Affinage

SKA2

Spindle and kinetochore-associated protein 2 · UniProt Q8WVK7

Length
121 aa
Mass
14.2 kDa
Annotated
2026-06-10
34 papers in source corpus 10 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2006 High

    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

    PMID:17093495

    Open questions at the time
    • No structural detail on how the SKA1/SKA2 complex engages microtubules or kinetochores
    • Mechanism of checkpoint silencing downstream of the complex unresolved
  2. 2008 Medium

    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

    PMID:18583474

    Open questions at the time
    • No reciprocal Co-IP reported
    • Molecular basis of GR potentiation not defined at this stage
  3. 2015 Medium

    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

    PMID:26162986

    Open questions at the time
    • Does not address tissue- or context-specific regulation
    • Co-regulation consequences for PRR11 vs SKA2 function not separated
  4. 2017 Medium

    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

    PMID:28257042

    Open questions at the time
    • Repression is indirect; no direct p53 binding to the promoter
    • Functional consequence for SKA2-dependent phenotypes not measured
  5. 2023 Medium

    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

    PMID:36860919

    Open questions at the time
    • Whether SKA2 binds DNA directly or only through Sp1 is unresolved
    • Generality of PDSS2 repression beyond lung cancer cells unknown
  6. 2024 High

    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

    PMID:39705315

    Open questions at the time
    • Structural detail of the FKBP4/FKBP5 exchange on GR not defined
    • Relationship to SKA2's mitotic pool unaddressed
  7. 2024 High

    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

    PMID:37066393 PMID:38528004

    Open questions at the time
    • Direct molecular target of SKA2 in the secretory autophagy machinery not pinpointed
    • Causal direction of SA hyperactivation in human AD not established
  8. 2025 Medium

    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

    PMID:41309933

    Open questions at the time
    • Whether the SKA2–EGFR interaction is direct or scaffolded is unclear
    • Mechanism by which SKA2 sustains AKT signaling not defined
  9. 2026 Medium

    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

    PMID:41847110

    Open questions at the time
    • Mechanism of SLC6A9 upregulation by SKA2 unknown
    • Link between metabolic and mitotic/GR functions unexamined

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No unifying structural or domain-level explanation for the multifunctionality
  • Subcellular pool controlling each function not delineated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0060090 molecular adaptor activity 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 1 R-HSA-9612973 Autophagy 1
Partners
EGFRFKBP4FKBP5GR (NR3C1)NF-YSKA1SP1
Complex memberships
SKA1/SKA2 complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 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. siRNA knockdown, immunofluorescence, live-cell imaging, Mad2 kinetochore recruitment assay The EMBO journal High 17093495
2008 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. Yeast two-hybrid screen, immunofluorescence co-localization, overexpression/knockdown transactivation assays, proliferation assays The Journal of endocrinology Medium 18583474
2015 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. Serial luciferase reporter assays, EMSA, ChIP, siRNA knockdown of NF-Y Biochimica et biophysica acta Medium 26162986
2017 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. Luciferase reporter assay (deletion/mutation analysis), co-immunoprecipitation, ChIP, siRNA knockdown International journal of molecular sciences Medium 28257042
2024 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. In vivo Ska2 knockdown (mouse), secretory autophagy assays, IL-1β release measurement, NLRP3/Gasdermin D pathway assays, co-immunoprecipitation of human postmortem brain Nature communications High 37066393 38528004
2024 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. In vitro cell assays (GR signaling reporters), co-immunoprecipitation of FKBP4/FKBP5/GR complex, in vivo conditional knockout/knockdown in Crh+ neurons (mouse) Proceedings of the National Academy of Sciences of the United States of America High 39705315
2023 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. Gene expression profiling after SKA2 knockdown, luciferase reporter assay (Sp1-binding site mutagenesis), co-immunoprecipitation (SKA2–Sp1), overexpression rescue experiments Journal of Cancer Medium 36860919
2025 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. Co-immunoprecipitation (SKA2–EGFR), CRISPRi repression of transcription unit, PI3K-AKT pathway activity assays, in vivo mouse tumor models Oncogene Medium 41309933
2026 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. siRNA knockdown, cell-cycle analysis, ROS measurement, SLC6A9/GSH metabolic assays, ATM/Chk2/JNK pathway analysis, in vitro and in vivo tumor models iScience Medium 41847110

Source papers

Stage 0 corpus · 34 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Timely anaphase onset requires a novel spindle and kinetochore complex comprising Ska1 and Ska2. The EMBO journal 207 17093495
2015 SKA2 methylation is associated with decreased prefrontal cortical thickness and greater PTSD severity among trauma-exposed veterans. Molecular psychiatry 84 26324104
2010 Intronic miR-301 feedback regulates its host gene, ska2, in A549 cells by targeting MEOX2 to affect ERK/CREB pathways. Biochemical and biophysical research communications 80 20470754
2015 Epigenetic and genetic variation at SKA2 predict suicidal behavior and post-traumatic stress disorder. Translational psychiatry 77 26305478
2015 SKA2 Methylation is Involved in Cortisol Stress Reactivity and Predicts the Development of Post-Traumatic Stress Disorder (PTSD) After Military Deployment. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 69 26361058
2008 Identification and functional analysis of SKA2 interaction with the glucocorticoid receptor. The Journal of endocrinology 65 18583474
2020 Circ_0008039 supports breast cancer cell proliferation, migration, invasion, and glycolysis by regulating the miR-140-3p/SKA2 axis. Molecular oncology 60 33244865
2016 Epigenetic modification of miR-141 regulates SKA2 by an endogenous 'sponge' HOTAIR in glioma. Oncotarget 58 27121316
2015 The gene pair PRR11 and SKA2 shares a NF-Y-regulated bidirectional promoter and contributes to lung cancer development. Biochimica et biophysica acta 54 26162986
2016 EPIGENETIC VARIATION AT SKA2 PREDICTS SUICIDE PHENOTYPES AND INTERNALIZING PSYCHOPATHOLOGY. Depression and anxiety 48 27038412
2016 The Expression of the Suicide-Associated Gene SKA2 Is Decreased in the Prefrontal Cortex of Suicide Victims but Not of Nonsuicidal Patients. The international journal of neuropsychopharmacology 41 26902949
2018 SKA2 mediates invasion and metastasis in human breast cancer via EMT. Molecular medicine reports 27 30387823
2024 SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration. Nature communications 26 38528004
2018 SKA2/FAM33A: A novel gene implicated in cell cycle, tumorigenesis, and psychiatric disorders. Genes & diseases 26 30906829
2017 The PRR11-SKA2 Bidirectional Transcription Unit Is Negatively Regulated by p53 through NF-Y in Lung Cancer Cells. International journal of molecular sciences 24 28257042
2019 PRR11 and SKA2 gene pair is overexpressed and regulated by p53 in breast cancer. BMB reports 23 30760381
2015 Peroxisome proliferator-activated receptor-α-mediated transcription of miR-301a and miR-454 and their host gene SKA2 regulates endothelin-1 and PAI-1 expression in sickle cell disease. Bioscience reports 17 26460070
2024 SKA2 enhances stress-related glucocorticoid receptor signaling through FKBP4-FKBP5 interactions in neurons. Proceedings of the National Academy of Sciences of the United States of America 15 39705315
2020 PRR11 and SKA2 promote the proliferation, migration and invasion of esophageal carcinoma cells. Oncology letters 14 32565988
2019 SKA2 gene - A novel biomarker for latent anxiety and preterm birth prediction. European journal of obstetrics, gynecology, and reproductive biology 11 31035118
2018 Long non-coding RNA SPRY4-IT1 promotes the proliferation and invasion of U251 cells through upregulation of SKA2. Oncology letters 11 29467908
2020 SKA2 promotes proliferation and invasion of hepatocellular carcinoma cells via activating the β-catenin signaling pathway. Neoplasma 7 32241158
2023 Circ_0001387 regulates SKA2 to accelerate breast cancer progression through miR-136-5p. Thoracic cancer 5 37132052
2023 The rs7208505 Polymorphism and Differential Expression of the SKA2 Gene in the Prefrontal Cortex of Suicide Victims from the Mexican Population. Archives of suicide research : official journal of the International Academy for Suicide Research 5 37204142
2021 HEDGEHOG/GLI Modulates the PRR11-SKA2 Bidirectional Transcription Unit in Lung Squamous Cell Carcinomas. Genes 5 33477943
2024 The role of SKA2 on affective disorder, post-traumatic stress disorder and suicide behavior: systematic review and in silico analysis. Metabolic brain disease 3 38722562
2020 The Correlation of SKA2 with Cortisol, IL-1β and Anxiety in Pregnant Women with the Risk of Preterm Delivery. Psychiatry investigation 3 32375462
2023 SKA2-mediated transcriptional downregulation of the key enzyme of CoQ10 biosynthesis PDSS2 in lung cancer cells. Journal of Cancer 2 36860919
2025 Genetic association between SKA2 rs7208505 and preterm birth in Korean women. Molecular biology reports 1 40402322
2025 Overexpressed PRR11-SKA2-miR301a/454 bidirectional transcription unit essentially and coordinately promotes PI3K-AKT pathway activation and lung cancer progression. Oncogene 1 41309933
2024 Oncogenic role of SKA2 and its ceRNA network in hepatocellular carcinoma based on a comprehensive analysis. Translational cancer research 1 39525023
2021 The Shift of HbF to HbA under Influence of SKA2 Gene; A Possible Link between Cortisol and Hematopoietic Maturation in Term and Preterm Newborns. Endocrine, metabolic & immune disorders drug targets 1 32364083
2026 SKA2 promotes gastric cancer progression by regulating glutathione metabolism. iScience 0 41847110
2023 SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration. bioRxiv : the preprint server for biology 0 37066393

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