Greatwall kinase at a glance

Castro, Anna; Lorca, Thierry

doi:10.1242/jcs.222364

Cited by 44 publications

(37 citation statements)

References 58 publications

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“…It is possible, for example, that both p31 and Cdc20 are dephosphorylated and are converted to their active forms by a phosphatase that is activated upon exit from mitotic checkpoint. Such a mechanism may resemble the regulation of the action of phosphatase PP2A-B55 in mitosis, under control of Greatwall/Mastl protein kinase (39,40).…”

Section: Discussionmentioning

confidence: 99%

Role of Polo-like kinase 1 in the regulation of the action of p31 ^comet in the disassembly of mitotic checkpoint complexes

Kaisari

Shomer

Ziv

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The Mad2-binding protein p31comet has important roles in the inactivation of the mitotic checkpoint system, which delays anaphase until chromosomes attach correctly to the mitotic spindle. The activation of the checkpoint promotes the assembly of a Mitotic Checkpoint Complex (MCC), which inhibits the action of the ubiquitin ligase APC/C (Anaphase-Promoting Complex/Cyclosome) to degrade inhibitors of anaphase initiation. The inactivation of the mitotic checkpoint requires the disassembly of MCC. p31comet promotes the disassembly of mitotic checkpoint complexes by liberating their Mad2 component in a joint action with the ATPase TRIP13. Here, we investigated the regulation of p31comet action. The release of Mad2 from checkpoint complexes in extracts from nocodazole-arrested HeLa cells was inhibited by Polo-like kinase 1 (Plk1), as suggested by the effects of selective inhibitors of Plk1. Purified Plk1 bound to p31comet and phosphorylated it, resulting in the suppression of its activity (with TRIP13) to disassemble checkpoint complexes. Plk1 phosphorylated p31comet on S102, as suggested by the prevention of the phosphorylation of this residue in checkpoint extracts by the selective Plk1 inhibitor BI-2536 and by the phosphorylation of S102 with purified Plk1. An S102A mutant of p31comet had a greatly decreased sensitivity to inhibition by Plk1 of its action to disassemble mitotic checkpoint complexes. We propose that the phosphorylation of p31comet by Plk1 prevents a futile cycle of MCC assembly and disassembly during the active mitotic checkpoint.

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Section: Discussionmentioning

confidence: 99%

Role of Polo-like kinase 1 in the regulation of the action of p31 ^comet in the disassembly of mitotic checkpoint complexes

Kaisari

Shomer

Ziv

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…33,35,36 MASTL is an important kinase for the progression of mitosis and maintenance of mitotic state by inhibiting PP2A-B55, a protein phosphatase that antagonizes the effects of cyclin B-Cdk1. [37][38][39] MASTL acts as a regulator of mitotic progression through the phosphorylation of α-endosulfine (ENSA) and/or cAMP-regulated phosphoprotein 19 (ARPP19), which subsequently inhibits the activity of protein phosphatase 2A complex (PP2A-B55). 21,[40][41][42] Thus, inhibition of PP2A-B55 is essential for the maintenance of cyclin B1-Cdk1 activity during normal mitosis.…”

Section: Mitosismentioning

confidence: 99%

MASTL: A novel therapeutic target for Cancer Malignancy

2020

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Targeting mitotic kinases is an emerging anticancer approach with promising preclinical outcomes. Microtubule‐associated serine/threonine kinase like (MASTL), also known as Greatwall (Gwl), is an important mitotic kinase that regulates mitotic progression of normal or transformed cells by blocking the activity of tumor suppressor protein phosphatase 2A (PP2A). MASTL upregulation has now been detected in multiple cancer types and associated with aggressive clinicopathological features. Apart, an aberrant MASTL activity has been implicated in oncogenic transformation through the development of chromosomal instability and alteration of key oncogenic signaling pathways. In this regard, recent publications have revealed potential role of MASTL in the regulation of AKT/mTOR and Wnt/β‐catenin signaling pathways, which may be independent of its regulation of PP2A‐B55 (PP2A holoenzyme containing a B55‐family regulatory subunit). Taken together, MASTL kinase has emerged as a novel target for cancer therapeutics, and hence development of small molecule inhibitors of MASTL may significantly improve the clinical outcomes of cancer patients. In this article, we review the role of MASTL in cancer progression and the current gaps in this knowledge. We also discuss potential efficacy of MASTL expression for cancer diagnosis and therapy.

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“…These oscillations are the result of the activation and inactivation of the master kinase Cyclin B/Cdk1 and of its counterbalancing phosphatase PP2A-B55 [1][2][3][4][5][6][7] . Although substrate phosphorylation is triggered at mitotic entry by the activation of Cyclin B/Cdk1, it is only fully achieved if PP2A-B55 activity is negatively regulated [8][9][10][11] . This regulation is in charge of Arpp19 and ENSA, two members of the endosulfine family can modulate PP2A-B55 inhibitory activity of the phospho-S67 form.…”

Section: Introductionmentioning

confidence: 99%

The study of the determinants controlling Arpp19 phosphatase-inhibitory activity reveals a new Arpp19/PP2A-B55 feedback loop

Labbé

Vigneron

Méchali

et al. 2020

Preprint

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Arpp19 is a potent inhibitor of PP2A-B55 that regulates this phosphatase to ensure the stable phosphorylation of mitotic/meiotic substrates. At G2-M, Arpp19 is phosphorylated by Greatwall on S67. This phosphorylated Arpp19 form displays a high affinity to PP2A-B55 and a slow dephosphorylation rate, acting as an "unfair" competitor of PP2A-B55 substrates. The molecular determinants conferring slow dephosphorylation kinetics to S67 are unknown. PKA also phosphorylates Arpp19. This phosphorylation performed on S109 is essential to maintain prophase I-arrest in Xenopus oocytes although the underlying signaling mechanism is elusive.Here, we characterized the molecular determinants conferring slow dephosphorylation to S67 and controlling PP2A-B55 inhibitory activity of Arpp19. Moreover, we showed that phospho-S109 restricts S67 phosphorylation by increasing its catalysis by PP2A-B55. Finally, we discovered a double feed-back loop between these two phospho-sites which is essential to coordinate the temporal pattern of Arpp19-dependent PP2A-B55 inhibition and Cyclin B/Cdk1 activation during cell division.of proteins recently identified as two potent inhibitors of PP2A-B55 3,4 . PP2A-B55 inhibition does not only control mitosis but also other phases of the cell cycle. In this line, ENSA has been involved in the negative regulation of this phosphatase during DNA replication by controlling the dephosphorylation and degradation of the replication factor Treslin 12 . Conversely, Arpp19 has been shown to be an essential gene controlling PP2A-B55 during mitotic division. Indeed, the ablation of this protein in Mouse Embryonic Fibroblasts (MEFs) promotes the premature dephosphorylation of mitotic substrates resulting in the disruption of the correct temporal 3 order of cellular events during mitotic progression 6 . Both Arpp19 and ENSA are the unique substrates of the kinase Greatwall (Gwl). At G2-M onset, Gwl is activated and phosphorylates Arpp19 at a single site, S67. Arpp19 phosphorylation then triggers its binding and the subsequent inhibition of PP2A-B55, hence allowing the stable phosphorylation of Cyclin B/Cdk1 substrates and mitotic entry 5,13 . At mitotic exit, Gwl is inactivated resulting in Arpp19 dephosphorylation, PP2A-B55 reactivation and the gradual dephosphorylation of mitotic substrates 14,15 . The mechanisms by which Arpp19/ENSA inhibit PP2A-B55 are still elusive, however, a previous report demonstrated that ENSA acts as an "unfair" substrate of PP2A-B55 16 . Accordingly, data established that S67 phosphorylated ENSA displays a high affinity for this phosphatase but a slow dephosphorylation rate and consequently acts as a major "unfair" competitor of PP2A-B55 substrates. The molecular determinants of Arpp19 and ENSA conferring these specific properties to phospho-S67 are completely unknown.Besides Gwl-dependent phosphorylation, Arpp19 is also phosphorylated by PKA. PKAdependent phosphorylation of the alternative splice variant of Arpp19, the protein Arpp16, was firstly described. Arpp16 is enriched in striatal...

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Greatwall kinase at a glance

Cited by 44 publications

References 58 publications

Role of Polo-like kinase 1 in the regulation of the action of p31 ^comet in the disassembly of mitotic checkpoint complexes

Role of Polo-like kinase 1 in the regulation of the action of p31 ^comet in the disassembly of mitotic checkpoint complexes

MASTL: A novel therapeutic target for Cancer Malignancy

The study of the determinants controlling Arpp19 phosphatase-inhibitory activity reveals a new Arpp19/PP2A-B55 feedback loop

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Greatwall kinase at a glance

Cited by 44 publications

References 58 publications

Role of Polo-like kinase 1 in the regulation of the action of p31 comet in the disassembly of mitotic checkpoint complexes

Role of Polo-like kinase 1 in the regulation of the action of p31 comet in the disassembly of mitotic checkpoint complexes

MASTL: A novel therapeutic target for Cancer Malignancy

The study of the determinants controlling Arpp19 phosphatase-inhibitory activity reveals a new Arpp19/PP2A-B55 feedback loop

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Role of Polo-like kinase 1 in the regulation of the action of p31 ^comet in the disassembly of mitotic checkpoint complexes

Role of Polo-like kinase 1 in the regulation of the action of p31 ^comet in the disassembly of mitotic checkpoint complexes