PP2A-B55 Holoenzyme Regulation and Cancer

Goguet-Rubio, Perrine; Amin, Priya; Awal, Sushil; Vigneron, Suzanne; Charrasse, Sophie; Méchali, Francisca; Labbé, Jean-Claude; Lorca, Thierry

doi:10.3390/biom10111586

Cited by 14 publications

(12 citation statements)

References 127 publications

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“…By mutation of the NLS that we identified, the nuclear function of PP2A-Tws in the DNA damage response could be tested. Our results suggest that the assembly of PP2A-Tws/B55 holoenzymes, which requires several enzymatic steps ( Goguet-Rubio et al, 2020 ), takes place preferentially in the cytoplasm. It will be interesting to determine whether the whole PP2A-Tws holoenzyme can be translocated across nuclear pores or if Tws is transported alone via its NLS.…”

Section: Discussionmentioning

confidence: 77%

Spatiotemporal coordination of Greatwall-Endos-PP2A promotes mitotic progression

Larouche

Kachaner

Wang

et al. 2021

Journal of Cell Biology

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Mitotic entry involves inhibition of protein phosphatase 2A bound to its B55/Tws regulatory subunit (PP2A-B55/Tws), which dephosphorylates substrates of mitotic kinases. This inhibition is induced when Greatwall phosphorylates Endos, turning it into an inhibitor of PP2A-Tws. How this mechanism operates spatiotemporally in the cell is incompletely understood. We previously reported that the nuclear export of Greatwall in prophase promotes mitotic progression. Here, we examine the importance of the localized activities of PP2A-Tws and Endos for mitotic regulation. We find that Tws shuttles through the nucleus via a conserved nuclear localization signal (NLS), but expression of Tws in the cytoplasm and not in the nucleus rescues the development of tws mutants. Moreover, we show that Endos must be in the cytoplasm before nuclear envelope breakdown (NEBD) to be efficiently phosphorylated by Greatwall and to bind and inhibit PP2A-Tws. Disrupting the cytoplasmic function of Endos before NEBD results in subsequent mitotic defects. Evidence suggests that this spatiotemporal regulation is conserved in humans.

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Section: Discussionmentioning

confidence: 77%

Spatiotemporal coordination of Greatwall-Endos-PP2A promotes mitotic progression

Larouche

Kachaner

Wang

et al. 2021

Journal of Cell Biology

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“…By pairing the same catalytic core with many exchangeable adaptors, cells can form multiple complexes with shared activity but unique substrate specificity. Illustrating the importance and prevalence of such modular signaling, human cells contain $40 PP2A phosphatases, $30 p97/VCP AAA-ATPases, and $300 Cullin-RING E3 ligases (CRLs) (Bennett et al, 2010;Buchberger et al, 2015;Goguet-Rubio et al, 2020;Reitsma et al, 2017). How these pivotal enzymes achieve their proper composition and select their targets at the right time and place remains a central question in biology.…”

Section: Introductionmentioning

confidence: 99%

Co-adaptor driven assembly of a CUL3 E3 ligase complex

2022

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“…CIP2A is an oncoprotein that prevents PP2A-mediated dephosphorylation of c-Myc at Ser 62 and contributes to the stabilization of c-Myc [15]. PP2A has been shown to regulate many cellular processes in gastric cancer including, but not limited to, growth, stemness, and apoptosis [17,18,19,20]. However, the link between PP2A and the Warburg effect remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Protein Phosphatase 2a Inhibits Gastric Cancer Cell Glycolysis by Reducing MYC Signaling

Cai

Zhang

Zhou

et al. 2022

Cell Biochem Biophys

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Background: The Warburg effect is closely associated malignant phenotypes and poor prognosis in cancer patients. PP2A is a highly conserved eukaryotic serine/threonine protein phosphatase that functions as a tumor suppressor in a variety of human cancers. However, the relationship between PP2A and the Warburg effect has yet to be fully understood.Methods: The expression pro le of two endogenous inhibitors of PP2A, SET and CIP2A, are detected by real-time qPCR. Loss-of-function and gain-of-function are performed to demonstrate the roles of PP2A in gastric cancer cell proliferation and glycolysis. Cell biological, molecular, and biochemical approaches are used to uncover the underlying mechanism.Results: In this study, we nd that SET and CIP2A are overexpressed in gastric cancer and associates a decreased PP2A activity. Pharmacological activation of PP2A with FTY-720 and DT-061 signi cantly reduces gastric cancer cell proliferation and glycolytic ability. Importantly, inhibition of PP2A activity by genetic silencing of PPP2R5A induces a growth advantage, which can be largely compromised by addition of the glycolysis inhibitor 2-Deoxy-D-glucose, suggesting a glycolysis-dependent effect of PP2A in gastric cancer. Mechanistically, the well known transcription factor and glycolysis regulator c-Myc is discovered as the functional mediator of PP2A in regulating cell glycolysis. Ectopic expression of a phosphorylation-mutant c-Myc resistant to PP2A (MycT58A) restores the inhibitory effect of FTY-720 and DT-061 on the lactate production and glucose uptake. Furthermore, there is a close association between SET and CIP2A expression and c-Myc gene signatures in gastric cancer samples.Conclusions: This study provides strong evidence of the involvement of PP2A in the Warburg effect and indicates that it could be a novel antitumor strategy to target tumor metabolism in gastric cancer.

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PP2A-B55 Holoenzyme Regulation and Cancer

Cited by 14 publications

References 127 publications

Spatiotemporal coordination of Greatwall-Endos-PP2A promotes mitotic progression

Spatiotemporal coordination of Greatwall-Endos-PP2A promotes mitotic progression

Co-adaptor driven assembly of a CUL3 E3 ligase complex

Protein Phosphatase 2a Inhibits Gastric Cancer Cell Glycolysis by Reducing MYC Signaling

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