Fcp1 phosphatase controls Greatwall kinase to promote PP2A-B55 activation and mitotic progression

Abstract

During cell division, progression through mitosis is driven by a protein phosphorylation wave. This wave namely depends on an activation-inactivation cycle of cyclin B-dependent kinase (Cdk) 1 while activities of major protein phosphatases, like PP1 and PP2A, appear directly or indirectly repressed by Cdk1. However, how Cdk1 inactivation is coordinated with reactivation of major phosphatases at mitosis exit still lacks substantial knowledge. We show here that activation of PP2A-B55, a major mitosis exit phosphatase, required the phosphatase Fcp1 downstream Cdk1 inactivation in human cells. During mitosis exit, Fcp1 bound Greatwall (Gwl), a Cdk1-stimulated kinase that phosphorylates Ensa/ARPP19 and converts these proteins into potent PP2A-B55 inhibitors during mitosis onset, and dephosphorylated it at Cdk1 phosphorylation sites. Fcp1-catalyzed dephosphorylation drastically reduced Gwl kinase activity towards Ensa/ARPP19 promoting PP2A-B55 activation. Thus, Fcp1 coordinates Cdk1 and Gwl inactivation to derepress PP2A-B55, generating a dephosphorylation switch that drives mitosis progression.DOI: http://dx.doi.org/10.7554/eLife.10399.001

Greatwall kinase at a glance

“…Besides these major phosphorylations, two additional phosphorylated residues of Gwl on Xenopus S89 or S90 (human S465 or S453) appear to participate in Gwl activation. However, the identity of the kinase(s) responsible for of these additional phosphorylations and their exact effect on Gwl activity remain elusive (Della Monica et al, 2015). At the metaphase-anaphase transition, concomitantly with cyclin B degradation, Gwl activity is downregulated by dephosphorylation.…”

“…At the metaphase-anaphase transition, concomitantly with cyclin B degradation, Gwl activity is downregulated by dephosphorylation. The activation of three phosphatasesprotein phosphatase 1 (PP1), PP2A-B55 and RNA polymerase II C-terminal domain phosphatase (Fcp1, also known as CTDP1)is essential for Gwl inactivation (Della Monica et al, 2015;Heim et al, 2015;Ma et al, 2016). PP2A-B55 and PP1 are inactivated during mitosis; the former by Arpp19 and/or ENSA, and the latter through its direct phosphorylation by cyclin-B-Cdk1 (Wu et al, 2009).…”

Silencing Arabidopsis CARBOXYL‐TERMINAL DOMAIN PHOSPHATASE‐LIKE 4 induces cytokinin‐oversensitive de novo shoot organogenesis

“…Instead, CPL4 RNAi might promote the overall cell cycle progression, resulting in the clearance of H3K27me3 at the promoter of WUS and perhaps other DNSO regulators. The progression of the cell cycle is regulated by a cascade of phosphorylation/dephosphorylation reactions, in which multiple targets for FCP1 have been identified in humans (Visconti et al ., , ; Hegarat et al ., ; Della Monica et al ., ). This result implies that CPL4 and potentially other CPLs (Koiwa et al ., , ; Koiwa, ; Ueda et al ., ; Feng et al ., ; Jin et al ., ) have more targets than just pol II CTD and could be directly involved in phosphoregulation of the cell cycle progression in plants.…”

Greatwall-Endosulfine: A Molecular Switch that Regulates PP2A/B55 Protein Phosphatase Activity in Dividing and Quiescent Cells

“…This is sufficient to promote Greatwall dephosphorylation on T194 and S875 residues by PP2A/B55 phosphatase activity [60][61][62], resulting in full inhibition of Greatwall kinase activity and in its translocation to the nucleus [55]. Recent studies have also described an additional layer of phosphatase regulation of Greatwall-Endosulfine because the RNA polymerase II C-terminal domain phosphatase (Fcp1) dephosphorylates Greatwall, ENSA, and ARPP-19 [63,64]. However, further work will be needed to better comprehend the effects of Fcp1 on the activity of the Greatwall-Endosulfine module.…”