Cdk1 orders mitotic events through coordination of a chromosome-associated phosphatase switch.

Junbin Qian,Monique Beullens,Bart Lesage,Mathieu Bollen,Sofie De Munter,Jin Huang

doi:10.1038/ncomms10215

Abstract

RepoMan is a scaffold for signalling by mitotic phosphatases at the chromosomes. During (pro)metaphase, RepoMan-associated protein phosphatases PP1 and PP2A-B56 regulate the chromosome targeting of Aurora-B kinase and RepoMan, respectively. Here we show that this task division is critically dependent on the phosphorylation of RepoMan by protein kinase Cyclin-dependent kinase 1 (Cdk1), which reduces the binding of PP1 but facilitates the recruitment of PP2A-B56. The inactivation of Cdk1 in early anaphase reverses this phosphatase switch, resulting in the accumulation of PP1-RepoMan to a level that is sufficient to catalyse its own chromosome targeting in a PP2A-independent and irreversible manner. Bulk-targeted PP1-RepoMan also inactivates Aurora B and initiates nuclear-envelope reassembly through dephosphorylation-mediated recruitment of Importin β. Bypassing the Cdk1 regulation of PP1-RepoMan causes the premature dephosphorylation of its mitotic-exit substrates in prometaphase. Hence, the regulation of RepoMan-associated phosphatases by Cdk1 is essential for the timely dephosphorylation of their mitotic substrates.

Highlights

RepoMan is a scaffold for signalling by mitotic phosphatases at the chromosomes
The chromosome targeting of RepoMan duringmetaphase is highly dynamic, because RepoMan-associated PP2A-B56 counteracts Aurora B by dephosphorylating RepoMan at S893
Since S893 phosphorylation or the S893D mutation preclude the binding of RepoMan to histones[13], these findings suggested that Cdk[1] inhibition caused the chromosome targeting of RepoMan through a reduced activity of Aurora B and/or the activation of a counteracting phosphatase

Summary

Introduction

During (pro)metaphase, RepoMan-associated protein phosphatases PP1 and PP2A-B56 regulate the chromosome targeting of Aurora-B kinase and RepoMan, respectively. The interplay between Haspin, Aurora B and RepoMan-associated phosphatases couples reciprocal positive and double-negative feedback loops to establish a robust and dynamic mechanism for the centromeric targeting of the CPC in (pro)metaphase (Supplementary Fig. 1)[6]. Cdk[1] promotes the centromeric targeting of the CPC at different levels (Supplementary Fig. 1) It phosphorylates and activates Haspin[3,4], and enhances CPC binding to centromeric Shugoshin through phosphorylation of the CPC subunit Borealin[2]. The inactivation of Cdk[1] at the beginning of anaphase induces a phosphatase switch on RepoMan that culminates in the bulk recruitment of PP1-RepoMan to chromosomes and the timely dephosphorylation of key regulators of the mitotic exit

Methods

Results

Conclusion