rab11 GTPase in mammalian cells.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15292201","citation_count":219,"is_preprint":false},{"pmid":"16137928","id":"PMC_16137928","title":"Sec15, a component of the exocyst, promotes notch signaling during the asymmetric division of Drosophila sensory organ precursors.","date":"2005","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/16137928","citation_count":161,"is_preprint":false},{"pmid":"2504727","id":"PMC_2504727","title":"The Sec15 protein responds to the function of the GTP binding protein, Sec4, to control vesicular traffic in yeast.","date":"1989","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/2504727","citation_count":119,"is_preprint":false},{"pmid":"15848801","id":"PMC_15848801","title":"Mutations in Drosophila sec15 reveal a function in neuronal targeting for a subset of exocyst components.","date":"2005","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/15848801","citation_count":119,"is_preprint":false},{"pmid":"11406615","id":"PMC_11406615","title":"The brain exocyst complex interacts with RalA in a GTP-dependent manner: identification of a novel mammalian Sec3 gene and a second Sec15 gene.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11406615","citation_count":119,"is_preprint":false},{"pmid":"20944747","id":"PMC_20944747","title":"Anthrax toxins cooperatively inhibit endocytic recycling by the Rab11/Sec15 exocyst.","date":"2010","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/20944747","citation_count":87,"is_preprint":false},{"pmid":"23435566","id":"PMC_23435566","title":"NDR2-mediated Rabin8 phosphorylation is crucial for ciliogenesis by switching binding specificity from phosphatidylserine to Sec15.","date":"2013","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/23435566","citation_count":83,"is_preprint":false},{"pmid":"1900300","id":"PMC_1900300","title":"Sec15 protein, an essential component of the exocytotic apparatus, is associated with the plasma membrane and with a soluble 19.5S particle.","date":"1991","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1900300","citation_count":72,"is_preprint":false},{"pmid":"34100549","id":"PMC_34100549","title":"Rab11 is required for lysosome exocytosis through the interaction with Rab3a, Sec15 and GRAB.","date":"2021","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/34100549","citation_count":37,"is_preprint":false},{"pmid":"26299925","id":"PMC_26299925","title":"A potential link between insulin signaling and GLUT4 translocation: Association of Rab10-GTP with the exocyst subunit Exoc6/6b.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26299925","citation_count":32,"is_preprint":false},{"pmid":"9664717","id":"PMC_9664717","title":"RMA1, an Arabidopsis thaliana gene whose cDNA suppresses the yeast sec15 mutation, encodes a novel protein with a RING finger motif and a membrane anchor.","date":"1998","source":"Plant & cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9664717","citation_count":26,"is_preprint":false},{"pmid":"11680821","id":"PMC_11680821","title":"Trichoderma reesei rho3 a homologue of yeast RH03 suppresses the growth defect of yeast sec15-1 mutation.","date":"2001","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11680821","citation_count":11,"is_preprint":false},{"pmid":"27225289","id":"PMC_27225289","title":"Sec15 links bud site selection to polarised cell growth and exocytosis in Candida albicans.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27225289","citation_count":10,"is_preprint":false},{"pmid":"35336762","id":"PMC_35336762","title":"EXOC6 (Exocyst Complex Component 6) Is Associated with the Risk of Type 2 Diabetes and Pancreatic β-Cell Dysfunction.","date":"2022","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/35336762","citation_count":6,"is_preprint":false},{"pmid":"26453654","id":"PMC_26453654","title":"Functional Analysis of the Exocyst Subunit Sec15 in Candida albicans.","date":"2015","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/26453654","citation_count":5,"is_preprint":false},{"pmid":"9175268","id":"PMC_9175268","title":"Synaptotagmin II expression partially rescues the growth defect of the yeast sec15 secretory mutant.","date":"1996","source":"Biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/9175268","citation_count":5,"is_preprint":false},{"pmid":"38086519","id":"PMC_38086519","title":"The exocyst subunit Sec15 is critical for proper synaptic development and function at the Drosophila NMJ.","date":"2023","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/38086519","citation_count":2,"is_preprint":false},{"pmid":"31071318","id":"PMC_31071318","title":"Developmental expression, co-localization and genetic interaction of exocyst component Sec15 with Rab11 during Drosophila development.","date":"2019","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31071318","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10199,"output_tokens":3402,"usd":0.040814},"stage2":{"model":"claude-opus-4-6","input_tokens":6789,"output_tokens":3157,"usd":0.169305},"total_usd":0.210119,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"Sec15 (yeast ortholog of EXOC6) functions at a late stage of the secretory pathway and responds to the Sec4 GTP-binding protein to control vesicular traffic; overproduction of Sec15 leads to accumulation of secretory vesicles, and sec4-8 and sec2-41 mutations prevent Sec15 protein patch formation\",\n      \"method\": \"Genetic suppression analysis, immunofluorescence, overexpression phenotype in yeast\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple mutant backgrounds, replicated functional readouts\",\n      \"pmids\": [\"2504727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Yeast Sec15p (EXOC6 ortholog) associates with the plasma membrane (23% of total) and with a soluble 19.5S particle; its membrane attachment is regulated by Sec8 and Sec10, as sec8-9 and sec10-2 mutations shift Sec15p to the plasma membrane\",\n      \"method\": \"Subcellular fractionation, sucrose gradient sedimentation, genetic analysis with sec mutants\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical fractionation combined with genetic analysis across multiple mutant backgrounds\",\n      \"pmids\": [\"1900300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Sec6 (yeast EXOC6 ortholog) is a stable component of the Sec6/8/15 multisubunit exocyst complex (~1-2 MDa); co-fractionates with Sec8 and Sec15 by affinity chromatography, gel filtration, and sucrose velocity centrifugation, and the complex localizes to small bud tips (sites of exocytosis)\",\n      \"method\": \"Immobilized metal affinity chromatography, co-immunoprecipitation, gel filtration, sucrose gradient centrifugation, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical methods establishing complex composition and localization; foundational paper with 257 citations\",\n      \"pmids\": [\"7615633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The mammalian exocyst complex (including rSec6 and rSec8, EXOC6 orthologs) interacts with RalA in a GTP-dependent manner in brain nerve terminals, placing the exocyst as an effector for activated RalA in directing sites of exocytosis\",\n      \"method\": \"GTP-dependent pulldown from brain lysates, MALDI-TOF MS identification, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — GTP-dependent binding demonstrated by pulldown with MS confirmation; replicated with Western blot for specific subunits\",\n      \"pmids\": [\"11406615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mammalian Sec15 (EXOC6) localizes to Rab11-positive recycling endosomal tubular/vesicular clusters in the perinuclear region and exhibits GTP-dependent interaction with Rab11, but not Rab4, Rab6, or Rab7, establishing the exocyst as a Rab11 effector complex in mammalian cells\",\n      \"method\": \"Colocalization by immunofluorescence, co-immunoprecipitation with GTP/GDP-locked Rab11 mutants, transferrin endocytosis assay, nocodazole treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — GTP-dependent interaction specificity demonstrated with multiple Rab GTPases, supported by colocalization and trafficking assay\",\n      \"pmids\": [\"15292201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Drosophila Sec15 (EXOC6 ortholog) regulates DE-Cadherin trafficking from Rab11 recycling endosomes to the plasma membrane; loss of sec5, sec6, or sec15 causes accumulation of DE-Cad in enlarged Rab11 compartments and inhibits DE-Cad membrane delivery\",\n      \"method\": \"Loss-of-function genetics in Drosophila epithelial cells, immunofluorescence, co-immunoprecipitation (Rab11-Sec15, Armadillo-Sec10)\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function combined with molecular interaction data; 231 citations\",\n      \"pmids\": [\"16224820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Drosophila Sec15 (EXOC6 ortholog) is required for Delta recycling to ensure proper Notch signaling during asymmetric SOP division; sec15 mutants accumulate Notch/Sanpodo/Delta in basal vesicles, and Sec15 colocalizes with Rab11 recycling endosomes\",\n      \"method\": \"Genetic screen, loss-of-function clonal analysis, immunofluorescence colocalization with Rab11 and trafficking markers\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with defined cell fate phenotype and molecular colocalization evidence; 161 citations\",\n      \"pmids\": [\"16137928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Drosophila Sec15 (EXOC6 ortholog) is required for neuronal targeting of photoreceptors and localization of specific cell adhesion/signaling molecules; loss of sec15 causes mislocalization of Sec5 and Sec8 but not Sec6 at neuronal terminals, suggesting Sec15 participates in an exocyst subcomplex with separable functions\",\n      \"method\": \"Genetic loss-of-function screen, immunofluorescence of exocyst subunit localization in sec15 mutant neurons\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis establishing differential subunit dependencies; 119 citations\",\n      \"pmids\": [\"15848801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Anthrax toxins EF and LF convergently inhibit the Rab11/Sec15 exocyst at the last step of endocytic recycling: EF reduces Rab11 levels and indirectly blocks Sec15-GFP vesicle formation, while LF more directly reduces Sec15-GFP vesicles, inhibiting Notch/Delta signaling and cadherin expression in both Drosophila and human endothelial cells\",\n      \"method\": \"Drosophila genetics, live imaging of Sec15-GFP vesicles, human endothelial cell experiments with toxin treatment, immunofluorescence\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic perturbation with defined molecular readouts validated in two species; published in Nature with 87 citations\",\n      \"pmids\": [\"20944747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NDR2-phosphorylated Rabin8 (at Ser-272) switches binding specificity from phosphatidylserine to Sec15 (EXOC6), promoting ciliogenesis; the phospho-mimetic S272E Rabin8 mutation increases affinity for Sec15 and decreases PS affinity, driving Rab8 activation and ciliary membrane assembly\",\n      \"method\": \"In vitro phosphorylation assay, GST pulldown, colocalization, ciliogenesis rescue assay with phospho-mimetic/dead mutants\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro phosphorylation combined with binding assays and mutational analysis establishing mechanistic switch\",\n      \"pmids\": [\"23435566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rab10-GTP binds directly to Exoc6 (EXOC6) and Exoc6b; both isoforms are present in 3T3-L1 adipocytes, and knockdown of Exoc6, Exoc6b, or both inhibits insulin-stimulated GLUT4 translocation, establishing Exoc6 as a molecular link between Rab10-GTP signaling and exocytic tethering of GLUT4 vesicles\",\n      \"method\": \"Co-immunoprecipitation with GTP/GDP Rab10 mutants, siRNA knockdown, GLUT4 translocation assay in 3T3-L1 adipocytes\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — GTP-dependent interaction combined with loss-of-function phenotype in relevant cell type\",\n      \"pmids\": [\"26299925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sec15 (EXOC6), acting as a Rab11 effector, is required for Ca2+-induced lysosome exocytosis; silencing of Sec15 impairs lysosome exocytosis, and Rab11-positive vesicles transiently interact with lysosomes at the cell periphery in a Rab11-Sec15-Rab3a cascade\",\n      \"method\": \"siRNA knockdown, live-cell imaging, lysosome exocytosis assay (plasma membrane repair), co-immunoprecipitation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined functional readout and molecular interaction data from single study\",\n      \"pmids\": [\"34100549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EXOC6 (and EXOC6B) are required for insulin secretion and exocytosis machinery in pancreatic β-cells; siRNA silencing of Exoc6/6b in INS1-832/13 cells impairs insulin secretion, insulin content, and exocytosis, with decreased expression of Ins1, Pdx1, Glut2, and Vamp2\",\n      \"method\": \"siRNA knockdown in rat β-cell line, insulin secretion assay, RT-PCR and Western blot for exocytosis machinery components\",\n      \"journal\": \"Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with functional secretion readout, but single lab and limited mechanistic depth\",\n      \"pmids\": [\"35336762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Presynaptic knockdown of Sec15 (EXOC6 ortholog) in Drosophila NMJ causes active zone defects devoid of essential presynaptic proteins, increased branching, decreased postsynaptic current amplitude, reduced spontaneous vesicle release frequency, and diminished extracellular vesicle release; these phenotypes are partially mediated by enhanced BMP signaling (elevated pMad), and are mimicked by Rab11 knockdown\",\n      \"method\": \"Transgenic RNAi in Drosophila NMJ, electrophysiology (mEJC, EJC recordings), immunofluorescence, extracellular vesicle assay, BMP signaling pathway epistasis\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple orthogonal phenotypic readouts and pathway epistasis, single study\",\n      \"pmids\": [\"38086519\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EXOC6 (Sec15) is a core subunit of the octameric exocyst complex that functions as a GTP-dependent effector for Rab11 (and Rab10) GTPases, tethering recycling endosomal vesicles to the plasma membrane to mediate polarized exocytosis of cargo including E-Cadherin, GLUT4, Delta/Notch ligands, and lysosomal content, with its interaction with Rabin8 regulated by NDR2 phosphorylation to couple vesicle tethering to ciliogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"EXOC6 (Sec15) is a core subunit of the octameric exocyst complex that couples Rab GTPase signaling to vesicle tethering at the plasma membrane, mediating polarized exocytosis and endocytic recycling across diverse cell types. EXOC6 functions as a direct GTP-dependent effector of Rab11 and Rab10, linking recycling endosomal vesicles to membrane fusion sites to deliver cargoes including E-Cadherin, Delta/Notch ligands, GLUT4, and lysosomal contents [PMID:15292201, PMID:16224820, PMID:26299925, PMID:34100549]. Its interaction with Rabin8, regulated by NDR2 phosphorylation, switches Rabin8 from lipid binding to exocyst engagement, coupling vesicle tethering to Rab8 activation and ciliogenesis [PMID:23435566]. Loss of EXOC6 disrupts active zone assembly and synaptic transmission at neuromuscular junctions, impairs insulin secretion in pancreatic β-cells, and blocks Notch signaling during asymmetric cell division, underscoring its role as a central node integrating vesicle trafficking with cell polarity, signaling, and secretion [PMID:38086519, PMID:35336762, PMID:16137928].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Establishing that Sec15 acts downstream of the Sec4 GTPase at a late secretory step resolved where in the exocytic pathway this protein functions, showing it responds to Rab-family signaling to control vesicle delivery.\",\n      \"evidence\": \"Genetic suppression analysis and overexpression phenotyping in yeast sec4 and sec2 mutant backgrounds\",\n      \"pmids\": [\"2504727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Sec4-Sec15 coupling unknown\", \"No direct binding demonstrated\", \"Mammalian relevance not tested\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Demonstrating that Sec15p partitions between the plasma membrane and a soluble 19.5S particle—regulated by Sec8 and Sec10—established that Sec15 cycles between a soluble complex and the membrane, defining the biophysical basis of exocyst dynamics.\",\n      \"evidence\": \"Subcellular fractionation and sucrose gradient sedimentation in sec8 and sec10 mutant yeast\",\n      \"pmids\": [\"1900300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of 19.5S particle subunits incomplete\", \"Membrane attachment mechanism unknown\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Biochemical isolation of a stable multisubunit exocyst complex containing Sec15, Sec8, and Sec6 at sites of active exocytosis established EXOC6 as an integral subunit of the exocyst tethering machinery.\",\n      \"evidence\": \"Affinity chromatography, gel filtration, sucrose gradient centrifugation, and immunofluorescence in yeast\",\n      \"pmids\": [\"7615633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full octameric composition not yet defined\", \"Subunit–subunit interaction hierarchy unclear\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying the mammalian exocyst as a GTP-dependent effector of RalA in brain tissue extended the exocyst's regulatory logic beyond yeast Sec4 to a mammalian GTPase, positioning the complex in Ral-dependent signaling.\",\n      \"evidence\": \"GTP-dependent pulldown from rat brain lysates with MALDI-TOF MS identification\",\n      \"pmids\": [\"11406615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct EXOC6–RalA contact not resolved\", \"Functional consequence of RalA–exocyst interaction not tested in vivo\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showing that mammalian Sec15 (EXOC6) directly and specifically binds Rab11-GTP on recycling endosomes identified EXOC6 as the Rab11 effector subunit, establishing the molecular bridge between recycling vesicles and the exocyst.\",\n      \"evidence\": \"Co-immunoprecipitation with GTP/GDP-locked Rab11 mutants and colocalization in mammalian cells\",\n      \"pmids\": [\"15292201\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Rab11–Sec15 interaction unknown\", \"Which exocyst subunits are co-recruited unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Genetic studies in Drosophila revealed that EXOC6 is required for recycling of DE-Cadherin and Delta from Rab11 endosomes to the plasma membrane, establishing its essential role in polarized cargo delivery for cell adhesion and Notch signaling.\",\n      \"evidence\": \"Loss-of-function clonal analysis in Drosophila epithelial cells and sensory organ precursors with immunofluorescence for cargo trafficking\",\n      \"pmids\": [\"16224820\", \"16137928\", \"15848801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo selectivity mechanism unknown\", \"Whether Sec15 recognizes cargo adaptors or acts generically unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that anthrax toxins EF and LF convergently target the Rab11–Sec15 axis to block endocytic recycling and Notch/cadherin signaling validated this pathway as a critical node exploited by pathogens, and confirmed its conservation between Drosophila and human endothelial cells.\",\n      \"evidence\": \"Live imaging of Sec15-GFP vesicles under toxin treatment in Drosophila and human endothelial cells\",\n      \"pmids\": [\"20944747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target of LF on the Sec15 pathway not identified\", \"Extent to which other exocyst subunits are affected unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealing that NDR2 phosphorylation of Rabin8 switches its binding from phosphatidylserine to Sec15, coupling vesicle tethering to Rab8 activation and ciliogenesis, uncovered a phospho-regulated mechanism that redirects exocyst function toward ciliary membrane assembly.\",\n      \"evidence\": \"In vitro phosphorylation, GST pulldown with phospho-mimetic mutants, and ciliogenesis rescue assays\",\n      \"pmids\": [\"23435566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the phospho-switch on Rabin8–Sec15 interface unknown\", \"Whether this mechanism operates in all ciliated cell types not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying Rab10-GTP as a second direct Rab binding partner of EXOC6, and showing that EXOC6 knockdown blocks insulin-stimulated GLUT4 translocation, established EXOC6 as a shared effector for multiple Rab GTPases with tissue-specific trafficking functions.\",\n      \"evidence\": \"Co-immunoprecipitation with GTP/GDP Rab10 mutants and siRNA knockdown with GLUT4 translocation assay in 3T3-L1 adipocytes\",\n      \"pmids\": [\"26299925\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Rab10 and Rab11 compete for the same binding site on EXOC6 unknown\", \"Relative contributions of EXOC6 vs EXOC6B in adipocytes not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that EXOC6, as a Rab11 effector, is required for Ca²⁺-triggered lysosome exocytosis via a Rab11–Sec15–Rab3a cascade extended the exocyst's role beyond conventional secretion to lysosomal fusion with the plasma membrane.\",\n      \"evidence\": \"siRNA knockdown, live-cell imaging of Rab11-positive vesicle–lysosome interactions, and lysosome exocytosis/plasma membrane repair assays\",\n      \"pmids\": [\"34100549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How Sec15 hands off vesicles to Rab3a mechanistically undefined\", \"Single study; independent replication needed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing that EXOC6 silencing impairs insulin secretion and reduces expression of key β-cell genes (Ins1, Pdx1, Glut2, Vamp2) revealed its importance in pancreatic β-cell exocytosis beyond GLUT4 trafficking.\",\n      \"evidence\": \"siRNA knockdown in INS1-832/13 rat β-cell line with insulin secretion assay and expression analysis\",\n      \"pmids\": [\"35336762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether gene expression changes are direct or secondary to trafficking defects unknown\", \"Not validated in primary human β-cells\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Presynaptic knockdown of Sec15 at Drosophila NMJs revealed its requirement for active zone integrity, synaptic vesicle release, and extracellular vesicle secretion, with phenotypes partly driven by aberrant BMP signaling, extending EXOC6's role to synapse organization.\",\n      \"evidence\": \"Transgenic RNAi in Drosophila NMJ with electrophysiology, immunofluorescence, extracellular vesicle assays, and BMP pathway epistasis\",\n      \"pmids\": [\"38086519\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Sec15 loss enhances BMP signaling unclear\", \"Whether mammalian synapses show analogous phenotypes not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A structural understanding of how EXOC6 simultaneously or sequentially engages Rab11, Rab10, and Rabin8—and how cargo selectivity is achieved—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of EXOC6 in complex with Rab partners\", \"Cargo adaptor recognition mechanism unknown\", \"How EXOC6 vs EXOC6B isoforms are differentially regulated in vivo unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 5, 9, 10]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4, 5, 6]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [4, 5, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5, 10, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 6, 9, 13]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [7, 13]}\n    ],\n    \"complexes\": [\"Exocyst complex\"],\n    \"partners\": [\"RAB11\", \"RAB10\", \"RALA\", \"RABIN8\", \"EXOC3\", \"EXOC4\", \"EXOC6B\"],\n    \"other_free_text\": []\n  }\n}\n```"}