Mitotic regulation of the mitotic centromere-associated kinesin

Abstract

Deregulated mitotic centromere-associated kinesin (MCAK) is associated with cancer invasiveness, metastasis and poor prognosis of patients. It is thus important to delineate the regulatory mechanisms responsible for regulating MCAK's turnover. MCAK depolymerizes microtubules, controls microtubule dynamics and has been tightly linked to the correction of fail-attachments between kinetochores and microtubules in mitosis. Its activity and localization are regulated via phosphorylation by important mitotic kinases. The exact picture of MCAK regulation by these kinases during mitosis remains elusive and needs to be clarified. We show here that S621 in the C-terminal domain is the major site for phosphorylation of MCAK by Polo-like kinase 1 (Plk1). Phosphorylation at this location does not directly affect its microtubule depolymerization activity but rather likely promotes recognition of MCAK by the Cdc20 subunit of APC/C leading to its proteasome dependent degradation at the transition from metaphase to anaphase. However, loss of Plk1 phosphorylation on S621 indirectly enhances its depolymerization activity in vivo by preventing MCAK's targeting for degradation, resulting in an accumulation of MCAK protein. By contrast, phosphomimetic MCAK S621D is constitutively targeted for degradation leading to reduced levels of protein and a consequent increase in amount of polymerized tubulin and decreased inter-centromere distance in cells expressing this form of MCAK. Finally, interfering with this phosphorylation results in defects in spindle formation as well as in chromosome alignment, likely due to the lack of regulation of MCAK protein levels during mitosis.