Control of mitotic exit by PP2A regulation of Cdc25C and Cdk1

Abstract

Inactivation of maturation-promoting factor [(MPF) Cdk1/Cyclin B]is a key event in the exit from mitosis. Although degradation of Cyclin B is important for MPF inactivation, recent studies indicate that Cdk1 phosphorylation and inactivation occur before Cyclin B degradation and, therefore, also may be important steps in the exit from mitosis. Cdk1 activity is controlled by the Cdc25C phosphatase, which is turned on at the G 2/M transition to catalyze Cdk1 activation. PP2A:B56␦ is a negative regulator of Cdc25C during interphase. We show here that PP2A:B56␦ also regulates Cdc25C at mitosis. Failure of PP2A:B56␦ to dephosphorylate Cdc25C at mitosis results in prolonged hyperphosphorylation and activation of Cdc25C, causing persistent dephosphorylation and, hence, activation of Cdk1. This constitutive activation of Cdc25C and Cdk1 leads to a delayed exit from mitosis. Consistent with Cdk1 as a major biological target of B56␦, stable knockdown and germ-line mouse KO of B56␦ leads to compensatory transcriptional up-regulation of Wee1 kinase to oppose the Cdc25C activity and permit cell survival. These observations place PP2A:B56␦ as a key upstream regulator of Cdk1 activity upon exit from mitosis.cell cycle ͉ cyclins ͉ protein phosphatase ͉ knockout ͉ Wee1

Antagonistic Roles of PP2A-Pab1 and Etd1 in the Control of Cytokinesis in Fission Yeast

“…Communication between the universal cell cycle regulator Cdc2 and cell morphology factors is essential to coordinate the cell cycle and cell morphology in eukaryotic cells (Moseley and Nurse 2009). This result suggests that PP2A-Pab1 phosphatase is involved in morphogenesis by inactivating Cdc2 (Kinoshita et al 1996;Janssens and Goris 2001;Forester et al 2007) and/or by counteracting its activity through dephosphorylation of Cdc2-phosphorylated substrates (Sopko et al 2007;Zheng et al 2007;Burgess et al 2010;Lorca et al 2010).…”

Mice lacking phosphatase PP2A subunit PR61/B’δ ( Ppp2r5d ) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3β

“…Specifically PR61/B'δ also dephosphorylates the Cdc25 Thr138 site to control mitosis (32), but how this might occur in the KO remains unclear given no overt growth abnormalities were observed. Notably, a functional compensation exists for this dephosphorylation as overexpression of Wee-1 (the Cdc25 opposing kinase) was observed in PR61δ KO MEFs (33). Recently, a role was identified specifically for PR61/B'δ in mast cell degranulation (34), but if and how this is affected in the KO remains to be defined.…”

Protein Phosphatases Drive Mitotic Exit

“…Consistent with this idea, in the early stages of mitotic exit, Cdk1 is transiently inhibited by phosphorylation prior to the degradation of cyclin B1 (D'Angiolella et al, 2007). It is possible that the transient phosphorylation of Cdk1 is also due to inhibition of the Cdc25C phosphatase by the PP2A phosphatase, which is the same 216 phosphatase that keeps Cdc25C inactive during interphase (Forester et al, 2007). However, recent evidence indicates that the Cdc14B phosphatase dephosphorylates Cdc25C resulting in its inhibition and consequent phosphorylation of Cdk1 (Tumurbaatar et al, 2011).…”