Which kinase phosphorylates the linker proteins between centrioles to allow centrosome separation?
Centriole pair remains linked throughout interphase by fibrous proteinaceous linker extending between proximal ends. Core constituents include large coiled-coil protein C-Nap1 anchored to centriole, rootletin forming 60 nm striated fibers, Cep68 and LRRC45 bridging. Dissolution in late G2 permits centrosome movement mediated by Eg5. Nek2A kinase, NIMA-related serine-threonine kinase, executes linker disassembly. Expression rises in S/G2, activity restrained in G1 by PP1 phosphatase binding and association with HEF1, MST2 and Hippo pathway components. Upon activation, Nek2 phosphorylates C-Nap1 at multiple sites reducing centriole anchoring, rootletin Ser or Thr clusters breaking polymerization, and Cep68 inducing recognition by SCF-betaTrCP E3 ligase for degradation. Phosphorylation also creates electrostatic repulsion destabilizing oligomers. Polo-like kinase 1 further cooperates by phosphorylating C-Nap1. Premature Nek2 activation causes premature splitting leading to chromosome missegregation, while depletion yields monopolar spindles. Nek2 overexpression observed in many cancers correlating with aneuploidy, emphasizing precisely timed linker phosphorylation as prerequisite for bipolar spindle formation during prophase. Additional feedback loops involving polo-like kinases, phosphatases and SCF-mediated degradation reinforce irreversibility and protect against premature progression that would compromise genome integrity and viability.
Ref: Fry et al., Nek2 Kinase and Centrosome Linker Disassembly, Biochem J 2012; NCBI, Centrosome Separation Controls.