The Greatwall kinase: a new pathway in the control of the cell cycle. Thierry Lorca, A. Castro To cite this version: Thierry Lorca, A. Castro. The Greatwall kinase: a new pathway in the control of the cell cycle.. Oncogene, Nature Publishing Group, 2012, epub ahead of print. 10.1038/onc.2012.79. hal-00715010 HAL Id: hal-00715010 https://hal.archives-ouvertes.fr/hal-00715010 Submitted on 23 Jun 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Oncogene (2013) 32, 537 --543 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc REVIEW The Greatwall kinase: a new pathway in the control of the cell cycle T Lorca and A Castro New data have recently established that protein phosphorylation during mitosis is the result of a controlled balance between kinase and phosphatase activities and that, as for mitotic kinases, phosphatases are also regulated during cell division. This regulation is at least in part induced by the activation of the Greatwall (Gwl) kinase at mitotic entry. Activated Gwl phosphorylates its substrates cAMP-regulated phospho protein 19 (Arpp19) and a-endosulfine (ENSA), promoting their binding to and the inhibition of PP2A. Interestingly, besides the role of the Gwl-Arpp19/ENSA in the control of mitotic division, new data in yeast support the involvement of this pathway in mRNA stabilization during G0 program initiation, although in this case the phosphatase PP2A appears not to be implicated. Finally, Gwl activity has been shown to be required for DNA checkpoint recovery. These new findings support the view that Gwl, Arpp19 and ENSA could function as the core of a new signalization pathway that, by targeting different final substrates, could participate in a variety of physiological functions. Oncogene (2013) 32, 537--543; doi:10.1038/onc.2012.79; published online 2 April 2012 Keywords: Greatwall; PP2A; cyclin B--Cdc2; mitosis; mRNA; checkpoint INTRODUCTION kinase, including a role in the DNA-damage checkpoint and in the Most of the sequential events of cell division depend on protein post-transcriptional mRNA protection during the initiation of the phosphorylation. These events are controlled by a network of yeast quiescence program. kinases and phosphatases that coordinate protein phosphoryla- tion and dephosphorylation. The regulation of protein kinases during cell cycle has been largely reported, whereas the control of phosphatases has lagged far behind that of the kinases. The ROLE OF THE Gwl KINASE IN THE REGULATION OF MITOTIC identification of the Greatwall (Gwl) kinase has importantly DIVISION contributed to the understanding of the mechanisms controlling A role of Gwl in the regulation of mitotic division was first phosphatase activity during cell cycle. suggested in Drosophila.1 Mutation of this protein in flys promoted The Drosophila gene coding for the Gwl kinase was first improper chromosome condensation and a delay in either G2 or identified in 2004 in Drosophila. In this model Gwl was first the metaphase of larval neuroblasts. Despite the presence of proposed to have a role in the control of mitotic progression,1 undercondensed chromosomes in mutant cells, they were positive a function that was confirmed in subsequent studies in the same for phosphohistone H3 and for the condensing component model.2 However, the most important advance in the character- Barren. Furthermore, 20% of cells never reached a stable ization of the signalization pathway of the Gwl kinase was metaphase and were arrested in prometaphase with an activated performed in Xenopus egg extracts. Biochemical studies performed spindle assembly checkpoint. It was then hypothesized that Gwl in this model allowed the identification of the targets of Gwl was directly involved either in the chromosome condensation or involved in the control of mitotic division,3--6 a mechanism that in the basic cell cycle machinery. Data from a subsequent study was subsequently shown to be conserved in mammalian cells.7--9 supported the second hypothesis. Depletion of Gwl from mitotic Finally, besides its function in the regulation of mitosis, two Xenopus egg extracts resulted in a rapid exit of mitosis. This exit additional roles of Gwl have recently been identified: one of them was concomitant with the inactivation of the Cdk1--cyclin B in the DNA-damage checkpoint recovery described in the Xenopus complex by the phosphorylation of the inhibitory residue Tyr 15 of egg extract model,10 and the other, characterized in yeast, in the Cdk1. Moreover, depletion of Gwl from cycling extracts prevented stabilization of specific mRNA transcripts required for the establish- Cdk1--cyclin B activation and mitotic entry, indicating that this 11 ment of the G0 program after nutrient deprivation. These diverse kinase could be required to trigger and to maintain Cdk1--cyclin B functions of Gwl suggest an involvement of this kinase in a activity probably by regulating the MPF amplification loop.3 conserved signalization pathway that would target different Accordingly, the addition of activated Gwl to cycling Xenopus egg downstream substrates to control a diversity of biological extracts promoted Cdc25 partial phosphorylation even in the processes. absence of Cdk1, Plx1 or MAPK activity, suggesting that Gwl would In this review, we discuss in detail the recent results derived be involved in the phosphorylation and activation of Cdc25. from genetic, biochemical and cellular approaches showing a role However, Gwl does not directly phosphorylate Cdc25, raising the of Gwl in the control of mitotic division. Moreover, we overview question of the identity of the kinase responsible for this recent evidences about new functions attributed to the Gwl phosphorylation.12 Centre de Recherche de Biochimie Macromole´culaire, CNRS UMR 5237, Universite´s Montpellier 2 et 1, Montpellier, France. Correspondence: Dr A Castro or Dr T Lorca, Centre de Recherche de Biochimie Macromole´culaire, CNRS UMR 5237, Universite´s Montpellier 2 et 1, IFR 122, 1919 Route de Mende, 34293 Montpellier cedex 5, France. E-mail: [email protected] or [email protected] Received 22 October 2011; revised 1 February 2012; accepted 1 February 2012; published online 2 April 2012 The Greatwall kinase T Lorca and A Castro 538 This interpretation was significantly changed by the results confirmed in an independent study in which immunodepletion of showing that when the inactivation of Cdk1--Cyclin B was PP2A--B55d subcomplex corrected the inability of Gwl-depleted prevented in mitotic egg extracts by the immunodepletion of Xenopus egg extracts to enter into mitosis. These data suggested a the inhibitory kinases Wee1 and Myt1, the subsequent immuno- model in which Gwl, by negatively regulating PP2A--B55d, confers depletion of Gwl from these extracts still promoted mitotic exit.4 the correct oscillatory activity of this phosphatase during mitotic Strikingly, this exit of mitosis was accompanied by a dephos- division in Xenopus egg extracts. PP2A--B55d activity must be low phorylation of most of the substrates of Cdk1--cyclin B despite the at mitotic entry to permit Cdk1--cyclin B substrate phosphoryla- high activity of this kinase. However, this massive dephosphorylation tion, and high at mitotic exit to promote substrate dephos- was not observed when the mitotic egg extracts were submitted phorylation. The activation of Gwl at the G2 --M transition ensures to a codepletion of Gwl and PP2A. These were the first data the inhibition of PP2A--B55d and thus the phosphorylation of suggesting a role of Gwl in the inhibition of PP2A, the phosphatase Cdk1--cyclin B substrates, whereas the inactivation of this kinase that would be responsible for Cdk1--cyclin B substrate dephos- at mitotic exit results in the reactivation of PP2A--B55d and in the phorylation.4,13 subsequent massive dephosphorylation of these substrates The fact that PP2A was involved in Cdk1--cyclin B substrate (Figure 1).16 dephosphorylation was also supported by an additional biochemi- This model has been validated in human cells. Data from cal study in which the activity of PP2A was measured and two different studies showed that in HeLa cells the complete compared in interphase and mitotic Xenopus egg extracts. In this knockdown of MASTL, the human orthologue of Gwl, arrested study, the activity of PP2A was first analysed and shown to be high these cells in G2. Partial knockdown of MASTL enabled mitotic in interphase egg extracts and low in mitotic extracts. PP2A entry, although Cdk1--cyclin B substrates were rapidly dephos- phosphatase is a complex of a catalytic C-subunit, a non-catalytic phorylated, leading to mitotic exit despite the complete absence scaffolding A subunit and a third variable B-subunit that acts as a of chromosome congression. Premature Cdk1--cyclin B substrate substrate specifier. These B subunits have been classified into four dephosphorylation resulted in severe cytokinesis defects, such types: B (B55), B0 (B56), B00 (PR72) and B000 (PR93), and some of as the formation of DNA bridges or of mutinucleate cells.7,9