PP2A-B56 opposes Mps1 phosphorylation of Knl1 and thereby promotes spindle assembly checkpoint silencing

Espert, Antonio; Uluocak, Pelin; Bastos, Ricardo; Mangat, Davinderpreet; Graab, Philipp; Grüneberg, Ulrike

doi:10.1083/jcb.201406109

Cited by 128 publications

(194 citation statements)

References 39 publications

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“…Contrary to these findings, Espert et al demonstrates the exclusive and key role of PP2A-B56 in opposing both Aurora B and Mps1 activity in mammals. 49 Here, Knl1 is shown to be the direct substrate for PP2A-B56 49 and not PP1 as observed in yeast. 51 Interestingly, the phosphorylation of BUBR1 by Plk1 and Cdk1 exclusively happens at unattached tensionless kinetochores so that Aurora B activity can be neutralized but how these kinases monitor and relay the signal in response to the kMT attachment status is still unknown.…”

Section: Integration Of the Kmn Network With Sac Silencingmentioning

confidence: 99%

“…Once PP1 is docked on unphosphorylated RVSF/SSILK motifs, it dephosphorylates Knl1. 49 Thus, PP2A bound to BUBR1 dephosphorylates Aurora B sites on Knl1 thereby allowing PP1 binding to Knl1 to mediate dephosphorylation of MELT motifs and transition from SAC "C" to SAC "-" state. 48 Recent study by Nijenhuis et al further suggests that the kinetochore localized PP1 promotes removal of kinetochore-PP2A-B56 by dephosphorylating MELT and KARD motifs.…”

Section: Integration Of the Kmn Network With Sac Silencingmentioning

confidence: 99%

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How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling

Agarwal

Varma

2015

BioArchitecture

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ABSTRACT. Mitosis entails the bona fide segregation of duplicated chromosomes. This process is accomplished by the attachment of kinetochores on chromosomes to microtubules (MTs) of the mitotic spindle. Once the appropriate attachment is achieved, the spindle assembly checkpoint (SAC) that delays the premature onset of anaphase needs to be silenced for the cell to proceed to anaphase and cytokinesis. Therefore, while it is imperative to preserve the SAC when kinetochores are unattached, it is of paramount importance that SAC components are removed post kinetochore microtubule (kMT) attachment. Precise knowledge of how kMT attachments trigger the removal of SAC components from kinetochores or how the checkpoint proteins feedback in to the attachment machinery remains elusive. This review aims to describe the recent advances that provide an insight into the interplay of molecular events that coordinate and regulate the SAC activity in response to kMT attachment during cell division.

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Section: Integration Of the Kmn Network With Sac Silencingmentioning

confidence: 99%

Section: Integration Of the Kmn Network With Sac Silencingmentioning

confidence: 99%

How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling

Agarwal

Varma

2015

BioArchitecture

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“…It is not clear whether the deletion or inhibition of PP1 also causes a similarly strong mitoticarrest phenotype in vertebrate cells. Various PIPs mediate the interaction of PP1 with the centrosomes, spindle and mitotic chromosomes in vertebrates, including CENP-E (Kim et al, 2010), Kif18A (Häfner et al, 2014), KNL1 (Espert et al, 2014;Liu et al, 2010;Nijenhuis et al, 2014), RepoMan (also known as CDCA2) (Qian et al, 2013b;Vagnarelli et al, 2011;Wurzenberger et al, 2012) and Sds22 (Eiteneuer et al, 2014;Wurzenberger et al, 2012). These mitotic pools of PP1 holoenzymes have functions throughout the M-phase.…”

Section: Introductionmentioning

confidence: 99%

The selective inhibition of protein phosphatase-1 results in mitotic catastrophe and impaired tumor growth

Winkler

Munter

Dessel

et al. 2015

Journal of Cell Science

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The serine/threonine protein phosphatase-1 (PP1) complex is a key regulator of the cell cycle. However, the redundancy of PP1 isoforms and the lack of specific inhibitors have hampered studies on the global role of PP1 in cell cycle progression in vertebrates. Here, we show that the overexpression of nuclear inhibitor of PP1 (NIPP1; also known as PPP1R8) in HeLa cells culminated in a prometaphase arrest, associated with severe spindle-formation and chromosome-congression defects. In addition, the spindle assembly checkpoint was activated and checkpoint silencing was hampered. Eventually, most cells either died by apoptosis or formed binucleated cells. The NIPP1-induced mitotic arrest could be explained by the inhibition of PP1 that was titrated away from other mitotic PP1 interactors. Consistent with this notion, the mitoticarrest phenotype could be rescued by the overexpression of PP1 or the inhibition of the Aurora B kinase, which acts antagonistically to PP1. Finally, we demonstrate that the overexpression of NIPP1 also hampered colony formation and tumor growth in xenograft assays in a PP1-dependent manner. Our data show that the selective inhibition of PP1 can be used to induce cancer cell death through mitotic catastrophe.

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“…However, depleting individual regulatory subunits had a smaller effect on S384 dephosphorylation than did PP2A catalytic subunit depletion (depicted in the last lane of Fig. 3A), consistent with functional redundancies among the individual B subunits (41)(42)(43).…”

Section: Figmentioning

confidence: 60%

The PP2A-B56 Phosphatase Opposes Cyclin E Autocatalytic Degradation via Site-Specific Dephosphorylation

Davis

Swanger

Hughes

et al. 2017

Molecular and Cellular Biology

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Cyclin E, in conjunction with its catalytic partner cyclin-dependent kinase 2 (CDK2), regulates cell cycle progression as cells exit quiescence and enter S-phase. Multiple mechanisms control cyclin E periodicity during the cell cycle, including phosphorylation-dependent cyclin E ubiquitylation by the SCF Fbw7 ubiquitin ligase. Serine 384 (S384) is the critical cyclin E phosphorylation site that stimulates Fbw7 binding and cyclin E ubiquitylation and degradation. Because S384 is autophosphorylated by bound CDK2, this presents a paradox as to how cyclin E can evade autocatalytically induced degradation in order to phosphorylate its other substrates. We found that S384 phosphorylation is dynamically regulated in cells and that cyclin E is specifically dephosphorylated at S384 by the PP2A-B56 phosphatase, thereby uncoupling cyclin E degradation from cyclin E-CDK2 activity. Furthermore, the rate of S384 dephosphorylation is high in interphase but low in mitosis. This provides a mechanism whereby interphase cells can oppose autocatalytic cyclin E degradation and maintain cyclin E-CDK2 activity while also enabling cyclin E destruction in mitosis, when inappropriate cyclin E expression is genotoxic.KEYWORDS cell cycle, cyclin-dependent kinases, cyclins, serine/threonine phosphatases, ubiquitination T he mammalian cell cycle is regulated by cyclin-dependent kinases (CDKs) and their associated cyclin regulatory subunits. Cyclin E-CDK2 has essential roles as cells exit quiescence and during endoreduplication. It also regulates numerous processes during the G 1 and S-phases of the cell cycle, including S-phase entry, DNA replication, and centrosome duplication (1-5).Cells must tightly regulate cyclin E-CDK2 activity, and this is accomplished through a variety of mechanisms, including E2F-dependent cyclin E transcription, binding of CDK inhibitor proteins (p27Kip1 and p21Cip1), activating and inhibitory phosphorylation of CDK2, and cyclin E degradation by the ubiquitin-proteasome system (1, 2). Abnormal cyclin E-CDK2 activity disrupts normal G 1 /S control and causes genomic instability (6-12). Importantly, cyclin E is oncogenic in multiple contexts: the cyclin E gene is amplified in human serous ovarian and basal breast cancers, and its deregulated activity promotes tumorigenesis in mice (13-16).The F-box protein Fbw7 is the substrate recognition component of an SCF ubiquitin ligase that targets cyclin E for degradation after cyclin E becomes phosphorylated within conserved motifs called Cdc4 phosphodegrons (CPDs) (17)(18)(19)(20)(21)(22). Fbw7 substrate CPDs contain two negative charges: a phosphorylated-Thr/Ser (pT/S) in the 0 position, and a second pT/S or an acidic amino acid in the ϩ4 position (23,24). Cyclin E contains two CPDs: a high-affinity C-terminal degron that is phosphorylated at T380 and S384 and is the primary determinant of Fbw7 binding and a low-affinity N-terminal degron that contains only one phosphorylation site, at T62 (Fig. 1A). Phosphorylation-

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PP2A-B56 opposes Mps1 phosphorylation of Knl1 and thereby promotes spindle assembly checkpoint silencing

Abstract: The kinetochore surveillance phosphatase PP2A-B56 dephosphorylates Knl1 to silence the spindle assembly checkpoint after all chromosomes have been correctly attached to microtubules.

Cited by 128 publications

References 39 publications

How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling

How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling

The selective inhibition of protein phosphatase-1 results in mitotic catastrophe and impaired tumor growth

The PP2A-B56 Phosphatase Opposes Cyclin E Autocatalytic Degradation via Site-Specific Dephosphorylation

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