Regulatory mechanisms that control mitotic kinesins

Abstract

During mitosis, the mitotic spindle is assembled to align chromosomes at the spindle equator in metaphase, and to separate the genetic material equally to daughter cells in anaphase. The spindle itself is a macromolecular machine composed of an array of dynamic microtubules and associated proteins that coordinate the diverse events of mitosis. Among the microtubule associated proteins are a plethora of molecular motor proteins that couple the energy of ATP hydrolysis to force production. These motors, including members of the kinesin superfamily, must function at the right time and in the right place to insure the fidelity of mitosis. Misregulation of mitotic motors in disease states, such as cancer, underlies their potential utility as targets for antitumor drug development and highlights the importance of understanding the molecular mechanisms for regulating their function. Here, we focus on recent progress about regulatory mechanisms that control the proper function of mitotic kinesins and highlight new findings that lay the path for future studies.

Figure 1

Mechanisms that Control Mitotic Kinesin Localization. (A) Mitotic kinesins are regulated during the cell cycle through synthesis and degradation. The numbered circles represent different kinesin families and are in general representative of vertebrate kinesins. (B) Distinct kinesin family members are localized to different regions of the spindle, which is often controlled by binding partners and by regulatory proteins. Note that the precise localization of individual motors may vary between systems, and this provides a general overview of motor localization as it relates to motor function. Cartoon representations are modeled after [37].

Figure 2

Regulation of Mitotic Motor Activity. (A) Eg5 diffuses on a single microtubule in an ATP-independent manner. When Eg5 binds to a second microtubule, its ATP hydrolysis activity is stimulated, and Eg5 switches from diffusive to directed movement toward the microtubule plus end. Eg5 can either crosslink and slide apart antiparallel microtubules or crosslink and generate force on parallel microtubules. (B) The motor activity of Cenp-E is autoinhibited by direct binding of the tail to the motor. This autoinhibition is reversed by phosphorylation of the tail by either MPS1 or Cdk1 kinase. Phosphorylation by Aurora A/Aurora B at T422 also contributes to regulation of Cenp-E during chromosome congression. After chromosome alignment, the activity of Cenp-E is fine-tuned by a balance between Aurora kinases and PP1γ phosphatase to maintain chromosome bi-orientation. Type 1 phosphatase (PP1γ) can bind to a docking motif adjacent to T422, blocking the binding of Aurora kinases and allowing Cenp-E to deliver PP1 to kinetochores, where it contributes to the stable bi-orientation of chromosomes.