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Cited by 276Protein Tyrosine PhosphatasesProtein Kinase Regulation and GTPase SignalingSignaling Pathways in Disease

Actions of PP2A on the MAP kinase pathway and apoptosis are mediated by distinct regulatory subunits

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Silverstein, Adam M., Barrow, Christina A., Davis, Anthony J., Mumby, Marc C.·2002·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.072071699PMC PMC123629
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Abstract

Individual subunits of protein phosphatase 2A (PP2A), protein phosphatase 4, and protein phosphatase 5 were knocked out in Drosophila Schneider 2 cells by using RNA interference. Ablation of either the scaffold (A) or catalytic (C) subunits of PP2A caused the disappearance of all PP2A subunits. Treating cells with double-stranded RNA targeting all four of the Drosophila PP2A regulatory subunits caused the disappearance of both the A and C subunits. The loss of PP2A subunits was associated with decreased protein stability indicating that only the heterotrimeric forms of PP2A are stable in intact cells. Ablation of total PP2A by using double-stranded RNA against either the A or C subunit, or specific ablation of the R2/B regulatory subunit, enhanced insulin-induced ERK activation. These results indicated that the R2/B subunit targets PP2A to the mitogen-activated protein (MAP) kinase cascade in Schneider 2 cells, where it acts as a negative regulator. A severe loss of viability occurred in cells in which total PP2A or both isoforms of the Drosophila R5/B56 subunit had been ablated. The reduced viability of these cells correlated with the induction of markers of apoptosis including membrane blebbing and stimulation of caspase-3-like activity. These observations indicated that PP2A has a powerful antiapoptotic activity that is specifically mediated by the R5/B56 regulatory subunits. In contrast to PP2A, ablation of protein phosphatase 4 caused only a slight reduction in cell growth but had no effect on MAP kinase signaling or apoptosis. Depletion of protein phosphatase 5 had no effects on MAP kinase, cell growth, or apoptosis.

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  • Destabilization of CIP2A upon B56 inhibition is reminiscent of B subunit destabilization upon inhibition of PP2A core complex components.

    “Interestingly, destabilization of CIP2A upon B56 inhibition is reminiscent of B subunit destabilization upon inhibition of PP2A core complex components [38]”

    From Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56 (2017) · cites this paper as [38]

  • PP2A regulates WNT, mTOR, and MAP kinase signaling pathways by dephosphorylating over 300 distinct substrates, including c-MYC, p53, and β-catenin, thereby modulating their activity and stability.

    “The functionality of PP2A is to regulate key signaling pathways, including WNT, mTOR, and MAP kinase, by dephosphorylating over 300 distinct substrates, such as c-MYC, p53, and β-catenin, thereby modulating their activity and stability [ 7 – 11 ].”

    From Targeting PP2A in cancer: an underrated option (2025) · cites this paper as [7]

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Research works printed but not linked: 3

  1. [4]Kamibayashi C, Estes R, Lickteig R L, Yang S-I, Craft C, Mumby M C. J Biol Chem. 1994;269:20139–20148. [PubMed] [Google Scholar]
  2. [8]Gause K C, Homma M K, Licciardi K A, Seger R, Ahn N G, Peterson M J, Krebs E G, Meier K E. J Biol Chem. 1993;268:16124–16129. [PubMed] [Google Scholar]
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Authors
Silverstein, A. M., Barrow, C. A., Davis, A. J., & Mumby, M. C.
Affiliations
The University of Texas Southwestern Medical Center (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2002-03-19
Volume
99
Issue
7
Pages
4221-4226
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.072071699
PMC
PMC123629
OpenAlex
W2101803513
Cited by
276
References
59
Citations by year
2026: 3 · 2025: 5 · 2023: 8 · 2022: 5 · 2021: 5 · 2020: 12 · 2019: 6 · 2018: 11 · 2017: 17 · 2016: 6 · 2015: 10 · 2014: 10 · 2013: 11 · 2012: 11
FWCI
6.84
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of General Medical Sciences (GM-20530, GM49505, R01GM049505, F32GM020530)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
protein phosphatase 2A, PP2A regulatory subunit, MAPK signaling, ERK activation, apoptosis, anti-apoptotic effects, protein stability, protein phosphatase 4, protein phosphatase 5, caspase-3, Drosophila
MeSH terms
Animals, Cells, Cultured, Drosophila, Enzyme Activation, Phosphoprotein Phosphatases, RNA, Double-Stranded, Apoptosis, MAP Kinase Signaling System, Protein Subunits, Protein Phosphatase 2

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