{"gene":"EXOC6B","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2015,"finding":"Rab10 in its GTP-bound form directly binds to Exoc6 and Exoc6b (the two highly homologous isotypes of an exocyst subunit); knockdown of Exoc6, Exoc6b, or both inhibits GLUT4 translocation in 3T3-L1 adipocytes, suggesting that Rab10-GTP association with Exoc6/6b is a molecular link between insulin signaling and the exocytic machinery.","method":"Co-immunoprecipitation / pulldown of Rab10-GTP with Exoc6/Exoc6b; siRNA knockdown of Exoc6, Exoc6b, or both with GLUT4 translocation readout in 3T3-L1 adipocytes","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal binding shown with GTP-state specificity plus clean KD with defined cellular phenotype; single lab, two orthogonal methods","pmids":["26299925"],"is_preprint":false},{"year":2001,"finding":"The brain exocyst complex (including rSec6 and rSec8, and identifying KIAA0919 as a second mammalian Sec15 homologue) binds RalA in a GTP-dependent manner in nerve terminals, placing RalA upstream of the exocyst as a regulator of exocytosis sites in mammalian neurons.","method":"Pulldown of brain proteins with GTP-loaded RalA followed by MALDI-TOF MS identification; Western blot confirmation of rSec6 and rSec8 binding to active RalA","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — GTP-state-specific pulldown confirmed by Western blot; identifies KIAA0919 (EXOC6B) as exocyst subunit; single lab","pmids":["11406615"],"is_preprint":false},{"year":2022,"finding":"Biallelic loss-of-function variants in EXOC6B abrogate exocytosis in patient-derived fibroblasts, leading to impaired primary ciliogenesis, as well as reduced osteogenesis differentiation and extracellular matrix-related pathways, establishing EXOC6B as essential for ciliogenesis downstream of its vesicle-tethering function.","method":"Patient fibroblast cell lines with biallelic EXOC6B variants; functional assays for exocytosis and primary ciliogenesis; gene expression profiling for osteogenesis/ECM pathways","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional assay in patient-derived cells with defined cellular phenotype; single lab, multiple readouts","pmids":["36150098"],"is_preprint":false},{"year":2024,"finding":"Exoc6b localizes to the perinuclear region and the base of primary cilia in ATDC5 prechondrocytes; shRNA knockdown of Exoc6b impedes primary ciliogenesis, attenuates Hedgehog signaling (including upon Smoothened agonist stimulation), and disrupts markers of chondrocyte proliferation (Col2a1, Ihh) and hypertrophy (Col10a1, Mmp13, Adamts4, Bglap) during chondrogenic differentiation.","method":"shRNA lentiviral knockdown; immunocytochemistry for localization; RT-qPCR and immunoblotting for pathway markers; Alizarin Red staining for ECM mineralization","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 — KD with defined cellular phenotypes and pathway placement; multiple orthogonal methods; single lab","pmids":["38305850"],"is_preprint":false},{"year":2022,"finding":"Exoc6/Exoc6b silencing in rat pancreatic β-cells (INS1-832/13) impairs insulin secretion, insulin content, exocytosis machinery, and glucose uptake, with decreased mRNA/protein levels of Ins1, Ins2, Pdx1, Glut2, and Vamp2, establishing Exoc6b as a component required for β-cell exocytosis.","method":"siRNA knockdown of Exoc6/6b in INS1-832/13 cells; insulin secretion assay; RT-qPCR and Western blot for exocytosis markers","journal":"Biology","confidence":"Medium","confidence_rationale":"Tier 2 — KD with defined cellular phenotype and multiple molecular readouts; single lab","pmids":["35336762"],"is_preprint":false},{"year":2024,"finding":"EXOC6B (Sec15b) interacts with STAT3 acetylated on K177/K180 and phosphorylated on Y293 in mouse embryonic stem cells; this interaction mediates STAT3 translocation into multivesicular endosomes (MVEs) and subsequent secretion, which downregulates ERK1/2 phosphorylation and upregulates GSK3β phosphorylation to maintain mESC self-renewal.","method":"Co-immunoprecipitation of STAT3 with Sec15b; site-directed mutagenesis (K177R/K180R, Y293F); live-cell imaging and fractionation for MVE localization; Sec15b knockout mice; genetic rescue experiments","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP, mutagenesis with defined loss-of-function phenotype, and in vivo knockout; single lab but multiple orthogonal methods","pmids":["39475099"],"is_preprint":false},{"year":2013,"finding":"EXOC6B haploinsufficiency in patient lymphoblasts (from 2p13.2 microdeletion) results in perturbed expression of Notch signaling pathway genes HES1 and RBPJ, placing EXOC6B upstream of Notch signaling in a cellular context.","method":"Expression analysis in patient-derived lymphoblasts by RT-PCR/quantitative PCR for HES1 and RBPJ; comparison with controls","journal":"Orphanet journal of rare diseases","confidence":"Low","confidence_rationale":"Tier 3 — single method (expression in patient cells), indirect pathway inference, single study","pmids":["23837398"],"is_preprint":false}],"current_model":"EXOC6B encodes a subunit of the octameric exocyst tethering complex that functions in vesicle docking and exocytosis at the plasma membrane; it directly binds Rab10-GTP (linking insulin signaling to GLUT4 translocation) and interacts with STAT3 to mediate its multivesicular endosome secretion, and is required for primary ciliogenesis, Hedgehog signaling, chondrogenic differentiation, and pancreatic β-cell insulin secretion, with loss-of-function causing impaired exocytosis across multiple cell types."},"narrative":{"teleology":[{"year":2001,"claim":"Identification of EXOC6B (KIAA0919) as a second mammalian Sec15 homologue within the brain exocyst complex established it as a bona fide exocyst subunit regulated by the small GTPase RalA.","evidence":"GTP-loaded RalA pulldown from rat brain extracts followed by MALDI-TOF MS identification of exocyst subunits including KIAA0919","pmids":["11406615"],"confidence":"Medium","gaps":["No direct binding assay between RalA and EXOC6B specifically (pulled down as part of whole complex)","Functional consequence of RalA–exocyst interaction for EXOC6B-dependent trafficking not tested"]},{"year":2015,"claim":"Demonstrating that Rab10-GTP directly binds EXOC6B and that its depletion inhibits GLUT4 translocation answered how insulin signaling engages the exocyst, identifying a specific GTPase–effector link for regulated exocytosis in adipocytes.","evidence":"Co-immunoprecipitation/pulldown with GTP-state specificity; siRNA knockdown of Exoc6/Exoc6b with GLUT4 translocation assay in 3T3-L1 adipocytes","pmids":["26299925"],"confidence":"Medium","gaps":["Structural basis of Rab10–EXOC6B interaction unresolved","Relative contributions of EXOC6 versus EXOC6B to GLUT4 trafficking in vivo not delineated"]},{"year":2022,"claim":"Showing that biallelic EXOC6B loss-of-function in human patient fibroblasts abrogates exocytosis and primary ciliogenesis established that exocyst-mediated vesicle tethering is required for cilia assembly and linked EXOC6B deficiency to a developmental phenotype.","evidence":"Patient-derived fibroblasts with biallelic EXOC6B variants; functional assays for exocytosis, ciliogenesis, and gene expression profiling for osteogenesis/ECM pathways","pmids":["36150098"],"confidence":"Medium","gaps":["Rescue experiment to confirm causality of EXOC6B variants not reported","Which specific vesicle cargo is required for ciliogenesis downstream of EXOC6B remains unknown"]},{"year":2022,"claim":"Demonstrating that Exoc6/Exoc6b knockdown in pancreatic β-cells impairs insulin secretion, insulin content, and expression of key exocytosis genes extended the exocytotic role of EXOC6B beyond adipocytes to endocrine cells.","evidence":"siRNA knockdown in INS1-832/13 cells; insulin secretion assays; RT-qPCR and Western blot for Ins1/2, Pdx1, Glut2, Vamp2","pmids":["35336762"],"confidence":"Medium","gaps":["Combined Exoc6/6b knockdown makes individual contribution of EXOC6B uncertain","In vivo β-cell phenotype of EXOC6B loss not assessed"]},{"year":2024,"claim":"Localizing EXOC6B to the ciliary base and showing that its depletion blocks both ciliogenesis and Hedgehog signaling in prechondrocytes defined a mechanism linking exocyst-dependent vesicle delivery to cilium-dependent developmental signaling during chondrogenesis.","evidence":"shRNA knockdown in ATDC5 cells; immunocytochemistry for ciliary-base localization; RT-qPCR/immunoblotting for Hedgehog and chondrogenic markers","pmids":["38305850"],"confidence":"Medium","gaps":["Direct cargo delivered by EXOC6B to the ciliary base not identified","Whether Hedgehog signaling defect is solely secondary to cilia loss or involves additional EXOC6B-dependent trafficking not resolved"]},{"year":2024,"claim":"Discovering that EXOC6B binds acetylated/phosphorylated STAT3 to mediate its sorting into multivesicular endosomes for secretion revealed a non-canonical exocyst function in signal transduction, linking EXOC6B to ERK1/2 and GSK3β regulation and embryonic stem cell self-renewal.","evidence":"Co-immunoprecipitation of STAT3 with Sec15b; site-directed mutagenesis (K177R/K180R, Y293F); live-cell imaging and fractionation for MVE localization; Sec15b knockout mice; genetic rescue","pmids":["39475099"],"confidence":"Medium","gaps":["Whether STAT3–EXOC6B interaction occurs independently of the full exocyst complex is unclear","In vivo phenotype of Sec15b knockout mice beyond mESC self-renewal not fully described","Whether MVE-mediated STAT3 secretion operates in somatic cell types is unknown"]},{"year":null,"claim":"The structural basis of EXOC6B's selective interactions with Rab10, STAT3, and other cargo adaptors, the identity of the vesicle cargoes it delivers to the ciliary base, and the in vivo developmental consequences of EXOC6B loss in mammalian models remain to be determined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of EXOC6B or its complexes with partners","In vivo conditional knockout phenotypes in skeletal and neuronal tissues not characterized","Functional redundancy between EXOC6 and EXOC6B not systematically addressed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[5]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,2,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,3]}],"complexes":["exocyst complex"],"partners":["RAB10","RALA","STAT3","EXOC1","EXOC2"],"other_free_text":[]},"mechanistic_narrative":"EXOC6B encodes a subunit of the octameric exocyst complex that tethers secretory vesicles to the plasma membrane, functioning in regulated exocytosis across multiple cell types. It binds Rab10-GTP to couple insulin signaling to GLUT4 vesicle translocation in adipocytes [PMID:26299925], is required for insulin secretion and expression of exocytotic machinery components (Vamp2, Glut2, Pdx1) in pancreatic β-cells [PMID:35336762], and interacts with post-translationally modified STAT3 to direct its translocation into multivesicular endosomes for secretion, thereby modulating ERK1/2 and GSK3β signaling in embryonic stem cell self-renewal [PMID:39475099]. EXOC6B is essential for primary ciliogenesis downstream of its vesicle-tethering function; biallelic loss-of-function variants in humans abrogate exocytosis and impair cilia formation, and knockdown in prechondrocytes attenuates Hedgehog signaling and disrupts chondrogenic differentiation [PMID:36150098, PMID:38305850]."},"prefetch_data":{"uniprot":{"accession":"Q9Y2D4","full_name":"Exocyst complex component 6B","aliases":["Exocyst complex component Sec15B","SEC15-like protein 2"],"length_aa":811,"mass_kda":94.2,"function":"Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9Y2D4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EXOC6B","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EXOC6B","total_profiled":1310},"omim":[{"mim_id":"618395","title":"SPONDYLOEPIMETAPHYSEAL DYSPLASIA WITH JOINT LAXITY, TYPE 3; SEMDJL3","url":"https://www.omim.org/entry/618395"},{"mim_id":"607880","title":"EXOCYST COMPLEX COMPONENT 6B; EXOC6B","url":"https://www.omim.org/entry/607880"},{"mim_id":"271640","title":"SPONDYLOEPIMETAPHYSEAL DYSPLASIA WITH JOINT LAXITY, TYPE 1, WITH OR WITHOUT FRACTURES; SEMDJL1","url":"https://www.omim.org/entry/271640"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear bodies","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":47.5}],"url":"https://www.proteinatlas.org/search/EXOC6B"},"hgnc":{"alias_symbol":["KIAA0919"],"prev_symbol":["SEC15L2","SEC15B"]},"alphafold":{"accession":"Q9Y2D4","domains":[{"cath_id":"-","chopping":"177-230_287-417","consensus_level":"medium","plddt":84.9211,"start":177,"end":417},{"cath_id":"1.10.357.30","chopping":"434-455_491-608","consensus_level":"high","plddt":87.5348,"start":434,"end":608},{"cath_id":"1.20.58.670","chopping":"629-634_641-739","consensus_level":"medium","plddt":86.4143,"start":629,"end":739},{"cath_id":"1.10.287","chopping":"742-811","consensus_level":"medium","plddt":74.3224,"start":742,"end":811}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2D4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2D4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2D4-F1-predicted_aligned_error_v6.png","plddt_mean":79.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EXOC6B","jax_strain_url":"https://www.jax.org/strain/search?query=EXOC6B"},"sequence":{"accession":"Q9Y2D4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y2D4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y2D4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2D4"}},"corpus_meta":[{"pmid":"18492870","id":"PMC_18492870","title":"An exocyst complex functions in plant cell growth in Arabidopsis and tobacco.","date":"2008","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/18492870","citation_count":215,"is_preprint":false},{"pmid":"20870962","id":"PMC_20870962","title":"The Arabidopsis exocyst complex is involved in cytokinesis and cell plate maturation.","date":"2010","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/20870962","citation_count":140,"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":"10231032","id":"PMC_10231032","title":"Prediction of the coding sequences of unidentified human genes. 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knockdown of Exoc6, Exoc6b, or both with GLUT4 translocation readout in 3T3-L1 adipocytes\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding shown with GTP-state specificity plus clean KD with defined cellular phenotype; single lab, two orthogonal methods\",\n      \"pmids\": [\"26299925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The brain exocyst complex (including rSec6 and rSec8, and identifying KIAA0919 as a second mammalian Sec15 homologue) binds RalA in a GTP-dependent manner in nerve terminals, placing RalA upstream of the exocyst as a regulator of exocytosis sites in mammalian neurons.\",\n      \"method\": \"Pulldown of brain proteins with GTP-loaded RalA followed by MALDI-TOF MS identification; Western blot confirmation of rSec6 and rSec8 binding to active RalA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — GTP-state-specific pulldown confirmed by Western blot; identifies KIAA0919 (EXOC6B) as exocyst subunit; single lab\",\n      \"pmids\": [\"11406615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Biallelic loss-of-function variants in EXOC6B abrogate exocytosis in patient-derived fibroblasts, leading to impaired primary ciliogenesis, as well as reduced osteogenesis differentiation and extracellular matrix-related pathways, establishing EXOC6B as essential for ciliogenesis downstream of its vesicle-tethering function.\",\n      \"method\": \"Patient fibroblast cell lines with biallelic EXOC6B variants; functional assays for exocytosis and primary ciliogenesis; gene expression profiling for osteogenesis/ECM pathways\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assay in patient-derived cells with defined cellular phenotype; single lab, multiple readouts\",\n      \"pmids\": [\"36150098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Exoc6b localizes to the perinuclear region and the base of primary cilia in ATDC5 prechondrocytes; shRNA knockdown of Exoc6b impedes primary ciliogenesis, attenuates Hedgehog signaling (including upon Smoothened agonist stimulation), and disrupts markers of chondrocyte proliferation (Col2a1, Ihh) and hypertrophy (Col10a1, Mmp13, Adamts4, Bglap) during chondrogenic differentiation.\",\n      \"method\": \"shRNA lentiviral knockdown; immunocytochemistry for localization; RT-qPCR and immunoblotting for pathway markers; Alizarin Red staining for ECM mineralization\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined cellular phenotypes and pathway placement; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"38305850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Exoc6/Exoc6b silencing in rat pancreatic β-cells (INS1-832/13) impairs insulin secretion, insulin content, exocytosis machinery, and glucose uptake, with decreased mRNA/protein levels of Ins1, Ins2, Pdx1, Glut2, and Vamp2, establishing Exoc6b as a component required for β-cell exocytosis.\",\n      \"method\": \"siRNA knockdown of Exoc6/6b in INS1-832/13 cells; insulin secretion assay; RT-qPCR and Western blot for exocytosis markers\",\n      \"journal\": \"Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined cellular phenotype and multiple molecular readouts; single lab\",\n      \"pmids\": [\"35336762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EXOC6B (Sec15b) interacts with STAT3 acetylated on K177/K180 and phosphorylated on Y293 in mouse embryonic stem cells; this interaction mediates STAT3 translocation into multivesicular endosomes (MVEs) and subsequent secretion, which downregulates ERK1/2 phosphorylation and upregulates GSK3β phosphorylation to maintain mESC self-renewal.\",\n      \"method\": \"Co-immunoprecipitation of STAT3 with Sec15b; site-directed mutagenesis (K177R/K180R, Y293F); live-cell imaging and fractionation for MVE localization; Sec15b knockout mice; genetic rescue experiments\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, mutagenesis with defined loss-of-function phenotype, and in vivo knockout; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39475099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EXOC6B haploinsufficiency in patient lymphoblasts (from 2p13.2 microdeletion) results in perturbed expression of Notch signaling pathway genes HES1 and RBPJ, placing EXOC6B upstream of Notch signaling in a cellular context.\",\n      \"method\": \"Expression analysis in patient-derived lymphoblasts by RT-PCR/quantitative PCR for HES1 and RBPJ; comparison with controls\",\n      \"journal\": \"Orphanet journal of rare diseases\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single method (expression in patient cells), indirect pathway inference, single study\",\n      \"pmids\": [\"23837398\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EXOC6B encodes a subunit of the octameric exocyst tethering complex that functions in vesicle docking and exocytosis at the plasma membrane; it directly binds Rab10-GTP (linking insulin signaling to GLUT4 translocation) and interacts with STAT3 to mediate its multivesicular endosome secretion, and is required for primary ciliogenesis, Hedgehog signaling, chondrogenic differentiation, and pancreatic β-cell insulin secretion, with loss-of-function causing impaired exocytosis across multiple cell types.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"EXOC6B encodes a subunit of the octameric exocyst complex that tethers secretory vesicles to the plasma membrane, functioning in regulated exocytosis across multiple cell types. It binds Rab10-GTP to couple insulin signaling to GLUT4 vesicle translocation in adipocytes [PMID:26299925], is required for insulin secretion and expression of exocytotic machinery components (Vamp2, Glut2, Pdx1) in pancreatic β-cells [PMID:35336762], and interacts with post-translationally modified STAT3 to direct its translocation into multivesicular endosomes for secretion, thereby modulating ERK1/2 and GSK3β signaling in embryonic stem cell self-renewal [PMID:39475099]. EXOC6B is essential for primary ciliogenesis downstream of its vesicle-tethering function; biallelic loss-of-function variants in humans abrogate exocytosis and impair cilia formation, and knockdown in prechondrocytes attenuates Hedgehog signaling and disrupts chondrogenic differentiation [PMID:36150098, PMID:38305850].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of EXOC6B (KIAA0919) as a second mammalian Sec15 homologue within the brain exocyst complex established it as a bona fide exocyst subunit regulated by the small GTPase RalA.\",\n      \"evidence\": \"GTP-loaded RalA pulldown from rat brain extracts followed by MALDI-TOF MS identification of exocyst subunits including KIAA0919\",\n      \"pmids\": [\"11406615\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct binding assay between RalA and EXOC6B specifically (pulled down as part of whole complex)\",\n        \"Functional consequence of RalA–exocyst interaction for EXOC6B-dependent trafficking not tested\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrating that Rab10-GTP directly binds EXOC6B and that its depletion inhibits GLUT4 translocation answered how insulin signaling engages the exocyst, identifying a specific GTPase–effector link for regulated exocytosis in adipocytes.\",\n      \"evidence\": \"Co-immunoprecipitation/pulldown with GTP-state specificity; siRNA knockdown of Exoc6/Exoc6b with GLUT4 translocation assay in 3T3-L1 adipocytes\",\n      \"pmids\": [\"26299925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of Rab10–EXOC6B interaction unresolved\",\n        \"Relative contributions of EXOC6 versus EXOC6B to GLUT4 trafficking in vivo not delineated\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing that biallelic EXOC6B loss-of-function in human patient fibroblasts abrogates exocytosis and primary ciliogenesis established that exocyst-mediated vesicle tethering is required for cilia assembly and linked EXOC6B deficiency to a developmental phenotype.\",\n      \"evidence\": \"Patient-derived fibroblasts with biallelic EXOC6B variants; functional assays for exocytosis, ciliogenesis, and gene expression profiling for osteogenesis/ECM pathways\",\n      \"pmids\": [\"36150098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Rescue experiment to confirm causality of EXOC6B variants not reported\",\n        \"Which specific vesicle cargo is required for ciliogenesis downstream of EXOC6B remains unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that Exoc6/Exoc6b knockdown in pancreatic β-cells impairs insulin secretion, insulin content, and expression of key exocytosis genes extended the exocytotic role of EXOC6B beyond adipocytes to endocrine cells.\",\n      \"evidence\": \"siRNA knockdown in INS1-832/13 cells; insulin secretion assays; RT-qPCR and Western blot for Ins1/2, Pdx1, Glut2, Vamp2\",\n      \"pmids\": [\"35336762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Combined Exoc6/6b knockdown makes individual contribution of EXOC6B uncertain\",\n        \"In vivo β-cell phenotype of EXOC6B loss not assessed\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Localizing EXOC6B to the ciliary base and showing that its depletion blocks both ciliogenesis and Hedgehog signaling in prechondrocytes defined a mechanism linking exocyst-dependent vesicle delivery to cilium-dependent developmental signaling during chondrogenesis.\",\n      \"evidence\": \"shRNA knockdown in ATDC5 cells; immunocytochemistry for ciliary-base localization; RT-qPCR/immunoblotting for Hedgehog and chondrogenic markers\",\n      \"pmids\": [\"38305850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct cargo delivered by EXOC6B to the ciliary base not identified\",\n        \"Whether Hedgehog signaling defect is solely secondary to cilia loss or involves additional EXOC6B-dependent trafficking not resolved\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovering that EXOC6B binds acetylated/phosphorylated STAT3 to mediate its sorting into multivesicular endosomes for secretion revealed a non-canonical exocyst function in signal transduction, linking EXOC6B to ERK1/2 and GSK3β regulation and embryonic stem cell self-renewal.\",\n      \"evidence\": \"Co-immunoprecipitation of STAT3 with Sec15b; site-directed mutagenesis (K177R/K180R, Y293F); live-cell imaging and fractionation for MVE localization; Sec15b knockout mice; genetic rescue\",\n      \"pmids\": [\"39475099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether STAT3–EXOC6B interaction occurs independently of the full exocyst complex is unclear\",\n        \"In vivo phenotype of Sec15b knockout mice beyond mESC self-renewal not fully described\",\n        \"Whether MVE-mediated STAT3 secretion operates in somatic cell types is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of EXOC6B's selective interactions with Rab10, STAT3, and other cargo adaptors, the identity of the vesicle cargoes it delivers to the ciliary base, and the in vivo developmental consequences of EXOC6B loss in mammalian models remain to be determined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of EXOC6B or its complexes with partners\",\n        \"In vivo conditional knockout phenotypes in skeletal and neuronal tissues not characterized\",\n        \"Functional redundancy between EXOC6 and EXOC6B not systematically addressed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 2, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [\n      \"exocyst complex\"\n    ],\n    \"partners\": [\n      \"RAB10\",\n      \"RALA\",\n      \"STAT3\",\n      \"EXOC1\",\n      \"EXOC2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}