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Cited by 113Protein Kinase Regulation and GTPase SignalingProtein Tyrosine PhosphatasesPI3K/AKT/mTOR signaling in cancer

The B56α Regulatory Subunit of Protein Phosphatase 2A Is a Target for Regulation by Double-Stranded RNA-Dependent Protein Kinase PKR

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Xu, Zan, Williams, Bryan R. G.·2000·Molecular and Cellular Biology
DOI 10.1128/mcb.20.14.5285-5299.2000PMC PMC85978
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Abstract

PKR is a cellular serine/threonine kinase that phosphorylates eukaryotic translation initiation factor 2alpha (eIF2alpha) to regulate protein synthesis. PKR also plays a role in the regulation of transcription, programmed cell death and the cell cycle, processes which likely involve other substrates. In a yeast two-hybrid screen, we isolated human protein phosphatase 2A (PP2A) regulatory subunit B56alpha as a PKR-interacting protein. The interaction between B56alpha and PKR was confirmed by in vitro binding assays as well as by in vivo coimmunoprecipitation, and this interaction is dependent on the catalytic activity of PKR. Moreover, recombinant B56alpha was efficiently phosphorylated by PKR in vitro and an isoelectric point shift in B56alpha was detected in extracts from cells induced with the PKR activator pIC. An in vitro dephosphorylation assay showed that when B56alpha was phosphorylated by PKR, the activity of PP2A trimeric holoenzyme was increased. A functional interaction between B56alpha and PKR was observed in cotransfection assays, where a B56alpha-mediated increase in luciferase expression was inhibited by cotransfection with wild-type PKR. This is likely due to a decreased level of eIF4E phosphorylation caused by an increase in PP2A activity following PKR phosphorylation of B56alpha. Taken together, our data indicate that PKR can modulate PP2A activity by phosphorylating B56alpha to regulate cellular activities.

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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 [84]

    The Results and Discussion (page unavailable) support a proposed mechanism in which PKR phosphorylates B56α, increases PP2A activity, and decreases phosphorylation of eIF4E—not 4E-BPs. The Discussion mentions apoptosis only as a possible effect of altered PP2A activity; it does not establish that this pathway leads to apoptosis. (LLM, conf=0.90)

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Sorted by citations

Authors
Xu, Z., & Williams, B. R. G.
Affiliations
Cleveland Clinic (US)
ORCID
Williams, Bryan R. G.
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2000-07
Volume
20
Issue
14
Pages
5285-5299
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1128/mcb.20.14.5285-5299.2000
PMC
PMC85978
OpenAlex
W2076945543
Cited by
113
References
1
Citations by year
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FWCI
2.15
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (AI 34039-02, R01AI034039)
Topics
  • 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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
PKR, protein phosphatase 2A, double-stranded RNA-dependent protein kinase, protein phosphorylation, eIF2α, eIF4E phosphorylation, protein-protein interaction, translational regulation
MeSH terms
Animals, Cells, Cultured, Enzyme Activation, Humans, Isoelectric Point, Mice, Inbred C57BL, Peptide Initiation Factors, Phosphoprotein Phosphatases, Phosphorylation, Precipitin Tests, Serine, Substrate Specificity, Threonine, Transfection, eIF-2 Kinase, Two-Hybrid System Techniques, Eukaryotic Initiation Factor-4E, Mice, Protein Phosphatase 2

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