Nur1 dephosphorylation confers positive feedback to mitotic exit phosphatase activation in budding yeast.

Molly Godfrey,Thomas Kuilman,Frank Uhlmann,David P Toczyski

doi:10.1371/journal.pgen.1004907

Abstract

Substrate dephosphorylation by the cyclin-dependent kinase (Cdk)-opposing phosphatase, Cdc14, is vital for many events during budding yeast mitotic exit. Cdc14 is sequestered in the nucleolus through inhibitory binding to Net1, from which it is released in anaphase following Net1 phosphorylation. Initial Net1 phosphorylation depends on Cdk itself, in conjunction with proteins of the Cdc14 Early Anaphase Release (FEAR) network. Later on, the Mitotic Exit Network (MEN) signaling cascade maintains Cdc14 release. An important unresolved question is how Cdc14 activity can increase in early anaphase, while Cdk activity, that is required for Net1 phosphorylation, decreases and the MEN is not yet active. Here we show that the nuclear rim protein Nur1 interacts with Net1 and, in its Cdk phosphorylated form, inhibits Cdc14 release. Nur1 is dephosphorylated by Cdc14 in early anaphase, relieving the inhibition and promoting further Cdc14 release. Nur1 dephosphorylation thus describes a positive feedback loop in Cdc14 phosphatase activation during mitotic exit, required for faithful chromosome segregation and completion of the cell division cycle.

Highlights

Cellular reproduction is a highly regulated process that is controlled on a multiplicity of levels, ensuring orderly progression through the different phases of the cell cycle and accurate partitioning of the genome
The events occurring during the final cell cycle phase – ‘‘mitotic exit’’ – are controlled by the phosphatase Cdc14
We have identified a new regulator of Cdc14 activity, the protein Nur1

Summary

Introduction

Cellular reproduction is a highly regulated process that is controlled on a multiplicity of levels, ensuring orderly progression through the different phases of the cell cycle and accurate partitioning of the genome. At the heart of eukaryotic cell cycle control lie cyclin-dependent kinases (Cdks) and their opposing phosphatases [1,2]. In Saccharomyces cerevisiae, the Cdk subunit Cdc associates with a series of cell cycle stage-specific cyclins to bring about Cdk activity. It is opposed by the main Cdkcounteracting phosphatase Cdc, which reverses Cdk phosphorylation events during mitotic exit [3]. The changing balance between Cdk and Cdc phosphatase activities at this stage of the cell cycle serves to order mitotic exit events, such as spindle elongation and chromosome segregation followed by spindle disassembly and cytokinesis [2,4]. Cdc is essential for the downregulation of Cdk activity, on the one hand by promoting mitotic cyclin degradation, via dephosphorylation of the Anaphase Promoting Complex (APC) activator Cdh, and on the other by promoting accumulation of the Cdk inhibitor Sic1 [3,10,11]

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