A PP1-PP2A phosphatase relay controls mitotic progression

Abstract

The widespread reorganization of cellular architecture in mitosis is achieved through extensive protein phosphorylation, driven by the coordinated activation of a mitotic kinase network and repression of counteracting phosphatases. Phosphatase activity must subsequently be restored to promote mitotic exit. Although Cdc14 phosphatase drives this reversal in budding yeast, protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) activities have each been independently linked to mitotic exit control in other eukaryotes1-6. Here we describe a mitotic phosphatase relay inwhichPP1 reactivation is required for the reactivation of both PP2A-B55 and PP2AB56 to coordinate mitotic progression and exit in fission yeast. The staged recruitment of PP1 (the Dis2 isoform) to the regulatory subunits of thePP2A-B55 andPP2A-B56 (B55 also knownas Pab1; B56 also known as Par1) holoenzymes sequentially activates each phosphatase. The pathway is blocked in early mitosis because the Cdk1- cyclin B kinase (Cdk1 also known as Cdc2) inhibits PP1 activity, but declining cyclinBlevels later inmitosis permitPP1to auto-reactivate1,7-10. PP1 first reactivates PP2A-B55; this enables PP2A-B55 in turn to promote the reactivation ofPP2A-B56 by dephosphorylating a PP1- docking site inPP2A-B56, thereby promoting the recruitment of PP1. PP1 recruitment to human, mitotic PP2A-B56 holoenzymes and the sequences of these conserved PP1-docking motifs11,12 suggest that PP1 regulates PP2A-B55 and PP2A-B56 activities in a variety of signalling contexts throughout eukaryotes.