Mitotic centromere-associated kinesin (MCAK): a potential cancer drug target

Mourad Sanhaji,Juping Yuan,Claire T Friel,Linda Wordeman,Frank Louwen

doi:10.18632/oncotarget.416

Abstract

The inability to faithfully segregate chromosomes in mitosis results in chromosome instability, a hallmark of solid tumors. Disruption of microtubule dynamics contributes highly to mitotic chromosome instability. The kinesin-13 family is critical in the regulation of microtubule dynamics and the best characterized member of the family, the mitotic centromere-associated kinesin (MCAK), has recently been attracting enormous attention. MCAK regulates microtubule dynamics as a potent depolymerizer of microtubules by removing tubulin subunits from the polymer end. This depolymerizing activity plays pivotal roles in spindle formation, in correcting erroneous attachments of microtubule-kinetochore and in chromosome movement. Thus, the accurate regulation of MCAK is important for ensuring the faithful segregation of chromosomes in mitosis and for safeguarding chromosome stability. In this review we summarize recent data concerning the regulation of MCAK by mitotic kinases, Aurora A/B, Polo-like kinase 1 and cyclin-dependent kinase 1. We propose a molecular model of the regulation of MCAK by these mitotic kinases and relevant phosphatases throughout mitosis. An ever-increasing quantity of data indicates that MCAK is aberrantly regulated in cancer cells. This deregulation is linked to increased malignance, invasiveness, metastasis and drug resistance, most probably due to increased chromosomal instability and remodeling of the microtubule cytoskeleton in cancer cells. Most interestingly, recent observations suggest that MCAK could be a novel molecular target for cancer therapy, as a new cancer antigen or as a mitotic regulator. This collection of new data indicates that MCAK could be a new star in the cancer research sky due to its critical roles in the control of genome stability and the cytoskeleton. Further investigations are required to dissect the fine details of the regulation of MCAK throughout mitosis and its involvements in oncogenesis.

Highlights

MITOSIS AND CHROMOSOME INSTABILITYThe cell cycle is the series of events that take place in a cell resulting in its DNA replication and division
We have found that the phenotype of depleting cyclin B1, the regulatory subunit of Cdk1, is reminiscent of that of the inhibition of mitotic centromere-associated kinesin (MCAK)
The finely tuned regulation of MCAK by various mitotic kinases and phosphatases is essential for the faithful segregation of chromosomes in mitosis and for safeguarding genome stability

Summary

INTRODUCTION

The cell cycle is the series of events that take place in a cell resulting in its DNA replication and division. Overexpression of a Plk phosphomimetic MCAK mutant causes a dramatic increase in misaligned chromosomes and in multipolar spindles in mitotic cells, while overexpression of a non-phosphorylatable MCAK mutant results in defects in anaphase with sister chromatid bridges These data imply that the enhanced enzymatic activity of MCAK by Plk is required for correction of mal-attachment of MTs. On the other hand, a temporal dephosphorylation of MCAK is of importance for proper chromosome alignment and bipolar spindle formation. During the cell division cycle, mitotic entry, centrosome separation, spindle assembly, chromosome congression/segregation, and cytokinesis must all be tightly coordinated to ensure that the two daughter cells inherit the same genetic material Central to this coordination are several protein kinases including Cdk, Plk, Aurora A and Aurora B, which regulate the functions of many molecules in a precisely coordinated and finely tuned manner.

CONCLUSIONS AND OUTLOOK

Paweletz N

Wordeman L

Findings

77. Strebhardt K