CENPK

CENPK is an inner kinetochore protein that forms a stable, salt-resistant heterodimeric coiled-coil subcomplex with CENP-H at approximately 1:1 stoichiometry within the constitutive centromere-associated network (PMID:19381461). Beyond this structural role, the available corpus characterizes CENPK predominantly as a transcriptionally controlled driver of malignant cell behavior across multiple cancers. Its transcription is directly activated by E2F1 (PMID:38670220) and CTCF (PMID:41797275), and its mRNA is stabilized by ZC3H13-mediated m6A modification (PMID:35418160). At the protein level, CENPK engages distinct partners to activate parallel pro-tumorigenic signaling axes: it binds XRCC5 (Ku80) to promote proliferation and migration (PMID:35715658), binds SOX6 and competitively disrupts CENPK–β-catenin interactions to drive β-catenin nuclear translocation, p53 ubiquitination, and Wnt/β-catenin activation (PMID:35418160), and interacts with GOLPH3 to activate mTOR signaling and confer rapamycin sensitivity (PMID:38670220). An exon-8-deleted splice variant (CENPK-delta8) acquires specific binding to FLNA and FLOT1 not seen with wild-type protein, linking it to cytoskeletal organization, migration, and abiraterone resistance in prostate cancer (PMID:39404386). The CTCF–CENPK axis additionally activates JAK1/STAT3 signaling (PMID:41797275). Beyond the kinetochore heterodimer with CENP-H (PMID:19381461), the mechanistic basis by which CENPK transduces these many signaling outputs has not been resolved into a unified biochemical model in the available corpus.

1. 2009 Medium

   Established that CENP-K is a stable structural component of the inner kinetochore by defining its direct partnership with CENP-H, addressing how these CCAN proteins assemble.

   Evidence Tandem affinity purification from HEK293 cells with coiled-coil prediction and deletion mapping of interacting regions

   PMID:19381461

   Open questions at the time

   • No in vitro reconstitution or structural validation of the heterodimer
   • Stoichiometry and architecture within the full CCAN not resolved
   • Single lab
2. 2017 Low

   First linked CENPK overexpression to oncogenic signaling, placing it upstream of the AKT/MDM2/TP53 axis in hepatocellular carcinoma proliferation.

   Evidence Overexpression/knockdown with western blot for phosphorylation and proliferation/migration assays in HCC lines

   PMID:29088763

   Open questions at the time

   • Single method (phospho-western), no direct binding or enzymatic mechanism
   • How CENPK affects phosphorylation is unknown
3. 2019 Low

   Positioned CENPK upstream of YAP1 in driving HCC malignant progression and EMT via a genetic rescue, establishing pathway order without molecular contact.

   Evidence shRNA knockdown with functional assays and YAP1 re-expression rescue in HCC cells

   PMID:30774374

   Open questions at the time

   • No direct CENPK–YAP1 interaction demonstrated
   • Mechanism connecting CENPK to YAP1 unknown
4. 2021 Low

   Connected CENPK to the PTEN-PI3K-AKT pathway in gastric cancer, refining the signaling context for its pro-survival role.

   Evidence shRNA knockdown with pathway westerns, in vitro proliferation and xenograft assays

   PMID:34382342

   Open questions at the time

   • Pathway association by western blot only, no direct interaction or epistasis rescue
   • Causal node unidentified
5. 2022 Medium

   Identified XRCC5 (Ku80) as a direct physical partner mediating CENPK's pro-proliferative and pro-migratory effects in gastric cancer.

   Evidence Co-IP plus LC-MS proteomics with functional rescue and xenograft validation

   PMID:35715658

   Open questions at the time

   • Interaction interface and stoichiometry not mapped
   • Mechanistic consequence of binding not biochemically defined
6. 2022 Medium

   Defined both an upstream regulatory mechanism (ZC3H13/m6A mRNA stabilization) and a downstream effector pathway, showing CENPK binds SOX6 and disrupts CENPK–β-catenin interactions to drive Wnt/β-catenin activation and p53 suppression in cervical cancer.

   Evidence MeRIP, Co-IP, ChIP, luciferase, cycloheximide chase and fractionation with tumorsphere and xenograft assays

   PMID:35418160

   Open questions at the time

   • Structural basis of the competitive SOX6/β-catenin binding not resolved
   • Generality beyond cervical cancer untested
7. 2022 Low

   Placed CENPK upstream of CUL4A regulation in colorectal cancer proliferation via a rescue experiment.

   Evidence shRNA knockdown with qPCR, western, MTT, flow cytometry, xenograft imaging, and CUL4A overexpression rescue

   PMID:36312839

   Open questions at the time

   • No direct CENPK–CUL4A interaction shown
   • Mechanism of CUL4A regulation unknown
8. 2024 Medium

   Revealed a splice-variant-specific interactome, with CENPK-delta8 acquiring FLNA and FLOT1 binding absent in wild-type protein, linking the isoform to cytoskeletal organization and abiraterone resistance.

   Evidence Variant-specific protein binding assays validated in PDX models, 3D organoids, and in vitro migration assays

   PMID:39404386

   Open questions at the time

   • Structural basis for exon-8-dependent partner specificity unknown
   • Single lab
9. 2024 Low

   Connected E2F1-driven CENPK transcription to mTOR pathway activation via a GOLPH3 interaction, explaining rapamycin sensitivity in ovarian cancer.

   Evidence TF reporter assays, siRNA knockdown with mTOR readouts, rapamycin sensitivity and Co-IP with GOLPH3

   PMID:38670220

   Open questions at the time

   • GOLPH3 interaction not structurally validated
   • Mechanism linking CENPK–GOLPH3 to mTOR not fully described
10. 2026 Medium

    Established CTCF as a direct transcriptional activator of CENPK driving JAK1/STAT3 signaling and tamoxifen resistance, and identified Zeylenone as a pharmacological inhibitor of this axis.

    Evidence ChIP-qPCR, luciferase reporter, thermal shift assay, molecular docking, and CENPK/JAK1 knockdown rescue in vitro and in vivo

    PMID:41797275

    Open questions at the time

    • How CENPK protein mechanistically activates JAK1/STAT3 not defined
    • Single lab

• It remains unresolved how a single inner-kinetochore protein mechanistically transduces such diverse and partner-specific signaling outputs (Wnt, mTOR, JAK/STAT, PI3K/AKT) and whether these activities are separable from its CCAN structural role.
• No structural model of CENPK signaling complexes
• Relationship between kinetochore function and oncogenic signaling unexplored
• Most downstream pathway links rest on single-lab western/rescue data