{"gene":"EXOC6","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1989,"finding":"Yeast Sec15 protein functions at a late stage of the secretory pathway, responding to the Sec4 GTPase; overproduction of Sec15 causes accumulation of secretory vesicles, and Sec4/Sec2 mutations (but not other SEC gene mutations) prevent formation of the Sec15 protein patch, establishing Sec15 as a downstream effector of Sec4.","method":"Genetic epistasis (suppressor analysis, sec4/sec2 mutant backgrounds), immunofluorescence localization, subcellular fractionation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic and biochemical methods, foundational yeast study replicated in subsequent work","pmids":["2504727"],"is_preprint":false},{"year":1991,"finding":"Yeast Sec15p localizes to both the plasma membrane (23%) and a soluble 19.5S particle; it is not found on Golgi or secretory vesicles, and the sec8-9 mutation shifts Sec15p to the plasma membrane, implicating Sec8 in regulating Sec15p membrane attachment/detachment.","method":"Subcellular fractionation, sucrose gradient sedimentation, genetic analysis with sec mutants","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple biochemical fractionation methods combined with genetic epistasis in yeast","pmids":["1900300"],"is_preprint":false},{"year":1995,"finding":"Sec15 is a stable component of the octameric Sec6/Sec8/Sec15 exocyst complex; the complex localizes to small bud tips and its composition is disrupted by sec3, sec5, and sec10 mutations, establishing a role at sites of exocytosis.","method":"Immobilized metal affinity chromatography, gel filtration, sucrose velocity centrifugation, co-immunoprecipitation, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical methods (affinity purification, gel filtration, velocity centrifugation, co-IP) with genetic validation","pmids":["7615633"],"is_preprint":false},{"year":2001,"finding":"The mammalian brain exocyst complex (containing EXOC6/Sec15 homologues) interacts with RalA in a GTP-dependent manner, identified by MALDI-TOF MS; a second Sec15 homologue (KIAA0919, later EXOC6) was found in the brain exocyst complex but not the previously identified rSec15.","method":"GTP-dependent pulldown from brain lysates, MALDI-TOF mass spectrometry, Western blot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GTP-dependent pulldown plus MS identification, single lab, no reciprocal co-IP","pmids":["11406615"],"is_preprint":false},{"year":2004,"finding":"Mammalian Sec15 (EXOC6) associates with recycling endosome tubular/vesicular clusters in the perinuclear region and exhibits a GTP-dependent interaction specifically with Rab11, but not with Rab4, Rab6, or Rab7, identifying the exocyst as a Rab11 effector complex in mammalian cells.","method":"Co-localization with organelle markers, nucleotide-dependent co-immunoprecipitation (GTP vs. GDP forms of Rab GTPases), transferrin endocytosis assay, nocodazole treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — GTP-specific binding assay with multiple Rab controls, colocalization, and endosomal trafficking assays; replicated by subsequent independent studies","pmids":["15292201"],"is_preprint":false},{"year":2005,"finding":"Drosophila Sec15 colocalizes with the Rab11 recycling endosomal compartment; loss of sec15 causes Rab11 mislocalization and aberrant distribution, supporting a role for Sec15 in Delta recycling during asymmetric cell division of sensory organ precursors, with loss of sec15 causing a Notch signaling defect.","method":"Genetic loss-of-function (sec15 mutant clones), immunofluorescence colocalization with Rab11 and trafficking markers, cell fate analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function combined with colocalization and cell fate assays; independently reported in the same year by multiple groups","pmids":["16137928"],"is_preprint":false},{"year":2005,"finding":"Drosophila Sec15 is required for DE-Cadherin trafficking from Rab11-positive recycling endosomes to the plasma membrane; loss of sec5, sec6, or sec15 causes DE-Cad accumulation in an enlarged Rab11 compartment, and Sec15 physically interacts with Rab11.","method":"Genetic loss-of-function in epithelial cells, immunofluorescence of DE-Cad and Rab11, co-immunoprecipitation (Sec15–Rab11 and Sec10–Armadillo interactions)","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis plus co-IP binding studies, independently consistent with parallel studies","pmids":["16224820"],"is_preprint":false},{"year":2005,"finding":"Loss of Drosophila sec15 causes photoreceptor targeting defects and mislocalization of Sec5 and Sec8, but not Sec6, at neuronal terminals, indicating that Sec15 is required for exocyst subcomplex localization in neurons and mediates trafficking of specific adhesion/signaling molecules.","method":"Genetic loss-of-function (sec15 null), immunofluorescence of exocyst components and cell adhesion molecules, neuroanatomical analysis","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic null with defined neuronal phenotype and exocyst subunit colocalization analysis, single lab","pmids":["15848801"],"is_preprint":false},{"year":2010,"finding":"Anthrax lethal factor (LF) acts on the Rab11/Sec15 exocyst step of endocytic recycling; EF reduces apical Rab11 levels and indirectly blocks Sec15-GFP vesicle formation, while LF more directly reduces Sec15-GFP vesicles, inhibiting Notch/Delta signaling and cadherin junction formation in both Drosophila and human endothelial cells.","method":"In vivo Drosophila genetics, live imaging of Sec15-GFP vesicles, RNAi knockdown, human endothelial cell assays, Notch signaling reporter","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (imaging, genetic, cross-species validation in human cells) in a high-rigor study","pmids":["20944747"],"is_preprint":false},{"year":2013,"finding":"Sec15 (EXOC6) is a binding partner of phospho-Rabin8 (phosphorylated at Ser-272 by NDR2) during ciliogenesis; NDR2-mediated phosphorylation switches Rabin8 from binding phosphatidylserine to binding Sec15, promoting Rab8 activation and ciliary membrane formation at the pericentrosome.","method":"In vitro kinase assay, phospho-mimetic/phospho-dead mutagenesis, co-immunoprecipitation, colocalization, siRNA knockdown with ciliogenesis readout","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay, mutagenesis, binding specificity switch demonstrated biochemically, multiple orthogonal methods","pmids":["23435566"],"is_preprint":false},{"year":2015,"finding":"Exoc6 (and its paralogue Exoc6b) binds Rab10 in its GTP-bound form; knockdown of Exoc6, Exoc6b, or both inhibits insulin-stimulated GLUT4 translocation in 3T3-L1 adipocytes, suggesting Rab10-GTP/Exoc6 interaction links insulin signaling to the exocytic tethering machinery.","method":"GTP-dependent co-immunoprecipitation (Rab10-GTP vs GDP pulldown), siRNA knockdown, GLUT4 translocation assay in 3T3-L1 adipocytes","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GTP-specific binding assay plus functional KD phenotype, single lab","pmids":["26299925"],"is_preprint":false},{"year":2021,"finding":"Silencing of exocyst subunit Sec15 (EXOC6), a Rab11 effector, impairs Ca2+-induced lysosome exocytosis in mammalian cells, positioning Sec15 as acting together with Rab11 in the regulation of lysosome exocytosis.","method":"siRNA knockdown, lysosome exocytosis assay (lysosomal enzyme release, LAMP1 surface exposure), co-immunoprecipitation of Rab11–Sec15","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD with defined exocytosis readout plus co-IP, single lab","pmids":["34100549"],"is_preprint":false},{"year":2022,"finding":"Silencing of Exoc6/6b in rat pancreatic β-cells (INS1-832/13) impairs insulin secretion, insulin content, exocytosis machinery, and glucose uptake, with decreased expression of Ins1, Ins2, Pdx1, Glut2, and Vamp2 mRNA and protein, establishing a role for EXOC6 in β-cell secretory function.","method":"siRNA silencing in INS1-832/13 cells, insulin secretion assay, Western blot, RT-qPCR","journal":"Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with multiple secretion readouts, single lab","pmids":["35336762"],"is_preprint":false},{"year":2023,"finding":"Presynaptic knockdown of Sec15 at the Drosophila NMJ disrupts active zone assembly, increases synaptic branching and satellite boutons, reduces evoked and spontaneous postsynaptic currents, and diminishes extracellular vesicle release; these phenotypes are partially dependent on BMP signaling (Wishful Thinking) and are phenocopied by knockdown of other exocyst components and Rab11.","method":"Transgenic RNAi knockdown, electrophysiology (mEJP, EJP), confocal imaging of synaptic markers, BMP pathway epistasis (wit knockdown)","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD with defined electrophysiological and morphological readouts plus epistasis analysis, single lab","pmids":["38086519"],"is_preprint":false},{"year":2019,"finding":"Drosophila Sec15 co-localizes with Rab11 throughout embryonic and larval development, and genetic interaction between Sec15 and Rab11 was demonstrated by wing blister formation in double-mutant combinations.","method":"Immunofluorescence colocalization, genetic interaction analysis (wing blister assay)","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, colocalization plus single genetic interaction assay without biochemical binding validation","pmids":["31071318"],"is_preprint":false}],"current_model":"EXOC6 (Sec15) is a subunit of the octameric exocyst complex that functions as a downstream effector of multiple Rab GTPases—most notably Rab11 (GTP-dependent interaction) and Rab10 (in adipocytes)—tethering recycling endosome-derived vesicles to the plasma membrane to mediate polarized exocytosis, DE-Cadherin/GLUT4 trafficking, Delta recycling for Notch signaling, lysosome exocytosis, ciliogenesis (via phospho-Rabin8 binding), and insulin secretion in β-cells."},"narrative":{"mechanistic_narrative":"EXOC6 (Sec15) is a subunit of the octameric exocyst tethering complex that acts as a Rab GTPase effector to couple recycling-endosome-derived vesicles to sites of polarized exocytosis at the plasma membrane [PMID:7615633, PMID:15292201]. Genetic and biochemical work in yeast established Sec15 as a downstream effector of the Sec4 GTPase that functions at a late secretory step and assembles, together with Sec6 and Sec8, into a stable exocyst complex localized to sites of active exocytosis [PMID:2504727, PMID:7615633]. In mammalian cells EXOC6 binds Rab11 specifically in its GTP-bound form and associates with perinuclear recycling endosomes, defining the exocyst as a Rab11 effector [PMID:15292201]; this Rab11–Sec15 axis is conserved in Drosophila, where Sec15 maintains Rab11 compartment organization and drives recycling of cargoes including DE-Cadherin and the Notch ligand Delta to control epithelial junction formation and asymmetric cell fate signaling [PMID:16137928, PMID:16224820]. Beyond Rab11, EXOC6 engages additional small-GTPase and regulatory inputs: it binds phospho-Rabin8 to promote Rab8 activation and ciliary membrane formation during ciliogenesis [PMID:23435566], binds Rab10-GTP to support insulin-stimulated GLUT4 translocation in adipocytes [PMID:26299925], and participates in Ca2+-induced lysosome exocytosis [PMID:34100549]. Functionally, EXOC6 is required for pancreatic β-cell insulin secretion and secretory machinery expression [PMID:35336762] and for presynaptic active zone assembly and neurotransmitter release at the neuromuscular junction [PMID:38086519], reflecting a broad role in delivering vesicular cargo to specialized membrane domains.","teleology":[{"year":1989,"claim":"Established that Sec15 acts at a late secretory step as a downstream effector of a Rab-family GTPase, defining its position in the vesicle delivery pathway.","evidence":"Genetic epistasis in sec4/sec2 yeast mutants with immunofluorescence and fractionation","pmids":["2504727"],"confidence":"High","gaps":["No molecular mechanism of how Sec4 controls Sec15 patch formation","Mammalian relevance not yet addressed"]},{"year":1991,"claim":"Defined Sec15 as partitioning between plasma membrane and a soluble particle, with its membrane attachment regulated by other Sec proteins.","evidence":"Subcellular fractionation and sucrose gradients in sec8-9 mutant yeast","pmids":["1900300"],"confidence":"High","gaps":["Biochemical basis of the membrane attachment/detachment switch unknown","Composition of the soluble particle not fully resolved"]},{"year":1995,"claim":"Showed Sec15 is a stable subunit of a multiprotein exocyst complex localized to sites of exocytosis, moving from a single protein to a defined molecular machine.","evidence":"Affinity purification, gel filtration, velocity centrifugation and co-IP with genetic validation in yeast","pmids":["7615633"],"confidence":"High","gaps":["Full octameric stoichiometry not yet defined","Structural architecture unknown"]},{"year":2001,"claim":"Identified the mammalian EXOC6 homologue within a brain exocyst complex regulated by a GTPase, extending exocyst biology to mammals.","evidence":"GTP-dependent pulldown and MALDI-TOF MS from brain lysates","pmids":["11406615"],"confidence":"Medium","gaps":["No reciprocal co-IP for the RalA interaction","Functional consequence of EXOC6 in brain not tested"]},{"year":2004,"claim":"Demonstrated that mammalian EXOC6 binds Rab11 specifically in the GTP state and localizes to recycling endosomes, defining the exocyst as a Rab11 effector.","evidence":"Nucleotide-dependent co-IP with multiple Rab controls, colocalization and transferrin recycling assays","pmids":["15292201"],"confidence":"High","gaps":["Direct vs indirect nature of the Rab11 interaction not resolved","Cargo specificity not defined in this system"]},{"year":2005,"claim":"Linked Sec15/Rab11 recycling to delivery of specific cargoes (Delta, DE-Cadherin) controlling Notch signaling, cell fate and epithelial junctions in vivo.","evidence":"Drosophila genetic loss-of-function, colocalization, cell fate analysis and co-IP of Sec15–Rab11","pmids":["16137928","16224820","15848801"],"confidence":"High","gaps":["Mechanism of cargo selection by Sec15 unknown","How exocyst recruitment is coordinated with vesicle fusion not defined"]},{"year":2010,"claim":"Showed the Rab11/Sec15 recycling step is a pathogen target, with anthrax factors blocking Sec15 vesicle formation to disrupt Notch and cadherin junction signaling.","evidence":"Drosophila genetics, live Sec15-GFP imaging, RNAi and human endothelial cell assays","pmids":["20944747"],"confidence":"High","gaps":["Direct molecular target of LF in the Sec15 step not pinpointed","Quantitative impact on endogenous cargo flux unmeasured"]},{"year":2013,"claim":"Connected EXOC6 to ciliogenesis via a phosphorylation-dependent binding switch in Rabin8 that activates Rab8 and builds ciliary membrane.","evidence":"In vitro kinase assay, phospho-mutant analysis, co-IP, colocalization and siRNA ciliogenesis readout","pmids":["23435566"],"confidence":"High","gaps":["Structural basis of the phospho-Rabin8/Sec15 interaction not solved","Whether full exocyst assembly is required at the cilium not addressed"]},{"year":2015,"claim":"Expanded the Rab repertoire by showing EXOC6 binds Rab10-GTP to support insulin-stimulated GLUT4 exocytosis, linking metabolic signaling to the tethering machinery.","evidence":"GTP-dependent co-IP and siRNA GLUT4 translocation assay in 3T3-L1 adipocytes","pmids":["26299925"],"confidence":"Medium","gaps":["Direct vs indirect Rab10 binding not established","Redundancy with paralogue Exoc6b not fully dissected"]},{"year":2021,"claim":"Extended EXOC6 function to Ca2+-induced lysosome exocytosis acting with Rab11, broadening its role beyond classical recycling-to-PM delivery.","evidence":"siRNA knockdown, lysosome exocytosis assays and Rab11–Sec15 co-IP","pmids":["34100549"],"confidence":"Medium","gaps":["Mechanism distinguishing lysosomal from recycling-endosome tethering unknown","Single-lab functional study"]},{"year":2022,"claim":"Established a requirement for EXOC6 in pancreatic β-cell insulin secretion and expression of the secretory machinery, implicating it in glucose homeostasis.","evidence":"siRNA silencing in INS1-832/13 cells with insulin secretion assays, Western blot and RT-qPCR","pmids":["35336762"],"confidence":"Medium","gaps":["Whether effects are direct trafficking defects or secondary to transcriptional changes unclear","Not validated in primary islets in vivo"]},{"year":2023,"claim":"Showed Sec15 is required presynaptically for active zone assembly, synaptic morphology and neurotransmitter release, in part through BMP signaling.","evidence":"Drosophila RNAi knockdown, electrophysiology, confocal imaging and wit epistasis at the NMJ","pmids":["38086519"],"confidence":"Medium","gaps":["Direct cargo mediating active zone defects not identified","Mechanistic link between exocyst and BMP receptor trafficking incomplete"]},{"year":null,"claim":"How EXOC6 integrates competing Rab inputs (Rab11, Rab10, Rab8 via Rabin8) to achieve cargo- and tissue-specific exocytosis, and the structural basis of these interactions, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of EXOC6 bound to its Rab partners","Mechanism of cargo selectivity across recycling, ciliary, lysosomal and secretory routes unknown","Human disease genetics for EXOC6 not established in this corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,4,6,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,9,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,6]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4,5,6]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[4,8]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2,4]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[4,6,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,6,8]}],"complexes":["exocyst"],"partners":["RAB11","RAB10","RAB8","RABIN8","RALA","EXOC4","EXOC5"],"other_free_text":[]}},"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":258,"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":222,"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":162,"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":84,"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":73,"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":"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":12,"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":3,"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":10688,"output_tokens":3656,"usd":0.043452,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11270,"output_tokens":3786,"usd":0.0755,"stage2_stop_reason":"end_turn"},"total_usd":0.118952,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"Yeast Sec15 protein functions at a late stage of the secretory pathway, responding to the Sec4 GTPase; overproduction of Sec15 causes accumulation of secretory vesicles, and Sec4/Sec2 mutations (but not other SEC gene mutations) prevent formation of the Sec15 protein patch, establishing Sec15 as a downstream effector of Sec4.\",\n      \"method\": \"Genetic epistasis (suppressor analysis, sec4/sec2 mutant backgrounds), immunofluorescence localization, subcellular fractionation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic and biochemical methods, foundational yeast study replicated in subsequent work\",\n      \"pmids\": [\"2504727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Yeast Sec15p localizes to both the plasma membrane (23%) and a soluble 19.5S particle; it is not found on Golgi or secretory vesicles, and the sec8-9 mutation shifts Sec15p to the plasma membrane, implicating Sec8 in regulating Sec15p membrane attachment/detachment.\",\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 / Strong — multiple biochemical fractionation methods combined with genetic epistasis in yeast\",\n      \"pmids\": [\"1900300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Sec15 is a stable component of the octameric Sec6/Sec8/Sec15 exocyst complex; the complex localizes to small bud tips and its composition is disrupted by sec3, sec5, and sec10 mutations, establishing a role at sites of exocytosis.\",\n      \"method\": \"Immobilized metal affinity chromatography, gel filtration, sucrose velocity centrifugation, co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical methods (affinity purification, gel filtration, velocity centrifugation, co-IP) with genetic validation\",\n      \"pmids\": [\"7615633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The mammalian brain exocyst complex (containing EXOC6/Sec15 homologues) interacts with RalA in a GTP-dependent manner, identified by MALDI-TOF MS; a second Sec15 homologue (KIAA0919, later EXOC6) was found in the brain exocyst complex but not the previously identified rSec15.\",\n      \"method\": \"GTP-dependent pulldown from brain lysates, MALDI-TOF mass spectrometry, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GTP-dependent pulldown plus MS identification, single lab, no reciprocal co-IP\",\n      \"pmids\": [\"11406615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mammalian Sec15 (EXOC6) associates with recycling endosome tubular/vesicular clusters in the perinuclear region and exhibits a GTP-dependent interaction specifically with Rab11, but not with Rab4, Rab6, or Rab7, identifying the exocyst as a Rab11 effector complex in mammalian cells.\",\n      \"method\": \"Co-localization with organelle markers, nucleotide-dependent co-immunoprecipitation (GTP vs. GDP forms of Rab GTPases), transferrin endocytosis assay, nocodazole treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — GTP-specific binding assay with multiple Rab controls, colocalization, and endosomal trafficking assays; replicated by subsequent independent studies\",\n      \"pmids\": [\"15292201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Drosophila Sec15 colocalizes with the Rab11 recycling endosomal compartment; loss of sec15 causes Rab11 mislocalization and aberrant distribution, supporting a role for Sec15 in Delta recycling during asymmetric cell division of sensory organ precursors, with loss of sec15 causing a Notch signaling defect.\",\n      \"method\": \"Genetic loss-of-function (sec15 mutant clones), immunofluorescence colocalization with Rab11 and trafficking markers, cell fate analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function combined with colocalization and cell fate assays; independently reported in the same year by multiple groups\",\n      \"pmids\": [\"16137928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Drosophila Sec15 is required for DE-Cadherin trafficking from Rab11-positive recycling endosomes to the plasma membrane; loss of sec5, sec6, or sec15 causes DE-Cad accumulation in an enlarged Rab11 compartment, and Sec15 physically interacts with Rab11.\",\n      \"method\": \"Genetic loss-of-function in epithelial cells, immunofluorescence of DE-Cad and Rab11, co-immunoprecipitation (Sec15–Rab11 and Sec10–Armadillo interactions)\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis plus co-IP binding studies, independently consistent with parallel studies\",\n      \"pmids\": [\"16224820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Loss of Drosophila sec15 causes photoreceptor targeting defects and mislocalization of Sec5 and Sec8, but not Sec6, at neuronal terminals, indicating that Sec15 is required for exocyst subcomplex localization in neurons and mediates trafficking of specific adhesion/signaling molecules.\",\n      \"method\": \"Genetic loss-of-function (sec15 null), immunofluorescence of exocyst components and cell adhesion molecules, neuroanatomical analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic null with defined neuronal phenotype and exocyst subunit colocalization analysis, single lab\",\n      \"pmids\": [\"15848801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Anthrax lethal factor (LF) acts on the Rab11/Sec15 exocyst step of endocytic recycling; EF reduces apical Rab11 levels and indirectly blocks Sec15-GFP vesicle formation, while LF more directly reduces Sec15-GFP vesicles, inhibiting Notch/Delta signaling and cadherin junction formation in both Drosophila and human endothelial cells.\",\n      \"method\": \"In vivo Drosophila genetics, live imaging of Sec15-GFP vesicles, RNAi knockdown, human endothelial cell assays, Notch signaling reporter\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (imaging, genetic, cross-species validation in human cells) in a high-rigor study\",\n      \"pmids\": [\"20944747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sec15 (EXOC6) is a binding partner of phospho-Rabin8 (phosphorylated at Ser-272 by NDR2) during ciliogenesis; NDR2-mediated phosphorylation switches Rabin8 from binding phosphatidylserine to binding Sec15, promoting Rab8 activation and ciliary membrane formation at the pericentrosome.\",\n      \"method\": \"In vitro kinase assay, phospho-mimetic/phospho-dead mutagenesis, co-immunoprecipitation, colocalization, siRNA knockdown with ciliogenesis readout\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay, mutagenesis, binding specificity switch demonstrated biochemically, multiple orthogonal methods\",\n      \"pmids\": [\"23435566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Exoc6 (and its paralogue Exoc6b) binds Rab10 in its GTP-bound form; knockdown of Exoc6, Exoc6b, or both inhibits insulin-stimulated GLUT4 translocation in 3T3-L1 adipocytes, suggesting Rab10-GTP/Exoc6 interaction links insulin signaling to the exocytic tethering machinery.\",\n      \"method\": \"GTP-dependent co-immunoprecipitation (Rab10-GTP vs GDP pulldown), siRNA knockdown, GLUT4 translocation assay in 3T3-L1 adipocytes\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GTP-specific binding assay plus functional KD phenotype, single lab\",\n      \"pmids\": [\"26299925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Silencing of exocyst subunit Sec15 (EXOC6), a Rab11 effector, impairs Ca2+-induced lysosome exocytosis in mammalian cells, positioning Sec15 as acting together with Rab11 in the regulation of lysosome exocytosis.\",\n      \"method\": \"siRNA knockdown, lysosome exocytosis assay (lysosomal enzyme release, LAMP1 surface exposure), co-immunoprecipitation of Rab11–Sec15\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD with defined exocytosis readout plus co-IP, single lab\",\n      \"pmids\": [\"34100549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Silencing of Exoc6/6b in rat pancreatic β-cells (INS1-832/13) impairs insulin secretion, insulin content, exocytosis machinery, and glucose uptake, with decreased expression of Ins1, Ins2, Pdx1, Glut2, and Vamp2 mRNA and protein, establishing a role for EXOC6 in β-cell secretory function.\",\n      \"method\": \"siRNA silencing in INS1-832/13 cells, insulin secretion assay, Western blot, RT-qPCR\",\n      \"journal\": \"Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with multiple secretion readouts, single lab\",\n      \"pmids\": [\"35336762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Presynaptic knockdown of Sec15 at the Drosophila NMJ disrupts active zone assembly, increases synaptic branching and satellite boutons, reduces evoked and spontaneous postsynaptic currents, and diminishes extracellular vesicle release; these phenotypes are partially dependent on BMP signaling (Wishful Thinking) and are phenocopied by knockdown of other exocyst components and Rab11.\",\n      \"method\": \"Transgenic RNAi knockdown, electrophysiology (mEJP, EJP), confocal imaging of synaptic markers, BMP pathway epistasis (wit knockdown)\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD with defined electrophysiological and morphological readouts plus epistasis analysis, single lab\",\n      \"pmids\": [\"38086519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Drosophila Sec15 co-localizes with Rab11 throughout embryonic and larval development, and genetic interaction between Sec15 and Rab11 was demonstrated by wing blister formation in double-mutant combinations.\",\n      \"method\": \"Immunofluorescence colocalization, genetic interaction analysis (wing blister assay)\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, colocalization plus single genetic interaction assay without biochemical binding validation\",\n      \"pmids\": [\"31071318\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EXOC6 (Sec15) is a subunit of the octameric exocyst complex that functions as a downstream effector of multiple Rab GTPases—most notably Rab11 (GTP-dependent interaction) and Rab10 (in adipocytes)—tethering recycling endosome-derived vesicles to the plasma membrane to mediate polarized exocytosis, DE-Cadherin/GLUT4 trafficking, Delta recycling for Notch signaling, lysosome exocytosis, ciliogenesis (via phospho-Rabin8 binding), and insulin secretion in β-cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EXOC6 (Sec15) is a subunit of the octameric exocyst tethering complex that acts as a Rab GTPase effector to couple recycling-endosome-derived vesicles to sites of polarized exocytosis at the plasma membrane [#2, #4]. Genetic and biochemical work in yeast established Sec15 as a downstream effector of the Sec4 GTPase that functions at a late secretory step and assembles, together with Sec6 and Sec8, into a stable exocyst complex localized to sites of active exocytosis [#0, #2]. In mammalian cells EXOC6 binds Rab11 specifically in its GTP-bound form and associates with perinuclear recycling endosomes, defining the exocyst as a Rab11 effector [#4]; this Rab11–Sec15 axis is conserved in Drosophila, where Sec15 maintains Rab11 compartment organization and drives recycling of cargoes including DE-Cadherin and the Notch ligand Delta to control epithelial junction formation and asymmetric cell fate signaling [#5, #6]. Beyond Rab11, EXOC6 engages additional small-GTPase and regulatory inputs: it binds phospho-Rabin8 to promote Rab8 activation and ciliary membrane formation during ciliogenesis [#9], binds Rab10-GTP to support insulin-stimulated GLUT4 translocation in adipocytes [#10], and participates in Ca2+-induced lysosome exocytosis [#11]. Functionally, EXOC6 is required for pancreatic β-cell insulin secretion and secretory machinery expression [#12] and for presynaptic active zone assembly and neurotransmitter release at the neuromuscular junction [#13], reflecting a broad role in delivering vesicular cargo to specialized membrane domains.\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Established that Sec15 acts at a late secretory step as a downstream effector of a Rab-family GTPase, defining its position in the vesicle delivery pathway.\",\n      \"evidence\": \"Genetic epistasis in sec4/sec2 yeast mutants with immunofluorescence and fractionation\",\n      \"pmids\": [\"2504727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No molecular mechanism of how Sec4 controls Sec15 patch formation\", \"Mammalian relevance not yet addressed\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Defined Sec15 as partitioning between plasma membrane and a soluble particle, with its membrane attachment regulated by other Sec proteins.\",\n      \"evidence\": \"Subcellular fractionation and sucrose gradients in sec8-9 mutant yeast\",\n      \"pmids\": [\"1900300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical basis of the membrane attachment/detachment switch unknown\", \"Composition of the soluble particle not fully resolved\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Showed Sec15 is a stable subunit of a multiprotein exocyst complex localized to sites of exocytosis, moving from a single protein to a defined molecular machine.\",\n      \"evidence\": \"Affinity purification, gel filtration, velocity centrifugation and co-IP with genetic validation in yeast\",\n      \"pmids\": [\"7615633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full octameric stoichiometry not yet defined\", \"Structural architecture unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified the mammalian EXOC6 homologue within a brain exocyst complex regulated by a GTPase, extending exocyst biology to mammals.\",\n      \"evidence\": \"GTP-dependent pulldown and MALDI-TOF MS from brain lysates\",\n      \"pmids\": [\"11406615\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reciprocal co-IP for the RalA interaction\", \"Functional consequence of EXOC6 in brain not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated that mammalian EXOC6 binds Rab11 specifically in the GTP state and localizes to recycling endosomes, defining the exocyst as a Rab11 effector.\",\n      \"evidence\": \"Nucleotide-dependent co-IP with multiple Rab controls, colocalization and transferrin recycling assays\",\n      \"pmids\": [\"15292201\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect nature of the Rab11 interaction not resolved\", \"Cargo specificity not defined in this system\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linked Sec15/Rab11 recycling to delivery of specific cargoes (Delta, DE-Cadherin) controlling Notch signaling, cell fate and epithelial junctions in vivo.\",\n      \"evidence\": \"Drosophila genetic loss-of-function, colocalization, cell fate analysis and co-IP of Sec15–Rab11\",\n      \"pmids\": [\"16137928\", \"16224820\", \"15848801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of cargo selection by Sec15 unknown\", \"How exocyst recruitment is coordinated with vesicle fusion not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed the Rab11/Sec15 recycling step is a pathogen target, with anthrax factors blocking Sec15 vesicle formation to disrupt Notch and cadherin junction signaling.\",\n      \"evidence\": \"Drosophila genetics, live Sec15-GFP imaging, RNAi and human endothelial cell assays\",\n      \"pmids\": [\"20944747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target of LF in the Sec15 step not pinpointed\", \"Quantitative impact on endogenous cargo flux unmeasured\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected EXOC6 to ciliogenesis via a phosphorylation-dependent binding switch in Rabin8 that activates Rab8 and builds ciliary membrane.\",\n      \"evidence\": \"In vitro kinase assay, phospho-mutant analysis, co-IP, colocalization and siRNA ciliogenesis readout\",\n      \"pmids\": [\"23435566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the phospho-Rabin8/Sec15 interaction not solved\", \"Whether full exocyst assembly is required at the cilium not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Expanded the Rab repertoire by showing EXOC6 binds Rab10-GTP to support insulin-stimulated GLUT4 exocytosis, linking metabolic signaling to the tethering machinery.\",\n      \"evidence\": \"GTP-dependent co-IP and siRNA GLUT4 translocation assay in 3T3-L1 adipocytes\",\n      \"pmids\": [\"26299925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect Rab10 binding not established\", \"Redundancy with paralogue Exoc6b not fully dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended EXOC6 function to Ca2+-induced lysosome exocytosis acting with Rab11, broadening its role beyond classical recycling-to-PM delivery.\",\n      \"evidence\": \"siRNA knockdown, lysosome exocytosis assays and Rab11–Sec15 co-IP\",\n      \"pmids\": [\"34100549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism distinguishing lysosomal from recycling-endosome tethering unknown\", \"Single-lab functional study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a requirement for EXOC6 in pancreatic β-cell insulin secretion and expression of the secretory machinery, implicating it in glucose homeostasis.\",\n      \"evidence\": \"siRNA silencing in INS1-832/13 cells with insulin secretion assays, Western blot and RT-qPCR\",\n      \"pmids\": [\"35336762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether effects are direct trafficking defects or secondary to transcriptional changes unclear\", \"Not validated in primary islets in vivo\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed Sec15 is required presynaptically for active zone assembly, synaptic morphology and neurotransmitter release, in part through BMP signaling.\",\n      \"evidence\": \"Drosophila RNAi knockdown, electrophysiology, confocal imaging and wit epistasis at the NMJ\",\n      \"pmids\": [\"38086519\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cargo mediating active zone defects not identified\", \"Mechanistic link between exocyst and BMP receptor trafficking incomplete\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EXOC6 integrates competing Rab inputs (Rab11, Rab10, Rab8 via Rabin8) to achieve cargo- and tissue-specific exocytosis, and the structural basis of these interactions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of EXOC6 bound to its Rab partners\", \"Mechanism of cargo selectivity across recycling, ciliary, lysosomal and secretory routes unknown\", \"Human disease genetics for EXOC6 not established in this corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 4, 6, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4, 5, 6]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [4, 6, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 6, 8]}\n    ],\n    \"complexes\": [\"exocyst\"],\n    \"partners\": [\"RAB11\", \"RAB10\", \"RAB8\", \"Rabin8\", \"RalA\", \"EXOC4\", \"EXOC5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}