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Serine/Threonine phosphatase PP2A is essential for optimal B cell function

ABSTRACT: Protein phosphatase 2A (PP2A), a serine/threonine phosphatase, has been shown to control T cell function. We found that in vitro activated B cells and B cells from various lupus-prone mice and patients with systemic lupus erythematosus display increased PP2A activity. To understand the contribution of PP2A to B cell function, we generated a Cd19CrePpp2r1aflox/flox (flox/flox) mouse which lacks functional PP2A only in B cells. Flox/flox mice displayed reduced spontaneous germinal center formation and decreased responses to T-dependent and T-independent antigens while their B cells responded poorly in vitro to stimulation with an anti-CD40 antibody or CpG in the presence of IL-4. Transcriptome and metabolome studies revealed altered NAD and purine/pyrimidine metabolism and increased expression of purine nucleoside phosphorylase in PP2A-deficient B cells. Our results demonstrate that PP2A is required for optimal B cell function and may contribute to increased B cell activity in systemic autoimmunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE144700 | GEO | 2020/02/04

REPOSITORIES: GEO

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PP2A is essential for Th17 differentiaiton

Project description:Phosphatase PP2A expression level is positively correlated to the clinical severity of systemic lupus erythematosus (SLE) and IL17A cytokine overproduction, indicating a potential role of PP2A in controlling TH17 differentiation and inflammation. By generating a mouse strain with the ablation of the catalytic subunit α of PP2A in peripheral mature T cells (PP2A cKO), we provide evidence here that PP2A complex is essential in TH17 differentiation. Hence, PP2A cKO mice exhibited a selective reduction of TH17 cell numbers and an attenuated disease severity in an experimental autoimmune encephalomyelitis (EAE) model. Importantly, PP2A deficiency ablated c-terminal phosphorylation of SMAD2 whereas increased c-terminal phosphorylation of SMAD3. Through direct binding to and regulating the activity of RORγt, the phosphorylational changes of these R-SMADs subsequently reduced Il17a transcription. Finally, PP2A inhibitors recapitulated the phenotype of PP2A cKO mice, i.e., inhibiting TH17 differentiation and protecting mice from EAE. Together, the current study proves that phosphatase PP2A is essential for TH17 differentiation, and inhibition of PP2A could be a possible therapeutic approach for the controlling of TH17-driven autoimmune diseases.

2018-09-13 | GSE119836 | GEO

The yeast PP2A-CDC55 phosphatase regulates the transcriptional response to hyperosmolarity stress by regulating Msn2 and Msn4

Project description:This SuperSeries is composed of the following subset Series: GSE38565: The yeast PP2A-CDC55 phosphatase regulates the transcriptional response to hyperosmolarity stress by regulating Msn2 and Msn4 [Time course 1] GSE42033: The yeast PP2A-CDC55 phosphatase regulates the transcriptional response to hyperosmolarity stress by regulating Msn2 and Msn4 [Time course 2] Refer to individual Series

2012-11-06 | E-GEOD-42034 | biostudies-arrayexpress

Serine/Threonine phosphatase PP2A is essential for optimal B cell function

Project description:Serine/Threonine phosphatase PP2A is essential for optimal B cell function

| PRJNA604601 | ENA

STRIPAK directs PP2A activity to promote oncogenic transformation

Project description:We evaluated the effects of suppressing MAP4K4 on transcriptome and YAP1 pathway based on the observation that partial suppression of MAP4K4 leads to transformation through activation of YAP1. Mutations and deletions involving subunits of the serine-threonine phosphatase PP2A occur in a broad range of human cancers, and partial loss of PP2A function contributes to cell transformation. In particular, displacement of regulatory B subunits by the viral oncoprotein SV40 small-t antigen (ST) or mutation or deletion of PP2A subunits alters the abundance and types of PP2A complexes in cells and induces cell transformation in human cells. Here we show that ST not only displaces common PP2A B subunits but also promotes PP2A A-C subunit interactions with a set of alternative B subunits (B’’’, striatins) that are components of the Striatin-interacting phosphatase and kinase (STRIPAK) complex. We found that members of the STRIPAK complex are required for ST-PP2A induced cell transformation. PP2A interacts with and dephosphorylates the STRIPAK-associated kinase MAP4K4, which induces cell transformation in part through the regulation of the Hippo pathway effector YAP1. These observations identify an unanticipated role of MAP4K4 in transformation and show that the STRIPAK complex plays a key role in defining PP2A specificity and activity.

2019-12-01 | GSE118272 | GEO

PP2A dependent modulation of c-Myc and p21 leads to differentiation and cell cycle control in Acute Myeloid Leukemia

Project description:Aberrant kinase and phosphatase activity frequently contribute to Acute Myeloid Leukemia. Here we characterize the Protein Phosphatase 2A (PP2A) as a mediator of differentiation and cell cycle arrest in AML. Using a novel PP2A activator OSU-2S, we show that PP2A activation results in differentiation, growth arrest and cell death in AML, via depletion of c-Myc and upregulation of p21. Gene expression and mass cytometric profiling further show modulation of cell cycle regulators and differentiation factors, and importantly, decreased CD34+/CD38- stem cells in patient derived AML blasts treated with OSU-2S. Finally, we demonstrate in-vivo therapeutic efficacy of OSU-2S as seen by increased differentiation, decreased clonogenicity and improved survival in a Tet2-/-Flt3ITD murine AML model and human AML models.

2022-03-16 | GSE148018 | GEO

The yeast PP2A-CDC55 phosphatase regulates the transcriptional response to hyperosmolarity stress by regulating Msn2 and Msn4

Project description:The yeast PP2A-Cdc55 Serine/Threonine phosphatase regulates transcription under certain conditions. It is required for full activation of the environmental stress response mediated by the transcription factors Msn2 and Msn4. PP2A-Cdc55 contributes to sustained nuclear accumulation of Msn2 and Msn4 and extended chromatin recruitment under stress conditions such as hyperosmolarity stress. Transcript profiles of Msn2 and Msn4 double mutants are similar to cdc55 and the corresponding triple mutants. This argues for a Msn2/4 specific function of PP2A-Cdc55. Time course of 10 20 and 30 minutes hyperosmolarity treated yeast cells of wild type (W303), msn2msn4, cdc55, msn2msn5cdc55 genetic background.

2012-06-07 | E-GEOD-38565 | biostudies-arrayexpress

RAS and PP2A activities converge on epigenetic gene regulation [BS-Seq]

Project description:RAS-mediated human cell transformation requires inhibition of the tumor suppressor Protein Phosphatase 2A (PP2A). Both RAS and PP2A mediate their effects by phosphoregulation, but phosphoprotein targets and cellular processes in which RAS and PP2A activities converge in human cancers have not been systematically analyzed. Here, based on mass spectrometry phosphoproteome data we discover that phosphosites co-regulated by RAS and PP2A are enriched on proteins involved in epigenetic gene regulation. As examples, RAS and PP2A co-regulate the same phosphorylation sites on HDAC1/2, KDM1A, MTA1/2, RNF168 and TP53BP1. Mechanistically, we validate co-regulation of NuRD chromatin repressor complex by RAS and PP2A. Consistent with their known synergistic effects in cancer, RAS activation and PP2A inhibition resulted in epigenetic reporter de-repression and activation of oncogenic transcription. Notably, transcriptional de-repression by PP2A inhibition was associated with increased euchromatin and decrease in global DNA methylation. Further, targeting of RAS- and PP2A-regulated epigenetic proteins decreased viability of KRAS-mutant human lung cancer cells. Collectively the results indicate that epigenetic protein complexes involved in oncogenic gene expression constitute a significant point of convergence for RAS hyperactivity and PP2A inhibition in cancer. Further, this work provides a resource for future studies focusing on phosphoregulation as a previously unappreciated layer of regulation of epigenetic gene regulation in cancer, and in other RAS/PP2A-regulated cellular processes.

2023-02-06 | GSE220592 | GEO

RAS and PP2A activities converge on epigenetic gene regulation [RNA-Seq]

2023-02-06 | GSE220591 | GEO

RAS and PP2A activities converge on epigenetic gene regulation [ATAC-Seq]

2023-02-06 | GSE220590 | GEO

The yeast PP2A-CDC55 phosphatase regulates the transcriptional response to hyperosmolarity stress by regulating Msn2 and Msn4 [Time course 2]

Project description:The yeast PP2A-Cdc55 Serine/Threonine phosphatase regulates transcription under certain conditions. It is required for full activation of the environmental stress response mediated by the transcription factors Msn2 and Msn4. PP2A-Cdc55 contributes to sustained nuclear accumulation of Msn2 and Msn4 and extended chromatin recruitment under stress conditions such as hyperosmolarity stress. Transcript profiles of Msn2 and Msn4 double mutants are similar to cdc55 and the corresponding triple mutants. This argues for a Msn2/4 specific function of PP2A-Cdc55. Time course of 0, 10 20 and 30 minutes hyperosmolarity treated yeast cells of msn2msn4 or msn2msn4cdc55 genetic background, both carrying plasmid pMsn2pMsn2DNES; reference hybridization: untreated W303 msn2msn4 pMsn2pMsn2DNES labelled with Cy3

2012-11-06 | E-GEOD-42033 | biostudies-arrayexpress

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