Regulation and role of the PP2A-B56 holoenzyme family in cancer

Peris, Irene; Romero-Murillo, Silvia; Vicente, Carmen; Narla, Goutham; Odero, Marı́a D.

doi:10.1016/j.bbcan.2023.188953

Cited by 5 publications

(3 citation statements)

References 185 publications

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“…These findings connect with our previous observation that mutants in fission yeast Sds23, a poorly understood regulator of PP2A and PP6 phosphatases, have defects in Mid1 levels and cytokinesis (Schutt & Moseley, 2020). These results follow a general theme that tightly controlled formation and regulation of specific PP2A holoenzymes is required to control cell division events in time and space (Peris et al, 2023).…”

Section: Discussionsupporting

confidence: 90%

PP2A-B56 regulates Mid1 protein levels for proper cytokinesis in fission yeast

Chrupcala,

Moseley

2024

Preprint

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Protein phosphorylation regulates many steps in the cell division process including cytokinesis. In the fission yeastS. pombe, the anillin-like protein Mid1 sets the cell division plane and is regulated by phosphorylation. Multiple protein kinases act on Mid1, but no protein phosphatases have been shown to regulate Mid1. Here, we discovered that the conserved protein phosphatase PP2A-B56 is required for proper cytokinesis by promoting Mid1 protein levels. We find thatpar1Δ cells lacking the primary B56 subunit divide asymmetrically due to the assembly of misplaced cytokinetic rings that slide toward cell tips. Thesepar1Δ mutants have reduced whole-cell levels of Mid1 protein, leading to reduced Mid1 at the cytokinetic ring. Restoring proper Mid1 expression suppressespar1Δ cytokinesis defects. This work identifies a new PP2A-B56 pathway regulating cytokinesis through Mid1, with implications for control of cytokinesis in other organisms.

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Section: Discussionsupporting

confidence: 90%

PP2A-B56 regulates Mid1 protein levels for proper cytokinesis in fission yeast

Chrupcala,

Moseley

2024

Preprint

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“…76 A major challenge for developing more effective cancer therapies is to identify the specieic PP2A complexes to be targeted. 77 In this context, B55α and B56α target PP2A catalytic activity to different amino acid residues on the proto-oncogene c-Myc, with opposite effects on c-Myc stabilisation and oncogenic signalling. 42 PP2A-B55α-mediated dephosphorylation of Thr58 leads to c-Myc stabilisation and tumorigenesis, while PP2A-B56α-mediated dephosphorylation of Ser62 leads to c-Myc destabilisation and tumour suppression, revealing distinct roles for different PP2A holoenzymes.…”

Section: Discussionmentioning

confidence: 99%

Sex-specific regulation of the cardiac transcriptome by the protein phosphatase 2A regulatory subunit B55α

Sergienko,

Trewin,

Kiriazis

et al. 2024

Preprint

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Protein phosphatase 2A (PP2A) enzymes containing the regulatory subunit isoform B55α (PP2A-B55α) suppress HDAC5/MEF2 signalling in cardiac myocytes, implicating B55α in the transcriptional regulation of cardiac growth and fibrosis. The role of B55α in the heart has not been investigated. In this study, we generated and characterised two loss-of-function mouse models, with global or cardiomyocyte-specific disruption of the gene encoding B55α (Ppp2r2a). Mice with global homozygous knockout of B55α diedin utero, but cardiac morphology was unremarkable compared with wildtype littermates. Mice with global heterozygous knockout of B55α had thinner left ventricular walls compared with wildtype mice at 12 months of age, an effect that was more pronounced in males. Mice with cardiomyocyte-specific deletion of B55α displayed normal cardiac morphology at 10-12 weeks of age, demonstrating that cardiomyocyte B55α is not required for postnatal heart growth. Despite no obvious morphological differences, gene expression analyses revealed extensive remodelling of the cardiac transcriptome in male, but not female, mice. In males, B55α knockout increased the expression of genes associated with extracellular matrix composition, and downregulated genes associated with mitochondrial energy production. This study reveals a sexually dimorphic role for B55α in postnatal cardiac transcriptional regulation and provides a foundation for future work investigating the role of B55α in cardiac stress settings.

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“…Protein phosphorylation is a highly functionally coordinated and temporally regulated process by protein kinases and phosphatases. Disorders of this balance underlie the pathogenesis of many human diseases, such as cancer [ 1 ]. While there are approximately 500 identified protein kinases, paradoxically, there are only about 60 identified phosphatases [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Emerging Roles of B56 Phosphorylation and Binding Motif in PP2A-B56 Holoenzyme Biological Function

Zhang,

Jiang,

Yin

et al. 2024

IJMS

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Protein serine/threonine phosphatase 2A (PP2A) regulates diverse cellular processes via the formation of ~100 heterotrimeric holoenzymes. However, a scarcity of knowledge on substrate recognition by various PP2A holoenzymes has greatly prevented the deciphering of PP2A function in phosphorylation-mediated signaling in eukaryotes. The review summarized the contribution of B56 phosphorylation to PP2A-B56 function and proposed strategies for intervening B56 phosphorylation to treat diseases associated with PP2A-B56 dysfunction; it especially analyzed recent advancements in LxxIxEx B56-binding motifs that provide the molecular details of PP2A-B56 binding specificity and, on this basis, explored the emerging role of PP2A-B56 in the mitosis process, virus attack, and cancer development through LxxIxE motif-mediated PP2A-B56 targeting. This review provides theoretical support for discriminatingly targeting specific PP2A holoenzymes to guide PP2A activity against specific pathogenic drivers.

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Regulation and role of the PP2A-B56 holoenzyme family in cancer

Cited by 5 publications

References 185 publications

PP2A-B56 regulates Mid1 protein levels for proper cytokinesis in fission yeast

PP2A-B56 regulates Mid1 protein levels for proper cytokinesis in fission yeast

Sex-specific regulation of the cardiac transcriptome by the protein phosphatase 2A regulatory subunit B55α

Emerging Roles of B56 Phosphorylation and Binding Motif in PP2A-B56 Holoenzyme Biological Function

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