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

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.

Figure 1. Scheme of MCAK regulation by mitotic kinases and phosphatases

Current data suggest that MCAK undergoes complex spatiotemporal regulation by mitotic kinases Aurora A/B, Plk1 and Cdk1/cyclin B1. In early mitosis, S196 phosphorylation of MCAK by Aurora A reduces its activity and facilitates the transition from asters to bipolar spindles, whilst MCAK localization at spindle poles is regulated through another Aurora A phosphorylation site S719 and positively enhances bipolar spindle formation. Cdk1 phosphorylates T537 in the core domain of MCAK, attenuates its activity, and drives MCAK from spindle poles to other locations and promotes proper spindle formation. Thus, the localization and activity of MCAK at centrosomes and spindle poles appear to be mainly controlled by coordinated regulation of Aurora A and Cdk1. In prometaphase, the localization of MCAK to the chromosome arms is controlled by Aurora B, possibly supported by Plk1. In metaphase, the localization and activity of MCAK at the centromeres and kinetochores are finely regulated via phosphorylation by Aurora B. By contrast, Plk1 promotes the activity of MCAK at kinetochores. Co-ordinated regulation of MCAK by Aurora B and Plk1 might fine-tune its activity for correction of mal-attachments. Finally, in anaphase, the activity of MCAK is further coordinated and controlled by Aurora B and Plk1, possibly balanced by phosphatases.

Figure 2. Summary of MCAK's involvements in oncogenesis

In gastric, colorectal and breast cancer, MCAK is overexpressed, which could be contributed by defects in promoter control, mRNA stability and protein turnover, possibly associated with deregulated kinases/phosphatases in cancer cells. The highly expressed MCAK could result in abnormal spindle formation, erroneous attachment and failure in chromosome segregation, leading to chromosomal instability and promoting cancer progression. Enhanced MCAK is linked to invasiveness/metastasis of cancer patients, which could be caused by remodeling MT cytoskeleton and altering cell shape and migration. Elevated MCAK could reorganize MT morphology/dynamics and contribute to resistance of the MT binding agents. In addition, MCAK could be considered as a potential target for molecular intervention: either as a novel antigen, provoking immunoreaction of cancer patients, or as a MT regulator/modulator, in combination with other chemotherapeutic drugs.