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

Abstract

During the cell cycle, hundreds of proteins become phosphorylated and dephosphorylated, indicating that protein kinases and protein phosphatases play a central role in its regulation. It has been widely recognized that oscillation in cyclin-dependent kinase (CDK) activity promotes DNA replication, during S-phase, and chromosome segregation, during mitosis. Each CDK substrate phosphorylation status is defined by the balance between CDKs and CDK-counteracting phosphatases. In fission yeast and animal cells, PP2A/B55 is the main protein phosphatase that counteracts CDK activity. PP2A/B55 plays a key role in mitotic entry and mitotic exit, and it is regulated by the Greatwall-Endosulfine (ENSA) molecular switch that inactivates PP2A/B55 at the onset of mitosis, allowing maximal CDK activity at metaphase. The Greatwall-ENSA-PP2A/B55 pathway is highly conserved from yeast to animal cells. In yeasts, Greatwall is negatively regulated by nutrients through TORC1 and S6 kinase, and couples cell growth, regulated by TORC1, to cell cycle progression, driven by CDK activity. In animal cells, Greatwall is phosphorylated and activated by Cdk1 at G2/M, generating a bistable molecular switch that results in full activation of Cdk1/CyclinB. Here we review the current knowledge of the Greatwall-ENSA-PP2A/B55 pathway and discuss its role in cell cycle progression and as an integrator of nutritional cues.

The Cell Cycle Checkpoint System MAST(L)-ENSA/ARPP19-PP2A is Targeted by cAMP/PKA and cGMP/PKG in Anucleate Human Platelets

“…We suggest that PP2A checkpoint systems not only control the cell cycle, but also other essential cell functions, especially in platelets. Research efforts with yeast presenting a well-established Greatwall-ENSA-PP2A pathway, very recently emphasized the need to search for novel PP2A substrates and their functions [87,88]. The various PP2A holoenzymes present in human platelets could have overlapping, distinct and also opposing effects on important disease-relevant platelet responses, such as integrin activation, secretion and thrombin generation.…”

Spatiotemporal coordination of Greatwall-Endos-PP2A promotes mitotic progression

“…The Gwl-Endos-PP2A module is strongly conserved, regulating mitosis in fungi, insects, and vertebrates ( García-Blanco et al, 2019 ). In frog and starfish oocytes, Gwl is required for M-phase entry and maintenance ( Hara et al, 2012 ; Lorca et al, 2010 ; Yu et al, 2006 ).…”

A phosphatase‐centric mechanism drives stress signaling response

“…Considering that in our study as much as 30% of stress‐induced phosphorylation is regulated by PP2A Cdc55 , the impact of such phosphatase signaling could be quite significant. The extent to which phosphorylation can be fine‐tuned would also be severely increased due to potential synergistic interaction between phosphatase and kinase pathways on shared substrates (García‐Blanco et al , 2019). We therefore argue that our unexpected findings of phosphatase inhibition as a mechanism to induce a positive phosphorylation response could be pivotal for a holistic understanding of cellular signaling.…”