CEP68

CEP68 is an intercentrosomal linker protein that maintains centrosome cohesion during interphase by cooperating with rootletin and C-Nap1 in the fibrous tether that joins the two centrioles (PMID:18042621). It localizes to fibres emanating from the proximal centriole ends and dissociates from centrosomes at mitosis; its depletion causes premature centrosome splitting, and its centriolar association is mutually dependent on rootletin and C-Nap1 (PMID:18042621). Super-resolution imaging places CEP68 within a periodic rootletin/CEP68 network anchored at C-Nap1 rings, where CEP68 binds the C-terminal spectrin-repeat region of rootletin and modulates the branching and thickness of rootletin filaments (PMID:29463719); centlein bridges CEP68 to C-Nap1 and is required for CEP68 recruitment to centrosomes (PMID:24554434). A C-terminal region of CEP68 governs its interphase centriolar localization and its mitotic dissociation (PMID:25704143). Linker disassembly at mitotic onset is driven by regulated proteolysis: PLK1 phosphorylates CEP68 on Ser332 to create a phosphodegron recognized by SCF(βTrCP), and degradation of the CEP68–Cep215–pericentrin complex permits removal of Cep215 from the peripheral PCM to license centriole separation (PMID:25503564, PMID:25704143). During interphase, rootletin shields CEP68 from VHL-mediated ubiquitination and degradation, and MCM7 antagonizes this protection by enhancing the CEP68–VHL interaction (PMID:28089774, PMID:28578000). CEP68 is additionally a tyrosine-phosphorylation substrate of EGFR signaling, with the functional consequence of this modification uncharacterized in the available corpus (PMID:17570516).

1. 2007 High

   Established CEP68 as a required component of the interphase intercentrosomal linker, defining its core cellular role in centrosome cohesion.

   Evidence siRNA knockdown with centrosome-splitting readout, immunofluorescence localization, and ectopic rootletin fibre recruitment in human cells

   PMID:18042621

   Open questions at the time

   • Did not resolve the direct binding interface between CEP68 and rootletin/C-Nap1
   • Molecular structure and stoichiometry of the linker not defined
2. 2007 Medium

   Identified CEP68 as a tyrosine-phosphorylation target downstream of EGFR, linking it to growth-factor signaling.

   Evidence cICAT LC-MS/MS phosphoproteomics with IP/immunoblot validation under EGFR inhibitor (gefitinib) treatment in cancer cells

   PMID:17570516

   Open questions at the time

   • Functional consequence of EGFR-driven tyrosine phosphorylation on CEP68 not determined
   • Phosphosite(s) and responsible kinase relationship to centrosome function unestablished
3. 2014 High

   Defined the mitotic destruction pathway that dismantles the linker, showing how phosphorylation-triggered proteolysis licenses centrosome separation.

   Evidence Interactome MS, reciprocal Co-IP, in vitro ubiquitylation, Ser332 phospho-site mutagenesis, and siRNA with centrosome phenotype

   PMID:25503564

   Open questions at the time

   • Did not address how PLK1 access to CEP68 is temporally controlled
   • Relationship between Cep215 release and PCM expansion mechanistically incomplete
4. 2014 High

   Identified centlein as the molecular bridge connecting CEP68 to C-Nap1, explaining how CEP68 is recruited to the proximal centriole.

   Evidence Yeast two-hybrid, Co-IP, siRNA knockdown with splitting phenotype, and in vitro Nek2A kinase assay

   PMID:24554434

   Open questions at the time

   • Functional consequence of Nek2A phosphorylation of CEP68/centlein not resolved
   • Spatial arrangement of the centlein bridge within the fibre not defined
5. 2015 Medium

   Mapped the CEP68 regions controlling interphase centriolar localization versus mitotic dissociation and implicated Nek2 phosphorylation in its mitotic degradation.

   Evidence Truncation/deletion localization constructs, in vivo phosphorylation assay, and Co-IP with βTrCP

   PMID:25704143

   Open questions at the time

   • Precise localization determinants within the C-terminus not defined at residue level
   • Interplay of Nek2 and PLK1 phosphorylation in degradation not reconciled
6. 2017 High

   Revealed an interphase stabilization mechanism in which rootletin protects CEP68 from VHL-mediated degradation, coupling linker integrity to CEP68 abundance.

   Evidence In vitro ubiquitylation, Co-IP, double siRNA epistasis, and stable CEP68 mutant rescue of splitting

   PMID:28089774

   Open questions at the time

   • How rootletin physically occludes VHL from CEP68 not structurally defined
   • Whether this pathway operates outside rootletin-deficient conditions unclear
7. 2017 Medium

   Identified MCM7 as an enhancer of CEP68–VHL engagement, providing a counterweight to rootletin-based protection.

   Evidence In vitro pull-down, in vivo Co-IP, overexpression/knockdown with splitting readout, and ubiquitination assay

   PMID:28578000

   Open questions at the time

   • Physiological trigger for MCM7-driven CEP68 degradation not established
   • Single-lab finding without reciprocal in vivo validation across systems

• How EGFR-driven tyrosine phosphorylation of CEP68 intersects with its centrosome-linker and degradation functions remains unresolved.
• No functional readout connecting EGFR signaling to centrosome cohesion via CEP68
• Tyrosine phosphosite identity and downstream effect unknown