Regulation of Greatwall kinase by protein stabilization and nuclear localization

Yamamoto, Tomomi M.; Fisher, Laura A.; Eckerdt, Frank; Peng, Aimin

doi:10.4161/15384101.2014.962942

Cited by 15 publications

(14 citation statements)

References 43 publications

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“…In agreement with the nuclear localization of Gwl, importin-α and -β have been found to be associated with this kinase in Xenopus S3 cells (Yamamoto et al, 2014). Importin binds a functional nuclear localization signal (NLS) on Gwl, and this binding is essential for the function of Gwl in promoting mitotic entry (Yamamoto et al, 2014). In Drosophila, two NLSs that are present in the central region of Gwl mediate the nuclear localization of this kinase during interphase.…”

Section: Gwl Localizationmentioning

confidence: 74%

“…Gwl is predominantly nuclear during interphase and becomes cytoplasmic at prophase just prior to nuclear envelope breakdown (NEB) (Alvarez-Fernandez et al, 2013;Wang et al, 2013;Yamamoto et al, 2014). In agreement with the nuclear localization of Gwl, importin-α and -β have been found to be associated with this kinase in Xenopus S3 cells (Yamamoto et al, 2014). Importin binds a functional nuclear localization signal (NLS) on Gwl, and this binding is essential for the function of Gwl in promoting mitotic entry (Yamamoto et al, 2014).…”

Section: Gwl Localizationmentioning

confidence: 80%

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Greatwall kinase at a glance

Castro

Lorca

2018

Journal of Cell Science

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Mitosis is controlled by a subtle balance between kinase and phosphatase activities that involve the master mitotic kinase cyclin-B-Cdk1 and its antagonizing protein phosphatase 2A-B55 (PP2A-B55). Importantly, the Greatwall (Gwl; known as Mastl in mammals, Rim15 in budding yeast and Ppk18 in fission yeast) kinase pathway regulates PP2A-B55 activity by phosphorylating two proteins, cAMPregulated phosphoprotein 19 (Arpp19) and α-endosulfine (ENSA). This phosphorylation turns these proteins into potent inhibitors of PP2A-B55, thereby promoting a correct timing and progression of mitosis. In this Cell Science at a Glance article and the accompanying poster, we discuss how Gwl is regulated in space and time, and how the Gwl-Arpp19-ENSA-PP2A-B55 pathway plays an essential role in the control of M and S phases from yeast to human. We also summarize how Gwl modulates oncogenic properties of cells and how nutrient deprivation influences Gwl activity.

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Section: Gwl Localizationmentioning

confidence: 74%

Section: Gwl Localizationmentioning

confidence: 80%

Greatwall kinase at a glance

Castro

Lorca

2018

Journal of Cell Science

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“…18,19 The Hsp90 and Cdc37 chaperones are also required to stabilize Gwl. 20 Gwl contains a long region which splits its kinase domain into N-terminal and C-terminal sub-domains, and contributes to its regulation. 10 Although this region is conserved in all Gwl orthologs, its amino-acid sequence is poorly conserved.…”

Section: Introductionmentioning

confidence: 99%

Spatial regulation of greatwall by Cdk1 and PP2A-Tws in the cell cycle

et al. 2016

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Entry into mitosis requires the phosphorylation of multiple substrates by cyclin B-Cdk1, while exit from mitosis requires their dephosphorylation, which depends largely on the phosphatase PP2A in complex with its B55 regulatory subunit (Tws in Drosophila). At mitotic entry, cyclin B-Cdk1 activates the Greatwall kinase, which phosphorylates Endosulfine proteins, thereby activating their ability to inhibit PP2A-B55 competitively. The inhibition of PP2A-B55 at mitotic entry facilitates the accumulation of phosphorylated Cdk1 substrates. The coordination of these enzymes involves major changes in their localization. In interphase, Gwl is nuclear while PP2A-B55 is cytoplasmic. We recently showed that Gwl suddenly relocalizes from the nucleus to the cytoplasm in prophase, before nuclear envelope breakdown and that this controlled localization of Gwl is required for its function. We and others have shown that phosphorylation of Gwl by cyclin B-Cdk1 at multiple sites is required for its nuclear exclusion, but the precise mechanisms remained unclear. In addition, how Gwl returns to its nuclear localization was not explored. Here we show that cyclin B-Cdk1 directly inactivates a Nuclear Localization Signal in the central region of Gwl. This phosphorylation facilitates the cytoplasmic retention of Gwl, which is exported to the cytoplasm in a Crm1-dependent manner. In addition, we show that PP2A-Tws promotes the return of Gwl to its nuclear localization during cytokinesis. Our results indicate that the cyclic changes in Gwl localization at mitotic entry and exit are directly regulated by the antagonistic cyclin B-Cdk1 and PP2A-Tws enzymes.

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“…Greatwall is phosphorylated by Polo kinase, which results in binding to 14-3-3Ɛ proteins and cytosolic retention [56]. In mammals, Mastl is also exported from the nucleus in a CRM1-dependent manner before nuclear envelope breakdown (NEB) [48]; in Xenopus cells, importin proteins are responsible for Gwl relocalization [57]. Cytosolic Greatwall phosphorylates ARPP-19 and ENSA proteins, triggering their binding to and inhibition of PP2A/B55.…”

Section: The Greatwall-endosulfine Switch Inactivates Pp2a/b55 At Mitmentioning

confidence: 99%

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

García-Blanco

Vázquez-Bolado

Moreno

2019

IJMS

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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.

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Regulation of Greatwall kinase by protein stabilization and nuclear localization

Cited by 15 publications

References 43 publications

Greatwall kinase at a glance

Greatwall kinase at a glance

Spatial regulation of greatwall by Cdk1 and PP2A-Tws in the cell cycle

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

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