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Vol. 14, Issue 7, 2876-2889, July 2003
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Department of Biochemistry, University of Leicester, Leicester LE1 7RH, United Kingdom
Submitted February 25, 2003;
Revised March 21, 2003;
Accepted March 24, 2003
Monitoring Editor: Trisha Davis
Nek2A is a cell cycle-regulated kinase of the never in mitosis A (NIMA) family that is highly enriched at the centrosome. One model for Nek2A function proposes that it regulates cohesion between the mother and daughter centriole through phosphorylation of C-Nap1, a large coiled-coil protein that localizes to centriolar ends. Phosphorylation of C-Nap1 at the G2/M transition may trigger its displacement from centrioles, promoting their separation and subsequent bipolar spindle formation. To test this model, we generated tetracycline-inducible cell lines overexpressing wild-type and kinase-dead versions of Nek2A. Live cell imaging revealed that active Nek2A stimulates the sustained splitting of interphase centrioles indicative of loss of cohesion. However, this splitting is accompanied by only a partial reduction in centriolar C-Nap1. Strikingly, induction of kinase-dead Nek2A led to formation of monopolar spindles with unseparated spindle poles that lack C-Nap1. Furthermore, kinase-dead Nek2A interfered with chromosome segregation and cytokinesis and led to an overall change in the DNA content of the cell population. These results provide the first direct evidence in human cells that Nek2A function is required for the correct execution of mitosis, most likely through promotion of centrosome disjunction. However, they suggest that loss of centriole cohesion and C-Nap1 displacement may be distinct mitotic events.
Abbreviations used: Nek2, NIMA-related kinase 2; NIMA, never in mitosis A; C-Nap1, centrosomal Nek2-associated protein 1; PP1, protein phosphatase 1; PCM, pericentriolar material.
* Corresponding author. E-mail address: amf5{at}le.ac.uk.
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