PP 1 inactivates Greatwall to release PP 2A‐B55 from mitotic confinement

Abstract

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.

Unfair competition governs the interaction of pCPI-17 with myosin phosphatase (PP1-MYPT1)

“…Positive feedback also probably occurs at the end of M phase, when Gwl becomes dephosphorylated and turned ‘off’. Although PP1 ( Heim et al, 2015 ; Ma et al, 2016 ; Mochida, 2015 ; Rogers et al, 2016 ) and perhaps other enzymes ( Della Monica et al, 2015 ) initiate Gwl inactivation, PP2A-B55 also likely plays a role in completing and then maintaining Gwl dephosphorylation ( Mochida et al, 2016 ; Yamamoto et al, 2011 ).…”

MPF, starfish oocyte and cell-free extract in the background - an interview with Takeo Kishimoto

“…When the cell physiologically performs the G2/Mphase transition, the intracellular state is first inclined to cause the initial activation of cyclin B-Cdk1 (for example, the balance between Cdc25 and Myt1 is tipped by Akt/PKB in starfish oocytes). And small amount of the initially activated cyclin B-Cdk1 may start to phosphorylate Gwl and also PP1; the Gwl phosphorylation initiates its autophosphorylation, and the PP1 phosphorylation suppresses its counteraction against the Gwl autophosphorylation (Heim et al, 2015;Mochida 2015), leading to initiation of Gwl activation. Thus, prior to the start of the autoactivation loop, its upstream events have already accomplished and hence, the intracellular condition is "primed" for the autoregulatory activation of cyclin B-Cdk1.…”

Mitotic exit: Determining the PP2A dephosphorylation program

“…By deciphering the B55 and B56 binding codes, Cundell et al (2016) and Hertz et al (2016) moved the study of protein dephosphorylation during mitotic exit from one of passive observation to a realm in which direct modulation and engineering of PP2A programs becomes an option. See text for details (Gharbi-Ayachi et al, 2010;Cundell et al, 2013;Heim et al, 2015;Mochida, 2015;Ma et al, 2016). (B) Model for the PP2A-B55 timer of substrate recognition according to Cundell et al (2016).…”

“…Regulation of mitotic exit by a timely dephosphorylation cascade. (A) Regulation of PP2A-B55 in metaphase and during mitotic exit.See text for details(Gharbi-Ayachi et al, 2010;Cundell et al, 2013;Heim et al, 2015;Mochida, 2015;Ma et al, 2016). (B) Model for the PP2A-B55 timer of substrate recognition according toCundell et al (2016).…”