Abstract
Proper bi-orientation of chromosomes is critical for the accurate segregation of chromosomes in mitosis. A key regulator of this process is MCAK, the mitotic centromere-associated kinesin. During mitosis the activity and localization of MCAK are regulated by mitotic key kinases including Plk1 and Aurora B. We show here that S621 in the MCAK's C-terminal domain is the major phosphorylation site for Plk1. This phosphorylation regulates MCAK's stability and facilitates its recognition by the ubiquitin/proteasome dependent APC/C(Cdc20) pathway leading to its D-box dependent degradation in mitosis. While phosphorylation of S621 does not directly affect its microtubule depolymerising activity, loss of Plk1 phosphorylation on S621 indirectly enhances its depolymerization activity in vivo by stabilizing MCAK, leading to an increased level of protein. Interfering with phosphorylation at S621 causes spindle formation defects and chromosome misalignments. Therefore, this study suggests a new mechanism by which Plk1 regulates MCAK: by regulating its degradation and hence controlling its turnover in mitosis.
Highlights
The mitotic spindle is the main cellular tool required for ensuring chromosome segregation and it consists of an array of highly dynamic microtubules (MTs) [1]
MCAK and Polo-like kinase 1 (Plk1) showed a similar expression pattern with a peak at 9-10 h post release from a thymidine block (Figure S1A, 1st and 2nd row). At these time points (9-10 h) MCAK is displayed as double band indicating the existence of a phosphorylated and a non-phosphorylated pool during mitosis. These results suggest a physical interaction of Plk1 and MCAK during mitosis, in accordance with previous reports [12,34]
It has been reported that phosphorylation at S628 and S629 in MCAK is linked to MCAK degradation [34]
Summary
The mitotic spindle is the main cellular tool required for ensuring chromosome segregation and it consists of an array of highly dynamic microtubules (MTs) [1]. The kinesin-13 family is critically involved in the process of spindle assembly Unlike other kinesin, this family makes use of the energy produced by ATP-hydrolysis to destabilize MTs from both ends, rather than to move along the MT-surface [3,4]. This family makes use of the energy produced by ATP-hydrolysis to destabilize MTs from both ends, rather than to move along the MT-surface [3,4] It encompasses three members, Kif2a [5], Kif2b [6] and MCAK/Kif2c [7] sharing a highly conserved motor domain at the middle of their protein sequence, which is essential for regulating MT dynamics during mitosis and interphase [7,8]. Deregulated MCAK has been closely linked to cancer invasiveness, metastasis and poor prognosis in these cancer types [19,20,21]
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