CCDC86

CCDC86 (cyclon) is a phosphorylated nuclear protein with an N-terminal repetitive region and a C-terminal coiled-coil domain that operates in two distinct contexts: immune cell death regulation and the mitotic chromosome periphery (PMID:17300783, PMID:36695333). It was first identified as an immediate-early gene induced by IL-3 in hematopoietic cells (PMID:17300783), and in T cells its induction following TCR ligation drives activation-induced cell death by upregulating Fas expression, placing CCDC86 upstream of Fas in immune homeostasis as shown by reciprocal allele deletion and transgenic overexpression (PMID:19528538). During mitosis, CCDC86 associates with the chromosome periphery and, together with nucleolin (NCL) and NPM1/B23, forms subcomplexes required for spindle regulation and correct kinetochore-microtubule attachments; its depletion disorganizes the chromosome periphery, mislocalizes Ki-67 (MKI67) and nucleolin, and produces chromosome alignment errors and increased apoptosis (PMID:36695333). CCDC86 physically interacts with NPM1, linking it to the nucleolus, RNA processing, MYC signaling, and cell cycle progression (PMID:34885010). In cancer contexts, CCDC86 acts through partner proteins to drive oncogenic signaling: it binds NPM1 to upregulate EGFR and activate PI3K/Akt in nasopharyngeal carcinoma (PMID:38247332), and binds BHLHE40 to stabilize ATF3 and activate ERK-driven aerobic glycolysis in glioma (PMID:40837407).

1. 2007 Medium

   Established CCDC86/cyclon as a cytokine-responsive immediate-early gene and defined its basic protein architecture, framing it as a regulated nuclear factor rather than a constitutive housekeeping protein.

   Evidence Transient reporter assay of the mouse cyclon promoter plus protein characterization (phosphorylation, domain analysis) in IL-3-responsive hematopoietic cells

   PMID:17300783

   Open questions at the time

   • No molecular function assigned to the protein
   • Coiled-coil binding partners not identified
   • Phosphorylation sites and responsible kinases unknown
2. 2009 High

   Answered what cyclon does functionally in immune cells, showing it promotes T-cell activation-induced cell death by upregulating Fas and contributes to immune homeostasis.

   Evidence Conditional allele deletion (loss-of-function), transgenic overexpression, AICD assays, and Fas expression measurement in mouse CD4+ T cells and IL-2R-deficient mice

   PMID:19528538

   Open questions at the time

   • Molecular mechanism by which CCDC86 controls Fas expression unresolved
   • Direct DNA or protein targets not identified
   • Link between nuclear localization and Fas regulation unestablished
3. 2021 Medium

   Identified NPM1 as a physical partner and connected CCDC86 to the nucleolus, RNA processing, MYC signaling, and cell cycle, while linking its subcellular localization to disease prognosis.

   Evidence Protein interaction network characterization and immunohistochemistry for subcellular localization in DLBCL

   PMID:34885010

   Open questions at the time

   • Full Co-IP/proteomics validation details not specified
   • Functional consequence of the NPM1 interaction not tested here
   • Mechanism linking extra-nucleolar localization to outcome unknown
4. 2023 High

   Defined a concrete mitotic role: CCDC86 is a chromosome periphery component that, with nucleolin and NPM1, forms subcomplexes required for spindle regulation and kinetochore-microtubule attachment fidelity.

   Evidence RNAi depletion, fluorescence microscopy, biochemical fractionation, and Co-immunoprecipitation identifying Ki-67/MKI67, NCL, and NPM1 partners

   PMID:36695333

   Open questions at the time

   • Structural basis of subcomplex assembly unknown
   • How CCDC86 is recruited to the chromosome periphery unresolved
   • Direct molecular activity at the kinetochore not defined
5. 2023 Medium

   Showed CCDC86 drives carcinoma cell proliferation and invasion indirectly, acting through NPM1 to upregulate EGFR and activate PI3K/Akt rather than binding EGFR directly.

   Evidence In vitro proliferation/invasion/migration assays, xenograft, Co-IP of CCDC86-NPM1, siRNA knockdown, and EGFR/PI3K-Akt pathway analysis in nasopharyngeal carcinoma

   PMID:38247332

   Open questions at the time

   • Mechanism by which the NPM1 complex regulates EGFR expression unclear
   • Single lab, single tumor type
   • Whether mitotic and oncogenic NPM1 complexes are the same is untested
6. 2025 Medium

   Extended the oncogenic role to glioma via a distinct partner, showing CCDC86 binds BHLHE40 to stabilize ATF3 and activate ERK-driven aerobic glycolysis.

   Evidence Knockdown functional assays, in vivo tumorigenesis, Co-IP of CCDC86-BHLHE40, and ATF3 rescue experiments in glioma cells

   PMID:40837407

   Open questions at the time

   • Direct biochemical basis of ATF3 stabilization unknown
   • Relationship between BHLHE40 and NPM1 pathways unresolved
   • Single lab finding

• The intrinsic molecular activity of CCDC86 and how a single coiled-coil protein bridges chromosome periphery assembly, Fas-mediated apoptosis, and multiple oncogenic partner complexes remains unresolved.
• No enzymatic or defined biochemical activity established
• No structure of CCDC86 or its complexes
• Mechanism unifying immune, mitotic, and oncogenic roles unknown