PKR Regulates B56α-mediated BCL2 Phosphatase Activity in Acute Lymphoblastic Leukemia-derived REH Cells
Open accessAbstract
Protein phosphatase 2A (PP2A) is a heterotrimer comprising catalytic, scaffold, and regulatory (B) subunits. There are at least 21 B subunit family members. Thus PP2A is actually a family of enzymes defined by which B subunit is used. The B56 family member B56alpha is a phosphoprotein that regulates dephosphorylation of BCL2. The stress kinase PKR has been shown to phosphorylate B56alpha at serine 28 in vitro, but it has been unclear how PKR might regulate the BCL2 phosphatase. In the present study, PKR regulation of B56alpha in REH cells was examined, because these cells exhibit robust BCL2 phosphatase activity. PKR was found to be basally active in REH cells as would be predicted if the kinase supports B56alpha-mediated dephosphorylation of BCL2. Suppression of PKR promoted BCL2 phosphorylation with concomitant loss of B56alpha phosphorylation at serine 28 and inhibition of mitochondrial PP2A activity. PKR supports stress signaling in REH cells, as suppression of PKR promoted chemoresistance to etoposide. Suppression of PKR promoted B56alpha proteolysis, which could be blocked by a proteasome inhibitor. However, the mechanism by which PKR supports B56alpha protein does not involve PKR-mediated phosphorylation of the B subunit at serine 28 but may involve eIF2alpha activation of AKT. Phosphorylation of serine 28 by PKR promotes mitochondrial localization of B56alpha, because wild-type but not mutant S28A B56alpha promoted mitochondrial PP2A activity. Cells expressing wild-type B56alpha but not S28A B56alpha were sensitized to etoposide. These results suggest that PKR regulates B56alpha-mediated PP2A signaling in REH cells.
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PKR can induce dephosphorylation of 4E-BPs by increasing the activity of phosphatase 2A after its interaction with the regulatory subunit B56α, leading to cell apoptosis.
“PKR can induce dephosphorylation of the proteins 4E-BPs by increasing the activity of the phosphatase 2A after its interaction with the regulatory subunit B56α, leading to cell apoptosis [82–84].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [82]
The Abstract and the section on PKR suppression in REH cells link PKR, B56α-regulated mitochondrial PP2A activity, and apoptosis. They identify BCL2—not 4E-BPs—as the protein dephosphorylated in this pathway. A search for 4E-BPs and 4E-BP1 found no passage supporting that part of the claim. (LLM, conf=0.88)
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Cites
The dsRNA protein kinase PKR: Virus and cell control
García, M. A., Meurs, E. F., & Esteban, M. (2007) · Biochimie · doi:10.1016/j.biochi.2007.03.001 · Cited by 644 · see citing works
Structure of the Protein Phosphatase 2A Holoenzyme
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Ruvolo, P. P. (2016) · BBA Clinical · doi:10.1016/j.bbacli.2016.08.002 · Cited by 143 · see citing works
Self-citationMeeusen, B., & Janssens, V. (2018) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2017.10.002 · Cited by 96 · see citing works
PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease
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PPP2R5A: A multirole protein phosphatase subunit in regulating cancer development
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- Authors
- Ruvolo, V. R., Kurinna, S. M., Karanjeet, K. B., Schuster, T. F., Martelli, A. M., McCubrey, J. A., & Ruvolo, P. P.
- Affiliations
- University of Minnesota (US)
- The University of Texas Health Science Center at Houston (US)
- University of Bologna (IT)
- East Carolina University (US)
- Corresponding author
- Ruvolo, Peter P.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-12
- Volume
- 283
- Issue
- 51
- Pages
- 35474-35485
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2602900
- OpenAlex
- W2135657761
- Cited by
- 48
- References
- 2
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 4 · 2017: 4 · 2016: 5 · 2015: 4 · 2014: 3 · 2013: 2 · 2012: 5
- FWCI
- 1.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, cc-by)
- The Scholarship East Carolina University's Institutional Repository (East Carolina University) (submittedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Funders
- Hormel Foundation
- University of Minnesota
- National Institutes of Health
- National Cancer Institute (CA30715, R01CA030715)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- PKR, protein phosphatase 2A, acute lymphoblastic leukemia, REH cells, eIF2α, Akt activation, stress signaling
- MeSH terms
- Antineoplastic Agents, Phytogenic, Etoposide, Humans, Phosphorylation, Signal Transduction, Proto-Oncogene Proteins c-bcl-2, eIF-2 Kinase, Amino Acid Substitution, Mutation, Missense, Eukaryotic Initiation Factor-2B, Cell Line, Tumor, Proto-Oncogene Proteins c-akt, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Protein Phosphatase 2
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