MST1 Limits the Kinase Activity of Aurora B to Promote Stable Kinetochore-Microtubule Attachment

Abstract

The establishment and maintenance of proper attachment of kinetochores to microtubules are required to prevent chromosome missegregation and consequent chromosomal instability and tumorigenesis. Although MST1 (mammalian sterile 20-like kinase 1) has been implicated in many aspects of cell cycle regulation and tumor suppression [1], its precise mechanism of action has remained largely unknown. We now show that MST1 promotes accurate kinetochore-microtubule attachment by modulating the kinase activity of Aurora B. HeLa cells depleted of MST1 failed to develop stable end-on kinetochore-microtubule attachment, giving rise to unaligned mitotic chromosomes. The misaligned chromosomes activated the Mad2- and BubR1-dependent spindle checkpoint response, resulting in a delay in anaphase onset. The kinase activity of Aurora B, which promotes destabilization of kinetochore-microtubule attachment [2-4], was increased in cells depleted of MST1 or NDR1, a downstream kinase of MST1. MST1 and NDR1 associated with Aurora B. Moreover, MST1 directly phosphorylated Aurora B and inhibited its kinase activity in vitro. Depletion of Aurora B restored the stability of kinetochore-microtubule attachment in cells depleted of MST1 or NDR1. MST1 is thus a key regulator of Aurora B activity that ensures mitotic chromosome congression and accurate chromosome segregation.