{"gene":"SKA2","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2006,"finding":"SKA2 (Ska2) forms a complex with SKA1 (Ska1) at spindle and kinetochore structures; Ska1 is required for Ska2 stability in vivo, depletion of either protein abolishes both from kinetochores, and loss of the complex results in a prolonged Mad2-dependent checkpoint delay in a metaphase-like state with cold-sensitive kinetochore fibres, establishing a role in spindle checkpoint silencing and metaphase plate maintenance.","method":"siRNA knockdown, immunofluorescence, live-cell imaging, Mad2 kinetochore recruitment assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal depletion phenotype with specific molecular readouts (Mad2 recruitment, kinetochore fibre cold-sensitivity), replicated across both subunits; foundational paper with multiple orthogonal approaches","pmids":["17093495"],"is_preprint":false},{"year":2008,"finding":"SKA2 physically interacts with the glucocorticoid receptor (GR) in the cytoplasm (identified by yeast two-hybrid screen and co-localization); SKA2 overexpression increases GC transactivation in HepG2 cells, while SKA2 knockdown decreases GC transactivation and prevents dexamethasone-mediated inhibition of proliferation in A549 cells; SKA2 also potentiates the proliferative response to IGF-I.","method":"Yeast two-hybrid screen, immunofluorescence co-localization, overexpression/knockdown transactivation assays, proliferation assays","journal":"The Journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus functional rescue, single lab, two complementary methods but no reciprocal Co-IP reported in abstract","pmids":["18583474"],"is_preprint":false},{"year":2015,"finding":"The PRR11-SKA2 bidirectional promoter is directly transactivated by the transcription factor NF-Y, which binds the minimal 80-bp intergenic core promoter region, as demonstrated by EMSA and ChIP; NF-Y depletion by siRNA significantly downregulates both PRR11 and SKA2 expression.","method":"Serial luciferase reporter assays, EMSA, ChIP, siRNA knockdown of NF-Y","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated by EMSA and ChIP, functional readout by reporter assay, single lab with multiple orthogonal methods","pmids":["26162986"],"is_preprint":false},{"year":2017,"finding":"p53 represses transcription of the PRR11-SKA2 bidirectional unit indirectly through NF-Y: wild-type (but not mutant) p53 co-immunoprecipitates with NF-Y in lung cancer cells, reduces NF-Y occupancy at the PRR11-SKA2 promoter by ChIP, and the repression depends on intact NF-Y binding sites; siRNA depletion of NF-YB attenuates p53-mediated repression.","method":"Luciferase reporter assay (deletion/mutation analysis), co-immunoprecipitation, ChIP, siRNA knockdown","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ChIP plus functional reporter rescue, single lab, multiple orthogonal methods","pmids":["28257042"],"is_preprint":false},{"year":2024,"finding":"SKA2 inhibits secretory autophagy (SA)-dependent IL-1β release by counteracting FKBP5 function; hippocampal Ska2 knockdown in mice hyperactivates SA, triggering NLRP3-inflammasome activation, Gasdermin D-mediated neurotoxicity, neuroinflammation, and complete hippocampal atrophy within six weeks; co-immunoprecipitation of postmortem human brains shows SA is hyperactivated in Alzheimer's disease.","method":"In vivo Ska2 knockdown (mouse), secretory autophagy assays, IL-1β release measurement, NLRP3/Gasdermin D pathway assays, co-immunoprecipitation of human postmortem brain","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockdown with defined mechanistic pathway readouts (IL-1β, NLRP3, GSDMD), co-IP in human tissue, published in peer-reviewed journal; peer-reviewed version of preprint PMID:37066393","pmids":["38528004","37066393"],"is_preprint":false},{"year":2024,"finding":"SKA2 promotes glucocorticoid receptor (GR) signaling in neurons by enhancing GR–FKBP4 interaction, leading to dissociation of FKBP5 from the GR complex; in CRH+ paraventricular nucleus neurons, SKA2 is required for HPA axis responsiveness and maintenance of the glucocorticoid negative feedback loop.","method":"In vitro cell assays (GR signaling reporters), co-immunoprecipitation of FKBP4/FKBP5/GR complex, in vivo conditional knockout/knockdown in Crh+ neurons (mouse)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo cell-type-specific loss-of-function with HPA axis readout combined with co-IP mechanistic dissection of FKBP4/FKBP5/GR ternary complex, multiple orthogonal methods in one study","pmids":["39705315"],"is_preprint":false},{"year":2023,"finding":"SKA2 transcriptionally represses PDSS2 (first key enzyme of CoQ10 biosynthesis) through its Sp1-binding sites in the PDSS2 promoter; co-immunoprecipitation demonstrates SKA2 associates with the transcription factor Sp1; PDSS2 overexpression rescues SKA2-promoted malignant phenotypes in lung cancer cells via a non-enzymatic tumor-suppressive mechanism.","method":"Gene expression profiling after SKA2 knockdown, luciferase reporter assay (Sp1-binding site mutagenesis), co-immunoprecipitation (SKA2–Sp1), overexpression rescue experiments","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus promoter mutagenesis reporter assay plus functional rescue, single lab with multiple orthogonal methods","pmids":["36860919"],"is_preprint":false},{"year":2025,"finding":"SKA2 interacts with EGFR (as shown by co-immunoprecipitation) and contributes to sustained PI3K-AKT pathway activation in lung cancer cells; the PRR11-SKA2-miR301a/miR454 bidirectional transcription unit components compensate for each other to maintain PI3K-AKT activation, with PTEN translation repressed by miR301a/miR454.","method":"Co-immunoprecipitation (SKA2–EGFR), CRISPRi repression of transcription unit, PI3K-AKT pathway activity assays, in vivo mouse tumor models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus CRISPRi functional rescue plus in vivo model, single lab, multiple orthogonal methods","pmids":["41309933"],"is_preprint":false},{"year":2026,"finding":"SKA2 silencing in gastric cancer cells induces G2/M arrest, apoptosis, and ROS accumulation; mechanistically, SKA2 upregulates the glycine transporter SLC6A9 to enhance glycine uptake and glutathione (GSH) synthesis for redox homeostasis; SKA2 depletion disrupts this axis, activating ATM/Chk2 (cell-cycle arrest) and ATM/JNK (apoptosis) pathways.","method":"siRNA knockdown, cell-cycle analysis, ROS measurement, SLC6A9/GSH metabolic assays, ATM/Chk2/JNK pathway analysis, in vitro and in vivo tumor models","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional and metabolic assays with mechanistic pathway identification, single lab, in vitro and in vivo validation","pmids":["41847110"],"is_preprint":false}],"current_model":"SKA2 is a multifunctional protein that, as part of the SKA1/SKA2 complex, is essential for spindle checkpoint silencing and timely anaphase onset at kinetochores during mitosis; outside of mitosis, SKA2 acts as a glucocorticoid receptor co-activator by promoting GR–FKBP4 interaction and FKBP5 dissociation to enhance GR signaling and HPA axis negative feedback in neurons; it also functions as a transcriptional repressor (via Sp1 association suppressing PDSS2) and a metabolic regulator (upregulating SLC6A9/GSH synthesis), and inhibits secretory autophagy-dependent IL-1β release by counteracting FKBP5, thereby restraining neuroinflammation-driven neurodegeneration."},"narrative":{"mechanistic_narrative":"SKA2 is a multifunctional protein originally defined as a kinetochore component that, in a complex with SKA1, is essential for spindle checkpoint silencing and progression from a metaphase-like state to anaphase; SKA1 stabilizes SKA2, and loss of either subunit triggers a prolonged Mad2-dependent checkpoint delay with cold-sensitive kinetochore fibres [PMID:17093495]. Beyond mitosis, SKA2 is a cytoplasmic modulator of glucocorticoid receptor (GR) signaling: it physically interacts with GR and potentiates glucocorticoid transactivation [PMID:18583474], and in neurons it enhances the GR–FKBP4 interaction while promoting dissociation of FKBP5 from the GR complex, an activity required for HPA-axis responsiveness and glucocorticoid negative feedback in CRH+ paraventricular neurons [PMID:39705315]. SKA2 also restrains secretory autophagy by counteracting FKBP5, and hippocampal Ska2 loss hyperactivates secretory autophagy-dependent IL-1β release, driving NLRP3-inflammasome activation, Gasdermin D-mediated neurotoxicity, and hippocampal atrophy [PMID:38528004, PMID:37066393]. In cancer contexts SKA2 acts as a transcriptional and metabolic regulator: it associates with Sp1 to repress PDSS2 transcription [PMID:36860919], interacts with EGFR to sustain PI3K-AKT activation [PMID:41309933], and upregulates the glycine transporter SLC6A9 to support glutathione synthesis and redox homeostasis, with depletion activating ATM/Chk2 and ATM/JNK stress pathways [PMID:41847110]. Its own expression is governed by the PRR11-SKA2 bidirectional promoter, which is activated by NF-Y [PMID:26162986] and repressed by p53 acting through NF-Y [PMID:28257042].","teleology":[{"year":2006,"claim":"Established SKA2's foundational role in mitosis by showing it partners with SKA1 at kinetochores to permit checkpoint silencing and anaphase onset, answering how cells exit the metaphase-like state.","evidence":"siRNA knockdown, immunofluorescence, live-cell imaging and Mad2 recruitment assays in human cells","pmids":["17093495"],"confidence":"High","gaps":["No structural detail on how the SKA1/SKA2 complex engages microtubules or kinetochores","Mechanism of checkpoint silencing downstream of the complex unresolved"]},{"year":2008,"claim":"Extended SKA2 beyond mitosis by identifying it as a cytoplasmic GR-interacting co-activator that tunes glucocorticoid transactivation and proliferative responses.","evidence":"Yeast two-hybrid screen, co-localization, overexpression/knockdown transactivation and proliferation assays in HepG2/A549 cells","pmids":["18583474"],"confidence":"Medium","gaps":["No reciprocal Co-IP reported","Molecular basis of GR potentiation not defined at this stage"]},{"year":2015,"claim":"Defined the transcriptional control of SKA2 by showing NF-Y directly drives the shared PRR11-SKA2 bidirectional promoter.","evidence":"Luciferase reporter, EMSA, ChIP and NF-Y siRNA knockdown","pmids":["26162986"],"confidence":"Medium","gaps":["Does not address tissue- or context-specific regulation","Co-regulation consequences for PRR11 vs SKA2 function not separated"]},{"year":2017,"claim":"Placed SKA2 expression under tumor-suppressor control by showing p53 represses the PRR11-SKA2 unit indirectly via NF-Y.","evidence":"Reporter deletion/mutation analysis, co-IP of p53 with NF-Y, ChIP and NF-YB siRNA in lung cancer cells","pmids":["28257042"],"confidence":"Medium","gaps":["Repression is indirect; no direct p53 binding to the promoter","Functional consequence for SKA2-dependent phenotypes not measured"]},{"year":2023,"claim":"Identified a transcriptional-repressor activity for SKA2, linking it to CoQ10 biosynthesis control via Sp1-dependent PDSS2 repression in lung cancer.","evidence":"Expression profiling after knockdown, Sp1-site mutagenesis reporter, SKA2–Sp1 co-IP and PDSS2 overexpression rescue","pmids":["36860919"],"confidence":"Medium","gaps":["Whether SKA2 binds DNA directly or only through Sp1 is unresolved","Generality of PDSS2 repression beyond lung cancer cells unknown"]},{"year":2024,"claim":"Resolved the molecular basis of SKA2's GR co-activation by showing it promotes GR–FKBP4 interaction and FKBP5 dissociation, and demonstrated in vivo that this maintains HPA-axis negative feedback.","evidence":"GR reporter assays, FKBP4/FKBP5/GR co-IP, and conditional knockout/knockdown in Crh+ neurons in mice","pmids":["39705315"],"confidence":"High","gaps":["Structural detail of the FKBP4/FKBP5 exchange on GR not defined","Relationship to SKA2's mitotic pool unaddressed"]},{"year":2024,"claim":"Connected SKA2 to neuroinflammation and neurodegeneration by showing it restrains secretory autophagy-dependent IL-1β release through FKBP5 antagonism.","evidence":"In vivo hippocampal Ska2 knockdown, secretory autophagy/IL-1β/NLRP3/GSDMD assays and co-IP in human postmortem brain","pmids":["38528004","37066393"],"confidence":"High","gaps":["Direct molecular target of SKA2 in the secretory autophagy machinery not pinpointed","Causal direction of SA hyperactivation in human AD not established"]},{"year":2025,"claim":"Implicated SKA2 in oncogenic growth signaling by showing it interacts with EGFR and sustains PI3K-AKT activation within a self-compensating bidirectional transcription unit.","evidence":"SKA2–EGFR co-IP, CRISPRi repression of the transcription unit, PI3K-AKT activity assays and mouse tumor models","pmids":["41309933"],"confidence":"Medium","gaps":["Whether the SKA2–EGFR interaction is direct or scaffolded is unclear","Mechanism by which SKA2 sustains AKT signaling not defined"]},{"year":2026,"claim":"Defined a metabolic role for SKA2 in redox homeostasis, showing it upregulates SLC6A9 to drive glycine uptake and glutathione synthesis and thereby suppresses ATM-dependent stress responses.","evidence":"siRNA knockdown, cell-cycle/ROS and SLC6A9/GSH metabolic assays, ATM/Chk2/JNK pathway analysis in gastric cancer models","pmids":["41847110"],"confidence":"Medium","gaps":["Mechanism of SLC6A9 upregulation by SKA2 unknown","Link between metabolic and mitotic/GR functions unexamined"]},{"year":null,"claim":"How SKA2's distinct activities — kinetochore function, GR/FKBP modulation, secretory autophagy restraint, and transcriptional/metabolic regulation — are partitioned across cell types and subcellular pools remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural or domain-level explanation for the multifunctionality","Subcellular pool controlling each function not delineated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4]}],"complexes":["SKA1/SKA2 complex"],"partners":["SKA1","GR (NR3C1)","FKBP4","FKBP5","SP1","EGFR","NF-Y"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WVK7","full_name":"Spindle and kinetochore-associated protein 2","aliases":["Protein FAM33A"],"length_aa":121,"mass_kda":14.2,"function":"Component of the SKA1 complex, a microtubule-binding subcomplex of the outer kinetochore that is essential for proper chromosome segregation (PubMed:17093495, PubMed:19289083, PubMed:23085020). Required for timely anaphase onset during mitosis, when chromosomes undergo bipolar attachment on spindle microtubules leading to silencing of the spindle checkpoint (PubMed:17093495). The SKA1 complex is a direct component of the kinetochore-microtubule interface and directly associates with microtubules as oligomeric assemblies (PubMed:19289083). The complex facilitates the processive movement of microspheres along a microtubule in a depolymerization-coupled manner (PubMed:17093495, PubMed:19289083). In the complex, it is required for SKA1 localization (PubMed:19289083). Affinity for microtubules is synergistically enhanced in the presence of the ndc-80 complex and may allow the ndc-80 complex to track depolymerizing microtubules (PubMed:23085020)","subcellular_location":"Cytoplasm, cytoskeleton, spindle; Chromosome, centromere, kinetochore","url":"https://www.uniprot.org/uniprotkb/Q8WVK7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SKA2","classification":"Common Essential","n_dependent_lines":946,"n_total_lines":1208,"dependency_fraction":0.7831125827814569},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SKA2","total_profiled":1310},"omim":[{"mim_id":"619247","title":"SPINDLE- AND KINETOCHORE-ASSOCIATED COMPLEX, SUBUNIT 3; SKA3","url":"https://www.omim.org/entry/619247"},{"mim_id":"616674","title":"SPINDLE- AND KINETOCHORE-ASSOCIATED COMPLEX, SUBUNIT 2; SKA2","url":"https://www.omim.org/entry/616674"},{"mim_id":"616673","title":"SPINDLE- AND KINETOCHORE-ASSOCIATED COMPLEX, SUBUNIT 1; SKA1","url":"https://www.omim.org/entry/616673"},{"mim_id":"615920","title":"PROLINE-RICH PROTEIN 11; PRR11","url":"https://www.omim.org/entry/615920"},{"mim_id":"615675","title":"MICRO RNA 301A; MIR301A","url":"https://www.omim.org/entry/615675"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SKA2"},"hgnc":{"alias_symbol":["FLJ12758"],"prev_symbol":["FAM33A"]},"alphafold":{"accession":"Q8WVK7","domains":[{"cath_id":"-","chopping":"13-94","consensus_level":"medium","plddt":90.6835,"start":13,"end":94}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WVK7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WVK7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WVK7-F1-predicted_aligned_error_v6.png","plddt_mean":88.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SKA2","jax_strain_url":"https://www.jax.org/strain/search?query=SKA2"},"sequence":{"accession":"Q8WVK7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WVK7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WVK7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WVK7"}},"corpus_meta":[{"pmid":"17093495","id":"PMC_17093495","title":"Timely anaphase onset requires a novel spindle and kinetochore complex comprising Ska1 and Ska2.","date":"2006","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/17093495","citation_count":207,"is_preprint":false},{"pmid":"26324104","id":"PMC_26324104","title":"SKA2 methylation is associated with decreased prefrontal cortical thickness and greater PTSD severity among trauma-exposed veterans.","date":"2015","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/26324104","citation_count":84,"is_preprint":false},{"pmid":"20470754","id":"PMC_20470754","title":"Intronic miR-301 feedback regulates its host gene, ska2, in A549 cells by targeting MEOX2 to affect ERK/CREB pathways.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20470754","citation_count":80,"is_preprint":false},{"pmid":"26305478","id":"PMC_26305478","title":"Epigenetic and genetic variation at SKA2 predict suicidal behavior and post-traumatic stress 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methylation and the cortisol response to an acute psychological stressor: a systematic review and meta-analysis","date":"2025-10-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.23.25338702","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19663,"output_tokens":2656,"usd":0.049415,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9895,"output_tokens":3354,"usd":0.066662,"stage2_stop_reason":"end_turn"},"total_usd":0.116077,"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\": 2006,\n      \"finding\": \"SKA2 (Ska2) forms a complex with SKA1 (Ska1) at spindle and kinetochore structures; Ska1 is required for Ska2 stability in vivo, depletion of either protein abolishes both from kinetochores, and loss of the complex results in a prolonged Mad2-dependent checkpoint delay in a metaphase-like state with cold-sensitive kinetochore fibres, establishing a role in spindle checkpoint silencing and metaphase plate maintenance.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, live-cell imaging, Mad2 kinetochore recruitment assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal depletion phenotype with specific molecular readouts (Mad2 recruitment, kinetochore fibre cold-sensitivity), replicated across both subunits; foundational paper with multiple orthogonal approaches\",\n      \"pmids\": [\"17093495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SKA2 physically interacts with the glucocorticoid receptor (GR) in the cytoplasm (identified by yeast two-hybrid screen and co-localization); SKA2 overexpression increases GC transactivation in HepG2 cells, while SKA2 knockdown decreases GC transactivation and prevents dexamethasone-mediated inhibition of proliferation in A549 cells; SKA2 also potentiates the proliferative response to IGF-I.\",\n      \"method\": \"Yeast two-hybrid screen, immunofluorescence co-localization, overexpression/knockdown transactivation assays, proliferation assays\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus functional rescue, single lab, two complementary methods but no reciprocal Co-IP reported in abstract\",\n      \"pmids\": [\"18583474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The PRR11-SKA2 bidirectional promoter is directly transactivated by the transcription factor NF-Y, which binds the minimal 80-bp intergenic core promoter region, as demonstrated by EMSA and ChIP; NF-Y depletion by siRNA significantly downregulates both PRR11 and SKA2 expression.\",\n      \"method\": \"Serial luciferase reporter assays, EMSA, ChIP, siRNA knockdown of NF-Y\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated by EMSA and ChIP, functional readout by reporter assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26162986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"p53 represses transcription of the PRR11-SKA2 bidirectional unit indirectly through NF-Y: wild-type (but not mutant) p53 co-immunoprecipitates with NF-Y in lung cancer cells, reduces NF-Y occupancy at the PRR11-SKA2 promoter by ChIP, and the repression depends on intact NF-Y binding sites; siRNA depletion of NF-YB attenuates p53-mediated repression.\",\n      \"method\": \"Luciferase reporter assay (deletion/mutation analysis), co-immunoprecipitation, ChIP, siRNA knockdown\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ChIP plus functional reporter rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28257042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SKA2 inhibits secretory autophagy (SA)-dependent IL-1β release by counteracting FKBP5 function; hippocampal Ska2 knockdown in mice hyperactivates SA, triggering NLRP3-inflammasome activation, Gasdermin D-mediated neurotoxicity, neuroinflammation, and complete hippocampal atrophy within six weeks; co-immunoprecipitation of postmortem human brains shows SA is hyperactivated in Alzheimer's disease.\",\n      \"method\": \"In vivo Ska2 knockdown (mouse), secretory autophagy assays, IL-1β release measurement, NLRP3/Gasdermin D pathway assays, co-immunoprecipitation of human postmortem brain\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockdown with defined mechanistic pathway readouts (IL-1β, NLRP3, GSDMD), co-IP in human tissue, published in peer-reviewed journal; peer-reviewed version of preprint PMID:37066393\",\n      \"pmids\": [\"38528004\", \"37066393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SKA2 promotes glucocorticoid receptor (GR) signaling in neurons by enhancing GR–FKBP4 interaction, leading to dissociation of FKBP5 from the GR complex; in CRH+ paraventricular nucleus neurons, SKA2 is required for HPA axis responsiveness and maintenance of the glucocorticoid negative feedback loop.\",\n      \"method\": \"In vitro cell assays (GR signaling reporters), co-immunoprecipitation of FKBP4/FKBP5/GR complex, in vivo conditional knockout/knockdown in Crh+ neurons (mouse)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo cell-type-specific loss-of-function with HPA axis readout combined with co-IP mechanistic dissection of FKBP4/FKBP5/GR ternary complex, multiple orthogonal methods in one study\",\n      \"pmids\": [\"39705315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SKA2 transcriptionally represses PDSS2 (first key enzyme of CoQ10 biosynthesis) through its Sp1-binding sites in the PDSS2 promoter; co-immunoprecipitation demonstrates SKA2 associates with the transcription factor Sp1; PDSS2 overexpression rescues SKA2-promoted malignant phenotypes in lung cancer cells via a non-enzymatic tumor-suppressive mechanism.\",\n      \"method\": \"Gene expression profiling after SKA2 knockdown, luciferase reporter assay (Sp1-binding site mutagenesis), co-immunoprecipitation (SKA2–Sp1), overexpression rescue experiments\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus promoter mutagenesis reporter assay plus functional rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36860919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SKA2 interacts with EGFR (as shown by co-immunoprecipitation) and contributes to sustained PI3K-AKT pathway activation in lung cancer cells; the PRR11-SKA2-miR301a/miR454 bidirectional transcription unit components compensate for each other to maintain PI3K-AKT activation, with PTEN translation repressed by miR301a/miR454.\",\n      \"method\": \"Co-immunoprecipitation (SKA2–EGFR), CRISPRi repression of transcription unit, PI3K-AKT pathway activity assays, in vivo mouse tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus CRISPRi functional rescue plus in vivo model, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41309933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SKA2 silencing in gastric cancer cells induces G2/M arrest, apoptosis, and ROS accumulation; mechanistically, SKA2 upregulates the glycine transporter SLC6A9 to enhance glycine uptake and glutathione (GSH) synthesis for redox homeostasis; SKA2 depletion disrupts this axis, activating ATM/Chk2 (cell-cycle arrest) and ATM/JNK (apoptosis) pathways.\",\n      \"method\": \"siRNA knockdown, cell-cycle analysis, ROS measurement, SLC6A9/GSH metabolic assays, ATM/Chk2/JNK pathway analysis, in vitro and in vivo tumor models\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional and metabolic assays with mechanistic pathway identification, single lab, in vitro and in vivo validation\",\n      \"pmids\": [\"41847110\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SKA2 is a multifunctional protein that, as part of the SKA1/SKA2 complex, is essential for spindle checkpoint silencing and timely anaphase onset at kinetochores during mitosis; outside of mitosis, SKA2 acts as a glucocorticoid receptor co-activator by promoting GR–FKBP4 interaction and FKBP5 dissociation to enhance GR signaling and HPA axis negative feedback in neurons; it also functions as a transcriptional repressor (via Sp1 association suppressing PDSS2) and a metabolic regulator (upregulating SLC6A9/GSH synthesis), and inhibits secretory autophagy-dependent IL-1β release by counteracting FKBP5, thereby restraining neuroinflammation-driven neurodegeneration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SKA2 is a multifunctional protein originally defined as a kinetochore component that, in a complex with SKA1, is essential for spindle checkpoint silencing and progression from a metaphase-like state to anaphase; SKA1 stabilizes SKA2, and loss of either subunit triggers a prolonged Mad2-dependent checkpoint delay with cold-sensitive kinetochore fibres [#0]. Beyond mitosis, SKA2 is a cytoplasmic modulator of glucocorticoid receptor (GR) signaling: it physically interacts with GR and potentiates glucocorticoid transactivation [#1], and in neurons it enhances the GR–FKBP4 interaction while promoting dissociation of FKBP5 from the GR complex, an activity required for HPA-axis responsiveness and glucocorticoid negative feedback in CRH+ paraventricular neurons [#5]. SKA2 also restrains secretory autophagy by counteracting FKBP5, and hippocampal Ska2 loss hyperactivates secretory autophagy-dependent IL-1β release, driving NLRP3-inflammasome activation, Gasdermin D-mediated neurotoxicity, and hippocampal atrophy [#4]. In cancer contexts SKA2 acts as a transcriptional and metabolic regulator: it associates with Sp1 to repress PDSS2 transcription [#6], interacts with EGFR to sustain PI3K-AKT activation [#7], and upregulates the glycine transporter SLC6A9 to support glutathione synthesis and redox homeostasis, with depletion activating ATM/Chk2 and ATM/JNK stress pathways [#8]. Its own expression is governed by the PRR11-SKA2 bidirectional promoter, which is activated by NF-Y [#2] and repressed by p53 acting through NF-Y [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established SKA2's foundational role in mitosis by showing it partners with SKA1 at kinetochores to permit checkpoint silencing and anaphase onset, answering how cells exit the metaphase-like state.\",\n      \"evidence\": \"siRNA knockdown, immunofluorescence, live-cell imaging and Mad2 recruitment assays in human cells\",\n      \"pmids\": [\"17093495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural detail on how the SKA1/SKA2 complex engages microtubules or kinetochores\", \"Mechanism of checkpoint silencing downstream of the complex unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended SKA2 beyond mitosis by identifying it as a cytoplasmic GR-interacting co-activator that tunes glucocorticoid transactivation and proliferative responses.\",\n      \"evidence\": \"Yeast two-hybrid screen, co-localization, overexpression/knockdown transactivation and proliferation assays in HepG2/A549 cells\",\n      \"pmids\": [\"18583474\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reciprocal Co-IP reported\", \"Molecular basis of GR potentiation not defined at this stage\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the transcriptional control of SKA2 by showing NF-Y directly drives the shared PRR11-SKA2 bidirectional promoter.\",\n      \"evidence\": \"Luciferase reporter, EMSA, ChIP and NF-Y siRNA knockdown\",\n      \"pmids\": [\"26162986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address tissue- or context-specific regulation\", \"Co-regulation consequences for PRR11 vs SKA2 function not separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed SKA2 expression under tumor-suppressor control by showing p53 represses the PRR11-SKA2 unit indirectly via NF-Y.\",\n      \"evidence\": \"Reporter deletion/mutation analysis, co-IP of p53 with NF-Y, ChIP and NF-YB siRNA in lung cancer cells\",\n      \"pmids\": [\"28257042\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Repression is indirect; no direct p53 binding to the promoter\", \"Functional consequence for SKA2-dependent phenotypes not measured\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a transcriptional-repressor activity for SKA2, linking it to CoQ10 biosynthesis control via Sp1-dependent PDSS2 repression in lung cancer.\",\n      \"evidence\": \"Expression profiling after knockdown, Sp1-site mutagenesis reporter, SKA2–Sp1 co-IP and PDSS2 overexpression rescue\",\n      \"pmids\": [\"36860919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SKA2 binds DNA directly or only through Sp1 is unresolved\", \"Generality of PDSS2 repression beyond lung cancer cells unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the molecular basis of SKA2's GR co-activation by showing it promotes GR–FKBP4 interaction and FKBP5 dissociation, and demonstrated in vivo that this maintains HPA-axis negative feedback.\",\n      \"evidence\": \"GR reporter assays, FKBP4/FKBP5/GR co-IP, and conditional knockout/knockdown in Crh+ neurons in mice\",\n      \"pmids\": [\"39705315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the FKBP4/FKBP5 exchange on GR not defined\", \"Relationship to SKA2's mitotic pool unaddressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected SKA2 to neuroinflammation and neurodegeneration by showing it restrains secretory autophagy-dependent IL-1β release through FKBP5 antagonism.\",\n      \"evidence\": \"In vivo hippocampal Ska2 knockdown, secretory autophagy/IL-1β/NLRP3/GSDMD assays and co-IP in human postmortem brain\",\n      \"pmids\": [\"38528004\", \"37066393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target of SKA2 in the secretory autophagy machinery not pinpointed\", \"Causal direction of SA hyperactivation in human AD not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated SKA2 in oncogenic growth signaling by showing it interacts with EGFR and sustains PI3K-AKT activation within a self-compensating bidirectional transcription unit.\",\n      \"evidence\": \"SKA2–EGFR co-IP, CRISPRi repression of the transcription unit, PI3K-AKT activity assays and mouse tumor models\",\n      \"pmids\": [\"41309933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the SKA2–EGFR interaction is direct or scaffolded is unclear\", \"Mechanism by which SKA2 sustains AKT signaling not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a metabolic role for SKA2 in redox homeostasis, showing it upregulates SLC6A9 to drive glycine uptake and glutathione synthesis and thereby suppresses ATM-dependent stress responses.\",\n      \"evidence\": \"siRNA knockdown, cell-cycle/ROS and SLC6A9/GSH metabolic assays, ATM/Chk2/JNK pathway analysis in gastric cancer models\",\n      \"pmids\": [\"41847110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of SLC6A9 upregulation by SKA2 unknown\", \"Link between metabolic and mitotic/GR functions unexamined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SKA2's distinct activities — kinetochore function, GR/FKBP modulation, secretory autophagy restraint, and transcriptional/metabolic regulation — are partitioned across cell types and subcellular pools remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural or domain-level explanation for the multifunctionality\", \"Subcellular pool controlling each function not delineated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\"SKA1/SKA2 complex\"],\n    \"partners\": [\"SKA1\", \"GR (NR3C1)\", \"FKBP4\", \"FKBP5\", \"Sp1\", \"EGFR\", \"NF-Y\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}