Kinase and Phosphatase Cross-Talk at the Kinetochore

Abstract

Multiple kinases and phosphatases act on the kinetochore to control chromosome segregation: Aurora B, Mps1, Bub1, Plk1, Cdk1, PP1, and PP2A-B56, have all been shown to regulate both kinetochore-microtubule attachments and the spindle assembly checkpoint. Given that so many kinases and phosphatases converge onto two key mitotic processes, it is perhaps not surprising to learn that they are, quite literally, entangled in cross-talk. Inhibition of any one of these enzymes produces secondary effects on all the others, which results in a complicated picture that is very difficult to interpret. This review aims to clarify this picture by first collating the direct effects of each enzyme into one overarching schematic of regulation at the Knl1/Mis12/Ndc80 (KMN) network (a major signaling hub at the outer kinetochore). This schematic will then be used to discuss the implications of the cross-talk that connects these enzymes; both in terms of why it may be needed to produce the right type of kinetochore signals and why it nevertheless complicates our interpretations about which enzymes control what processes. Finally, some general experimental approaches will be discussed that could help to characterize kinetochore signaling by dissociating the direct from indirect effect of kinase or phosphatase inhibition in vivo. Together, this review should provide a framework to help understand how a network of kinases and phosphatases cooperate to regulate two key mitotic processes.

Keywords: Cdk1; PP1; PP2A; kinase; kinetochore; mitosis; phosphatase; spindle assembly checkpoint.

Figure 1

A schematic to depict kinase and phosphatase regulation at the KMN network. The model displays regulatory components that are known to localize to the KMN network and regulate either kinetochore-microtubule (KT-MT) attachments or the SAC. The regulatory inputs are indicated by numbered arrows that are explained fully at the appropriate place in the text.

Figure 2

A schematic to depict how Cdk1 regulates the KMN network to control mitotic exit. (A) Colored phosphate symbols indicate either positive (green) or negative (red) regulation from Cdk1. (B) An arrow-style schematic to depict how Cdk1 promotes (green arrows) and inhibits (red arrows) mitotic exit.

Figure 3

Models focussed on each enzyme at the KMN network (A–I) to depict the different types of direct and indirect regulation.

Figure 4

Generic approaches that can be used to dissociate the direct and indirect effects of kinase (A) or phosphatase (B) inhibition in vivo.