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Cited by 94Protein Tyrosine PhosphatasesProtein Kinase Regulation and GTPase SignalingPI3K/AKT/mTOR signaling in cancer

PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer

Open access
Holly A. Fowle, Ziran Zhao, Xavier Graña·2019·Advances in Cancer Research
DOI 10.1016/bs.acr.2019.03.009PMC PMC9994639
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Abstract

PP2A is a highly conserved eukaryotic serine/threonine protein phosphatase of the PPP family of phosphatases with fundamental cellular functions. In cells, PP2A targets specific subcellular locations and substrates by forming heterotrimeric holoenzymes, where a core dimer consisting of scaffold (A) and catalytic (C) subunits complexes with one of many B regulatory subunits. PP2A plays a key role in positively and negatively regulating a myriad of cellular processes, as it targets a very sizable fraction of the cellular substrates phosphorylated on Ser/Thr residues. This review focuses on insights made towards the understanding on how the subunit composition and structure of PP2A holoenzymes mediates substrate specificity, the role of substrate modulation in the signaling of cellular division, growth, and differentiation and its deregulation in cancer.

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Written from the paper’s full text.

TL;DR

This review describes how PP2A heterotrimeric holoenzymes achieve substrate specificity through diverse B regulatory subunits and how their deregulation contributes to cancer. It synthesizes structural, biochemical, cell-cycle, developmental, and cancer data to argue that PP2A has context-dependent tumor-suppressive and oncogenic roles.

Key findings

  • PP2A forms a heterodimeric A/C core and heterotrimeric holoenzymes with B subunits; isoform diversity can generate up to 60 distinct holoenzymes. PP2A can make up close to 1% of total cellular protein in certain tissues, and PP2A/Aα is approximately 10-fold more abundant than PP2A/Aβ, while PP2A/Cα is about 10-fold more abundant than PP2A/Cβ.
  • The B regulatory subunit is the key determinant of substrate specificity and subcellular localization. B56 uses an LxxIxE SLIM motif; B55 substrates have a bipartite polybasic motif; and PP2A/B55 prefers phosphothreonine over phosphoserine, with turnover for short TP peptides at least 34-fold higher than for otherwise identical SP substrates.
  • PP2A regulates cell-cycle progression, including G2/M, mitosis, and G1/S, partly through pocket protein dephosphorylation and Greatwall/ENSA/ARPP19-mediated inhibition of PP2A/B55. It also regulates MAPK and PI3K/AKT signaling, differentiation, development, and immune signaling.
  • Cancer-associated alterations include PPP2R1A mutations in 18.4%–43.2% of various cancer cases; B56δ knockout mice developed hematologic malignancies in 33% of cases at 0–6 months and hepatocellular carcinomas at frequencies from 17% (12–18 months) to 57% (18–24 months); CIP2A mRNA overexpression was found in 39% of breast cancers and 87% of gastric cancers. PP2A inhibitors SET, CIP2A, and Greatwall are linked to cancer, while PP2A activators and inhibitor combinations are explored therapeutically.

Methods

  • Narrative review; no primary experimental design, sample, or statistical analysis is reported.
  • Synthesizes published structural, biochemical, genetic, cell-cycle, developmental, and cancer studies, including mouse models, cell lines, patient mutation data, and cited mechanistic experiments.
  • Main analysis is qualitative integration of PP2A holoenzyme structure/assembly, substrate-recognition mechanisms, cellular functions, and cancer deregulation.

Limitations

  • Not stated in the paper: the review does not include an explicit limitations section.
  • Evident from the text: as a narrative review, it lacks a systematic search strategy, meta-analysis, or primary data, so conclusions depend on the cited literature and may be subject to selection or reporting bias.
  • The text identifies unresolved mechanistic questions, including that the molecular basis for B55α substrate contacts and phosphosite positioning remains elusive, whether B55α binds SLIMs is unknown, and the molecular details governing PP2A/B55’s phosphothreonine preference remain unclear.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/bs.acr.2019.03.009

Cites

189 of 189 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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  • Premiseown data

    PR70 binding maximally stretches the scaffold, making PR70-containing holoenzymes the most elongated among B subunit families.

    “PR70 binding to the scaffold subunit causes it to maximally stretch and makes PR70-containing holoenzymes the most elongated relative to the other B subunit families (Fig 2).”
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  • Premisecitation

    B′ subunits have an acidic surface oriented toward the catalytic active site.

    “Structural analysis has also revealed an acidic surface of B’ that is oriented toward the active site of the catalytic subunit (Fig. 2).”
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  • Premisecitation

    The HEAT repeats of PP2A/A can twist open to different degrees to allow binding of regulatory and catalytic subunits.

    “This structural composition allows for a high degree of flexibility, as the HEAT repeats are able to twist open to varying degrees to accommodate the binding of the regulatory and catalytic subunits (reviewed in Shi, 2009b).”
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  • Premisecitation

    The highly conserved C-terminal tail of the catalytic subunit mediates contacts with B-family substrates.

    “For example, the contacts between the catalytic subunit and B family substrates are mediated by its highly-conserved C-terminal tail (Xu et al., 2008).”
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  • Premisecitation

    Tau and p107 share very little overlap in the residues required for B55α binding.

    “It is conceivable that this acidic top may use substrate-specific sequences to discriminate between its various binding partners, as Tau and p107 have been shown to share very little overlap between residues necessary for binding (Jayadeva et al., 2010).”
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    Premisecitation

    PP2A/Aα is expressed in many tissues, whereas PP2A/Aβ is mostly expressed in testis.

    “The tissue-specific expression of the two isoforms of PP2A/A is variable too, as the PP2A/Aα isoform is expressed across many tissue types, while the PP2A/Aβ isoform is mostly expressed in the testis (Zhou et al., 2003).”
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    Premisecitation

    PP2A/Cα and PP2A/Cβ share about 98% sequence identity, with the N-terminus being the most variable region.

    “The two isoforms share approximately 98% sequence identity, with the most variable region being the N-terminus (Stone et al., 1987).”
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    Premisecitation

    The B′′ family has three members and requires calcium, through EF-hand motifs, for binding to the PP2A core enzyme.

    “Unlike the other three families of regulatory subunits, the B” family possess Ca2+-binding EF-hand motifs as they require the presence of calcium for binding to the PP2A core enzyme (Janssens et al., 2003).”
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    Premisecitation

    The PP2A scaffold has 15 tandem HEAT repeats, each made of two antiparallel α-helices, and these repeats form an elongated horseshoe-shaped structure.

    “Structural analysis has revealed that the PP2A scaffold subunit contains 15 tandem HEAT (huntingtin-elongation-A subunit-TOR) repeats, each of which is made up of a pair of antiparallel α-helices (Fig. 1A). These HEAT repeats come together to form an elongated, horseshoe-shaped structure (Groves et al., 1999).”
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    Premisecitation

    The B′ family has five members, and alternative splicing or translation yields ten total B′ products.

    “The B’ family of regulatory subunits (also referred to as B56, PR61, or PPP2R5) is comprised of 5 different members: B56α, B56β, B56γ, B56δ, and B56ε. B56γ and B56δ have 3 alternative splicing isoforms, and B56ε has an alternative translation isoform, which account for the 10 total B’ products identified (reviewed in Yang and Phiel, 2010).”
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    Premisecitation

    The catalytic subunit contacts the C-terminal HEAT repeats of the scaffold, and its contacts with regulatory subunits differ among B families.

    “The catalytic subunit interacts with the C-terminal HEAT repeats of the scaffold subunit (Fig. 1B); this is different from its contacts with regulatory subunits, which are unique for each B-family (Cho and Xu, 2007; Wlodarchak et al., 2013; Xu et al., 2008; Xu et al., 2006).”
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    Premisenone given

    Sequence conservation is high within each B regulatory subunit family but low between families.

    “While sequence conservation within each regulatory subunit family is high, there is very little sequence similarity across families.”
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    Premisereasoning

    Because each of the three PP2A subunit classes is encoded by several isoform genes, up to 60 distinct PP2A holoenzymes can potentially form.

    “There are several genes encoding isoforms within each of the three classes of PP2A subunits, allowing for the potential generation of up to 60 distinct PP2A holoenzymes.”
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    Premisenone given

    The B regulatory subunit comprises four major families, each with two to five genes and many splice variants.

    “The B regulatory subunit of PP2A is comprised of 4 major families (B, B’, B”, and B”’), with each of these families comprising two to five genes and many containing multiple splice variants (Fig. 1A).”
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    Premisecitation

    Methylation of L309 increases the PP2A core enzyme's affinity for some regulatory subunits, such as B55α in cells, but not for every subunit family.

    “Methylation of L309 has been shown to increase the binding affinity of the PP2A core enzyme for certain regulatory subunits (such as B55α in cells) (Longin et al., 2007; Yu et al., 2001), but not every subunit family (Ikehara et al., 2007; Ogris et al., 1997; Tolstykh et al., 2000; Wei et al., 2001; Xing et al., 2006; Xu et al., 2008; Xu et al., 2006).”
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    Premisenone given

    The B subunit determines subcellular localization and is considered the main determinant of PP2A substrate specificity.

    “This subunit is responsible for subcellular localization and is thought to be the key determinant of substrate specificity for the PP2A complex.”
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    Premisecitation

    The PP2A/Aα and PP2A/Aβ isoforms share about 87% sequence identity.

    “There are 2 known isoforms of PP2A/A, PP2A/Aα and PP2A/Aβ, which share approximately 87% sequence identity (Hemmings et al., 1990).”
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    Premisenone given

    The B55 family has four isoforms; B55α and B55δ are ubiquitously expressed, while B55β and B55γ are enriched in brain.

    “The B family of regulatory subunits (also referred to as B55, PR55, or PPP2R2) is comprised of 4 major isoforms: B55α, B55β, B55γ, and B55δ. B55α and B55δ are ubiquitously expressed, while B55β and B55γ have been found to be enriched in the brain.”
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    Premisecitation

    N-terminal HEAT repeats of PP2A/A contact regulatory subunits, while C-terminal HEAT repeats 11-15 contact the catalytic subunit.

    “It has been shown that N-terminal HEAT repeats of PP2A/A make contact with the various regulatory subunits, while C-terminal HEAT repeats (11–15) mediate contacts with the catalytic subunit (Cho and Xu, 2007; Wlodarchak et al., 2013; Xu et al., 2008; Xu et al., 2006)(Fig. 1B).”
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    Premisecitation

    PHLPP dephosphorylates AKT at Thr473 and suppresses AKT-mediated survival.

    “Moreover, the PH-domain-leucin-rich protein phosphatase, PHLPP, also dephosphorylates AKT Thr473, suppressing AKT-mediated survival (Gao et al., 2005).”
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    Premisecitation

    KSR1 is a PP2A dephosphorylation target, and PP2A core dimer and B55α were identified in immunopurified KSR1.

    “Kinase Suppressor of Ras 1 (KSR1), the molecular scaffold that assembles the MAPK pathway, is also a dephosphorylation target of PP2A, as mass spectrometry analysis identified the PP2A core dimer and B55α in immunopurified KSR1.”
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    Premisecitation

    PP2A/B55α holoenzyme subunits were found in immunopurified RAF1, and PDGF stimulated B55α recruitment to RAF1-PP2A/AC.

    “The three subunits of the PP2A/B55α holoenzyme were detected in immunopurified RAF1 by mass spectrometry and B55α recruitment to the RAF1-PP2A/AC complex was stimulated by PDGF, which stimulates RAF1-Ser259 dephosphorylation (Ory et al., 2003).”
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    Premisecitation

    The C-terminus of B′′ subunits binds the catalytic subunit and is thought to serve as a substrate-binding site, with CDC6 binding there.

    “The C-terminus of B” subunits mediates binding to the catalytic subunit and is also thought to act as a substrate binding site, as known interactors including CDC6 have been shown to bind here (Davis et al., 2008; Wlodarchak et al., 2013).”
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    Premisecitation

    B56β dephosphorylates AKT at both Thr308 and Ser473 and helps attenuate insulin signaling.

    “More recent work has shown that B56β also targets AKT for dephosphorylation on both Thr308 and Ser473, facilitating the attenuation of insulin signaling (Rodgers et al., 2011).”
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    Premisecitation

    STRIPAK complexes participate in cell cycle control and cell signaling.

    “These STRIPAK complexes are involved in several key cellular processes including cell cycle control and cell signaling (reviewed in Hwang and Pallas, 2014).”
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    Premisecitation

    GEF-H1 links KSR1 to PP2A and is needed for KSR1 dephosphorylation and oncogenic RAS signaling through KSR1.

    “More recent studies have found that the guanine nucleotide exchange factor GEF-H1 serves as the bridge linking KSR1 to PP2A, as it is required for KSR1 dephosphorylation and oncogenic RAS signaling via KSR1 (Cullis et al., 2014).”
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    Premisecitation

    SG2NA homodimerization is required for its interaction with PP2A and for STRIPAK assembly.

    “Mutational studies have revealed that SG2NA homodimerization is required for its interaction with PP2A and thus the assembly of STRIPAK complexes (Chen et al., 2014).”
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    Premisecitation

    The PP2A/C active site contains a Zn2+ ion, and ATP is needed to load a catalytic Mg2+ ion for activation.

    “Guo et al. provide evidence that the active site is occupied by a Zn2+ ion and ATP is necessary for the loading of a catalytic Mg2+ ion for PP2A/C activation.”
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    Premisecitation

    The B′′′ family consists of Striatin, Striatin-3, and Striatin-4, which localize mainly to dendritic spines of the corpus striatum.

    “The B”’ family of regulatory subunits is comprised of 3 members: Striatin, Striatin-3 (also known as SG2NA), and Striatin-4 (also known as Zinedin). They are localized primarily in dendritic spines of the corpus striatum, which is an essential component of the motor system (Castets et al., 1996; Moqrich et al., 1998; Salin et al., 1998).”
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    Premisecitation

    PP2A removes phosphate from pocket proteins throughout the cell cycle; pRB is a target of PP2A/PR70, and p107, p130 and probably pRB are targets of PP2A/B55α.

    “As previously mentioned, PP2A can dephosphorylate pocket proteins in all phases in cell cycle, with pRB as a target of PP2A/PR70 and p107, p130 and likely pRB as targets of PP2A/B55α (Jayadeva et al., 2010; Kurimchak et al., 2013; Magenta et al., 2008).”
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    Premisecitation

    The MAPK and PI3K/AKT pathways are regulated by PP2A.

    “Two well-studied signaling pathways that promote cell proliferation and growth have been shown to be regulated by PP2A: mitogen-activated protein kinase (MAPK) and PI3K/AKT pathways.”
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    Premisecitation

    Methylation of L309 is essential for binding of B-family subunits to the core dimer in cells, but not for the other three regulatory subunit families.

    “It is known that methylation of L309 is essential for binding of B family subunits to the core dimer in cells, but not members of the other three regulatory subunit families (Longin et al., 2007; Yu et al., 2001).”
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    Premisecitation

    Loss of LCMT-1 causes apoptosis, indicating that PP2A methylation is required for cell function.

    “Loss of LCMT-1 causes apoptosis in cells, indicating the requirement of PP2A methylation for cell function (Lee and Pallas, 2007).”
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    Premisecitation

    Striatin family members share a coiled-coil domain, a caveolin-binding domain, and a calmodulin-binding domain in the N-terminus, plus a C-terminal WD40 repeat domain.

    “The three Striatin family members share four conserved domains: a coiled coil domain, a caveolin-binding domain, and a calmodulin-binding domain within the N-terminus; and a WD40 repeat domain within the C-terminus (Chen et al., 2014; Moreno et al., 2000).”
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    Premisecitation

    PP2A/B56 can dephosphorylate cyclin E at Ser384, preventing its degradation and possibly allowing Cyclin E/CDK2 to act beyond G1/S.

    “Of note, PP2A may also regulate progression through interphase via PP2A/B56, which dephosphorylates cyclin E on Ser384 to prevent cyclin E degradation potentially mediating Cyclin E/CDK2 phosphorylation of substrates beyond the G1/S transition (Davis et al., 2017).”
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    Premisecitation

    In metazoans, passage through the late-G1 restriction point generally requires extracellular mitogenic signals.

    “In metazoans, except for specific embryonic cycles, progression through the restriction point in late G1 requires extracellular mitogenic signals (Pardee, 1989).”
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    Premisecitation

    PTPA stabilizes an active conformation of the catalytic site and mediates loading of catalytic metal ions.

    “This is facilitated by the phosphotyrosyl phosphatase activator (PTPA), which is a specific for PP2A. PTPA plays a critical role in stabilizing an active conformation of the catalytic active site and mediates the loading of catalytic metal ions (Guo et al., 2014).”
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    Premisecitation

    PDGF treatment causes PP2A/B55 to dephosphorylate KSR1 at Ser392, releasing it from 14-3-3 and allowing membrane translocation that helps activate MAPK.

    “Upon PDGF treatment, PP2A/B55 dephosphorylates KSR1 on Ser392, which releases it from 14-3-3 and allows it to translocate to the cell membrane to facilitate MAPK pathway activation (Ory et al., 2003).”
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    Premisecitation

    α4 binds partially folded PP2A/C, stabilizing it in a latent state and preventing its ubiquitination and degradation by MID1.

    “It has been shown that partially folded PP2A/C is stabilized for latency by the binding of α4, which in part prevents its ubiquitination and subsequent degradation by Midline 1 (MID1) (Jiang et al., 2013; Liu et al., 2001; Short et al., 2002).”
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    PP2A is important in development, and its dysfunction has been linked to developmental diseases.

    “PP2A plays a critical role in regulating development and its dysfunction has been implicated in developmental diseases.”
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    Premisecitation

    Most cancer-associated PPP2R1A mutations encode inactive PP2A/Aα or PP2A/Aβ scaffolds that prevent proper holoenzyme formation and promote carcinogenesis.

    “Most cancer-associated mutations encode inactive PP2A/Aα or PP2A/Aβ scaffolds, which prevent proper PP2A holoenzyme formation and promote carcinogenesis (Haesen et al., 2016).”
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    Interpretationreasoning

    Because PP2A/B55α has many substrates with diverse functions, it may act either as a tumor suppressor or as an oncogene depending on context.

    “Given the large number of PP2A/B55α substrates with diverse functions, it is conceivable that this key phosphatase bears context-dependent tumor suppressive or oncogenic functions.”
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    Premisecitation

    FGF1 rapidly dephosphorylates p107 in RCS cells, followed by p130 and pRB, leading to chondrocyte maturation and cell cycle exit.

    “Upon FGF1 treatment, p107 is rapidly dephosphorylated in rat chondrosarcoma (RCS) cells, followed by dephosphorylation of p130 and pRB, leading to chondrocyte maturation and cell cycle exit.”
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    Premisecitation

    Ppp2r1a knockout in mice is embryonic lethal between E5 and E10.5, suggesting the PP2A/Aα scaffold is required for embryonic development.

    “It has been shown that Ppp2r1a knockout in mice is embryonic lethal (between E5 and E10.5), suggesting that the scaffold subunit PP2A/Aα is required for embryonic development (Ruediger et al., 2011).”
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    Premisecitation

    Greatwall kinase inhibits PP2A/B55 by phosphorylating Arpp19 and/or ENSA, and its upregulation promotes tumorigenesis.

    “As mentioned earlier, the main function of the Greatwall kinase (known as MASTL in mammals) is to inhibit PP2A/B55 by phosphorylating Arpp19 and/or ENSA, which are inhibitors of PP2A/B55 (reviewed in Castro and Lorca, 2018). Growing evidence suggests that upregulation of Greatwall promotes tumorigenesis (Rogers et al., 2018; Sun et al., 2017; Uppada et al., 2018).”
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    Premisecitation

    SET is a physiological PP2A inhibitor that binds directly to PP2A/C and appears to act as an oncogene.

    “SET is a physiologic PP2A inhibitor that binds directly to the PP2A/C subunit (Switzer et al., 2011). Consistent with the prevalent view that a fraction of PP2A holoenzymes exhibit tumor suppressor functions, SET appears to act as an oncogene.”
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    Premisecitation

    p70S6K and PHD2 are negatively regulated by PP2A.

    “Downstream substrates of the AKT signaling pathway such as p70S6K and PHD2 have also been reported to be negatively regulated by PP2A.”
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    Premisecitation

    PP2A associates with CD28 and CTLA-4, and their cytoplasmic domains can interact with PP2A/C.

    “PP2A has also been reported to associate with CD28 and CTLA-4 (Chuang et al., 2000). GST pulldowns from HEK293 cells have shown that the cytoplasmic domains of CTLA-4 and CD28 can interact with PP2A/C.”
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    Constitutive homozygous Ppp2ca knockout is embryonic lethal at E6.5, while heterozygous embryos develop normally.

    “Similar to the scaffold subunit, constitutive homozygous knockout of Ppp2ca is embryonic lethal (E6.5), whereas heterozygous embryos developed normally (Gu et al., 2012; Götz et al., 1998).”
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    • cites Götz et al., 1998

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mutations in PP2A/B56 family genes correlate with childhood overgrowth and intellectual disability in five individuals.

    “It has been reported that mutations of PP2A/B56 family genes correlate with childhood overgrowth and intellectual disability in 5 individuals (Loveday et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Loveday et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    B56γ is critical for heart development; B56γ−/− mice show increased neonatal death and ventricular septal defects from E16 due to apoptosis.

    “In addition, B56γ is also critical for heart development. Although not embryonic lethal, B56γ−/− leads to increased neonatal death in mice. Starting from E16, B56γ−/− mice exhibit ventricular septal defects in the heart due to increased apoptosis (Varadkar et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Varadkar et al., 2014 source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    Ppp2r5d knockout in mice causes frequent spontaneous tumors, including hematologic malignancies and hepatocellular carcinomas.

    “Although PPP2R5D alterations are not frequently seen in human cancers, Ppp2r5d knockout in mice results in frequent spontaneous tumor development (Lambrecht et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lambrecht et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During amino acid starvation, PP2A is activated by α4 dissociation from PP2A/C and increased PP2A/B55α formation, leading to ULK1 dephosphorylation and autophagy induction.

    “It has been reported that during amino acid starvation, PP2A is activated due to dissociation of α4 from PP2A/C and increased formation of PP2A/B55α, leading to dephosphorylation of the mTORC1 substrate ULK1 and activation, which promotes the induction of autophagy (Wong et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wong et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Knockdown of PP2A/B55α in oocytes causes defective spindle assembly, chromosome misalignment and a DNA damage response at MII.

    “Knockdown of PP2A/B55α in oocytes leads to defective spindle assembly, chromosome misalignment and DNA damage response in MII stage.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Liang et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CIP2A interacts with c-MYC, protecting Ser62 from PP2A-mediated dephosphorylation and stabilizing c-MYC.

    “CIP2A also interacts with c-MYC, protecting c-MYC Ser62 from PP2A-mediated dephosphorylation and thus stabilizing it (Junttila et al., 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Junttila et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Knockdown of B55γ in bone marrow mesenchymal stem cells reduces mineralization, calcium deposits and cuboidal morphology.

    “Knockdown of B55γ in BM-MSCs reduced mineralization with insufficient calcium depoisits and a lack of the characteristic cuoidal cell morphology (Serguienko et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Serguienko et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Early evidence for PP2A as a tumor suppressor came from studies showing that PP2A inhibitors caused tumors in mice and that SV40 small t antigen, which disrupts PP2A holoenzymes, was oncogenic.

    “Early support for a role of PP2A as a tumor suppressor came from studies demonstrating that okadaic acid and other potent toxins that inhibit PP2A caused tumors in mice and the observation that the small t antigen of SV40, which disrupts PP2A holoenzymes, was oncogenic (reviewed in Hahn and Weinberg, 2002; Kurimchak and Graña, 2013).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hahn and Weinberg, 2002 source

      Not checked in the free run.

    • cites Kurimchak and Graña, 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    B55α overexpression is observed in pancreatic ductal adenocarcinoma and correlates with poor patient prognosis.

    “While there is growing evidence supporting a tumor suppressor role for PPP2R2A, B55α overexpression has been observed in pancreatic ductal adenocarcinoma tissues and correlated with poor patient prognosis (Hein et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hein et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PPP2R2D is downregulated in hepatocellular carcinoma tumors and cell lines, possibly through miR133b upregulation.

    “The B55δ-encoding gene PPP2R2D is downregulated in hepatocellular carcinoma (HCC) tumors and cell lines, by a mechanism that may involve upregulation of miR133b.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zhuang et al., 2016 source

      Not checked in the free run.

54 of 54

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • PP2A is a tumour suppressor based on its negative regulation of pro-survival and proliferation factors.

    “It is not only a tumour suppressor, based on its negative regulation of pro-survival and proliferation factors1, but also implicated in a variety of other diseases as well as in cellular physiology2.”

    From Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A (2023) · cites this paper as [1]

  • B′ subunits require an intact A subunit for binding, as deduced from in vitro experiments and mouse models.

    “Limited insights have been gained from the B’ subunits, which require an intact A subunit for binding, as deduced from in vitro experiments and mouse models.”

    From Targeting PP2A in cancer: an underrated option (2025) · cites this paper as [33]

  • The Aα paralog of PP2A is 10-fold more abundant than the Aβ paralog and is ubiquitously expressed.

    “The Aα-paralog is 10-fold more abundant than the Aβ-paralog [ 29 ] and is ubiquitously expressed [ 33 ].”

    From Targeting PP2A in cancer: an underrated option (2025) · cites this paper as [33]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • B56δ is mislabeled as B55δ

    Minor

    The list assigns PPP2R5D to B55δ, but an earlier list identifies B56δ as the B' family member. Elsewhere, the paper assigns B55δ to PPP2R2D.

  • AKT site 473 is called both Thr and Ser

    Minor

    The paper identifies AKT site 473 as Ser473, but later calls the same site Thr473 when discussing its dephosphorylation by PHLPP.

2 of 2

Cites

Flagged first, then by citations

3 of the 192 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Fowle, H. A., Zhao, Z., & Graña, X.
Affiliations
Temple University (US)
Corresponding author
Xavier Graña
ORCID
Venue
Advances in Cancer Research
Publisher
Elsevier
Published
2019
Volume
144
Pages
55-93
ISSN
0065-230X (ISSN-L)
DOI
10.1016/bs.acr.2019.03.009
PMC
PMC9994639
OpenAlex
W2939469066
Semantic Scholar
ddf871a86597af919aff6986e43e5088d6405ad8
Cited by
93
References
192
Citations by year
2026: 14 · 2025: 13 · 2024: 14 · 2023: 21 · 2022: 12 · 2021: 13 · 2020: 5 · 2019: 1
FWCI
8.82
Type
book chapter
Language
en
Open access
Licence
Locations
  • Advances in cancer research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • May and Stanley Smith Charitable Trust
  • Foundation for the National Institutes of Health (R03 CA216134-01, R01 GM117437)
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 › PI3K/AKT/mTOR signaling in cancer
Keywords
protein phosphatase 2A, holoenzyme, substrate specificity, catalytic subunit, serine/threonine phosphatase, cell cycle regulation, cell growth and differentiation
MeSH terms
Animals, Cell Cycle, Cell Differentiation, Humans, Neoplasms, Phosphorylation, Substrate Specificity, Signal Transduction, Holoenzymes, Cell Proliferation, Protein Phosphatase 2

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

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