{"gene":"SEPTIN10","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2003,"finding":"SEPTIN10 protein contains a conserved GTP-binding motif, can bind GTP, and exerts GTPase activity. When expressed as a GFP-fusion protein, it localizes to the cytoplasm and nucleus in a pattern independent of filamentous actin state.","method":"In vitro GTP-binding/GTPase assay; GFP-fusion live-cell imaging","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 (GTPase assay) / Weak — single lab, single study, no mutagenesis or structural validation reported","pmids":["12711328"],"is_preprint":false},{"year":2013,"finding":"In squamous cell carcinoma DJM-1 cells, SEPT10 forms a distinct septin complex with SEPT7, SEPT8, SEPT9, SEPT11, and SEPT14 (excluding SEPT5), and localizes along microtubules rather than at lamellipodia.","method":"Immunoprecipitation; immunofluorescence co-localization","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal co-IP identifying complex membership, replicated with localization data, single lab","pmids":["23087102"],"is_preprint":false},{"year":2012,"finding":"SEPT10 knockdown (siRNA) confers paclitaxel resistance, while SEPT10 overexpression increases paclitaxel sensitivity; SEPT10 was identified as an important regulator of microtubule stability.","method":"Lentiviral siRNA library functional genomics screen; siRNA knockdown; overexpression assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined cellular phenotype (paclitaxel sensitivity/resistance) with loss-of-function and gain-of-function, single lab","pmids":["22320903"],"is_preprint":false},{"year":2017,"finding":"siRNA silencing of SEPT10 in mouse podocytes leads to cytoskeletal injury, establishing a required role for SEPT10 in maintaining the podocyte cytoskeleton.","method":"siRNA knockdown with cytoskeletal phenotype readout in primary mouse podocytes","journal":"Kidney international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown experiment in a screen, no detailed mechanism or pathway placement reported","pmids":["28709640"],"is_preprint":false},{"year":2022,"finding":"Androglobin (Adgb) physically interacts with SEPT10 (confirmed by co-immunoprecipitation in vitro and in testis lysates in vivo). Loss of Adgb causes mislocalization of SEPT10 in sperm, indicating defective manchette and sperm annulus formation. In vitro data suggest Adgb contributes to SEPT10 proteolysis in a calmodulin-dependent manner.","method":"Immunoprecipitation/mass spectrometry; reciprocal co-immunoprecipitation in vitro and in vivo; immunofluorescence localization in Adgb knockout mice","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP confirmed both in vitro and in vivo, loss-of-function mouse model with defined localization phenotype, multiple orthogonal methods","pmids":["35700329"],"is_preprint":false},{"year":2020,"finding":"SEPT10 forms a complex with SEPT1, SEPT2, SEPT11, and SEPT12 at the sperm neck; a mutation in SEPT12 (D197N) disrupts this complex, impairing connecting piece assembly and causing acephalic, immotile spermatozoa.","method":"Co-immunoprecipitation; immunofluorescence in SEPT12 D197N knock-in mice; electron microscopy","journal":"Molecular human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP defining complex membership supported by genetic KI model and EM phenotype, single lab","pmids":["32392324"],"is_preprint":false},{"year":2024,"finding":"SEPTIN10 interacts with actin and microtubule filaments: it promotes actin stress fiber formation and intracellular tension by binding to CAPZA2, while concurrently inhibiting microtubule polymerization by blocking MAP4 function. Loss of SEPTIN10 abrogates actin stress fiber formation after microtubule disruption, establishing SEPTIN10 as a molecular switch mediating crosstalk between the actin and microtubule cytoskeletons that feeds back to activate YAP/TAZ in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation (SEPTIN10-CAPZA2, SEPTIN10-MAP4); siRNA loss-of-function with actin/microtubule phenotype readouts; YAP/TAZ reporter assays; overexpression studies","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (co-IP for binding partners, KD phenotype with specific cytoskeletal and signaling readouts, epistasis-like rescue experiments), single lab","pmids":["38242197"],"is_preprint":false},{"year":2023,"finding":"miR-124-3p directly targets SEPT10 in retinal progenitor cells (RPCs): miR-124-3p overexpression reduces SEPT10 expression, decreases RPC proliferation and increases differentiation; SEPT10 overexpression rescues the proliferation defect caused by miR-124-3p, placing SEPT10 downstream of miR-124-3p in RPC fate determination.","method":"miRNA overexpression and antisense knockdown; SEPT10 overexpression rescue experiment; proliferation and differentiation assays in RPCs","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — genetic epistasis via rescue experiment, single lab, no direct binding validation of miR-124-3p:SEPT10 interaction reported in abstract","pmids":["36802303"],"is_preprint":false}],"current_model":"SEPTIN10 is a GTPase-active cytoskeletal septin that assembles into heteromeric septin complexes (e.g., with SEPT7, SEPT8, SEPT9, SEPT11 in somatic cells; with SEPT1, SEPT2, SEPT11, SEPT12 at the sperm neck), localizes along microtubules and, in spermatids, at the manchette and sperm annulus where it is regulated by androglobin-dependent proteolysis; in cancer cells, SEPTIN10 acts as a molecular switch linking actin and microtubule dynamics by binding CAPZA2 (promoting stress fibers) and blocking MAP4 (inhibiting microtubule polymerization), thereby feeding back to activate YAP/TAZ mechanosignaling, and it also regulates microtubule stability in a manner that determines sensitivity to microtubule-targeting agents such as paclitaxel."},"narrative":{"mechanistic_narrative":"SEPTIN10 is a GTP-binding, GTPase-active member of the septin cytoskeletal family that assembles into heteromeric septin complexes and regulates the interplay between the actin and microtubule cytoskeletons [PMID:12711328, PMID:23087102, PMID:38242197]. It binds and hydrolyzes GTP and localizes to both cytoplasm and nucleus independently of the filamentous actin state [PMID:12711328]. In cells it partitions into distinct higher-order septin assemblies—co-precipitating with SEPT7, SEPT8, SEPT9, SEPT11, and SEPT14 along microtubules in carcinoma cells [PMID:23087102], and with SEPT1, SEPT2, SEPT11, and SEPT12 at the sperm neck where it supports connecting-piece assembly [PMID:32392324]. Mechanistically, SEPTIN10 functions as a molecular switch coupling the two cytoskeletons: it binds CAPZA2 to promote actin stress fiber formation and intracellular tension while blocking MAP4 to inhibit microtubule polymerization, with loss of SEPTIN10 abrogating actin stress fiber formation after microtubule disruption and feeding back to activate YAP/TAZ mechanosignaling in hepatocellular carcinoma cells [PMID:38242197]. Consistent with a role in microtubule stability, SEPTIN10 levels set sensitivity to the microtubule-targeting agent paclitaxel [PMID:22320903], and the protein is required to maintain the podocyte cytoskeleton [PMID:28709640]. In the male germline, SEPTIN10 physically interacts with androglobin, which directs its localization at the manchette and sperm annulus and contributes to its calmodulin-dependent proteolysis [PMID:35700329].","teleology":[{"year":2003,"claim":"Establishing whether SEPTIN10 is a functional GTPase defined its core biochemical identity as a nucleotide-binding septin and showed its localization is uncoupled from the actin cytoskeleton.","evidence":"In vitro GTP-binding/GTPase assay and GFP-fusion live-cell imaging","pmids":["12711328"],"confidence":"Medium","gaps":["No mutagenesis of the GTP-binding motif to link catalysis to function","No structural model of nucleotide binding","Subcellular targeting determinants unresolved"]},{"year":2012,"claim":"A functional genomics screen connected SEPTIN10 dosage to microtubule stability and chemosensitivity, showing it regulates a drug-relevant cytoskeletal phenotype.","evidence":"Lentiviral siRNA screen with siRNA knockdown and overexpression assays scoring paclitaxel sensitivity","pmids":["22320903"],"confidence":"Medium","gaps":["Molecular basis of microtubule regulation not defined","Direct microtubule-binding partners not identified at this stage","Single lab, single cell context"]},{"year":2013,"claim":"Defining SEPTIN10's septin complex membership and microtubule-associated localization placed it in a specific heteromeric assembly distinct from lamellipodial septins.","evidence":"Reciprocal immunoprecipitation and immunofluorescence co-localization in squamous carcinoma cells","pmids":["23087102"],"confidence":"Medium","gaps":["Stoichiometry and filament architecture of the complex unresolved","Whether SEPT10 is required for complex assembly not tested","Functional consequence of microtubule association not addressed"]},{"year":2017,"claim":"A knockdown screen extended SEPTIN10's cytoskeletal role to a physiological cell type, showing it is required to maintain the podocyte cytoskeleton.","evidence":"siRNA knockdown with cytoskeletal injury readout in primary mouse podocytes","pmids":["28709640"],"confidence":"Low","gaps":["Single knockdown experiment without mechanistic follow-up","No pathway placement","No rescue or specificity controls reported"]},{"year":2020,"claim":"Identifying a sperm-neck septin complex containing SEPTIN10 and linking a SEPT12 mutation to its disruption tied this assembly to connecting-piece integrity and sperm morphology.","evidence":"Co-immunoprecipitation, immunofluorescence in SEPT12 D197N knock-in mice, and electron microscopy","pmids":["32392324"],"confidence":"Medium","gaps":["SEPTIN10's individual contribution versus other subunits not isolated","No SEPT10-specific genetic perturbation","Assembly mechanism at the connecting piece unresolved"]},{"year":2022,"claim":"Discovering the androglobin–SEPTIN10 interaction defined an upstream regulator controlling SEPTIN10 localization and turnover during spermatogenesis.","evidence":"IP/MS, reciprocal co-IP in vitro and in testis lysates, and immunofluorescence in Adgb knockout mice","pmids":["35700329"],"confidence":"High","gaps":["Direct proteolytic mechanism and cleavage sites not defined","Calmodulin dependence shown in vitro only","Whether proteolysis regulates septin filament dynamics in vivo unresolved"]},{"year":2023,"claim":"Placing SEPTIN10 downstream of miR-124-3p linked its expression level to cell-fate decisions in retinal progenitor proliferation and differentiation.","evidence":"miRNA overexpression/knockdown and SEPT10 overexpression rescue with proliferation/differentiation assays in RPCs","pmids":["36802303"],"confidence":"Medium","gaps":["Direct miR-124-3p:SEPT10 binding not validated in abstract","Cytoskeletal mechanism in RPCs not defined","Single lab, single context"]},{"year":2024,"claim":"Identifying CAPZA2 and MAP4 as opposing SEPTIN10 partners established it as a molecular switch coordinating actin and microtubule dynamics that feeds back to YAP/TAZ mechanosignaling.","evidence":"Co-IP of SEPTIN10–CAPZA2 and SEPTIN10–MAP4, siRNA loss-of-function with cytoskeletal readouts, YAP/TAZ reporter and rescue assays in hepatocellular carcinoma cells","pmids":["38242197"],"confidence":"High","gaps":["Whether GTPase activity gates the switch not tested","Structural basis of CAPZA2/MAP4 binding unknown","Generality beyond hepatocellular carcinoma unresolved"]},{"year":null,"claim":"How SEPTIN10's GTPase cycle, its alternative septin complex memberships, and its actin/microtubule switch activity are mechanistically integrated remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of SEPTIN10-containing filaments","GTP hydrolysis not linked to partner binding or switch function","Tissue-specific selection of distinct septin partners not explained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[6]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[4,5]}],"complexes":["septin complex (SEPT7/8/9/11/14)","sperm-neck septin complex (SEPT1/2/11/12)"],"partners":["CAPZA2","MAP4","ADGB","SEPT12","SEPT11","SEPT7","SEPT9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P0V9","full_name":"Septin-10","aliases":[],"length_aa":454,"mass_kda":52.6,"function":"Filament-forming cytoskeletal GTPase. May play a role in cytokinesis (Potential)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton; Cell projection, cilium, flagellum","url":"https://www.uniprot.org/uniprotkb/Q9P0V9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEPTIN10","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1090,"dependency_fraction":0.005504587155963303},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SEPT8","stoichiometry":10.0},{"gene":"SEPT11","stoichiometry":0.2},{"gene":"SEPT2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SEPTIN10","total_profiled":1310},"omim":[{"mim_id":"620078","title":"FAMILY WITH SEQUENCE SIMILARITY 168, MEMBER B; FAM168B","url":"https://www.omim.org/entry/620078"},{"mim_id":"611737","title":"SEPTIN 10; SEPTIN10","url":"https://www.omim.org/entry/611737"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Actin filaments","reliability":"Supported"},{"location":"Microtubules","reliability":"Additional"},{"location":"Annulus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEPTIN10"},"hgnc":{"alias_symbol":["FLJ11619","Septin-10"],"prev_symbol":["SEPT10"]},"alphafold":{"accession":"Q9P0V9","domains":[{"cath_id":"3.40.50.300","chopping":"60-331","consensus_level":"high","plddt":89.7851,"start":60,"end":331},{"cath_id":"1.20.5","chopping":"353-429","consensus_level":"medium","plddt":90.6649,"start":353,"end":429}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P0V9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P0V9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P0V9-F1-predicted_aligned_error_v6.png","plddt_mean":80.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEPTIN10","jax_strain_url":"https://www.jax.org/strain/search?query=SEPTIN10"},"sequence":{"accession":"Q9P0V9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P0V9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P0V9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P0V9"}},"corpus_meta":[{"pmid":"12475938","id":"PMC_12475938","title":"Mammalian septins nomenclature.","date":"2002","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/12475938","citation_count":102,"is_preprint":false},{"pmid":"16434371","id":"PMC_16434371","title":"The predictive value of lipoprotein lipase for survival in chronic lymphocytic leukemia.","date":"2006","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/16434371","citation_count":87,"is_preprint":false},{"pmid":"28709640","id":"PMC_28709640","title":"Genome-wide identification of genes essential for podocyte cytoskeletons based on single-cell RNA sequencing.","date":"2017","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/28709640","citation_count":69,"is_preprint":false},{"pmid":"16617321","id":"PMC_16617321","title":"Deregulated expression of fat and muscle genes in B-cell chronic lymphocytic leukemia with high lipoprotein lipase expression.","date":"2006","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/16617321","citation_count":66,"is_preprint":false},{"pmid":"23087102","id":"PMC_23087102","title":"Possible role of a septin, SEPT1, in spreading in squamous cell carcinoma DJM-1 cells.","date":"2013","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23087102","citation_count":44,"is_preprint":false},{"pmid":"17922164","id":"PMC_17922164","title":"Characterization of a SEPT9 interacting protein, SEPT14, a novel testis-specific septin.","date":"2007","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/17922164","citation_count":44,"is_preprint":false},{"pmid":"20195767","id":"PMC_20195767","title":"Linking the septin expression with carcinogenesis.","date":"2010","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/20195767","citation_count":37,"is_preprint":false},{"pmid":"35700329","id":"PMC_35700329","title":"Androglobin, a chimeric mammalian globin, is required for male fertility.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/35700329","citation_count":25,"is_preprint":false},{"pmid":"12711328","id":"PMC_12711328","title":"Cloning and functional characterization of human septin 10, a novel member of septin family cloned from dendritic cells.","date":"2003","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12711328","citation_count":19,"is_preprint":false},{"pmid":"32392324","id":"PMC_32392324","title":"The SEPT12 complex is required for the establishment of a functional sperm head-tail junction.","date":"2020","source":"Molecular human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/32392324","citation_count":18,"is_preprint":false},{"pmid":"29526576","id":"PMC_29526576","title":"An invertebrate β-integrin mediates coelomocyte phagocytosis via activation of septin2 and 7 but not septin10.","date":"2018","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/29526576","citation_count":13,"is_preprint":false},{"pmid":"22320903","id":"PMC_22320903","title":"Identification of a novel role of Septin 10 in paclitaxel-resistance in cancers through a functional genomics screen.","date":"2012","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/22320903","citation_count":12,"is_preprint":false},{"pmid":"26038121","id":"PMC_26038121","title":"Surrogate molecular markers for IGHV mutational status in chronic lymphocytic leukemia for predicting time to first treatment.","date":"2015","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/26038121","citation_count":12,"is_preprint":false},{"pmid":"38242197","id":"PMC_38242197","title":"SEPTIN10-mediated crosstalk between cytoskeletal networks controls mechanotransduction and oncogenic YAP/TAZ signaling.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/38242197","citation_count":10,"is_preprint":false},{"pmid":"24367716","id":"PMC_24367716","title":"Septins of Platyhelminths: identification, phylogeny, expression and localization among developmental stages of Schistosoma mansoni.","date":"2013","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/24367716","citation_count":9,"is_preprint":false},{"pmid":"36139690","id":"PMC_36139690","title":"Systematic Analysis of Genetic and Pathway Determinants of Eribulin Sensitivity across 100 Human Cancer Cell Lines from the Cancer Cell Line Encyclopedia (CCLE).","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36139690","citation_count":8,"is_preprint":false},{"pmid":"39025256","id":"PMC_39025256","title":"Novel lipid-interaction motifs within the C-terminal domain of Septin10 from Schistosoma mansoni.","date":"2024","source":"Biochimica et biophysica acta. Biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/39025256","citation_count":7,"is_preprint":false},{"pmid":"39728605","id":"PMC_39728605","title":"Identification of Tumor-Suppressive miR-30a-3p Controlled Genes: ANLN as a Therapeutic Target in Breast Cancer.","date":"2024","source":"Non-coding RNA","url":"https://pubmed.ncbi.nlm.nih.gov/39728605","citation_count":6,"is_preprint":false},{"pmid":"36802303","id":"PMC_36802303","title":"miR-124-3p regulates the proliferation and differentiation of retinal progenitor cells through SEPT10.","date":"2023","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/36802303","citation_count":3,"is_preprint":false},{"pmid":"36950992","id":"PMC_36950992","title":"Exosomal circCLIP1 regulates PM2.5-induced airway obstruction via targeting SEPT10 in vitro.","date":"2023","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/36950992","citation_count":2,"is_preprint":false},{"pmid":"39672481","id":"PMC_39672481","title":"Sept10 and sept12 are expressed in specific proliferating cells in zebrafish brain.","date":"2024","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/39672481","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12345,"output_tokens":2010,"usd":0.033592,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8992,"output_tokens":3095,"usd":0.061167,"stage2_stop_reason":"end_turn"},"total_usd":0.094759,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"SEPTIN10 protein contains a conserved GTP-binding motif, can bind GTP, and exerts GTPase activity. When expressed as a GFP-fusion protein, it localizes to the cytoplasm and nucleus in a pattern independent of filamentous actin state.\",\n      \"method\": \"In vitro GTP-binding/GTPase assay; GFP-fusion live-cell imaging\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 (GTPase assay) / Weak — single lab, single study, no mutagenesis or structural validation reported\",\n      \"pmids\": [\"12711328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In squamous cell carcinoma DJM-1 cells, SEPT10 forms a distinct septin complex with SEPT7, SEPT8, SEPT9, SEPT11, and SEPT14 (excluding SEPT5), and localizes along microtubules rather than at lamellipodia.\",\n      \"method\": \"Immunoprecipitation; immunofluorescence co-localization\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal co-IP identifying complex membership, replicated with localization data, single lab\",\n      \"pmids\": [\"23087102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SEPT10 knockdown (siRNA) confers paclitaxel resistance, while SEPT10 overexpression increases paclitaxel sensitivity; SEPT10 was identified as an important regulator of microtubule stability.\",\n      \"method\": \"Lentiviral siRNA library functional genomics screen; siRNA knockdown; overexpression assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined cellular phenotype (paclitaxel sensitivity/resistance) with loss-of-function and gain-of-function, single lab\",\n      \"pmids\": [\"22320903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"siRNA silencing of SEPT10 in mouse podocytes leads to cytoskeletal injury, establishing a required role for SEPT10 in maintaining the podocyte cytoskeleton.\",\n      \"method\": \"siRNA knockdown with cytoskeletal phenotype readout in primary mouse podocytes\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown experiment in a screen, no detailed mechanism or pathway placement reported\",\n      \"pmids\": [\"28709640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Androglobin (Adgb) physically interacts with SEPT10 (confirmed by co-immunoprecipitation in vitro and in testis lysates in vivo). Loss of Adgb causes mislocalization of SEPT10 in sperm, indicating defective manchette and sperm annulus formation. In vitro data suggest Adgb contributes to SEPT10 proteolysis in a calmodulin-dependent manner.\",\n      \"method\": \"Immunoprecipitation/mass spectrometry; reciprocal co-immunoprecipitation in vitro and in vivo; immunofluorescence localization in Adgb knockout mice\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP confirmed both in vitro and in vivo, loss-of-function mouse model with defined localization phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"35700329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SEPT10 forms a complex with SEPT1, SEPT2, SEPT11, and SEPT12 at the sperm neck; a mutation in SEPT12 (D197N) disrupts this complex, impairing connecting piece assembly and causing acephalic, immotile spermatozoa.\",\n      \"method\": \"Co-immunoprecipitation; immunofluorescence in SEPT12 D197N knock-in mice; electron microscopy\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP defining complex membership supported by genetic KI model and EM phenotype, single lab\",\n      \"pmids\": [\"32392324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SEPTIN10 interacts with actin and microtubule filaments: it promotes actin stress fiber formation and intracellular tension by binding to CAPZA2, while concurrently inhibiting microtubule polymerization by blocking MAP4 function. Loss of SEPTIN10 abrogates actin stress fiber formation after microtubule disruption, establishing SEPTIN10 as a molecular switch mediating crosstalk between the actin and microtubule cytoskeletons that feeds back to activate YAP/TAZ in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation (SEPTIN10-CAPZA2, SEPTIN10-MAP4); siRNA loss-of-function with actin/microtubule phenotype readouts; YAP/TAZ reporter assays; overexpression studies\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (co-IP for binding partners, KD phenotype with specific cytoskeletal and signaling readouts, epistasis-like rescue experiments), single lab\",\n      \"pmids\": [\"38242197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-124-3p directly targets SEPT10 in retinal progenitor cells (RPCs): miR-124-3p overexpression reduces SEPT10 expression, decreases RPC proliferation and increases differentiation; SEPT10 overexpression rescues the proliferation defect caused by miR-124-3p, placing SEPT10 downstream of miR-124-3p in RPC fate determination.\",\n      \"method\": \"miRNA overexpression and antisense knockdown; SEPT10 overexpression rescue experiment; proliferation and differentiation assays in RPCs\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic epistasis via rescue experiment, single lab, no direct binding validation of miR-124-3p:SEPT10 interaction reported in abstract\",\n      \"pmids\": [\"36802303\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEPTIN10 is a GTPase-active cytoskeletal septin that assembles into heteromeric septin complexes (e.g., with SEPT7, SEPT8, SEPT9, SEPT11 in somatic cells; with SEPT1, SEPT2, SEPT11, SEPT12 at the sperm neck), localizes along microtubules and, in spermatids, at the manchette and sperm annulus where it is regulated by androglobin-dependent proteolysis; in cancer cells, SEPTIN10 acts as a molecular switch linking actin and microtubule dynamics by binding CAPZA2 (promoting stress fibers) and blocking MAP4 (inhibiting microtubule polymerization), thereby feeding back to activate YAP/TAZ mechanosignaling, and it also regulates microtubule stability in a manner that determines sensitivity to microtubule-targeting agents such as paclitaxel.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEPTIN10 is a GTP-binding, GTPase-active member of the septin cytoskeletal family that assembles into heteromeric septin complexes and regulates the interplay between the actin and microtubule cytoskeletons [#0, #1, #6]. It binds and hydrolyzes GTP and localizes to both cytoplasm and nucleus independently of the filamentous actin state [#0]. In cells it partitions into distinct higher-order septin assemblies—co-precipitating with SEPT7, SEPT8, SEPT9, SEPT11, and SEPT14 along microtubules in carcinoma cells [#1], and with SEPT1, SEPT2, SEPT11, and SEPT12 at the sperm neck where it supports connecting-piece assembly [#5]. Mechanistically, SEPTIN10 functions as a molecular switch coupling the two cytoskeletons: it binds CAPZA2 to promote actin stress fiber formation and intracellular tension while blocking MAP4 to inhibit microtubule polymerization, with loss of SEPTIN10 abrogating actin stress fiber formation after microtubule disruption and feeding back to activate YAP/TAZ mechanosignaling in hepatocellular carcinoma cells [#6]. Consistent with a role in microtubule stability, SEPTIN10 levels set sensitivity to the microtubule-targeting agent paclitaxel [#2], and the protein is required to maintain the podocyte cytoskeleton [#3]. In the male germline, SEPTIN10 physically interacts with androglobin, which directs its localization at the manchette and sperm annulus and contributes to its calmodulin-dependent proteolysis [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing whether SEPTIN10 is a functional GTPase defined its core biochemical identity as a nucleotide-binding septin and showed its localization is uncoupled from the actin cytoskeleton.\",\n      \"evidence\": \"In vitro GTP-binding/GTPase assay and GFP-fusion live-cell imaging\",\n      \"pmids\": [\"12711328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis of the GTP-binding motif to link catalysis to function\", \"No structural model of nucleotide binding\", \"Subcellular targeting determinants unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"A functional genomics screen connected SEPTIN10 dosage to microtubule stability and chemosensitivity, showing it regulates a drug-relevant cytoskeletal phenotype.\",\n      \"evidence\": \"Lentiviral siRNA screen with siRNA knockdown and overexpression assays scoring paclitaxel sensitivity\",\n      \"pmids\": [\"22320903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of microtubule regulation not defined\", \"Direct microtubule-binding partners not identified at this stage\", \"Single lab, single cell context\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defining SEPTIN10's septin complex membership and microtubule-associated localization placed it in a specific heteromeric assembly distinct from lamellipodial septins.\",\n      \"evidence\": \"Reciprocal immunoprecipitation and immunofluorescence co-localization in squamous carcinoma cells\",\n      \"pmids\": [\"23087102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and filament architecture of the complex unresolved\", \"Whether SEPT10 is required for complex assembly not tested\", \"Functional consequence of microtubule association not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A knockdown screen extended SEPTIN10's cytoskeletal role to a physiological cell type, showing it is required to maintain the podocyte cytoskeleton.\",\n      \"evidence\": \"siRNA knockdown with cytoskeletal injury readout in primary mouse podocytes\",\n      \"pmids\": [\"28709640\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single knockdown experiment without mechanistic follow-up\", \"No pathway placement\", \"No rescue or specificity controls reported\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying a sperm-neck septin complex containing SEPTIN10 and linking a SEPT12 mutation to its disruption tied this assembly to connecting-piece integrity and sperm morphology.\",\n      \"evidence\": \"Co-immunoprecipitation, immunofluorescence in SEPT12 D197N knock-in mice, and electron microscopy\",\n      \"pmids\": [\"32392324\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SEPTIN10's individual contribution versus other subunits not isolated\", \"No SEPT10-specific genetic perturbation\", \"Assembly mechanism at the connecting piece unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovering the androglobin–SEPTIN10 interaction defined an upstream regulator controlling SEPTIN10 localization and turnover during spermatogenesis.\",\n      \"evidence\": \"IP/MS, reciprocal co-IP in vitro and in testis lysates, and immunofluorescence in Adgb knockout mice\",\n      \"pmids\": [\"35700329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct proteolytic mechanism and cleavage sites not defined\", \"Calmodulin dependence shown in vitro only\", \"Whether proteolysis regulates septin filament dynamics in vivo unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placing SEPTIN10 downstream of miR-124-3p linked its expression level to cell-fate decisions in retinal progenitor proliferation and differentiation.\",\n      \"evidence\": \"miRNA overexpression/knockdown and SEPT10 overexpression rescue with proliferation/differentiation assays in RPCs\",\n      \"pmids\": [\"36802303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct miR-124-3p:SEPT10 binding not validated in abstract\", \"Cytoskeletal mechanism in RPCs not defined\", \"Single lab, single context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying CAPZA2 and MAP4 as opposing SEPTIN10 partners established it as a molecular switch coordinating actin and microtubule dynamics that feeds back to YAP/TAZ mechanosignaling.\",\n      \"evidence\": \"Co-IP of SEPTIN10–CAPZA2 and SEPTIN10–MAP4, siRNA loss-of-function with cytoskeletal readouts, YAP/TAZ reporter and rescue assays in hepatocellular carcinoma cells\",\n      \"pmids\": [\"38242197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GTPase activity gates the switch not tested\", \"Structural basis of CAPZA2/MAP4 binding unknown\", \"Generality beyond hepatocellular carcinoma unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SEPTIN10's GTPase cycle, its alternative septin complex memberships, and its actin/microtubule switch activity are mechanistically integrated remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of SEPTIN10-containing filaments\", \"GTP hydrolysis not linked to partner binding or switch function\", \"Tissue-specific selection of distinct septin partners not explained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [\"septin complex (SEPT7/8/9/11/14)\", \"sperm-neck septin complex (SEPT1/2/11/12)\"],\n    \"partners\": [\"CAPZA2\", \"MAP4\", \"ADGB\", \"SEPT12\", \"SEPT11\", \"SEPT7\", \"SEPT9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}