α4 Is an Essential Regulator of PP2A Phosphatase Activity
Open accessAbstract
The activity and specificity of serine/threonine phosphatases are governed largely by their associated proteins. alpha4 is an evolutionarily conserved noncatalytic subunit for PP2A-like phosphatases. Though alpha4 binds to only a minority of PP2A-related catalytic subunits, alpha4 deletion leads to progressive loss of all PP2A, PP4, and PP6 phosphatase complexes. In healthy cells, association with alpha4 renders catalytic (C) subunits enzymatically inactive while protecting them from proteasomal degradation until they are assembled into a functional phosphatase complex. During cellular stress, existing PP2A complexes can become unstable. Under such conditions, alpha4 sequesters released C subunits and is required for the adaptive increase in targeted PP2A activity that can dephosphorylate stress-induced phosphorylated substrates. Consistent with this, overexpression of alpha4 protects cells from a variety of stress stimuli, including DNA damage and nutrient limitation. These findings demonstrate that alpha4 plays a required role in regulating the assembly and maintenance of adaptive PP2A phosphatase complexes.
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These PP2A defects were accompanied by an overall increase in basal phosphorylation of several known PP2A substrates (p53, RelA, FoxO1; ATM, S6K, AMPK; Histone H2AX) and a decreased ability of the cells to reverse stress-induced phosphorylations.
“These PP2A defects were accompanied by an overall increase in basal phosphorylation of several known PP2A substrates (e.g.transcription (co-)factors p53, RelA and FoxO1; kinases ATM, S6K and AMPK; and Histone H2AX) and a decreased ability of the cells to reverse stress-induced phosphorylations [25].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [25]
In isolated adipocytes with induced α4 knockout and in vivo upon conditional knockout of α4 in liver, decreased levels of PP2A A and C subunits, decreased PP2A-C methylation, increased H2AX phosphorylation, and induced stress response signals were observed.
“These in vitro biochemical data were further underscored in isolated adipocytes with induced α4 KO [44], as well as in vivo, upon conditional KO of α4 in liver, where, again, decreased levels of PP2A A and C subunits were observed, decreased PP2A-C methylation, increased phosphorylation of H2AX and induced stress response signals [25].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [25]
Alpha4-/- MEFs showed increased rates of apoptosis and a 70% reduced activity of immunoprecipitated PP2A-C, decreased levels of A and C subunits, and decreased levels of AC dimers.
“Αlpha4 -/-MEFs showed increased rates of apoptosis and a 70% reduced activity of immunoprecipitated PP2A-C, decreased levels of A and C subunits, and decreased levels of AC dimers.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [25]
In Igbp1 -/- MEFs, reversal of stress-induced phosphorylations is decreased.
“-In -/-MEFs: increased basal phosphorylation of several established | PP2A substrates; decreased reversal of stress-induced | phosphorylations”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [25]
In these cells, cell adhesion is decreased.
“-In Bcl-x L -expressing MEFs: slower cell spreading; decreased cell | adhesion; reduced cell migration; reduced Rac1 activation; | phenotypes rescued by active Rac1 V12 mutant”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [25]
In Igbp1 -/- adipocytes, apoptosis occurs, with c-jun, p53 and caspase-3 activation.
“-In -/-adipocytes: apoptosis (c-jun, p53, caspase-3 activation)”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [25]
In Igbp1 -/- MEFs, several known PP2A substrates show higher basal phosphorylation.
“-In -/-MEFs: increased basal phosphorylation of several established | PP2A substrates; decreased reversal of stress-induced | phosphorylations”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [25]
In Igbp1 -/- liver, there were signs of apoptosis together with p53 and c-Jun activation.
“-In liver: all mice died 6 days after adeno-Cre injection; livers showed | signs of apoptosis and p53 and c-Jun activation”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [25]
In these cells, cell migration is reduced.
“-In Bcl-x L -expressing MEFs: slower cell spreading; decreased cell | adhesion; reduced cell migration; reduced Rac1 activation; | phenotypes rescued by active Rac1 V12 mutant”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [25]
In Igbp1 -/- mice, T-cell development is impaired.
“-Impaired T-cell development [25,44,45]”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [25]
In Igbp1 -/- MEFs, apoptosis occurs, accompanied by activation of c-jun, p53 and caspase-3 and by PARP cleavage.
“-In -/-MEFs: apoptosis (c-jun, p53 and caspase-3 activation, PARP | cleavage); (partially) rescued by expression of papilloma E6 protein, | or Bcl-xL”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [25]
In Bcl-xL-expressing Igbp1 -/- MEFs, cell spreading is slower.
“-In Bcl-x L -expressing MEFs: slower cell spreading; decreased cell | adhesion; reduced cell migration; reduced Rac1 activation; | phenotypes rescued by active Rac1 V12 mutant”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [25]
In Igbp1 -/- liver, every mouse died six days after adeno-Cre injection.
“-In liver: all mice died 6 days after adeno-Cre injection; livers showed | signs of apoptosis and p53 and c-Jun activation”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [25]
In Igbp1 -/- MEFs, apoptosis is partly reversed by papilloma E6 protein or Bcl-xL expression.
“-In -/-MEFs: apoptosis (c-jun, p53 and caspase-3 activation, PARP | cleavage); (partially) rescued by expression of papilloma E6 protein, | or Bcl-xL”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [25]
In these cells, the phenotypes are rescued by active Rac1 V12 mutant.
“-In Bcl-x L -expressing MEFs: slower cell spreading; decreased cell | adhesion; reduced cell migration; reduced Rac1 activation; | phenotypes rescued by active Rac1 V12 mutant”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [25]
In these cells, Rac1 activation is reduced.
“-In Bcl-x L -expressing MEFs: slower cell spreading; decreased cell | adhesion; reduced cell migration; reduced Rac1 activation; | phenotypes rescued by active Rac1 V12 mutant”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [25]
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- Authors
- Kong, M., Ditsworth, D., Lindsten, T., & Thompson, C. B.
- Affiliations
- Abramson Cancer Center (US)
- Corresponding author
- Thompson, Craig B.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 36
- Issue
- 1
- Pages
- 51-60
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC2761955
- OpenAlex
- W2041171080
- Cited by
- 162
- References
- 44
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 11 · 2022: 11 · 2021: 8 · 2020: 10 · 2019: 13 · 2018: 10 · 2017: 13 · 2016: 15 · 2015: 12 · 2014: 12 · 2013: 13 · 2012: 8
- FWCI
- 3.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P01CA104838, R01CA092660, R01CA105463)
- 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
- alpha4 subunit, protein phosphatase 2A, serine/threonine phosphatase, proteasomal degradation, cellular stress response, DNA damage, nutrient limitation, dephosphorylation
- MeSH terms
- Animals, Camptothecin, Cell Line, Cell Survival, DNA Damage, DNA-Binding Proteins, Doxorubicin, Enzyme Stability, Female, Histones, Humans, Liver, Male, Phosphoprotein Phosphatases, Phosphoproteins, Phosphorylation, Gene Expression, Tumor Suppressor Protein p53, Protein Serine-Threonine Kinases, Mice, Knockout, Cell Cycle Proteins, Molecular Chaperones, Heat-Shock Response, Tumor Suppressor Proteins, Intercellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, Protein Phosphatase 2, Ubiquitination, Protein Multimerization, Ataxia Telangiectasia Mutated Proteins
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