A PP1/PP2A phosphatase relay controls mitotic progression

The widespread reorganisation 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 eukaryotes(1-6). We now describe a mitotic phosphatase relay in which PP1 reactivation is required for the reactivation of both PP2A-B55 and PP2A-B56 to coordinate mitotic progression and exit in fission yeast. The staged recruitment of PP1 to the regulatory subunits of PP2A-B55 and PP2A-B56 holoenzymes sequentially activates each phosphatase. The pathway is blocked in early mitosis because Cdk1-Cyclin B inhibits PP1 activity but declining Cyclin B levels later in mitosis permit PP1 to auto-reactivate(1,7-10). PP1 first reactivates PP2A-B55; this enables PP2A-B55, in turn, to promote the reactivation of PP2A-B56 by dephosphorylating a PP1 docking site in PP2A-B56, thereby promoting the recruitment of PP1. PP1 recruitment to human, mitotic, PP2A holoenzymes and the sequences of these conserved PP1 docking motifs(11,12) suggest that PP1 regulates PP2A-B55 and PP2A-B56 activities in a variety of signalling contexts throughout eukaryotes.