The M Phase Kinase Greatwall (Gwl) Promotes Inactivation of PP2A/B55δ, a Phosphatase Directed Against CDK Phosphosites

Castilho, Priscila V.; Williams, Byron; Mochida, Satoru; Zhao, Yong; Goldberg, Michael L.

doi:10.1091/mbc.e09-07-0643

Cited by 179 publications

(224 citation statements)

References 37 publications

(87 reference statements)

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“…It is capable of reversing the effects of CDK-mediated positive regulation through dephosphorylating Cdc25 and Wee1 (refs 32,33). In addition, PP2A is particularly important for timely dephosphorylation of various CDK substrates during mitotic exit 34 . PP2A, thus, opposes not only CDK activation but also its activity by dephosphorylating downstream effectors to promote efficient cell cycle progression.…”

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confidence: 99%

PP2A and Aurora differentially modify Cdc13 to promote telomerase release from telomeres at G2/M phase

Shen

Hsu

et al. 2014

Nat Commun

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In yeast, the initiation of telomere replication at the late S phase involves in combined actions of kinases on Cdc13, the telomere binding protein. Cdc13 recruits telomerase to telomeres through its interaction with Est1, a component of telomerase. However, how cells terminate the function of telomerase at G2/M is still elusive. Here we show that the protein phosphatase 2A (PP2A) subunit Pph22 and the yeast Aurora kinase homologue Ipl1 coordinately inhibit telomerase at G2/M by dephosphorylating and phosphorylating the telomerase recruitment domain of Cdc13, respectively. While Pph22 removes Tel1/Mec1-mediated Cdc13 phosphorylation to reduce Cdc13-Est1 interaction, Ipl1-dependent Cdc13 phosphorylation elicits dissociation of Est1-TLC1, the template RNA component of telomerase. Failure of these regulations prevents telomerase from departing telomeres, causing perturbed telomere lengthening and prolonged M phase. Together our results demonstrate that differential and additive actions of PP2A and Aurora on Cdc13 limit telomerase action by removing active telomerase from telomeres at G2/M phase.

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confidence: 99%

PP2A and Aurora differentially modify Cdc13 to promote telomerase release from telomeres at G2/M phase

Shen

Hsu

et al. 2014

Nat Commun

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“…Similarly, inactivation of the cyclin B-Cdc2 complex by cyclin B degradation was sufficient to trigger mitotic exit. However, recent data from our and other laboratories has demonstrated that PP2A is highly regulated during mitotic entry and exit (3,10,11). Therefore, the old cell-cycle model now must be updated to include a different regulator of mitosis that modulates PP2A during this phase of the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

“…It has been previously shown that depletion of Gwl in Xenopus egg extracts both prevents mitotic entry and promotes mitotic exit (8,10,11).…”

Section: Mast-l Is the Functional Human Homolog Of Xenopus Greatwallmentioning

confidence: 99%

“…It has been recently shown that the inhibition of PP2A phosphastase activity is required to allow the phosphorylation of cyclin B-Cdc2 substrates, which promotes entry and maintains mitosis (3,10,11). Therefore, we next analyzed the capacity of these cells to phosphorylate the different cyclin B-Cdc2 substrates at the different doses of siRNA (Fig.…”

Section: Mast-l Is the Functional Human Homolog Of Xenopus Greatwallmentioning

confidence: 99%

“…Work done in Xenopus egg extracts suggested that Gwl promoted mitotic entry by controlling the auto-amplification loop of cyclin B/Cdc2 (8,9). However, it has been recently demonstrated that the main role of this kinase is not the regulation of cyclin B-Cdc2 activity but the inhibition of PP2A, the phosphatase that de-phosphorylates cyclin B-Cdc2 substrates (10,11).…”

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Loss of human Greatwall results in G2 arrest and multiple mitotic defects due to deregulation of the cyclin B-Cdc2/PP2A balance

Burgess

Vigneron

Brioudes

et al. 2010

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

642

605

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Here we show that the functional human ortholog of Greatwall protein kinase (Gwl) is the microtubule-associated serine/threonine kinase-like protein, MAST-L. This kinase promotes mitotic entry and maintenance in human cells by inhibiting protein phosphatase 2A (PP2A), a phosphatase that dephosphorylates cyclin B-Cdc2 substrates. The complete depletion of Gwl by siRNA arrests human cells in G2. When the levels of this kinase are only partially depleted, however, cells enter into mitosis with multiple defects and fail to inactivate the spindle assembly checkpoint (SAC). The ability of cells to remain arrested in mitosis by the SAC appears to be directly proportional to the amount of Gwl remaining. Thus, when Gwl is only slightly reduced, cells arrest at prometaphase. More complete depletion correlates with the premature dephosphorylation of cyclin B-Cdc2 substrates, inactivation of the SAC, and subsequent exit from mitosis with severe cytokinesis defects. These phenotypes appear to be mediated by PP2A, as they could be rescued by either a double Gwl/PP2A knockdown or by the inhibition of this phosphatase with okadaic acid. These results suggest that the balance between cyclin B-Cdc2 and PP2A must be tightly regulated for correct mitotic entry and exit and that Gwl is crucial for mediating this regulation in somatic human cells.spindle assembly checkpoint | cell cycle | phosphatase | kinase | slippage I n eukaryotic cells, the mitotic state is maintained by the mitotic kinase cyclin B-Cdc2. Historically, mitotic entry and exit was thought to be the direct consequence of cyclin B-Cdc2 activation and inactivation, respectively (1). Recent results have expanded this model to include phosphatases (2). Specifically, recent evidence indicates that protein phosphatase 2A (PP2A) is responsible for dephosphorylation of cyclin B-Cdc2 substrates and that the regulation of this dephosphorylation is required in mitotic entry and exit (3). This finding suggests a previously unexplored model in which the balance between cyclin B-Cdc2 and PP2A controls mitotic entry and exit. Thus, during G2 PP2A activity is high and cyclin B-Cdc2 activity low, thereby preventing phosphorylation of mitotic substrates, whereas at mitotic entry the balance flips, allowing entry into mitosis. The mechanisms controlling cyclin B-Cdc2 activity have been largely described (4). Briefly, cyclin B-Cdc2 is inhibited during G2 by inhibitory phosphorylations on threonine 14 and tyrosine 15 by Wee1 and Myt1 kinases. Upon mitotic entry, these are removed by the Cdc25 phosphatase (4). Finally, at mitotic exit cyclin B-Cdc2 is inhibited by the ubiquitin-dependent degradation of its regulatory subunit cyclin B (5). Unlike cyclin B-Cdc2 regulation, very little is known about the mechanisms controlling PP2A activity during mitosis, and therefore our understanding of G2 and mitosis is incomplete.Recently, Greatwall (Gwl), a unique critical mitotic regulator, has been discovered in Drosophila (6, 7). It is a member of the AGC family of serine/threonine kinases that ph...

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Getting out of mitosis: spatial and temporal control of mitotic exit and cytokinesis by PP1 and PP2A

2019

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Here, we will review the evidence showing that mitotic exit is initiated by regulated proteolysis and then driven by the PPP family of phosphoserine/threonine phosphatases. Rapid APC/CCDC20 and ubiquitin‐dependent proteolysis of cyclin B and securin initiates sister chromatid separation, the first step of mitotic exit. Because proteolysis of Aurora and Polo family kinases dependent on APC/CCDH1 is relatively slow, this creates a new regulatory state, anaphase, different to G2 and M‐phase. We will discuss how the CDK1‐counteracting phosphatases PP1 and PP2A‐B55, together with Aurora and Polo kinases, contribute to the temporal regulation and order of events in the different stages of mitotic exit from anaphase to cytokinesis. For PP2A‐B55, these timing properties are created by the ENSA‐dependent inhibitory pathway and differential recognition of phosphoserine and phosphothreonine. Finally, we will discuss how Aurora B and PP2A‐B56 are needed for the spatial regulation of anaphase spindle formation and how APC/C‐dependent destruction of PLK1 acts as a timer for abscission, the final event of cytokinesis.

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The M Phase Kinase Greatwall (Gwl) Promotes Inactivation of PP2A/B55δ, a Phosphatase Directed Against CDK Phosphosites

Cited by 179 publications

References 37 publications

PP2A and Aurora differentially modify Cdc13 to promote telomerase release from telomeres at G2/M phase

PP2A and Aurora differentially modify Cdc13 to promote telomerase release from telomeres at G2/M phase

Loss of human Greatwall results in G2 arrest and multiple mitotic defects due to deregulation of the cyclin B-Cdc2/PP2A balance

Getting out of mitosis: spatial and temporal control of mitotic exit and cytokinesis by PP1 and PP2A

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