SPC24

SPC24 is a conserved subunit of the Ndc80 kinetochore complex that couples chromosomes to spindle microtubules and supports faithful chromosome segregation (PMID:11952896, PMID:27713128). In yeast it physically associates with Spc25 and Ndc80 within this complex and additionally interacts with Mps2, and its loss disrupts chromosome segregation without affecting spindle pole body duplication (PMID:11952896); it is also required for spindle integrity under replication stress, in part by recruiting the microtubule-associated protein Stu2 to kinetochores so that loss of SPC24 causes premature spindle expansion and segregation of incompletely replicated DNA (PMID:17507656). During mouse oocyte meiosis SPC24 localizes to kinetochores and is needed for proper kinetochore-microtubule attachment, chromosome alignment, and kinetochore recruitment of the spindle assembly checkpoint protein Mad2, with its depletion producing aneuploidy (PMID:27713128). In cancer, SPC24 is positioned upstream of mitogenic signaling, promoting EGFR/Ras/ERK activity and EMT and PI3K/AKT-driven proliferation (PMID:29285250, PMID:35543858), and its expression is set by multiple regulatory inputs: transcriptional activation by E2F7, which links SPC24 to aerobic glycolysis reprogramming and stemness (PMID:40663204), promoter activation by the lncRNA LINC02154 (PMID:35543858), and post-transcriptional control by miR-7-5p targeting and METTL14-mediated m6A modification of its mRNA (PMID:34020142, PMID:40848939).

1. 2002 High

   Established SPC24 as a physical member of the Ndc80 kinetochore complex required for chromosome segregation, distinguishing its role from spindle pole body duplication.

   Evidence Co-IP, in vitro recombinant interaction, TAP-tag purification and thermosensitive mutant analysis in yeast

   PMID:11952896

   Open questions at the time

   • No structural model of how SPC24 bridges Spc25/Ndc80 to microtubules
   • Functional significance of the Mps2 interaction unresolved
2. 2007 High

   Showed SPC24 maintains spindle integrity under replication stress by recruiting the microtubule-associated protein Stu2 to kinetochores, linking the complex to controlled spindle expansion.

   Evidence Genetic epistasis with hydroxyurea, overexpression rescue, and fluorescence localization in yeast

   PMID:17507656

   Open questions at the time

   • Direct SPC24-Stu2 binding not demonstrated
   • Conservation of the Stu2 recruitment role in metazoans untested
3. 2016 Medium

   Extended SPC24 function to meiosis, demonstrating it is required for kinetochore-microtubule attachment and Mad2-dependent checkpoint signaling to prevent aneuploidy.

   Evidence siRNA knockdown, immunofluorescence localization and Mad2 recruitment analysis in mouse oocytes

   PMID:27713128

   Open questions at the time

   • Mechanism of Mad2 recruitment by SPC24 not defined
   • Single-lab knockdown without rescue
4. 2018 Low

   Implicated SPC24 in cancer cell growth and survival via PI3K/AKT signaling.

   Evidence shRNA knockdown with pathway western blotting and xenografts in breast cancer cells

   PMID:30180968

   Open questions at the time

   • No direct biochemical link between SPC24 and PI3K/AKT components
   • Effect may be secondary to mitotic defects
5. 2017 Medium

   Positioned SPC24 upstream of EGFR/Ras/ERK signaling and EMT in solid tumors.

   Evidence siRNA/shRNA knockdown with western blotting and xenografts in osteosarcoma

   PMID:29285250

   Open questions at the time

   • Mechanism by which a kinetochore subunit modulates EGFR/ERK signaling unclear
   • Single lab, single tumor type
6. 2022 Medium

   Identified transcriptional and non-coding RNA inputs controlling SPC24 abundance, with LINC02154 enhancing its promoter activity and driving PI3K/AKT and EMT programs.

   Evidence Dual-luciferase promoter assay, RNA-seq, fractionation and FISH in HCC cells

   PMID:35543858

   Open questions at the time

   • Link to PI3K/AKT is indirect
   • Direct downstream effectors of SPC24 not identified
7. 2021 Medium

   Defined miR-7-5p as a direct post-transcriptional repressor of SPC24 mRNA controlling HCC proliferation and apoptosis.

   Evidence Luciferase reporter, RNA pull-down and functional rescue overexpression in HCC cells

   PMID:34020142

   Open questions at the time

   • Physiological context of miR-7-5p regulation unclear
   • Single lab
8. 2025 Medium

   Revealed m6A-based control of SPC24 mRNA stability through a LOH12CR2-METTL14 axis that degrades SPC24 transcript to suppress tumor growth.

   Evidence RNA immunoprecipitation, m6A modification assays and xenografts in colorectal cancer

   PMID:40848939

   Open questions at the time

   • m6A reader mediating decay not identified
   • Single lab
9. 2025 Medium

   Linked E2F7-driven transcription of SPC24 to metabolic reprogramming toward aerobic glycolysis and cancer cell stemness.

   Evidence Dual-luciferase reporter, ChIP, glycolysis marker WB and ECAR/OCR measurements in breast cancer

   PMID:40663204

   Open questions at the time

   • Mechanistic link between SPC24 and glycolytic gene expression undefined
   • Single lab
10. 2025 Low

    Proposed non-catalytic SRC promotes SPC24 transcription to drive resistance to SRC kinase inhibitors.

    Evidence Promoter binding/ChIP and resistance assays in cancer cell lines (preprint)

    PMID:bio_10.1101_2025.02.15.638389

    Open questions at the time

    • Preprint, limited methodological detail
    • Direct SRC-promoter binding not independently confirmed

• How SPC24's core kinetochore function mechanistically connects to the diverse oncogenic signaling and metabolic phenotypes attributed to it remains unresolved.
• No direct biochemical bridge between SPC24 and EGFR/ERK, PI3K/AKT, or glycolytic machinery
• Human kinetochore localization not directly demonstrated in the corpus
• Whether oncogenic effects are downstream of mitotic fidelity or separable functions is untested