PP1 inactivates Greatwall to release PP2A-B55 from mitotic confinement.

Entry into and exit from mitosis are brought about by the increase and decrease, respectively, in the activity of cyclin-dependent kinases (CDKs). Many examples are known of how the properties of particular proteins can be altered by phosphorylation, promoting processes like nuclear envelope breakdown or assembly of the mitotic spindle. The regulation of protein phosphatases is shedding new light on how this quantitative change of protein phosphorylation is achieved by a tight linkage between CDK activity and CDK-antagonizing phosphatases. On entering mitosis, increasing CDK activity ignites a repressive pathway that acts on PP2A-B55, one of the major phosphatases for CDK substrates in higher eukaryotes. This repression allows rapid and near complete substrate phosphorylation. But this raises a serious bootstrapping problem at mitotic exit. Because the phosphatase responsible for CDK substrates has been shut off, how can the repression pathway, which was activated by CDK, be reversed? In the current issue, Heim and colleagues propose an answer to this question [1]. Their data show that dephosphorylation of Greatwall kinase (Gwl) at its auto-phosphorylation site(s) is targeted by PP1, which leads to significant decrease in Gwl kinase activity. This early action by PP1 seems to be a prerequisite for PP2A-B55 to escape from repression and to return Gwl back to its inactive hypophosphorylated interphase state. This study provides an important piece of evidence for how the repression mechanism of PP2A-B55 is made reversible, and offers a solution to the bootstrap problem. See also: A Heim et al (November 2015)