{"gene":"SKA3","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2009,"finding":"SKA3 (C13Orf3) was identified as a novel third component of the Ska complex (with Ska1 and Ska2) by mass spectrometry. It localizes to the spindle and kinetochore throughout mitosis. Concomitant depletion of Ska1 and Ska3 causes chromosome congression failure and destabilizes kinetochore-microtubule attachments (reduced cold stability of KT fibres), while only marginally impairing KMN network localization at kinetochores.","method":"Mass spectrometry, RNAi depletion, cold-stability assay, immunofluorescence","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal MS identification plus functional RNAi phenotype with direct KT-MT cold-stability readout; replicated by three independent labs simultaneously","pmids":["19360002"],"is_preprint":false},{"year":2009,"finding":"Ska3 is required for spindle checkpoint silencing and timely anaphase onset. Ska3-depleted cells accumulate high Bub1 at kinetochores and fail to silence the spindle checkpoint despite achieving metaphase alignment. Ska3 kinetochore accumulation in prometaphase is dependent on Sgo1, whereas Sgo1 localization is not dependent on Ska3.","method":"RNAi knockdown, live-cell imaging, immunofluorescence for kinetochore proteins","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean RNAi with multiple specific phenotypic readouts (checkpoint silencing, Bub1 accumulation, epistasis with Sgo1), replicated across labs","pmids":["19646878"],"is_preprint":false},{"year":2009,"finding":"RAMA1 (SKA3) localizes to spindle and outer kinetochores throughout mitosis and its kinetochore recruitment depends on the core kinetochore-microtubule attachment factor Hec1. Unlike Hec1, RAMA1 association with kinetochores is highly dynamic (not a stable structural component). RAMA1 depletion reduces kinetochore-microtubule attachments, causing severe chromosome alignment defects and checkpoint-dependent mitotic arrest.","method":"High-throughput RNAi screen, immunofluorescence, live-cell imaging, kinetochore protein localization analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RNAi functional readout with Hec1 epistasis and direct localization dynamics; multiple orthogonal methods in a single rigorous study","pmids":["19549680"],"is_preprint":false},{"year":2009,"finding":"C13orf3 (Ska3) localizes to centrosomes, mitotic spindle, kinetochores, spindle midzone, and cleavage furrow during cell division and is specifically phosphorylated during mitosis. Proteomic analyses identified a direct interaction between Ska3 and a regulatory subunit of protein phosphatase PP2A.","method":"Phenotypic profiling, mass spectrometry/proteomics, immunofluorescence, co-immunoprecipitation","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification of PP2A interaction and localization data with multiple methods, single lab","pmids":["19387489"],"is_preprint":false},{"year":2016,"finding":"Ska3 directly interacts with tubulin monomers (microtubule binding) and also interacts with tubulin-contacting regions of Ska1, suggesting allosteric regulation of the Ska complex microtubule-binding capability. Perturbing either the Ska3-microtubule interaction or Ska3-Ska1 interaction reduces microtubule binding by the Ska complex in vitro and delays anaphase onset in cells.","method":"In vitro microtubule binding assays, mutagenesis of interaction domains, cell-based anaphase onset assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution assay with mutagenesis plus functional cell-based validation; multiple orthogonal approaches in one study","pmids":["27667719"],"is_preprint":false},{"year":2017,"finding":"Cdk1 phosphorylates Ska3 specifically during mitosis, and this phosphorylation promotes direct binding of Ska3 to the Ndc80 complex (Ndc80C), a core outer kinetochore component. This phosphorylation is required for kinetochore localization of the entire Ska complex. Ska3 phospho-mutants deficient in Cdk1 phosphorylation retain microtubule localization and support chromosome alignment but delay anaphase onset. Aurora B phosphorylation of Ska1 and Ska3 inhibits Ska complex kinetochore localization.","method":"In vitro kinase assay, direct binding assay (Ska3-Ndc80C), phospho-mutant cell lines, live-cell imaging, immunofluorescence","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus direct binding assay plus phospho-mutant functional analysis; multiple orthogonal methods establishing mechanism","pmids":["28479321"],"is_preprint":false},{"year":2020,"finding":"SKA3 binds and stabilizes PLK1 protein by suppressing ubiquitin-mediated degradation in laryngeal squamous cell carcinoma cells. The accumulation of PLK1 activates AKT and upregulates glycolytic enzymes HK2, PFKFB3, and PDK1, enhancing glycolysis. Phosphorylation of SKA3 at Thr360 is critical for its binding to PLK1 and the increase in glycolysis.","method":"Co-immunoprecipitation, western blotting, ubiquitination assay, site-directed mutagenesis (Thr360), in vitro and in vivo functional assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with mutagenesis and ubiquitination assay; single lab, multiple orthogonal methods","pmids":["33106477"],"is_preprint":false},{"year":2018,"finding":"SKA3 overexpression activates the PI3K/Akt signaling pathway in cervical cancer cells, increasing levels of p-Akt, cyclin E2, CDK2, cyclin D1, CDK4, E2F1, and p-Rb. An Akt inhibitor (GSK690693) significantly reversed the cell proliferation capacity induced by SKA3 overexpression, placing SKA3 upstream of PI3K/Akt in this context.","method":"Stable overexpression/knockdown cell lines, RNA-seq, western blotting, Akt inhibitor rescue, xenograft model","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with inhibitor rescue plus RNA-seq pathway analysis; single lab","pmids":["30459531"],"is_preprint":false},{"year":2019,"finding":"SKA3 knockdown in hepatocellular carcinoma cells inhibits CDK2/p53 phosphorylation and causes G2/M phase arrest, increased apoptosis, and downregulation of BAX/Bcl-2 expression, placing SKA3 upstream of the CDK2/p53 phosphorylation axis in HCC cell cycle regulation.","method":"RNAi knockdown, western blotting, flow cytometry, subcutaneous xenograft, lung metastasis model, GSEA","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular readouts (CDK2/p53 phosphorylation, Bcl-2 family); single lab, multiple assays","pmids":["31804459"],"is_preprint":false},{"year":2020,"finding":"SKA3 binds and activates EGFR to activate PI3K-AKT signaling in lung adenocarcinoma cells, and also induces expression of MMP-2, -7, and -9 downstream of this pathway to promote metastasis.","method":"Co-immunoprecipitation (SKA3-EGFR binding), knockdown experiments, western blotting for pathway components","journal":"Bioscience reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP for SKA3-EGFR binding with pathway readout; single lab, limited validation of direct interaction","pmids":["32068236"],"is_preprint":false},{"year":2020,"finding":"SKA3 promotes cell growth in breast cancer by interacting with PLK1 and preventing its degradation, as demonstrated by co-immunoprecipitation between SKA3 and PLK1.","method":"Co-immunoprecipitation, shRNA knockdown, CCK-8, colony formation assay, western blotting","journal":"Technology in cancer research & treatment","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP, single lab, limited mechanistic follow-up beyond showing interaction","pmids":["32799774"],"is_preprint":false},{"year":2022,"finding":"ZEB1 transcriptionally activates SKA3 (and PLK1) expression. PLK1 in turn mediates phosphorylation of SKA3 and enhances SKA3 protein stability, promoting lung cancer cell proliferation, migration and cell cycle progression. This was established via ChIP, luciferase reporter assays, and in vitro phosphorylation assays.","method":"ChIP, luciferase reporter assay, co-immunoprecipitation, in vitro phosphorylation assay, functional cell assays","journal":"Anti-cancer drugs","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro phosphorylation assay plus ChIP and luciferase for transcriptional regulation; single lab, multiple orthogonal methods","pmids":["36728910"],"is_preprint":false},{"year":2023,"finding":"Under hypoxic conditions, SKA3 recruits PARP1 to bind to HIF-1α, enhancing poly ADP-ribosylation (PARylation) of HIF-1α. This PARylation enhances HIF-1α binding to USP7, triggering deubiquitylation and stabilization of HIF-1α, which then upregulates fatty acid synthesis enzymes to promote cholangiocarcinoma cell proliferation. Additionally, HIF-1α directly binds to the HRE in the SKA3 promoter, creating a positive feedback loop.","method":"IP/MS analysis, western blot, co-immunoprecipitation, siRNA knockdown, RNA-seq, in vitro and in vivo functional assays","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP/MS plus co-IP demonstrating SKA3-PARP1-HIF-1α complex, multiple methods; single lab","pmids":["37821935"],"is_preprint":false},{"year":2025,"finding":"SKA3 competitively binds to prolyl hydroxylase domain-containing protein 2 (PHD2), disrupting its interaction with HIF-1α and thereby stabilizing HIF-1α to enhance glycolytic enzyme transcription in lung adenocarcinoma. HIF-1α in turn binds the HRE in the SKA3 promoter (positive feedback). Hypoxia-induced MDM2 ubiquitinates and degrades p53, relieving p53-mediated repression of SKA3.","method":"Co-immunoprecipitation (SKA3-PHD2 binding), HIF-1α stabilization assay, ChIP (HIF-1α on SKA3 promoter), ubiquitination assay (p53-MDM2), functional in vitro and in vivo assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for SKA3-PHD2 interaction with ChIP and ubiquitination validation; single lab, multiple orthogonal methods","pmids":["41298345"],"is_preprint":false},{"year":2025,"finding":"SKA3 binds to integrin β1 and promotes its activation, which further activates EGFR. EGFR activation in turn upregulates SKA3 expression via E2F1-mediated transcriptional regulation, forming a positive feedback loop (EGFR/E2F1/SKA3/integrin β1). EGFR inhibition with AZD9291 blocked E2F1-mediated SKA3 upregulation.","method":"Co-immunoprecipitation (SKA3-integrin β1), ChIP/luciferase (E2F1 on SKA3 promoter), pharmacological inhibition (AZD9291), in vitro and in vivo functional assays","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for SKA3-integrin β1, transcriptional ChIP/luciferase assay, pharmacological validation; single lab","pmids":["40056339"],"is_preprint":false},{"year":2022,"finding":"SKA3 negatively regulates the tumor suppressor DUSP2, thereby activating the MAPK/ERK pathway to promote gastric cancer progression and epithelial-mesenchymal transition.","method":"siRNA knockdown, western blotting, in vitro functional assays (proliferation, migration, invasion, EMT), in vivo tumor and peritoneal metastasis models","journal":"Frontiers in pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — loss-of-function with pathway readout but no direct binding assay between SKA3 and DUSP2; mechanism inferred from expression changes","pmids":["35295342"],"is_preprint":false}],"current_model":"SKA3 is a core subunit of the trimeric Ska complex (Ska1/Ska2/Ska3) that localizes to the spindle and outer kinetochore throughout mitosis; it directly contacts microtubules and allosterically modulates Ska1 microtubule binding, is recruited to kinetochores via Cdk1-mediated phosphorylation that drives direct binding to the Ndc80 complex, is negatively regulated at kinetochores by Aurora B phosphorylation, and is required for spindle checkpoint silencing and timely anaphase onset; beyond its canonical mitotic role, SKA3 has been shown to stabilize PLK1 protein (inhibiting its ubiquitin-mediated degradation), interact with PHD2 to stabilize HIF-1α under hypoxia, recruit PARP1 to PARylate HIF-1α, and bind integrin β1 and EGFR to activate PI3K/Akt signaling in multiple cancer contexts."},"narrative":{"mechanistic_narrative":"SKA3 (C13orf3/RAMA1) is a core subunit of the trimeric Ska complex (Ska1/Ska2/Ska3) that localizes to the spindle and outer kinetochore throughout mitosis and stabilizes kinetochore-microtubule attachments required for chromosome congression [PMID:19360002, PMID:19549680]. It contributes to attachment stability through dual microtubule contacts: SKA3 binds tubulin directly and engages the tubulin-contacting region of Ska1, allosterically tuning the microtubule-binding capacity of the whole complex [PMID:27667719]. Kinetochore recruitment of the Ska complex is governed by mitotic phosphorylation — Cdk1 phosphorylation of SKA3 drives its direct binding to the Ndc80 complex and is required for Ska complex kinetochore localization, while Aurora B phosphorylation of Ska1/Ska3 opposes this localization [PMID:28479321]; recruitment also depends on Hec1 and Sgo1 [PMID:19549680, PMID:19646878]. Functionally, SKA3 is required for spindle checkpoint silencing and timely anaphase onset, and its depletion produces persistent Bub1 accumulation and mitotic arrest [PMID:19646878, PMID:19549680]. Beyond mitosis, SKA3 has been characterized as an oncogenic driver in multiple carcinomas, where it binds and stabilizes PLK1 against ubiquitin-mediated degradation to enhance glycolysis [PMID:33106477], and engages receptor and hypoxia signaling — binding integrin β1 and EGFR to activate PI3K/Akt [PMID:30459531, PMID:40056339] and stabilizing HIF-1α either by competing with PHD2 or by recruiting PARP1 to PARylate HIF-1α [PMID:37821935, PMID:41298345]. SKA3 expression itself is embedded in feedback loops driven by ZEB1, E2F1, and HIF-1α [PMID:36728910, PMID:41298345, PMID:40056339].","teleology":[{"year":2009,"claim":"Established SKA3 as the third subunit of the Ska complex and showed it is functionally required for stable kinetochore-microtubule attachments, defining its core mitotic role.","evidence":"Mass spectrometry identification, RNAi co-depletion with Ska1, and cold-stability assays of kinetochore fibres","pmids":["19360002","19549680"],"confidence":"High","gaps":["Did not resolve how SKA3 binds microtubules at the molecular level","Dependence on upstream kinetochore factors only partially defined"]},{"year":2009,"claim":"Showed SKA3 acts in spindle checkpoint silencing and anaphase timing rather than purely structurally, linking attachment stabilization to checkpoint resolution.","evidence":"RNAi depletion with live-cell imaging, Bub1 kinetochore quantification, and epistasis with Sgo1 and Hec1","pmids":["19646878","19549680"],"confidence":"High","gaps":["Molecular mechanism coupling Ska to checkpoint silencing not defined","Recruitment hierarchy with Hec1/Sgo1 left mechanistically incomplete"]},{"year":2009,"claim":"Identified SKA3 as a mitotically phosphorylated protein interacting with a PP2A regulatory subunit, raising the possibility of phosphoregulation of its function.","evidence":"Proteomics, immunofluorescence localization, and co-immunoprecipitation","pmids":["19387489"],"confidence":"Medium","gaps":["Functional consequence of the PP2A interaction not established","Phosphosites not mapped in this study"]},{"year":2016,"claim":"Defined the biochemical basis of Ska-microtubule binding by showing SKA3 contacts tubulin directly and allosterically regulates Ska1, explaining how the complex achieves robust attachment.","evidence":"In vitro microtubule-binding assays with domain mutagenesis and cell-based anaphase-onset readouts","pmids":["27667719"],"confidence":"High","gaps":["No high-resolution structure of the SKA3-tubulin interface","Stoichiometry of the assembled complex on microtubules not resolved"]},{"year":2017,"claim":"Resolved how the Ska complex is recruited to kinetochores by showing Cdk1 phosphorylation of SKA3 drives direct Ndc80C binding, with Aurora B phosphorylation opposing localization.","evidence":"In vitro kinase and direct binding assays plus phospho-mutant cell lines with live imaging","pmids":["28479321"],"confidence":"High","gaps":["Exact phosphosites and Ndc80C contact residues not fully mapped","Quantitative balance between Cdk1 and Aurora B inputs unresolved"]},{"year":2018,"claim":"Extended SKA3 function beyond mitosis by placing it upstream of PI3K/Akt-driven cell-cycle progression in cervical cancer.","evidence":"Overexpression/knockdown cell lines, RNA-seq, western blotting, Akt inhibitor rescue, and xenografts","pmids":["30459531"],"confidence":"Medium","gaps":["Direct molecular link between SKA3 and PI3K/Akt not identified here","Whether effect is separable from mitotic role unclear"]},{"year":2019,"claim":"Linked SKA3 to the CDK2/p53 axis and apoptotic regulation in hepatocellular carcinoma, broadening its oncogenic phenotypic footprint.","evidence":"RNAi knockdown, western blotting, flow cytometry, xenograft and metastasis models, GSEA","pmids":["31804459"],"confidence":"Medium","gaps":["No direct binding partner identified for the CDK2/p53 effect","Mechanism of phosphorylation regulation unresolved"]},{"year":2020,"claim":"Identified PLK1 as a direct SKA3 partner whose stabilization links SKA3 to glycolytic reprogramming, providing a concrete biochemical mechanism for its oncogenic activity.","evidence":"Co-immunoprecipitation, ubiquitination assays, Thr360 mutagenesis, and glycolysis readouts in laryngeal and breast cancer cells","pmids":["33106477","32799774"],"confidence":"Medium","gaps":["Breast cancer evidence rests on a single co-IP without reciprocal validation","How SKA3 blocks PLK1 ubiquitination structurally unknown"]},{"year":2020,"claim":"Proposed SKA3-EGFR binding as an upstream activator of PI3K/Akt and matrix metalloproteinase-driven metastasis in lung adenocarcinoma.","evidence":"Single co-immunoprecipitation with knockdown and pathway western blots","pmids":["32068236"],"confidence":"Low","gaps":["Single co-IP without reciprocal validation of direct SKA3-EGFR binding","Direct versus indirect interaction not distinguished"]},{"year":2022,"claim":"Placed SKA3 within transcriptional feedback by showing ZEB1 activates SKA3 and PLK1, with PLK1 reciprocally phosphorylating and stabilizing SKA3.","evidence":"ChIP, luciferase reporters, co-IP, and in vitro phosphorylation assays","pmids":["36728910"],"confidence":"Medium","gaps":["Phosphosites mediating PLK1-dependent stabilization not mapped","Single-lab evidence"]},{"year":2022,"claim":"Connected SKA3 to MAPK/ERK activation through negative regulation of DUSP2 in gastric cancer.","evidence":"siRNA knockdown, western blotting, and in vitro/in vivo functional assays","pmids":["35295342"],"confidence":"Low","gaps":["No direct binding assay between SKA3 and DUSP2","Mechanism inferred from expression changes only"]},{"year":2023,"claim":"Defined a hypoxia mechanism in which SKA3 recruits PARP1 to PARylate HIF-1α, promoting its USP7-dependent stabilization and lipogenic output in cholangiocarcinoma.","evidence":"IP/MS, co-IP, siRNA knockdown, RNA-seq, and in vitro/in vivo assays","pmids":["37821935"],"confidence":"Medium","gaps":["Direct versus complex-mediated SKA3-PARP1 contact not fully resolved","Single-lab evidence"]},{"year":2025,"claim":"Provided an alternative HIF-1α stabilization route in which SKA3 competitively binds PHD2 to block HIF-1α hydroxylation, with p53/MDM2 and HIF-1α feedback controlling SKA3 levels.","evidence":"Co-IP, HIF-1α stabilization and ubiquitination assays, ChIP, and functional models in lung adenocarcinoma","pmids":["41298345"],"confidence":"Medium","gaps":["Relationship between the PHD2-competition and PARP1-PARylation routes not reconciled","Single-lab evidence"]},{"year":2025,"claim":"Identified SKA3 binding to integrin β1 driving EGFR activation within an EGFR/E2F1/SKA3/integrin β1 feedback loop.","evidence":"Co-IP, ChIP/luciferase, pharmacological EGFR inhibition (AZD9291), and functional assays","pmids":["40056339"],"confidence":"Medium","gaps":["Direct integrin β1 binding site not mapped","Single-lab evidence"]},{"year":null,"claim":"How SKA3's mitotic kinetochore function mechanistically relates to its many reported cytoplasmic oncogenic interactions (PLK1, EGFR, integrin β1, PHD2/PARP1) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No study integrates the mitotic and signaling roles","Most cancer interactions rest on single-lab co-IPs without structural mapping","Whether signaling roles require kinetochore-associated SKA3 is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,6]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,14]}],"complexes":["Ska complex (Ska1/Ska2/Ska3)"],"partners":["SKA1","NDC80","PLK1","EGFR","ITGB1","PHD2 (EGLN1)","PARP1","PP2A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IX90","full_name":"Spindle and kinetochore-associated protein 3","aliases":[],"length_aa":412,"mass_kda":46.4,"function":"Component of the SKA1 complex, a microtubule-binding subcomplex of the outer kinetochore that is essential for proper chromosome segregation (PubMed:19289083, PubMed:19360002, PubMed:23085020). The SKA1 complex is a direct component of the kinetochore-microtubule interface and directly associates with microtubules as oligomeric assemblies (PubMed:19289083, PubMed:19360002). The complex facilitates the processive movement of microspheres along a microtubule in a depolymerization-coupled manner (PubMed:19289083). In the complex, it mediates the microtubule-stimulated oligomerization (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/Q8IX90/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SKA3","classification":"Common Essential","n_dependent_lines":973,"n_total_lines":1208,"dependency_fraction":0.8054635761589404},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"BRD2","stoichiometry":4.0},{"gene":"PHAX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SKA3","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"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Mitotic spindle","reliability":"Uncertain"},{"location":"Centrosome","reliability":"Uncertain"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"bone marrow","ntpm":4.5},{"tissue":"lymphoid tissue","ntpm":11.3},{"tissue":"testis","ntpm":5.9}],"url":"https://www.proteinatlas.org/search/SKA3"},"hgnc":{"alias_symbol":["MGC4832","RAMA1"],"prev_symbol":["C13orf3"]},"alphafold":{"accession":"Q8IX90","domains":[{"cath_id":"1.20.5","chopping":"2-33","consensus_level":"medium","plddt":95.935,"start":2,"end":33}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IX90","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IX90-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IX90-F1-predicted_aligned_error_v6.png","plddt_mean":63.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SKA3","jax_strain_url":"https://www.jax.org/strain/search?query=SKA3"},"sequence":{"accession":"Q8IX90","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IX90.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IX90/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IX90"}},"corpus_meta":[{"pmid":"19360002","id":"PMC_19360002","title":"Stable kinetochore-microtubule interactions depend on the Ska complex and its new component Ska3/C13Orf3.","date":"2009","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/19360002","citation_count":188,"is_preprint":false},{"pmid":"19646878","id":"PMC_19646878","title":"Ska3 is required for spindle checkpoint silencing and the maintenance of chromosome cohesion in mitosis.","date":"2009","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/19646878","citation_count":145,"is_preprint":false},{"pmid":"19549680","id":"PMC_19549680","title":"RAMA1 is a novel kinetochore protein involved in kinetochore-microtubule attachment.","date":"2009","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/19549680","citation_count":89,"is_preprint":false},{"pmid":"19387489","id":"PMC_19387489","title":"Comparative profiling identifies C13orf3 as a component of the Ska complex required for mammalian cell division.","date":"2009","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/19387489","citation_count":82,"is_preprint":false},{"pmid":"27329586","id":"PMC_27329586","title":"Over-expression of AURKA, SKA3 and DSN1 contributes to colorectal adenoma to carcinoma progression.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27329586","citation_count":68,"is_preprint":false},{"pmid":"28479321","id":"PMC_28479321","title":"Ska3 Phosphorylated by Cdk1 Binds Ndc80 and Recruits Ska to Kinetochores to Promote Mitotic Progression.","date":"2017","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/28479321","citation_count":67,"is_preprint":false},{"pmid":"33106477","id":"PMC_33106477","title":"Targeting SKA3 suppresses the proliferation and chemoresistance of laryngeal squamous cell carcinoma via impairing PLK1-AKT axis-mediated glycolysis.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33106477","citation_count":64,"is_preprint":false},{"pmid":"30459531","id":"PMC_30459531","title":"SKA3 promotes cell proliferation and migration in cervical cancer by activating the PI3K/Akt signaling pathway.","date":"2018","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/30459531","citation_count":57,"is_preprint":false},{"pmid":"31804459","id":"PMC_31804459","title":"SKA3 Promotes tumor growth by regulating CDK2/P53 phosphorylation in hepatocellular carcinoma.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31804459","citation_count":54,"is_preprint":false},{"pmid":"26429724","id":"PMC_26429724","title":"GNL3 and SKA3 are novel prostate cancer metastasis susceptibility genes.","date":"2015","source":"Clinical & experimental metastasis","url":"https://pubmed.ncbi.nlm.nih.gov/26429724","citation_count":44,"is_preprint":false},{"pmid":"32068236","id":"PMC_32068236","title":"SKA3 promotes lung adenocarcinoma metastasis through the EGFR-PI3K-Akt axis.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/32068236","citation_count":40,"is_preprint":false},{"pmid":"37821935","id":"PMC_37821935","title":"Hypoxia-induced SKA3 promoted cholangiocarcinoma progression and chemoresistance by enhancing fatty acid synthesis via the regulation of PAR-dependent HIF-1a deubiquitylation.","date":"2023","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/37821935","citation_count":38,"is_preprint":false},{"pmid":"27667719","id":"PMC_27667719","title":"Ska3 Ensures Timely Mitotic Progression by Interacting Directly With Microtubules and Ska1 Microtubule Binding Domain.","date":"2016","source":"Scientific 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Australasia","url":"https://pubmed.ncbi.nlm.nih.gov/33775353","citation_count":18,"is_preprint":false},{"pmid":"35295342","id":"PMC_35295342","title":"The SKA3-DUSP2 Axis Promotes Gastric Cancer Tumorigenesis and Epithelial-Mesenchymal Transition by Activating the MAPK/ERK Pathway.","date":"2022","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35295342","citation_count":17,"is_preprint":false},{"pmid":"32799774","id":"PMC_32799774","title":"SKA3 Promotes Cell Growth in Breast Cancer by Inhibiting PLK-1 Protein Degradation.","date":"2020","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/32799774","citation_count":16,"is_preprint":false},{"pmid":"34514096","id":"PMC_34514096","title":"miR-1207-5p suppresses laryngeal squamous cell carcinoma progression by downregulating SKA3 and inhibiting epithelial-mesenchymal transition.","date":"2021","source":"Molecular therapy 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461364 and IKK 16 Drugs.","date":"2024","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39214909","citation_count":4,"is_preprint":false},{"pmid":"36134741","id":"PMC_36134741","title":"Circular RNA circ_SKA3 enhances gastric cancer development by targeting miR-520h.","date":"2022","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/36134741","citation_count":3,"is_preprint":false},{"pmid":"41298345","id":"PMC_41298345","title":"SKA3-mediated hypoxia tolerance and metabolic reprogramming promote liver metastasis in lung adenocarcinoma.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41298345","citation_count":1,"is_preprint":false},{"pmid":"40056339","id":"PMC_40056339","title":"SKA3 promotes lung adenocarcinoma progression via the EGFR/E2F1/SKA3/integrin β1 signaling loop.","date":"2025","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40056339","citation_count":1,"is_preprint":false},{"pmid":"40642599","id":"PMC_40642599","title":"Chitosan-encapsulated Gloriosa superba nanoparticles suppress cervical cancer by inhibiting SKA3-mediated PI3K/AKT/mTOR pathway.","date":"2025","source":"Cytotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/40642599","citation_count":0,"is_preprint":false},{"pmid":"42077186","id":"PMC_42077186","title":"Transcriptional Activation of SKA3 by SOX9 Promotes the Malignant Progression of Laryngeal Squamous Cell Carcinoma by Regulating AKR1C1.","date":"2026","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/42077186","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.14.653945","title":"A Systems Biology Approach to Unveil Shared Therapeutic Targets and Pathological Pathways Across Major Human 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It localizes to the spindle and kinetochore throughout mitosis. Concomitant depletion of Ska1 and Ska3 causes chromosome congression failure and destabilizes kinetochore-microtubule attachments (reduced cold stability of KT fibres), while only marginally impairing KMN network localization at kinetochores.\",\n      \"method\": \"Mass spectrometry, RNAi depletion, cold-stability assay, immunofluorescence\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal MS identification plus functional RNAi phenotype with direct KT-MT cold-stability readout; replicated by three independent labs simultaneously\",\n      \"pmids\": [\"19360002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Ska3 is required for spindle checkpoint silencing and timely anaphase onset. Ska3-depleted cells accumulate high Bub1 at kinetochores and fail to silence the spindle checkpoint despite achieving metaphase alignment. Ska3 kinetochore accumulation in prometaphase is dependent on Sgo1, whereas Sgo1 localization is not dependent on Ska3.\",\n      \"method\": \"RNAi knockdown, live-cell imaging, immunofluorescence for kinetochore proteins\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean RNAi with multiple specific phenotypic readouts (checkpoint silencing, Bub1 accumulation, epistasis with Sgo1), replicated across labs\",\n      \"pmids\": [\"19646878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RAMA1 (SKA3) localizes to spindle and outer kinetochores throughout mitosis and its kinetochore recruitment depends on the core kinetochore-microtubule attachment factor Hec1. Unlike Hec1, RAMA1 association with kinetochores is highly dynamic (not a stable structural component). RAMA1 depletion reduces kinetochore-microtubule attachments, causing severe chromosome alignment defects and checkpoint-dependent mitotic arrest.\",\n      \"method\": \"High-throughput RNAi screen, immunofluorescence, live-cell imaging, kinetochore protein localization analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi functional readout with Hec1 epistasis and direct localization dynamics; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"19549680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"C13orf3 (Ska3) localizes to centrosomes, mitotic spindle, kinetochores, spindle midzone, and cleavage furrow during cell division and is specifically phosphorylated during mitosis. Proteomic analyses identified a direct interaction between Ska3 and a regulatory subunit of protein phosphatase PP2A.\",\n      \"method\": \"Phenotypic profiling, mass spectrometry/proteomics, immunofluorescence, co-immunoprecipitation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification of PP2A interaction and localization data with multiple methods, single lab\",\n      \"pmids\": [\"19387489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Ska3 directly interacts with tubulin monomers (microtubule binding) and also interacts with tubulin-contacting regions of Ska1, suggesting allosteric regulation of the Ska complex microtubule-binding capability. Perturbing either the Ska3-microtubule interaction or Ska3-Ska1 interaction reduces microtubule binding by the Ska complex in vitro and delays anaphase onset in cells.\",\n      \"method\": \"In vitro microtubule binding assays, mutagenesis of interaction domains, cell-based anaphase onset assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution assay with mutagenesis plus functional cell-based validation; multiple orthogonal approaches in one study\",\n      \"pmids\": [\"27667719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cdk1 phosphorylates Ska3 specifically during mitosis, and this phosphorylation promotes direct binding of Ska3 to the Ndc80 complex (Ndc80C), a core outer kinetochore component. This phosphorylation is required for kinetochore localization of the entire Ska complex. Ska3 phospho-mutants deficient in Cdk1 phosphorylation retain microtubule localization and support chromosome alignment but delay anaphase onset. Aurora B phosphorylation of Ska1 and Ska3 inhibits Ska complex kinetochore localization.\",\n      \"method\": \"In vitro kinase assay, direct binding assay (Ska3-Ndc80C), phospho-mutant cell lines, live-cell imaging, immunofluorescence\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus direct binding assay plus phospho-mutant functional analysis; multiple orthogonal methods establishing mechanism\",\n      \"pmids\": [\"28479321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SKA3 binds and stabilizes PLK1 protein by suppressing ubiquitin-mediated degradation in laryngeal squamous cell carcinoma cells. The accumulation of PLK1 activates AKT and upregulates glycolytic enzymes HK2, PFKFB3, and PDK1, enhancing glycolysis. Phosphorylation of SKA3 at Thr360 is critical for its binding to PLK1 and the increase in glycolysis.\",\n      \"method\": \"Co-immunoprecipitation, western blotting, ubiquitination assay, site-directed mutagenesis (Thr360), in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with mutagenesis and ubiquitination assay; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33106477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SKA3 overexpression activates the PI3K/Akt signaling pathway in cervical cancer cells, increasing levels of p-Akt, cyclin E2, CDK2, cyclin D1, CDK4, E2F1, and p-Rb. An Akt inhibitor (GSK690693) significantly reversed the cell proliferation capacity induced by SKA3 overexpression, placing SKA3 upstream of PI3K/Akt in this context.\",\n      \"method\": \"Stable overexpression/knockdown cell lines, RNA-seq, western blotting, Akt inhibitor rescue, xenograft model\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with inhibitor rescue plus RNA-seq pathway analysis; single lab\",\n      \"pmids\": [\"30459531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SKA3 knockdown in hepatocellular carcinoma cells inhibits CDK2/p53 phosphorylation and causes G2/M phase arrest, increased apoptosis, and downregulation of BAX/Bcl-2 expression, placing SKA3 upstream of the CDK2/p53 phosphorylation axis in HCC cell cycle regulation.\",\n      \"method\": \"RNAi knockdown, western blotting, flow cytometry, subcutaneous xenograft, lung metastasis model, GSEA\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular readouts (CDK2/p53 phosphorylation, Bcl-2 family); single lab, multiple assays\",\n      \"pmids\": [\"31804459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SKA3 binds and activates EGFR to activate PI3K-AKT signaling in lung adenocarcinoma cells, and also induces expression of MMP-2, -7, and -9 downstream of this pathway to promote metastasis.\",\n      \"method\": \"Co-immunoprecipitation (SKA3-EGFR binding), knockdown experiments, western blotting for pathway components\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP for SKA3-EGFR binding with pathway readout; single lab, limited validation of direct interaction\",\n      \"pmids\": [\"32068236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SKA3 promotes cell growth in breast cancer by interacting with PLK1 and preventing its degradation, as demonstrated by co-immunoprecipitation between SKA3 and PLK1.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, CCK-8, colony formation assay, western blotting\",\n      \"journal\": \"Technology in cancer research & treatment\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP, single lab, limited mechanistic follow-up beyond showing interaction\",\n      \"pmids\": [\"32799774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZEB1 transcriptionally activates SKA3 (and PLK1) expression. PLK1 in turn mediates phosphorylation of SKA3 and enhances SKA3 protein stability, promoting lung cancer cell proliferation, migration and cell cycle progression. This was established via ChIP, luciferase reporter assays, and in vitro phosphorylation assays.\",\n      \"method\": \"ChIP, luciferase reporter assay, co-immunoprecipitation, in vitro phosphorylation assay, functional cell assays\",\n      \"journal\": \"Anti-cancer drugs\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro phosphorylation assay plus ChIP and luciferase for transcriptional regulation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36728910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Under hypoxic conditions, SKA3 recruits PARP1 to bind to HIF-1α, enhancing poly ADP-ribosylation (PARylation) of HIF-1α. This PARylation enhances HIF-1α binding to USP7, triggering deubiquitylation and stabilization of HIF-1α, which then upregulates fatty acid synthesis enzymes to promote cholangiocarcinoma cell proliferation. Additionally, HIF-1α directly binds to the HRE in the SKA3 promoter, creating a positive feedback loop.\",\n      \"method\": \"IP/MS analysis, western blot, co-immunoprecipitation, siRNA knockdown, RNA-seq, in vitro and in vivo functional assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP/MS plus co-IP demonstrating SKA3-PARP1-HIF-1α complex, multiple methods; single lab\",\n      \"pmids\": [\"37821935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SKA3 competitively binds to prolyl hydroxylase domain-containing protein 2 (PHD2), disrupting its interaction with HIF-1α and thereby stabilizing HIF-1α to enhance glycolytic enzyme transcription in lung adenocarcinoma. HIF-1α in turn binds the HRE in the SKA3 promoter (positive feedback). Hypoxia-induced MDM2 ubiquitinates and degrades p53, relieving p53-mediated repression of SKA3.\",\n      \"method\": \"Co-immunoprecipitation (SKA3-PHD2 binding), HIF-1α stabilization assay, ChIP (HIF-1α on SKA3 promoter), ubiquitination assay (p53-MDM2), functional in vitro and in vivo assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for SKA3-PHD2 interaction with ChIP and ubiquitination validation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41298345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SKA3 binds to integrin β1 and promotes its activation, which further activates EGFR. EGFR activation in turn upregulates SKA3 expression via E2F1-mediated transcriptional regulation, forming a positive feedback loop (EGFR/E2F1/SKA3/integrin β1). EGFR inhibition with AZD9291 blocked E2F1-mediated SKA3 upregulation.\",\n      \"method\": \"Co-immunoprecipitation (SKA3-integrin β1), ChIP/luciferase (E2F1 on SKA3 promoter), pharmacological inhibition (AZD9291), in vitro and in vivo functional assays\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for SKA3-integrin β1, transcriptional ChIP/luciferase assay, pharmacological validation; single lab\",\n      \"pmids\": [\"40056339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SKA3 negatively regulates the tumor suppressor DUSP2, thereby activating the MAPK/ERK pathway to promote gastric cancer progression and epithelial-mesenchymal transition.\",\n      \"method\": \"siRNA knockdown, western blotting, in vitro functional assays (proliferation, migration, invasion, EMT), in vivo tumor and peritoneal metastasis models\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — loss-of-function with pathway readout but no direct binding assay between SKA3 and DUSP2; mechanism inferred from expression changes\",\n      \"pmids\": [\"35295342\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SKA3 is a core subunit of the trimeric Ska complex (Ska1/Ska2/Ska3) that localizes to the spindle and outer kinetochore throughout mitosis; it directly contacts microtubules and allosterically modulates Ska1 microtubule binding, is recruited to kinetochores via Cdk1-mediated phosphorylation that drives direct binding to the Ndc80 complex, is negatively regulated at kinetochores by Aurora B phosphorylation, and is required for spindle checkpoint silencing and timely anaphase onset; beyond its canonical mitotic role, SKA3 has been shown to stabilize PLK1 protein (inhibiting its ubiquitin-mediated degradation), interact with PHD2 to stabilize HIF-1α under hypoxia, recruit PARP1 to PARylate HIF-1α, and bind integrin β1 and EGFR to activate PI3K/Akt signaling in multiple cancer contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SKA3 (C13orf3/RAMA1) is a core subunit of the trimeric Ska complex (Ska1/Ska2/Ska3) that localizes to the spindle and outer kinetochore throughout mitosis and stabilizes kinetochore-microtubule attachments required for chromosome congression [#0, #2]. It contributes to attachment stability through dual microtubule contacts: SKA3 binds tubulin directly and engages the tubulin-contacting region of Ska1, allosterically tuning the microtubule-binding capacity of the whole complex [#4]. Kinetochore recruitment of the Ska complex is governed by mitotic phosphorylation — Cdk1 phosphorylation of SKA3 drives its direct binding to the Ndc80 complex and is required for Ska complex kinetochore localization, while Aurora B phosphorylation of Ska1/Ska3 opposes this localization [#5]; recruitment also depends on Hec1 and Sgo1 [#2, #1]. Functionally, SKA3 is required for spindle checkpoint silencing and timely anaphase onset, and its depletion produces persistent Bub1 accumulation and mitotic arrest [#1, #2]. Beyond mitosis, SKA3 has been characterized as an oncogenic driver in multiple carcinomas, where it binds and stabilizes PLK1 against ubiquitin-mediated degradation to enhance glycolysis [#6], and engages receptor and hypoxia signaling — binding integrin \\u03b21 and EGFR to activate PI3K/Akt [#7, #14] and stabilizing HIF-1\\u03b1 either by competing with PHD2 or by recruiting PARP1 to PARylate HIF-1\\u03b1 [#12, #13]. SKA3 expression itself is embedded in feedback loops driven by ZEB1, E2F1, and HIF-1\\u03b1 [#11, #13, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established SKA3 as the third subunit of the Ska complex and showed it is functionally required for stable kinetochore-microtubule attachments, defining its core mitotic role.\",\n      \"evidence\": \"Mass spectrometry identification, RNAi co-depletion with Ska1, and cold-stability assays of kinetochore fibres\",\n      \"pmids\": [\"19360002\", \"19549680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how SKA3 binds microtubules at the molecular level\", \"Dependence on upstream kinetochore factors only partially defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed SKA3 acts in spindle checkpoint silencing and anaphase timing rather than purely structurally, linking attachment stabilization to checkpoint resolution.\",\n      \"evidence\": \"RNAi depletion with live-cell imaging, Bub1 kinetochore quantification, and epistasis with Sgo1 and Hec1\",\n      \"pmids\": [\"19646878\", \"19549680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism coupling Ska to checkpoint silencing not defined\", \"Recruitment hierarchy with Hec1/Sgo1 left mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified SKA3 as a mitotically phosphorylated protein interacting with a PP2A regulatory subunit, raising the possibility of phosphoregulation of its function.\",\n      \"evidence\": \"Proteomics, immunofluorescence localization, and co-immunoprecipitation\",\n      \"pmids\": [\"19387489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the PP2A interaction not established\", \"Phosphosites not mapped in this study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the biochemical basis of Ska-microtubule binding by showing SKA3 contacts tubulin directly and allosterically regulates Ska1, explaining how the complex achieves robust attachment.\",\n      \"evidence\": \"In vitro microtubule-binding assays with domain mutagenesis and cell-based anaphase-onset readouts\",\n      \"pmids\": [\"27667719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of the SKA3-tubulin interface\", \"Stoichiometry of the assembled complex on microtubules not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved how the Ska complex is recruited to kinetochores by showing Cdk1 phosphorylation of SKA3 drives direct Ndc80C binding, with Aurora B phosphorylation opposing localization.\",\n      \"evidence\": \"In vitro kinase and direct binding assays plus phospho-mutant cell lines with live imaging\",\n      \"pmids\": [\"28479321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact phosphosites and Ndc80C contact residues not fully mapped\", \"Quantitative balance between Cdk1 and Aurora B inputs unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended SKA3 function beyond mitosis by placing it upstream of PI3K/Akt-driven cell-cycle progression in cervical cancer.\",\n      \"evidence\": \"Overexpression/knockdown cell lines, RNA-seq, western blotting, Akt inhibitor rescue, and xenografts\",\n      \"pmids\": [\"30459531\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between SKA3 and PI3K/Akt not identified here\", \"Whether effect is separable from mitotic role unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked SKA3 to the CDK2/p53 axis and apoptotic regulation in hepatocellular carcinoma, broadening its oncogenic phenotypic footprint.\",\n      \"evidence\": \"RNAi knockdown, western blotting, flow cytometry, xenograft and metastasis models, GSEA\",\n      \"pmids\": [\"31804459\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct binding partner identified for the CDK2/p53 effect\", \"Mechanism of phosphorylation regulation unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified PLK1 as a direct SKA3 partner whose stabilization links SKA3 to glycolytic reprogramming, providing a concrete biochemical mechanism for its oncogenic activity.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assays, Thr360 mutagenesis, and glycolysis readouts in laryngeal and breast cancer cells\",\n      \"pmids\": [\"33106477\", \"32799774\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Breast cancer evidence rests on a single co-IP without reciprocal validation\", \"How SKA3 blocks PLK1 ubiquitination structurally unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Proposed SKA3-EGFR binding as an upstream activator of PI3K/Akt and matrix metalloproteinase-driven metastasis in lung adenocarcinoma.\",\n      \"evidence\": \"Single co-immunoprecipitation with knockdown and pathway western blots\",\n      \"pmids\": [\"32068236\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single co-IP without reciprocal validation of direct SKA3-EGFR binding\", \"Direct versus indirect interaction not distinguished\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed SKA3 within transcriptional feedback by showing ZEB1 activates SKA3 and PLK1, with PLK1 reciprocally phosphorylating and stabilizing SKA3.\",\n      \"evidence\": \"ChIP, luciferase reporters, co-IP, and in vitro phosphorylation assays\",\n      \"pmids\": [\"36728910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosites mediating PLK1-dependent stabilization not mapped\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected SKA3 to MAPK/ERK activation through negative regulation of DUSP2 in gastric cancer.\",\n      \"evidence\": \"siRNA knockdown, western blotting, and in vitro/in vivo functional assays\",\n      \"pmids\": [\"35295342\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct binding assay between SKA3 and DUSP2\", \"Mechanism inferred from expression changes only\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a hypoxia mechanism in which SKA3 recruits PARP1 to PARylate HIF-1\\u03b1, promoting its USP7-dependent stabilization and lipogenic output in cholangiocarcinoma.\",\n      \"evidence\": \"IP/MS, co-IP, siRNA knockdown, RNA-seq, and in vitro/in vivo assays\",\n      \"pmids\": [\"37821935\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus complex-mediated SKA3-PARP1 contact not fully resolved\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided an alternative HIF-1\\u03b1 stabilization route in which SKA3 competitively binds PHD2 to block HIF-1\\u03b1 hydroxylation, with p53/MDM2 and HIF-1\\u03b1 feedback controlling SKA3 levels.\",\n      \"evidence\": \"Co-IP, HIF-1\\u03b1 stabilization and ubiquitination assays, ChIP, and functional models in lung adenocarcinoma\",\n      \"pmids\": [\"41298345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between the PHD2-competition and PARP1-PARylation routes not reconciled\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified SKA3 binding to integrin \\u03b21 driving EGFR activation within an EGFR/E2F1/SKA3/integrin \\u03b21 feedback loop.\",\n      \"evidence\": \"Co-IP, ChIP/luciferase, pharmacological EGFR inhibition (AZD9291), and functional assays\",\n      \"pmids\": [\"40056339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct integrin \\u03b21 binding site not mapped\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SKA3's mitotic kinetochore function mechanistically relates to its many reported cytoplasmic oncogenic interactions (PLK1, EGFR, integrin \\u03b21, PHD2/PARP1) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No study integrates the mitotic and signaling roles\", \"Most cancer interactions rest on single-lab co-IPs without structural mapping\", \"Whether signaling roles require kinetochore-associated SKA3 is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 14]}\n    ],\n    \"complexes\": [\"Ska complex (Ska1/Ska2/Ska3)\"],\n    \"partners\": [\"SKA1\", \"NDC80\", \"PLK1\", \"EGFR\", \"ITGB1\", \"PHD2 (EGLN1)\", \"PARP1\", \"PP2A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}