Affinage

SKA3

Spindle and kinetochore-associated protein 3 · UniProt Q8IX90

Length
412 aa
Mass
46.4 kDa
Annotated
2026-06-10
33 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2009 High

    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

    PMID:19360002 PMID:19549680

    Open questions at the time
    • Did not resolve how SKA3 binds microtubules at the molecular level
    • Dependence on upstream kinetochore factors only partially defined
  2. 2009 High

    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

    PMID:19549680 PMID:19646878

    Open questions at the time
    • Molecular mechanism coupling Ska to checkpoint silencing not defined
    • Recruitment hierarchy with Hec1/Sgo1 left mechanistically incomplete
  3. 2009 Medium

    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

    PMID:19387489

    Open questions at the time
    • Functional consequence of the PP2A interaction not established
    • Phosphosites not mapped in this study
  4. 2016 High

    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

    PMID:27667719

    Open questions at the time
    • No high-resolution structure of the SKA3-tubulin interface
    • Stoichiometry of the assembled complex on microtubules not resolved
  5. 2017 High

    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

    PMID:28479321

    Open questions at the time
    • Exact phosphosites and Ndc80C contact residues not fully mapped
    • Quantitative balance between Cdk1 and Aurora B inputs unresolved
  6. 2018 Medium

    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

    PMID:30459531

    Open questions at the time
    • Direct molecular link between SKA3 and PI3K/Akt not identified here
    • Whether effect is separable from mitotic role unclear
  7. 2019 Medium

    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

    PMID:31804459

    Open questions at the time
    • No direct binding partner identified for the CDK2/p53 effect
    • Mechanism of phosphorylation regulation unresolved
  8. 2020 Medium

    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

    PMID:32799774 PMID:33106477

    Open questions at the time
    • Breast cancer evidence rests on a single co-IP without reciprocal validation
    • How SKA3 blocks PLK1 ubiquitination structurally unknown
  9. 2020 Low

    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

    PMID:32068236

    Open questions at the time
    • Single co-IP without reciprocal validation of direct SKA3-EGFR binding
    • Direct versus indirect interaction not distinguished
  10. 2022 Medium

    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

    PMID:36728910

    Open questions at the time
    • Phosphosites mediating PLK1-dependent stabilization not mapped
    • Single-lab evidence
  11. 2022 Low

    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

    PMID:35295342

    Open questions at the time
    • No direct binding assay between SKA3 and DUSP2
    • Mechanism inferred from expression changes only
  12. 2023 Medium

    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

    PMID:37821935

    Open questions at the time
    • Direct versus complex-mediated SKA3-PARP1 contact not fully resolved
    • Single-lab evidence
  13. 2025 Medium

    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

    PMID:41298345

    Open questions at the time
    • Relationship between the PHD2-competition and PARP1-PARylation routes not reconciled
    • Single-lab evidence
  14. 2025 Medium

    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

    PMID:40056339

    Open questions at the time
    • Direct integrin β1 binding site not mapped
    • Single-lab evidence

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SKA3's mitotic kinetochore function mechanistically relates to its many reported cytoplasmic oncogenic interactions (PLK1, EGFR, integrin β1, PHD2/PARP1) remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005856 cytoskeleton 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-162582 Signal Transduction 2
Partners
EGFRITGB1NDC80PARP1PHD2 (EGLN1)PLK1PP2ASKA1
Complex memberships
Ska complex (Ska1/Ska2/Ska3)

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 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. Mass spectrometry, RNAi depletion, cold-stability assay, immunofluorescence The EMBO journal High 19360002
2009 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. RNAi knockdown, live-cell imaging, immunofluorescence for kinetochore proteins Current biology : CB High 19646878
2009 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. High-throughput RNAi screen, immunofluorescence, live-cell imaging, kinetochore protein localization analysis Journal of cell science High 19549680
2009 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. Phenotypic profiling, mass spectrometry/proteomics, immunofluorescence, co-immunoprecipitation The EMBO journal Medium 19387489
2016 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. In vitro microtubule binding assays, mutagenesis of interaction domains, cell-based anaphase onset assays Scientific reports High 27667719
2017 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. In vitro kinase assay, direct binding assay (Ska3-Ndc80C), phospho-mutant cell lines, live-cell imaging, immunofluorescence Current biology : CB High 28479321
2020 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. Co-immunoprecipitation, western blotting, ubiquitination assay, site-directed mutagenesis (Thr360), in vitro and in vivo functional assays Cell death & disease Medium 33106477
2018 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. Stable overexpression/knockdown cell lines, RNA-seq, western blotting, Akt inhibitor rescue, xenograft model Cancer cell international Medium 30459531
2019 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. RNAi knockdown, western blotting, flow cytometry, subcutaneous xenograft, lung metastasis model, GSEA Cell death & disease Medium 31804459
2020 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. Co-immunoprecipitation (SKA3-EGFR binding), knockdown experiments, western blotting for pathway components Bioscience reports Low 32068236
2020 SKA3 promotes cell growth in breast cancer by interacting with PLK1 and preventing its degradation, as demonstrated by co-immunoprecipitation between SKA3 and PLK1. Co-immunoprecipitation, shRNA knockdown, CCK-8, colony formation assay, western blotting Technology in cancer research & treatment Low 32799774
2022 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. ChIP, luciferase reporter assay, co-immunoprecipitation, in vitro phosphorylation assay, functional cell assays Anti-cancer drugs Medium 36728910
2023 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. IP/MS analysis, western blot, co-immunoprecipitation, siRNA knockdown, RNA-seq, in vitro and in vivo functional assays Journal of experimental & clinical cancer research : CR Medium 37821935
2025 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. 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 Cell death & disease Medium 41298345
2025 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. Co-immunoprecipitation (SKA3-integrin β1), ChIP/luciferase (E2F1 on SKA3 promoter), pharmacological inhibition (AZD9291), in vitro and in vivo functional assays Molecular and cellular biochemistry Medium 40056339
2022 SKA3 negatively regulates the tumor suppressor DUSP2, thereby activating the MAPK/ERK pathway to promote gastric cancer progression and epithelial-mesenchymal transition. siRNA knockdown, western blotting, in vitro functional assays (proliferation, migration, invasion, EMT), in vivo tumor and peritoneal metastasis models Frontiers in pharmacology Low 35295342

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Stable kinetochore-microtubule interactions depend on the Ska complex and its new component Ska3/C13Orf3. The EMBO journal 188 19360002
2009 Ska3 is required for spindle checkpoint silencing and the maintenance of chromosome cohesion in mitosis. Current biology : CB 145 19646878
2009 RAMA1 is a novel kinetochore protein involved in kinetochore-microtubule attachment. Journal of cell science 89 19549680
2009 Comparative profiling identifies C13orf3 as a component of the Ska complex required for mammalian cell division. The EMBO journal 82 19387489
2016 Over-expression of AURKA, SKA3 and DSN1 contributes to colorectal adenoma to carcinoma progression. Oncotarget 68 27329586
2017 Ska3 Phosphorylated by Cdk1 Binds Ndc80 and Recruits Ska to Kinetochores to Promote Mitotic Progression. Current biology : CB 67 28479321
2020 Targeting SKA3 suppresses the proliferation and chemoresistance of laryngeal squamous cell carcinoma via impairing PLK1-AKT axis-mediated glycolysis. Cell death & disease 64 33106477
2018 SKA3 promotes cell proliferation and migration in cervical cancer by activating the PI3K/Akt signaling pathway. Cancer cell international 57 30459531
2019 SKA3 Promotes tumor growth by regulating CDK2/P53 phosphorylation in hepatocellular carcinoma. Cell death & disease 54 31804459
2015 GNL3 and SKA3 are novel prostate cancer metastasis susceptibility genes. Clinical & experimental metastasis 44 26429724
2020 SKA3 promotes lung adenocarcinoma metastasis through the EGFR-PI3K-Akt axis. Bioscience reports 40 32068236
2023 Hypoxia-induced SKA3 promoted cholangiocarcinoma progression and chemoresistance by enhancing fatty acid synthesis via the regulation of PAR-dependent HIF-1a deubiquitylation. Journal of experimental & clinical cancer research : CR 38 37821935
2016 Ska3 Ensures Timely Mitotic Progression by Interacting Directly With Microtubules and Ska1 Microtubule Binding Domain. Scientific reports 34 27667719
2021 Circ-SKA3 Enhances Doxorubicin Toxicity in AC16 Cells Through miR-1303/TLR4 Axis. International heart journal 32 34544967
2018 Anti-tumor roles of both strands of the miR-455 duplex: their targets SKA1 and SKA3 are involved in the pathogenesis of renal cell carcinoma. Oncotarget 25 29928475
2021 Circ-SKA3 upregulates ID3 expression by decoying miR-326 to accelerate the development of medulloblastoma. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 18 33775353
2022 The SKA3-DUSP2 Axis Promotes Gastric Cancer Tumorigenesis and Epithelial-Mesenchymal Transition by Activating the MAPK/ERK Pathway. Frontiers in pharmacology 17 35295342
2020 SKA3 Promotes Cell Growth in Breast Cancer by Inhibiting PLK-1 Protein Degradation. Technology in cancer research & treatment 16 32799774
2021 miR-1207-5p suppresses laryngeal squamous cell carcinoma progression by downregulating SKA3 and inhibiting epithelial-mesenchymal transition. Molecular therapy oncolytics 15 34514096
2011 Proteomics of isolated mitotic chromosomes identifies the kinetochore protein Ska3/Rama1. Cold Spring Harbor symposia on quantitative biology 15 21289047
2021 SKA3 promotes glioblastoma proliferation and invasion by enhancing the activation of Wnt/β-catenin signaling via modulation of the Akt/GSK-3β axis. Brain research 14 33895155
2021 Spindle and kinetochore-associated complex subunit 3 (SKA3) promotes stem cell-like properties of hepatocellular carcinoma cells through activating Notch signaling pathway. Annals of translational medicine 10 34733913
2021 SKA3, negatively regulated by miR-128-3p, promotes the progression of non-small-cell lung cancer. Personalized medicine 8 34533066
2022 Transcription factor ZEB1 regulates PLK1-mediated SKA3 phosphorylation to promote lung cancer cell proliferation, migration and cell cycle. Anti-cancer drugs 6 36728910
2024 SKA3 targeted therapies in cancer precision surgery: bridging bench discoveries to clinical applications - review article. International journal of surgery (London, England) 5 38241327
2024 TFAP2A Upregulates SKA3 to Promote Glycolysis and Reduce the Sensitivity of Lung Adenocarcinoma Cells to Cisplatin. Pharmacology 5 38643755
2024 Therapeutic Potential of PLK1, KIF4A, CDCA5, UBE2C, CDT1, SKA3, AURKB, and PTTG1 Genes in Triple-Negative Breast Cancer: Correlating Their Expression with Sensitivity to GSK 461364 and IKK 16 Drugs. Biochemical genetics 4 39214909
2021 MiR-133b suppresses the proliferation, migration and invasion of lung adenocarcinoma cells by targeting SKA3. Cancer biology & therapy 4 34711122
2022 Circular RNA circ_SKA3 enhances gastric cancer development by targeting miR-520h. Histology and histopathology 3 36134741
2025 SKA3 promotes lung adenocarcinoma progression via the EGFR/E2F1/SKA3/integrin β1 signaling loop. Molecular and cellular biochemistry 1 40056339
2025 SKA3-mediated hypoxia tolerance and metabolic reprogramming promote liver metastasis in lung adenocarcinoma. Cell death & disease 1 41298345
2026 Transcriptional Activation of SKA3 by SOX9 Promotes the Malignant Progression of Laryngeal Squamous Cell Carcinoma by Regulating AKR1C1. Journal of biochemical and molecular toxicology 0 42077186
2025 Chitosan-encapsulated Gloriosa superba nanoparticles suppress cervical cancer by inhibiting SKA3-mediated PI3K/AKT/mTOR pathway. Cytotechnology 0 40642599

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