Protein Phosphatase 2A Is Targeted to Cell Division Control Protein 6 by a Calcium-binding Regulatory Subunit

Davis, Anthony J.; Yan, Zhen; Martinez, Bobbie; Mumby, Marc C.

doi:10.1074/jbc.m710313200

Cited by 42 publications

(60 citation statements)

References 39 publications

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“…It is important to point out that independent studies have also confirmed CDC6 as a bona fide substrate of PR70 trimeric holoenzymes, but no known common conserved domains have been found in these two substrates that could mediate binding to PR70. Interestingly, while Ca ++ mobilization does not affect the PR70/CDC6 interaction, it increases the association of CDC6 with the catalytic and scaffold subunits (Davis et al, 2008). Our lab has identified B55α PP2A holoenzymes as major modulators of the phosphorylation state of p107 in human cells, to a lesser extent, p130 and with little if any effect on pRB ( Fig.…”

Section: Identification Of Pp2a Holoenzymes That Modulate the Phosphomentioning

confidence: 95%

PP2A holoenzymes negatively and positively regulate cell cycle progression by dephosphorylating pocket proteins and multiple CDK substrates

Kurimchak¹,

Graña

2012

Gene

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Cell cycle progression is negatively regulated by the retinoblastoma family of pocket proteins and CDK inhibitors (CKIs). In contrast, CDKs promote progression through multiple phases of the cell cycle. One prominent way by which CDKs promote cell cycle progression is by inactivation of pocket proteins via hyperphosphorylation. Reactivation of pocket proteins to halt cell cycle progression requires dephosphorylation of multiple CDK-phosphorylated sites and is accomplished by PP2A and PP1 serine/threonine protein phosphatases. The same phosphatases are also implicated in dephosphorylation of multiple CDK substrates as cells exit mitosis and reenter the G1 phase of the cell cycle. This review is primarily focused on the role of PP2A and PP1 in the activation of pocket proteins during the cell cycle and in response to signaling cues that trigger cell cycle exit. Other functions of PP2A during the cell cycle will be discussed in brief, as comprehensive reviews on this topic have been published recently (De Wulf et al., 2009; Wurzenberger and Gerlich, 2011).

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Section: Identification Of Pp2a Holoenzymes That Modulate the Phosphomentioning

confidence: 95%

PP2A holoenzymes negatively and positively regulate cell cycle progression by dephosphorylating pocket proteins and multiple CDK substrates

Kurimchak¹,

Graña

2012

Gene

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“…Loss of protection from the APC Cdh1 (or other ubiquitin ligases) could involve dephosphorylation of Cdc6 -an activity that could be provided by protein phosphatase PP2A, which targets to Cdc6 and is critical for proper progression from G1-to S phase. 42 As cells proceed through S phase, Cyclin A/Cdk2-dependent phosphorylation of newly synthesized Cdc6 then results in its protection from proteasomal degradation and export to the cytoplasm by Crm1. 9,10,[17][18][19]36 Finally, exported Cdc6 binds to centrosomes in late G2 and throughout mitosis, where it may carry out a functional role in regulating proper chromosomal alignment.…”

Section: Discussionmentioning

confidence: 99%

Spatio-temporal regulation of the human licensing factor Cdc6 in replication and mitosis

et al. 2015

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To maintain genome stability, the thousands of replication origins of mammalian genomes must only initiate replication once per cell cycle. This is achieved by a strict temporal separation of ongoing replication in S phase, and the formation of pre-replicative complexes in the preceding G1 phase, which "licenses" each origin competent for replication. The contribution of the loading factor Cdc6 to the timing of the licensing process remained however elusive due to seemingly contradictory findings concerning stabilization, degradation and nuclear export of Cdc6. Using fluorescently tagged Cdc6 (Cdc6-YFP) expressed in living cycling cells, we demonstrate here that Cdc6-YFP is stable and chromatin-associated during mitosis and G1 phase. It undergoes rapid proteasomal degradation during S phase initiation followed by active export to the cytosol during S and G2 phases. Biochemical fractionation abolishes this nuclear exclusion, causing aberrant chromatin association of Cdc6-YFP and, likely, endogenous Cdc6, too. In addition, we demonstrate association of Cdc6 with centrosomes in late G2 and during mitosis. These results show that multiple Cdc6-regulatory mechanisms coexist but are tightly controlled in a cell cycle-specific manner.

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“…These modifications tag Cdc6 for nuclear export where it is degraded in the cytoplasm. Cdc6 degradation can only happen when the protective residues are dephosphorylated, and PP2A-PR70 has been shown to dephosphorylate Cdc6 in vivo (Davis et al ., 2008). Our recent study showed that Cdc6 is specifically dephosphorylated by PP2A-PR70 holoenzyme and not others (Wlodarchak et al ., 2013).…”

Section: Dna Synthesis and Regulation Of The Origin Recognition Complexmentioning

confidence: 99%

PP2A as a master regulator of the cell cycle

Wlodarchak

Xing

2016

Critical Reviews in Biochemistry and Molecular Biology

299

273

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Protein phosphatase 2A (PP2A) plays a critical multi-faceted role in the regulation of the cell cycle. It is known to dephosphorylate over 300 substrates involved in the cell cycle, regulating almost all major pathways and cell cycle checkpoints. PP2A is involved in such diverse processes by the formation of structurally distinct families of holoenzymes, which are regulated spatially and temporally by specific regulators. Here, we review the involvement of PP2A in the regulation of three cell signaling pathways: wnt, mTOR and MAP kinase, as well as the G1→S transition, DNA synthesis and mitotic initiation. These processes are all crucial for proper cell survival and proliferation and are often deregulated in cancer and other diseases.

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Protein Phosphatase 2A Is Targeted to Cell Division Control Protein 6 by a Calcium-binding Regulatory Subunit

Cited by 42 publications

References 39 publications

PP2A holoenzymes negatively and positively regulate cell cycle progression by dephosphorylating pocket proteins and multiple CDK substrates

PP2A holoenzymes negatively and positively regulate cell cycle progression by dephosphorylating pocket proteins and multiple CDK substrates

Spatio-temporal regulation of the human licensing factor Cdc6 in replication and mitosis

PP2A as a master regulator of the cell cycle

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