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Cited by 126Protein Tyrosine PhosphatasesProtein Kinase Regulation and GTPase SignalingSignaling Pathways in Disease

Physiologic functions of PP2A: Lessons from genetically modified mice

Open access
Reynhout, Sara, Janssens, Veerle·2019·Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
DOI 10.1016/j.bbamcr.2018.07.010
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Abstract

Protein Phosphatase 2A (PP2A) encompasses a large family of Ser/Thr phosphatases, consisting of a catalytic C subunit and a structural A subunit that are, in most cases, further bound to a regulatory B-type subunit. The B-type subunits determine function and regulation of PP2A trimers, but despite their importance in PP2A biology, their roles in controlling dephosphorylation of a given substrate in a given cell or tissue remain poorly defined, particularly in the context of a complete organism. Besides twenty PP2A subunit encoding genes, some of which are tissue-specifically expressed, five additional genes encode major regulators of active PP2A trimer assembly, and at least seven genes encode cellular PP2A inhibitors, further adding to the complexity of the mammalian PP2A system. In this review, we summarize current knowledge on physiologic functions of PP2A in germ cell maturation, embryonic development, metabolic regulation, tumor suppression, and homeostasis of adult brain, heart, liver, immune system, lung, intestine, kidney, skin, bone and eye, all retrieved from in vivo studies using PP2A transgenic, knockout or knockin mice. Data from 63 mouse models, generated between 1998 and now, reveal the essentiality of PP2A in vivo, and shed light on tissue-specific functions of particular PP2A subunits on the one hand, and functional redundancies on the other hand. In future, it remains of utmost importance to further characterize the existing models, as well as to generate novel models, with the aim of deepening our insights in PP2A (patho)physiology and, particularly, in the therapeutic potential of PP2A targeting in human disease.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes in vivo phenotypes from 63 genetically modified mouse models to map physiologic functions of PP2A across germ cells, development, brain, heart, metabolism, immunity, skin, eye, liver, bone, kidney, intestine, and cancer. It concludes PP2A is essential and highly tissue- and holoenzyme-specific, with B56-type complexes prominent in tumor suppression and many B-subunit functions still unresolved.

Key findings

  • Across 63 mouse models generated between 1998 and the review date, PP2A manipulation caused phenotypes in virtually every tissue examined, including embryonic lethality for constitutive Cα and Aα knockouts and tissue-specific defects in brain, heart, immune, metabolic, and other systems.
  • The models comprise 43 PP2A subunit strains and 20 PP2A regulatory/inhibitory strains; among subunit strains, 19 target C subunits, 10 target A subunits, and 14 target regulatory B-type subunits.
  • PP2A-B56-type complexes, particularly B56α and B56δ, show tumor-suppressive roles in vivo: B56δ loss produced spontaneous hematologic malignancies and hepatocellular carcinomas in up to 60% of mice in the oldest age category, while B56α loss accelerated DMBA/TPA-induced skin papillomas.
  • Distinct PP2A holoenzymes can have opposite metabolic effects: liver-specific Cα deletion improved glucose tolerance and insulin sensitivity, whereas hepatocyte-specific B56γ knockdown increased insulin sensitivity and glucose tolerance but worsened dyslipidemia.

Methods

  • Review and synthesis of published in vivo studies using PP2A transgenic, knockout, or knockin mice, covering 63 genetically modified strains.
  • Models are grouped by manipulated gene: catalytic C subunits, structural A subunits, regulatory B subunits, and PP2A biogenesis regulators or cellular inhibitors.
  • Tissue expression context is drawn from Mouse ENCODE RNA-seq data across adult or embryonic mouse tissues, displayed as a heat map with RPKM values.

Limitations

  • The paper states that interpretation of phenotypes is not always straightforward because total PP2A levels are tightly regulated; overexpression or knockout of one subunit may titrate other endogenous subunits, causing “competitive adaptation” rather than a direct effect of the targeted holoenzyme.
  • The paper states that several PP2A biogenesis regulators may also affect PP2A-like phosphatases PP4 and PP6, so their knockout or overexpression may not solely affect PP2A.
  • The paper states that many regulatory B-subunit genes have not been studied in vivo, and functional redundancy among PP2A subunits complicates interpretation of phenotypes or lack of phenotypes; it is evident from the text that this is a review of existing models rather than new primary experimental data.

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

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Registry

Crossref · 10.1016/j.bbamcr.2018.07.010

Cites

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Statistics

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Claims the paper makes

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  • Findingown data

    Relatively few PP2A strains have manipulated a single regulatory B-type subunit (14 models).

    “Despite their inferred importance in PP2A biology and the fact that they are represented by no less than 15 different mouse genes, relatively few PP2A strains have manipulated a single regulatory B-type subunit (Table 3, 14 models).”
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  • Findingcitation

    Mice heterozygous for a hypomorphic Ppp2r5d allele had approximately 50% reduction of B56δ protein in total brain lysates.

    “mice, heterozygous for a hypomorphic Ppp2r5d allele, and showing a ~50% reduction of B56δ protein levels in total brain lysates [57].”
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  • Findingcitation

    PME-1 overexpression caused additional impairments in cognitive/behavioral tests and long-term potentiation in the presence of pathological Aβ concentrations.

    “This was accompanied by an added impairment in several cognitive/behavioral tests and long-term potentiation (LTP) in the presence of pathological Aβ concentrations.”
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  • Findingcitation

    In Purkinje cells, increased phosphorylation of MEK/ERK/Elk and JNK/c-jun was observed.

    “a detailed analysis of the Purkinje cells also revealed increased phosphorylation of MEK/ERK/Elk and JNK/c-jun [53]”
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  • Findingcitation

    Decreased PP2A-C methylation through forebrain PME-1 overexpression increased tau phosphorylation at Ser396/Ser404, Ser202/Thr205, and Ser262, and APP phosphorylation at Thr668 in the hippocampus.

    “Decreased PP2A-C methylation, as observed in an overexpression model of the PP2A methylesterase PME-1 in the entire forebrain, resulted in increased phosphorylation of tau (Ser396/Ser404, Ser202/Thr205, Ser262) and of amyloid precursor protein (APP) at Thr668 in the hippocampus [55].”
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    Findingown data

    Data from 63 mouse models generated between 1998 and now show that PP2A is essential in vivo and reveal tissue-specific functions of particular PP2A subunits as well as functional redundancies.

    “Data from 63 mouse models, generated between 1998 and now, reveal the essentiality of PP2A in vivo, and shed light on tissue-specific functions of particular PP2A subunits on the one hand, and functional redundancies on the other hand.”
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    Findingown data

    Most PP2A strains manipulate C subunits (19 models) or A subunits (10 models).

    “The majority of PP2A strains represent models with genetic manipulation of the C subunits (Table 1, 19 models) or A subunits (Table 2, 10 models).”
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    Findingreasoning

    Data from 43 PP2A subunit strains and 20 regulatory/inhibitory strains reveal essential PP2A functions in virtually every tissue examined and a complex pattern of tissue-specific functions and functional redundancies.

    “The data reveal essential PP2A functions in virtually any tissue examined, and shed light on a complex pattern of tissue-specific functions of specific PP2A subunits on the one hand, and functional redundancies on the other hand.”
    Quote in the paperSubstantial claim

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    Findingreasoning

    Upon careful examination, clear phenotypes were observed in all B subunit models, underscoring the physiologic need for many regulatory B-subunits in mammals.

    “Nevertheless, it is clear that, upon careful examination of these mice, clear phenotypes could be observed in all cases, underscoring the physiologic need for the existence of the plethora of regulatory B-subunits in mammals.”
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    Findingcitation

    Constitutive Lcmt1 knockout is embryonically lethal, and constitutive Ppme1 knockout is perinatally lethal at P1 due to inability to start normal breathing or suckling.

    “constitutive KO of Lcmt1 was embryonically lethal, and constitutive KO of Ppme1 resulted in perinatal lethality, with all mice dying at P1 due to lack of ability to start normal breathing or suckling [39,56].”
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    Findingcitation

    Brainstem lysates from B56δ knockout mice had nearly complete absence of the CDK5 activator p35 and decreased CDK5 activity, correlating with decreased GSK-3β inactivating Ser9 phosphorylation.

    “a nearly complete absence of the CDK5 activator p35 and decreased CDK5 activity were found in brainstem lysates, correlating with decreased GSK-3β inactivating Ser9 phosphorylation.”
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    Findingcitation

    B56δ knockout mice showed delayed hot plate latency that was unaffected by tau overexpression.

    “the mice exhibited a delayed latency on a hot plate that was unaffected by tau overexpression.”
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    Findingcitation

    B56δ knockout mice had normal learning and memory but motor coordination defects that were more than additively worsened by additional tau overexpression.

    “The B56δ KO mice showed normal learning and memory, but had motor coordination defects that were more than additively affected in B56δ KO mice in which tau was additionally overexpressed.”
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    Findingcitation

    Increased acoustic startle response in B56δ knockout mice correlated with GSK-3β Ser9 hyperphosphorylation and decreased phosphorylation of KCNQ2.

    “The increased acoustic startle response in the B56δ KO mice correlated with GSK-3β hyperphosphorylation (Ser9), and decreased phosphorylation of the presumed GSK-3β substrate, KCNQ2, an M-type potassium channel protein [57].”
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    Findingcitation

    Forebrain LCMT-1 overexpression protected against Aβ-induced impairments despite no detectable changes in PP2A-C methylation.

    “Conversely, LCMT-1 overexpression in the forebrain protected against these Aβ-induced impairments, despite any detectable changes in PP2A-C methylation [55].”
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    Findingcitation

    No impact on motor performance, sensory perception, motivation, or LTP was seen in the absence of Aβ or at very low Aβ concentrations.

    “No impact on motor performance, sensory perception, motivation or LTP was seen in the absence of Aβ, or in the presence of very low Aβ concentrations.”
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    Findingcitation

    In LCMT-1 transgenic mice, tau phosphorylation was unchanged while APP Thr668 phosphorylation was decreased.

    “In these transgenic mice, no effects on tau phosphorylation were observed, while APP phosphorylation (Thr668) was decreased.”
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    Findingcitation

    B56δ knockout mice developed tauopathy in the brainstem and dorsal horn of the spinal cord, with altered tau conformation and increased tau phosphorylation, but without tau filaments, NFTs, or neurodegeneration.

    “In this model, tauopathy was observed in the brainstem and the dorsal horn of the spinal cord, characterized by an altered tau conformation (MC-1 positive) and progressively increased tau phosphorylation (AT8, AT180), without tau filament or NFT formation and with no neurodegeneration [54].”
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    Findingcitation

    These mice showed increased motivation to respond to a food reinforcer, decreased locomotor response to acute cocaine, and normal baseline locomotor activity.

    “These mice showed increased motivation to respond to a food reinforcer, and a decreased locomotor response to acute cocaine exposure, while exhibiting normal baseline locomotor activity.”
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    Findingcitation

    B56γ knockout mice showed increased neonatal death at P1-P2, were less active, and were smaller than wild-type littermates.

    “These mice showed increased neonatal death (P1-P2), were less active and smaller in mass than their WT littermates.”
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    Findingcitation

    B56γ knockout hearts had significantly thinner ventricular walls and less ventricular tissue, with total lack of a ventricular septum in half of fetuses at E16.5.

    “In their hearts, significantly thinner ventricular walls and less ventricular tissue were seen, with total lack of a ventricular septum observed in half of the B56γ KO fetuses at E16.5.”
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    Findingcitation

    This increased infarct size was not associated with decreased survival and unexpectedly improved survival in the subacute phase after infarction, potentially due to restoration of normal AKT and GSK-3β phosphorylation and β-catenin levels.

    “This was however not associated with a decreased survival, and unexpectedly, even resulted in improved survival in the subacute phase after infarction -potentially, because upon myocardial infarction, restoration of normal AKT and GSK-3β phosphorylation, and β-catenin levels could be noted [63].”
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    Findingcitation

    Adult cardiomyocyte-specific Ppp2ca knockout caused cardiac hypertrophy, fibrosis, impaired pump function, and increased ANP, BNP, α-MHC, and β-MHC expression.

    “when KO was induced in a cardiomyocytespecific way in 3-month-old adult mice, cardiac hypertrophy, fibrosis and impaired cardiac pump function were observed, again associated with increased expression of ANP, BNP, αand β-MHC [64].”
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    Findingcitation

    In the Ppp2ca knockout, Cα expression was reduced by 80% at P11.5, while in the transgene total PP2A activity was increased 1.7-fold.

    “In the KO, an 80% reduction in Cα expression was observed at P11.5 [62], while in the transgene, total PP2A activity was 1.7-fold increased [61].”
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    Findingcitation

    The AΔ5 phenotype included enlarged heart, impaired left ventricle function, reduced septum thickness, reduced left ventricular posterior wall thickness, and increased β-MHC transcripts.

    “This phenotype was characterized by an enlarged heart, impaired left ventricle function, reduced septum thickness, reduced thickness of the left ventricular posterior wall, and increased expression of β-MHC transcripts [65].”
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    Findingcitation

    In adult knockout mice, Cα was decreased by only 50% and total PP2A activity by 25%, with small compensatory upregulation of B55α and B56ε mRNA and no changes in other B subunits.

    “Although in these mice Cα levels were decreased by only 50% and total PP2A activity by only 25%, a small but significant compensatory upregulation of B55α and B56ε mRNA expression was observed, while expression of all other B subunits was unaffected.”
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    Findingcitation

    These phenotypes were associated with decreased basal DARPP-32 Thr57 and AKT Thr308 phosphorylation in striatal slices and loss of forskolin-induced ERK1 Thr202 phosphorylation.

    “The former phenotypes were associated with a decreased basal phosphorylation of DARPP-32 (Thr57) and AKT kinase (Thr308) in striatal slices, and a loss of forskolin-induced increase in phosphorylation of ERK1 (Thr202).”
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    Findingcitation

    Cα transgenic mice showed increased AKT and GSK-3β phosphorylation and increased β-catenin degradation.

    “Conversely, increased AKT and GSK-3β phosphorylation, and increased β-catenin degradation were seen in the Cα transgenic mice [63].”
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    Findingcitation

    Both cardiomyocyte-specific Ppp2ca overexpression and tamoxifen-induced cardiomyocyte-specific deletion at P6.5 caused cardiac hypertrophy, increased ANP and BNP, ventricular fibrosis, and impaired heart contractility.

    “both cardiomyocyte-specific overexpression as well as tamoxifen-induced, cardiomyocyte-specific deletion of Ppp2ca at P6.5 resulted in mice with cardiac hypertrophy and increased expression of hypertrophic markers ANP and BNP, ventricular fibrosis, and impaired heart contractility [61][62][63].”
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    Findingcitation

    Cα knockout mice had increased phospholamban Ser16 phosphorylation in the heart, while Cα transgenic mice had decreased phospholamban Ser16/Ser17 phosphorylation.

    “the Cα KO mice showed increased phosphorylation of phospholamban (PLB) (Ser16) in the heart [62], while in the Cα transgenes, PLB phosphorylation (Ser16, Ser17) was found decreased [61].”
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    Findingcitation

    Constitutive total-body knockout of ARPP16/19 was embryonically lethal, suggesting a major role during embryogenesis.

    “the constitutive, total body KO of ARPP16/19 was embryonically lethal, suggestive for a major role of these PP2A inhibitors during embryogenesis as well [60].”
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    Findingcitation

    These mice had normal body weights, normal liver-to-body weight ratios, and normal liver histology.

    “The mice showed normal body weights, normal liver-body weight ratios and normal liver histology.”
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    Findingcitation

    B56α overexpression decreased basal phosphorylation of cardiac troponin inhibitor Ser23/24, myosin-binding protein C Ser282, myosin light chain-2 Ser18, and troponin T Ser208, and decreased isoproterenol-induced phospholamban Ser16 phosphorylation.

    “a decreased basal phosphorylation was seen for several myofilament proteins, including cardiac troponin inhibitor (Ser23/24), myosin-binding protein C (Ser282), myosin light chain-2 (Ser18) and troponin T (Ser208), as well as a decreased isoproterenol-induced phosphorylation of PLB (Ser16).”
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    Findingcitation

    B56α knockout mice had reduced intrinsic heart rate, conduction defects, increased sensitivity to parasympathetic stimulation, and resistance to catecholamine- and exercise-induced arrhythmias.

    “These mice suffered from a reduced intrinsic heart rate, conduction defects, and increased sensitivity to parasympathetic stimulation, as evident from their relative resistance to catecholamine and exercise-induced arrhythmias.”
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    Findingcitation

    Increased cardiac B56α expression via adenoviral vector caused higher resting heart rate, increased peak heart rate in response to exercise or β-adrenergic stimulation, and a blunted parasympathetic response.

    “in a model with increased cardiac B56α expression through injection of an adenoviral B56α expression vector in the myocardium, a higher resting heart rate was found, alongside an increased peak heart rate in response to exercise or β-adrenergic stimulation and a blunted response to parasympathetic stimulation.”
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    Findingcitation

    Liver-specific deletion of Ppp2ca improved glucose tolerance and enhanced insulin sensitivity and signaling in liver, but not in muscle.

    “Liver-specific deletion of Ppp2ca resulted in improved glucose tolerance and enhanced insulin sensitivity and signaling in liver, but not in muscle [71].”
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    Findingcitation

    Cardiac-specific B56α overexpression increased basal contractility and myofilament Ca2+ sensitivity, but attenuated the contractile response to β-adrenergic stimulation.

    “in a cardiac-specific transgenic B56α overexpression model, increased basal contractility and myofilament Ca 2+ sensitivity were observed, while an attenuated contractile response was seen upon β-adrenergic stimulation [70].”
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    Findingcitation

    The livers also showed improved glycogen storage and decreased lipid deposition.

    “The livers also showed improved glycogen storage and decreased lipid deposition.”
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    Findingcitation

    Complete constitutive B56α knockout increased cardiac PP2A activity in both heterozygous and homozygous mice, leading to a distinct phenotype.

    “the complete, constitutive KO of B56α (Ppp2r5a), remarkably, increased cardiac PP2A activity (measured on pNPP as a substrate and using the selective pharmacological PP2A inhibitor fostriecin as a specificity control), both in heterozygous and homozygous mice, leading to a completely distinct phenotype [68].”
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    Findingcitation

    B56α knockout had diminished RyR2 Ser2808 and Ser2814 phosphorylation, correlating with reduced Ca2+ sensitivity of RyR2.

    “Further in-depth analysis revealed a diminished phosphorylation of the ryanodine receptor (RyR 2 ) at Ser2808 and Ser2814, correlating with reduced Ca 2+ sensitivity of RyR 2 [68].”
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    Findingcitation

    Serum triglycerides, cholesterol, HDL, and LDL were increased on both normal chow and high-fat diets.

    “increased levels of triglycerides (TGD), cholesterol (CHOL), and high-and low-density lipoproteins (HDL and LDL) in serum, both when mice were given normal chow or high-fat diets [71].”
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    Findingcitation

    In this model, 2-fold B56α overexpression correlated with 2-fold higher PP2A C subunit expression and 2-fold higher okadaic acid-inhibitable phosphorylase-a activity in cytoplasmic and myofilament fractions.

    “the observed 2-fold overexpression of B56α correlated with a 2-fold higher expression level of the PP2A C subunit and a 2-fold higher, okadaic acid-inhibitable, phosphorylase-a activity in the cytoplasmic and myofilament fraction.”
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    Findingcitation

    RyR2 Ser2808 hypophosphorylation was also seen in the cardiac Ppp2ca overexpression model, co-occurring with reductions in CaMKIIα and SERCA protein expression.

    “RyR 2 Ser2808 hypophosphorylation was also seen in the Ppp2ca cardiac overexpression model, co-occurring with reductions of CaMKIIα and sarcoplasmic reticulum Ca 2+ -ATPase (SERCA) protein expression [63].”
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    Findingcitation

    Hepatocyte-specific B56γ knockdown reduced B56γ mRNA by 85% and protein by 50% in the liver.

    “These mice showed a significant reduction in B56γ mRNA (85%) and protein (50%) levels in the liver.”
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    Findingcitation

    Surviving mice in the constitutive total-body Ppp2r5c knockout model became obese, with 30% increased body weights and increased white adipose tissue.

    “the surviving mice in the constitutive total-body KO model of Ppp2r5c (encoding the B56γ subunits) became obese, exhibiting 30% increased body weights and increased amounts of white adipose tissue [67].”
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    Findingcitation

    Increased insulin signaling included increased phosphorylation of AKT Ser473/Thr308, GSK-3α/β Ser21/Ser9, FoxO1 Ser264, and GS Ser641.

    “Increased insulin signaling was exemplified by increased phosphorylation of AKT (Ser473, Thr308), GSK-3α/β (Ser21/Ser9), FoxO1 (Ser264) and GS (Ser641).”
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    Findingcitation

    The digenic model had decreased total AKT levels, increased basal AKT Thr308/Ser473 phosphorylation, and decreased insulin-stimulated AKT, GSK-3β, and p70 S6K phosphorylation.

    “This was accompanied by decreased total AKT levels and increased basal AKT phosphorylation (Thr308, Ser473), but decreased insulin-stimulated AKT, GSK-3β and p70 S6K phosphorylation.”
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    Findingcitation

    These mice showed modest insulin resistance but no overt diabetes.

    “These mice showed modest insulin resistance, but no overt diabetes.”
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    Findingcitation

    Induced loss of Aα decreased PP2A-C expression and resulted in acute cell death in a B-cell lineage-specific manner.

    “Induced loss of Aα apparently decreased PP2A-C expression as well, and resulted in acute cell death in a B-cell lineagespecific manner.”
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    Findingcitation

    Aα knockout cells showed increased glycolysis without changes in mitochondrial respiration, alongside an amplified mTORC1 pathway.

    “Alongside an amplified mTORC1 pathway, the Aα KO cells showed increased glycolysis in the absence of any changes in mitochondrial respiration.”
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    Findingcitation

    Conditional Aα knockout in the B-cell lineage did not affect normal pro-B and early pre-B cell numbers, but severely diminished cell numbers once pre-BCR-dependent stages were reached, resulting in barely detectable mature B-cells.

    “Conditional KO of Aα in the B-cell lineage (at pro-B cell stage) did not affect normal pro-B and early pre-B cell numbers, but severely diminished cell numbers once the pre-B-Cell Receptor (BCR)-dependent stages were reached, resulting in barely detectable mature B-cell numbers [75].”
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    Findingcitation

    BIO-ID and PLA assays revealed a role for PP2A-B56γ in directly controlling AMPK activity, with enhanced Thr172 phosphorylation in B56γ knockdown livers, and in suppressing HIF1α transcriptional activity.

    “BIO-ID and PLA assays revealed a role for PP2A-B56γ in the direct control of AMP-activated protein Kinase (AMPK) activity (Thr172 phosphorylation was enhanced in the B56γ KD livers) and in the suppression of Hypoxia Inducible Factor 1α (HIF1α) transcriptional activity.”
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    Findingcitation

    In livers of type 2 diabetic patients, PPP2R5C expression was significantly increased, and visceral obesity correlated with PPP2R5C transcription in non-diabetic patients.

    “in livers of type 2 diabetic patients, PPP2R5C expression was significantly increased, and visceral obesity correlated with PPP2R5C transcription in non-diabetic patients [73].”
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    Findingcitation

    In diabetic db/db mice, liver-specific Ppp2r5c knockdown worsened dyslipidemia while considerably improving glucose metabolism.

    “in diabetic db/db mice, where liver-specific Ppp2r5c knockdown worsened their dyslipidemia, while their glucose metabolism was considerably improved.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] source

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  • May combine two claims.

    Findingcitation

    Increased cell death correlated with moderate increases in ERK and AKT phosphorylation, increased mTOR-S6 kinase signaling, inactivation of FoxO1 and FoxO3a, and decreased expression of antioxidant FoxO target genes.

    “The increased cell death correlated with moderate increases in ERK and AKT phosphorylation, increased activation of mTOR-S6 kinase signaling, inactivation of FoxO1 and -3a, and decreased expression of antioxidant, FoxO target genes (e.g.Cat).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] source

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  • May combine two claims.

    Findingcitation

    Elevated FoxO1 expression and increased Pepck and G6P mRNA levels were observed in both Ppp2r2a in vitro knockdown and the digenic in vivo model.

    “elevated FoxO1 expression, resulting in increased Pepck and G6P mRNA levels, were observed both in Ppp2r2a in vitro knockdown and in the digenic in vivo model [74].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] source

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  • May combine two claims.

    Findingcitation

    Homozygous mice for a hypomorphic gene-trapped Lcmt1 allele showed an insulin resistance phenotype, with decreased glucose tolerance and increased glucose-stimulated insulin secretion.

    “homozygous mice for a hypomorphic gene-trapped Lcmt1 allele, also showed an insulin resistance phenotype, with decreased glucose tolerance and increased glucose-stimulated insulin secretion [42].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] source

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  • May combine two claims.

    Findingcitation

    B56γ knockdown increased insulin sensitivity and glucose tolerance without affecting body weight, similar to liver-specific Cα knockout mice.

    “Although no effects on body weight could be detected, an increased insulin sensitivity and glucose tolerance phenotype was observed, very similar to the liver-specific Cα KO mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] source

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  • May combine two claims.

    Findingcitation

    In this model, decreased LCMT-1 expression was confirmed in cardiac and skeletal muscle (95%), liver (60%), brain (50%), and kidney (40%), accompanied by decreased PP2A-C methylation in these tissues.

    “decreased LCMT-1 expression was confirmed in cardiac and skeletal muscle (95% decrease), liver (60% decrease), brain (50% decrease) and kidney (40% decrease), and was accompanied by decreased PP2A-C methylation in these tissues [42].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] source

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  • May combine two claims.

    Findingcitation

    Aα-deficient regulatory T-cells showed increased proliferation and an altered metabolic profile, characterized by higher glycolytic and oxidative-phosphorylation rates.

    “Aα-deficient T reg cells showed increased proliferation and an altered metabolic profile, characterized by higher glycolytic and oxidative-phosphorylation rates.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] source

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  • The quote only partly states this claim.

    Findingcitation

    Transgenic mice with wild-type Cα overexpression specifically in T-cells achieved a 30% increase in Cα mRNA and protein expression.

    “A 30% increase in Cα mRNA and protein expression was achieved.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] source

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  • May combine two claims.

    Findingcitation

    By 10-14 weeks, these mice showed dermatitis, scaly tails and ears, eyelid crusting, skin rash, ulcerations, extensive inflammatory and lymphocytic infiltrates in multiple organs, and enlarged secondary lymphoid organs.

    “By 10-14 weeks, these mice showed dermatitis, scaly tails and ears, eyelid crusting, skin rash, ulcerations, extensive inflammatory and lymphocytic infiltrates in multiple organs, and enlarged secondary lymphoid organs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] source

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  • May combine two claims.

    Findingcitation

    This was accompanied by an increased number of activated CD4+ and CD8+ T-cells and increased production of several cytokines in these cells.

    “This was accompanied by an increased number of activated CD4 + and CD8 + T-cells, and increased production of several cytokines in these cells [81].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] source

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  • May combine two claims.

    Findingcitation

    When challenged with Listeria monocytogenes, CIP2A-deficient mice had an impaired adaptive immune response, with reduced numbers of CD4+ T-cells, CD8+ effector T-cells, and IFNγ-producing CD8+ T-cells, indicating reduced proliferation of CIP2A-deficient T-cells.

    “when challenged with Listeria monocytogenes, an impaired adaptive immune response was provoked, with reduced numbers of CD4 + T-cells, CD8 + effector T-cells and IFNγ-producing CD8 + T-cells, indicative for reduced proliferation of CIP2A-deficient T-cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] source

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  • May combine two claims.

    Findingcitation

    Biochemically, this was associated with upregulated mTORC1 activity and increased S6 phosphorylation, while AKT activity was unaltered.

    “Biochemically, this was associated with upregulated mTORC1 activity and increased S6 phosphorylation, while AKT activity was unaltered.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] source

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  • May combine two claims.

    Findingcitation

    Reduction of CIP2A levels resulted in differential expression of genes associated with regulation of autoimmune diseases, although these mice showed normal immune system development and no immunological defects under baseline conditions.

    “reduction of CIP2A levels resulted in a differential expression of genes associated with regulation of autoimmune diseases, although these mice showed normal immune system development and did not display any immunological defects under baseline conditions [83].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] source

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  • May combine two claims.

    Findingcitation

    This was associated with severely decreased JNK signaling and suppressed caspase-3 activation.

    “This was associated with severely decreased JNK signaling and suppressed caspase-3 activation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] source

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  • May combine two claims.

    Findingcitation

    G5PR knockout cells showed prolonged Bim phosphorylation after BCR cross-linking, accompanied by sustained JNK activation and enhanced mitochondrial membrane depolarization.

    “Upon analysis, cells showed prolonged Bim phosphorylation after BCR cross-linking, accompanied by sustained JNK activation and enhanced mitochondrial membrane depolarization.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] source

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  • May combine two claims.

    Findingcitation

    Upon immunization with nitrophenyl-conjugated chicken γ-globulin, G5PR transgenic mice had more germinal center B-cells, increased non-antigen-specific B-cells, decreased antigen-specific B-cells, and decreased antibody production.

    “upon immunization with nitrophenyl-conjugated chicken γ-globulin, more germinal center B-cells were noted, with an increase in non-antigen-specific B-cells and decreased numbers of antigen-specific B-cells, and decreased antibody production.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] source

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  • May combine two claims.

    Findingcitation

    This was associated with enhanced NF-κB signaling in peripheral blood mononuclear cells and increased type-I interferon signaling in peritoneal macrophages upon LPS or Sendai virus infection, with increased IRF3 Ser396 phosphorylation and increased Ifnb1, Isg15, and Rantes expression.

    “This was associated with enhanced NF-κB signaling in peripheral blood mononuclear cells (PBMCs) and increased type-I interferon signaling in peritoneal macrophages, when stimulated with LPS or upon Sendai virus infection, as shown by increased interferon regulatory factor 3 (IRF3) phosphorylation (Ser396), and increased expression of Ifnb1, Isg15 and Rantes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] source

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  • May combine two claims.

    Findingcitation

    Regulatory T-cell-specific knockout of the Aα subunit caused severe, progressive, multi-organ autoimmunity and a lymphoproliferative disorder.

    “A severe, progressive, multi-organ autoimmunity and lymphoproliferative disorder was also observed in regulatory T-cell (T reg )-specific KO mice of the Aα subunit [81].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] source

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  • May combine two claims.

    Findingcitation

    T-cell-specific loss of G5PR led to thymic atrophy and 10-fold reduced thymocyte numbers due to enhanced sensitivity of double positive thymocytes to apoptosis, while their proliferation and differentiation potential remained unaffected.

    “T-cell-specific loss of G5PR lead to thymic atrophy and 10-fold reduced thymocyte numbers, due to enhanced sensitivity of double positive (DP) thymocytes to apoptosis, while their proliferation and differentiation potential remained unaffected [79].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] source

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  • May combine two claims.

    Findingcitation

    Increased cell death upon Aα deficiency was also demonstrated in several B-cell lineage-specific cancer models in vitro and in vivo, but not in myeloid lineage cancer models.

    “increased cell death upon Aα deficiency was also demonstrated in several cell models of B-cell lineage-specific cancers in vitro and in vivo, but not in cancer models of the myeloid lineage”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] source

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  • May combine two claims.

    Findingcitation

    Upon activation by antigens, LPS, or anti-CD40 antibodies, α4 knockout B-cells proliferated significantly less, showing impaired G1/S transition, reduced p70 S6 kinase activation, and reduced rapamycin sensitivity.

    “Upon activation by antigens, LPS or anti-CD40 antibodies, B-cells significantly proliferated less, showing an impaired G1/S transition, reduced p70 S6 kinase activation and reduced rapamycin sensitivity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] source

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  • May combine two claims.

    Findingcitation

    Another conditional α4 knockout model confirmed impaired T-cell development, with more immature thymocytes in the thymus and no mature T-cells detectable in peripheral blood.

    “The impairment in T-cell development in the absence of α4 was also confirmed in another conditional KO model, where in the thymus more immature thymocytes were observed and no mature T-cells could be detected in peripheral blood [44].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] source

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  • May combine two claims.

    Findingcitation

    In bone marrow, normal pro-B cells and reduced pre-B cells were noted, while in spleen the number of mature B220+ B-cells was significantly decreased.

    “In bone marrow, a normal number of pro-B cells and a reduced number of pre-B cells was noted, while in spleen, the number of mature B220 + B-cells was significantly decreased.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] source

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  • May combine two claims.

    Findingcitation

    B-cell-specific knockout of α4 caused impaired B-cell differentiation and reduced proliferation of activated B-cells.

    “Impaired B-cell differentiation and a reduced proliferation of activated B-cells were phenotypes observed in a B-cell-specific KO mouse of α4 [87].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] source

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  • May combine two claims.

    Findingcitation

    α4-overexpressing T-cells exhibited enhanced migration in a transwell assay, correlating with increased levels of activated Rac1.

    “the α4 overexpressing T-cells exhibited enhanced migration in a transwell assay, correlating with increased levels of activated Rac1 [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] source

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  • May combine two claims.

    Findingcitation

    Thymocytes showed decreased cytokine- and anti-CD3-induced proliferation capacity but no increased apoptosis, and impaired CD3 signaling, exemplified by a lack of anti-CD3-induced IL-2R expression while anti-CD3-induced CD28 expression was normal.

    “Thymocytes showed a decreased cytokine-and anti-CD3-induced proliferation capacity but no increased apoptosis, and impaired CD3 signaling, exemplified by a lack of anti-CD3-induced IL-2R expression, while anti-CD3-induced CD28 expression was normal.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] source

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  • May combine two claims.

    Findingcitation

    α4 knockout mice showed reduced B-cell responses to immunization with T-cell independent and particularly T-cell-dependent antigens, with significant reductions in IgM and IgG production, isotype switching, V region somatic hypermutation, and germinal center formation.

    “The mice also showed reduced B-cell responses to immunization with T-cell independent, and particularly with T-cell-dependent antigens, as witnessed by a significant reduction in IgM and IgG production, isotype switching, V region somatic hypermutation and germinal center formation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] source

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  • May combine two claims.

    Findingcitation

    Epidermal-specific loss of Cα resulted in smaller animals with aberrant hair morphogenesis and disruption of the hair follicle regeneration cycle.

    “Epidermal-specific loss of Cα resulted in smaller animals with aberrant hair morphogenesis and disruption of the hair follicle regeneration cycle [89].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] source

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  • May combine two claims.

    Findingcitation

    Transgenic overexpression of α4 in the thymus did not result in any effects on T-cell viability, proliferation, or development.

    “transgenic overexpression of α4 in thymus did not result in any effects on T-cell viability, proliferation or development.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] source

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  • May combine two claims.

    Findingcitation

    Microarray analysis in naive and activated CD4+ T-cells from this model revealed 124 upregulated and only 6 downregulated genes, with upregulated genes primarily encoding cytokines and chemokines, including IL-17.

    “Additional microarray analysis in naïve and activated CD4 + T-cells from this model, revealed 124 upregulated and only 6 downregulated genes, with the upregulated genes primarily encoding cytokines and chemokines, including IL-17 [86].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] source

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  • May combine two claims.

    Findingcitation

    These mice showed increased susceptibility to immune-mediated glomerulonephritis, in the absence of other immune defects.

    “These mice showed increased susceptibility to immune-mediated glomerulonephritis, in the absence of other immune defects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] source

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  • May combine two claims.

    Findingcitation

    Some animals had severe stool obstruction, and 15% of mice died at 4-6 weeks of age.

    “Some animals had severe stool obstruction, and 15% of mice died at 4-6 weeks of age [89].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] source

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  • May combine two claims.

    Findingcitation

    Abnormal hair follicle morphogenesis occurred from the first post-natal hair cycle onwards, characterized by failure of hair cycling and a differentiation defect of matrix cells into the inner root sheath and hair shaft.

    “Abnormal hair follicle morphogenesis occurred from the first post-natal hair cycle onwards, and was characterized by failure of hair cycling and a differentiation defect of matrix cells into the inner root sheath and hair shaft.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] source

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  • May combine two claims.

    Findingcitation

    These mice displayed significant hair loss, a thicker epidermis with more fat cells, prominent melanin deposition in the paws and at the base of the claws and tail, and excessive keratinization of the tail.

    “Mice displayed significant hair loss, had a thicker epidermis with more fat cells, prominent melanin deposition in the paws and at the base of the claws and the tail, and excessive keratinization of the tail.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] source

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  • May combine two claims.

    Premisecitation

    Most B-type subunits appear ubiquitously expressed, but some are restricted to specific tissues and likely mediate tissue-specific PP2A functions.

    “While the large majority of B-type subunits appear ubiquitously expressed, some of them are restricted to specific tissues, and therefore, likely mediate tissue-specific PP2A functions (Fig. 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] source

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

    Premisecitation

    In mammals, the C and A subunits are each encoded by two genes, producing α and β isoforms.

    “In mammals, both subunits are each encoded by two distinct genes, leading to an α and β protein isoform.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] source

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    • cites [7] source

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

    Premisecitation

    PP2A is a family of Ser/Thr phosphatases made of a catalytic C subunit and a structural A subunit, usually bound to a regulatory B-type subunit.

    “Protein Phosphatase 2A (PP2A) encompasses a large family of Ser/Thr phosphatases, consisting of a catalytic C subunit and a structural A subunit that are, in most cases, further bound to a regulatory B-type subunit.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] source

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    • cites [7] source

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

    Premisecitation

    In mice, PP2A expression was detected in all thirty adult or embryonic tissues examined by RNA-seq, with highest expression in brain and lowest in adult liver.

    “In mice, PP2A expression was found in all of thirty adult or embryonic tissues examined by RNA-seq through the Mouse ENCODE Initiative, overall showing the highest expression in brain, and the lowest in adult liver (Fig. 2) [19].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] source

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

    Premisecitation

    About 30% of PP2A in cells is present as an AC dimer composed of a catalytic C subunit and a structural A subunit.

    “A substantial amount of PP2A (around 30%) resides in the cell as a dimer [8], consisting of a catalytic C subunit and a structural A subunit.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] source

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  • May combine two claims.

    Premisecitation

    B55γ is nearly exclusively expressed in brain and B′′α is highly expressed in heart, consistent with previous reports.

    “This is probably best illustrated for B55γ (nearly exclusively expressed in brain) and B″α (highly expressed in heart), in accordance with previously published work of others [20][21][22].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [20] source

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    • cites [21] source

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    • cites [22] source

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  • May combine two claims.

    Premisecitation

    B subunits bind the AC core dimer mutually exclusively and determine substrate specificity, regulation, subcellular localization and physiologic functions of trimeric PP2A complexes.

    “Given that they bind the core dimer in a mutually exclusive way, these regulatory subunits are known determinants of the substrate specificity, regulation and subcellular localization of the different PP2A holoenzymes, and, as such, largely determine the physiologic functions of the trimeric PP2A complexes [11,12].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] source

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    • cites [12] source

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

    Premisecitation

    In addition to about twenty PP2A subunit genes, five genes encode major regulators of active PP2A trimer assembly and at least seven genes encode cellular PP2A inhibitors.

    “Besides twenty PP2A subunit encoding genes, some of which are tissue-specifically expressed, five additional genes encode major regulators of active PP2A trimer assembly, and at least seven genes encode cellular PP2A inhibitors”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] source

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    • cites [14] source

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    • cites [18]

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  • May combine two claims.

    Premisecitation

    The Ppp2ca (Cα) knockout mouse is embryonically lethal, which implies a lack of redundancy between Cα and Cβ isoforms.

    “Despite Cα and Cβ sharing 97% amino acid identity, the Ppp2ca (Cα) knockout (KO) mouse is embryonically lethal [9], implying a lack of redundancy between these isoforms.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] source

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  • May combine two claims.

    Premisecitation

    Ppp2r1a (Aα) knockout mice are not viable despite 86% sequence identity between Aα and Aβ proteins.

    “Likewise, Ppp2r1a (Aα) KO mice are neither viable, despite 86% of sequence identity between Aα and Aβ proteins [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] source

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  • May combine two claims.

    Premisecitation

    Constitutive knockout of CIP2A showed a spermatogenesis defect as one of only two phenotypes.

    “Interestingly, a spermatogenesis defect was also one of only two phenotypes that could be found in a constitutive KO mouse model for CIP2A (Cancerous Inhibitor of PP2A) [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] source

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  • May combine two claims.

    Premisecitation

    Some PP2A genes are developmentally regulated: B55β and B55γ expression increases during embryonic brain development, while SET, ANP32A, ANP32E and CIP2A expression decreases during brain and liver development.

    “Finally, some PP2A genes appear developmentally regulated, best illustrated for B55β and B55γ, the expression of which increases during embryonic brain development, while expression of the PP2A inhibitors SET, ANP32A, ANP32E and CIP2A, conversely, decreases during brain development, and also during liver development (Fig. 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] source

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  • May combine two claims.

    Premisecitation

    In double knockout mice, ovary morphology and ovulation appeared normal, but defective oocytes were observed with lack of the first meiotic division, chromosome congression, alignment and segregation defects, and an abnormal acentrosomal spindle in meiosis-I.

    “While in these mice, ovary morphology and ovulation appeared normal, defective oocytes were observed, characterized by a lack of the first meiotic division, chromosome congression, alignment and segregation defects, and formation of an abnormal acentrosomal spindle in meiosis-I.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] source

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  • May combine two claims.

    Premisecitation

    CIP2A is an oncoprotein that presumably specifically targets PP2A-B56 complexes and inhibits PP2A-mediated dephosphorylation of a limited set of substrates including c-Myc.

    “CIP2A is an oncoprotein, presumably specifically targeting PP2A-B56 complexes [31] and inhibiting PP2A-mediated dephosphorylation of a very limited set of substrates, including e.g.c-Myc [32].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] source

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    • cites [32] source

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  • May combine two claims.

    Premisecitation

    Fertilization was followed by impaired embryonic development: at E0.5 efficient pronuclear formation was defective, and at E4.0 the blastocyst stage was rarely reached and signs of apoptosis were seen.

    “Fertilization was however followed by impaired embryonic development.At E0.5, efficient pronuclear formation was defective, and at E4.0, the blastocyst stage was rarely reached and signs of apoptosis were seen.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] source

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  • May combine two claims.

    Premisecitation

    Cα (Ppp2ca) is expressed about 10-fold higher than Cβ (Ppp2cb) in most tissues, mainly due to the more active promoter region of Ppp2ca.

    “In general, Cα (Ppp2ca) is expressed to a 10-fold higher extent than Cβ (Ppp2cb), mainly due to the more active promotor region of Ppp2ca in most tissues [33] (Fig. 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] source

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  • May combine two claims.

    Interpretationreasoning

    These data imply redundant roles of Cα and Cβ in oocyte formation at meiosis-I, but a nonredundant role of Cα in meiotic processes guiding spermatogenesis.

    “Thus, these data imply redundant roles of Cα and Cβ in oocyte formation at meiosis-I, but a nonredundant role of Cα in meiotic processes guiding spermatogenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The severe phenotypes of biogenesis regulator strains may reflect PP2A essentiality in vivo, while the subtle phenotypes of inhibitor strains might suggest that pharmacologic targeting of these inhibitors is feasible in diseases where their upregulation is pathogenic.

    “The former may again reflect the essentiality of PP2A in vivo, while the latter might suggest the feasibility of pharmacologic targeting of these inhibitors in diseases in which their upregulation is part of the pathogenic mechanism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    These defects correlated with increased phosphorylation of Aurora kinase substrates hKNL1 (Ser24) and Histone H3 (Ser10), and could be partially rescued by hesperadin.

    “These defects correlated with increased phosphorylation of the Aurora kinase substrates, hKNL1 (Ser24) and Histone H3 (Ser10), and could be partially rescued by the pharmacologic Aurora kinase B/C inhibitor, hesperadin.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] source

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  • May combine two claims.

    Premisecitation

    In that model, testes were smaller, normal tubules containing spermatogonia and primary and secondary spermatocytes were absent, germ cells were disorganized, and elongated spermatozoa were lacking.

    “Testes were smaller, normal tubules containing spermatogonia and primary and secondary spermatocytes were absent, germ cells were disorganized, and elongated spermatozoa were lacking all suggestive for a spermatogenesis and meiosis defect.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] source

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  • May combine two claims.

    Premisecitation

    At E6.5, gastrulation could not be initiated, resulting in absence of differentiated mesoderm and Wnt target gene markers Goosecoid and Brachyury in Cα-/- embryos.

    “At this stage, gastrulation could not be initiated, resulting in absence of differentiated mesoderm and accompanying Wnt target gene markers, Goosecoid and Brachyury in Cα -/-embryos [9].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] source

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  • May combine two claims.

    Premisecitation

    In these mice, a meiotic maturation defect was observed: normal meiosis-I, but abnormal elongated spindle formation during meiosis-II, precocious sister chromatid separation due to loss of centromeric cohesion, and increased germinal vesicle breakdown.

    “Again, a meiotic maturation defect was observed, with in this case, a normal meiosis-I, but abnormal elongated spindle formation during meiosis-II, precocious sister chromatid separation due to loss of centromeric cohesion, and increased germinal vesicle breakdown.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] source

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  • May combine two claims.

    Interpretationreasoning

    Together with C subunit knockout data, these data might infer redundant roles for Aα and Aβ in meiosis-I, while Aα would have a nonredundant role in meiosis-II of oocyte formation.

    “Together with the data from conditional C subunit KO mice, these data might infer redundant roles for Aα and Aβ in meiosis-I, while Aα would have a nonredundant role in meiosis-II of oocyte formation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Very similar observations were made in a conditional Ppp2ca knockout model: smaller, degenerated embryos at E6.5, no mesoderm formation, and no Brachyury expression.

    “Very similar observations were made in a conditional Ppp2ca KO mouse model, in which again smaller, degenerated embryos were observed at E6.5, with no mesoderm formation and no Brachyury expression [35].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] source

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  • May combine two claims.

    Premisecitation

    In E18 embryos, smaller lungs were found, lacking distal lung differentiation and peripheral airway formation, while proximal airway and blood vessel development were normal.

    “In E18 embryos, smaller lungs were found, lacking distal lung differentiation and peripheral airway formation, while proximal airway and blood vessel development were normal.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Primitive erythropoiesis was normal, but definitive erythropoiesis was impaired, as witnessed by increased pro-erythroblasts, decreased erythroid colony- and blast-forming units, and reduced β maj/min-globin expression.

    “Specifically, primitive erythropoiesis was normal, but definitive erythropoiesis was impaired, as witnessed by an increased number of pro-erythroblasts, a decreased number of erythroid colony-and blast-forming units and reduced expression of β maj/min -globin.”
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    • cites [38] source

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  • May combine two claims.

    Interpretationreasoning

    Because no gastrulation defects were observed in Lcmt1 knockout mice, it can be postulated that PP2A-B55α/δ trimers either do not play a role in mesoderm formation or play a redundant role.

    “In addition, as in the Lcmt1 KO mice, no gastrulation defects were observed, it can be postulated that PP2A-B55α/δ trimers either do not play a role in mesoderm formation, or play a redundant role in this process.”
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    Premisecitation

    Tamoxifen-inducible loss of Aα in Δ5-6/Δ5-6 knockout mice resulted in immediate weight loss and death six days after induction, with hunched backs and walking difficulties.

    “Apart from its role in embryogenesis, Aα remains important perinatally and in adult mice, since tamoxifen-inducible loss of Aα in a Δ5-6/Δ5-6 KO mouse model, lacking Ppp2r1a exons 5 and 6, resulted in immediate weight loss and subsequent death, six days after induction.The mice also displayed hunched backs and walking difficulties [10].”
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  • May combine two claims.

    Premisecitation

    At E12.5 and E14.5, total cellularity of fetal liver was dramatically reduced, with a pronounced 90% reduction in erythrocytes, while other hematopoietic lineages appeared in normal numbers.

    “At E12.5 and E14.5, total cellularity of fetal liver was dramatically reduced, with a pronounced 90% reduction in erythrocytes, while other hematopoietic lineages appeared in normal numbers.”
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    • cites [38] source

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  • May combine two claims.

    Premisecitation

    Increased apoptosis of committed erythroid cells was observed, correlating with decreased STAT5 phosphorylation (Tyr694) and decreased Bcl-XL expression in basal and EPO-stimulated cells.

    “In addition, increased apoptosis of committed erythroid cells was observed, correlating with decreased STAT5 phosphorylation (Tyr694) and decreased Bcl-X L expression in basal and EPO-stimulated cells [38].”
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    • cites [38] source

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  • May combine two claims.

    Premisecitation

    Ppp2cb conditional knockout mice showed no obvious embryonic or adult phenotype, behaved normally, and were fertile.

    “On the other hand, Ppp2cb conditional KO mice showed no obvious embryonic or adult phenotype, behaved normally and were fertile [35].”
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    • cites [35] source

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    Premisecitation

    The large majority of LCMT-1 knockout embryos died between E14.5 and E16.5; 5% died before E12.5.

    “The large majority of LCMT-1 KO embryos died between E14.5 and E16.5; 5% died before E12.5 [41].”
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    • cites [41] source

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  • May combine two claims.

    Interpretationreasoning

    Similarities between fetal liver phenotypes in conditional Cα knockout and constitutive LCMT-1 knockout suggest that PP2A-C is likely the main in vivo substrate of LCMT-1, and that hematopoiesis defects in both models are most probably attributable to a defect in PP2A-B55α/δ functionality.

    “Thus, the similarities between fetal liver phenotypes in both the conditional Cα KO and constitutive LCMT-1 KO mouse models [38,41], seem to suggest that PP2A-C is likely the main in vivo substrate of LCMT-1, and that the hematopoiesis defects seen in both models are most probably attributable to a defect in PP2A-B55α/δ functionality.”
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    Premisecitation

    Impaired Wnt signaling during development in the t w18 deletion model could be entirely attributed to loss of Ppp2r1a, as re-expression of the full Ppp2r1a gene rescued embryonic lethality at E10.5 and E18.5.

    “In line with the disorganized Wnt signaling in Cα KO mice, impaired Wnt signaling during development in this embryonically lethal t w18 deletion model could indeed be entirely attributed to the loss of Ppp2r1a, as re-expression of the full Ppp2r1a gene, including sequences 3 kb upstream and 20 kb downstream of the transcription initiation site, resulted in a complete rescue of the observed Embryo”
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    • cites [36] source

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  • May combine two claims.

    Interpretationcitation

    The underdeveloped lungs were completely devoid of β-catenin expression, suggesting an important restricting role of PP2A-B56γ complexes in Wnt signaling in lung tissue.

    “The underdeveloped lungs were completely devoid of β-catenin expression, suggesting an important restricting role of PP2A-B56γ complexes in Wnt signaling in lung tissue.”
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    • cites [37]

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  • May combine two claims.

    Premisecitation

    At E12.5 in Lcmt1 knockout, more than 95% decreased PP2A-C methylation was seen, accompanied by 30% reduction in total A and C subunit levels and 92% reduction in PP2A-B55α/δ formation.

    “At E12.5, > 95% decreased PP2A-C methylation was seen, accompanied by 30% reduction in total A and C subunit levels and a 92% reduction in PP2A-B55α/δ formation (due to 80% reduction in B55α/δ expression, and 40% reduction in C binding to B55).”
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    • cites [41] source

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    Premisecitation

    A selective decrease in PP2A-B56γ/ε activity was found in PTPA knockout, while PP2A-B55 activity was unaffected.

    “Interestingly, however, a selective decrease in PP2A-B56γ/ε activity was found, while PP2A-B55 activity was unaffected.”
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    • cites [43] source

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  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] source

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    • cites [44] source

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  • May combine two claims.

    Premisecitation

    Loss of NOSIP caused perinatal lethality and holoprosencephaly, a severe impairment in craniofacial development often associated with defective Hedgehog signaling.

    “Loss of NOSIP caused perinatal lethality and holoprosencephaly, a severe impairment in craniofacial development that is often associated with defective Hedgehog signaling.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] source

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  • May combine two claims.

    Premisecitation

    NOSIP interacts with the C, Aα and B55α subunits, and in vivo loss of NOSIP led to an increase in PP2A activity specifically in palatal and facial tissue.

    “NOSIP interacts with the C, Aα and B55α subunits, and in vivo loss of NOSIP lead to an increase in PP2A activity, specifically in palatal and facial tissue.”
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    • cites [46] source

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  • May combine two claims.

    Premisecitation

    Conditional loss of Ppp2ca in the nervous system resulted in severe microcephaly and cortical atrophy at P7, characterized by loss of cortical neurons and decreased thickness of cortical layers II-V.

    “Conditional loss of Ppp2ca in the nervous system resulted in severe microcephaly and cortical atrophy at P7, characterized by loss of cortical neurons and decreased thickness of cortical layers II-V [47].”
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    • cites [47] source

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  • May combine two claims.

    Premisecitation

    The animals performed poorly in a Morris water maze test, indicating learning and memory defects.

    “The animals performed poorly in a Morris water maze test, indicating learning and memory defects.”
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    • cites [47] source

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  • May combine two claims.

    Premisecitation

    p53-like protein p73 phosphorylation (Tyr99) was enhanced, which could additionally contribute to the observed increase in apoptotic signaling and diminished proliferation of the Cα-/- neuronal progenitor cells.

    “Furthermore, p53-like protein p73 phosphorylation (Tyr99) was enhanced, which could additionally contribute to the observed increase in apoptotic signaling and diminished proliferation of the Cα -/-NPCs [47].”
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  • May combine two claims.

    Interpretationcitation

    Overall, these data underscore the major role of α4 in preventing apoptosis and maintaining proper PP2A function and activity in vivo.

    “Overall, these data further underscore the major role of α4 in preventing apoptosis and maintaining proper PP2A function and activity in vivo.”
    Quote in the paperSubstantial claim

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    Premisecitation

    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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] source

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  • May combine two claims.

    Premisecitation

    All targeted mice died 6 days after induction of hepatic α4 knockout, with livers showing signs of severe apoptosis and increased phosphorylation of p53 and c-jun transcription factors.

    “Moreover, all targeted mice died 6 days after induction of hepatic α4 KO, with livers showing signs of severe apoptosis and increased phosphorylation of p53 and c-jun transcription factors [44].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] source

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  • May combine two claims.

    Premisecitation

    In vivo neuron-specific expression of a Cα mutant with the L309A substitution (which prevents B55 subunit binding) resulted in increased tau phosphorylation (Ser202/Thr205) and impaired dephosphorylation of vimentin, but no neurodegeneration.

    “In vivo neuron-specific expression of a Cα mutant, harboring the L309A substitution in the C-terminal tail that does not affect PP2A-C methylation but specifically prevents B55 subunit binding [40], resulted in increased tau phosphorylation (Ser202/Thr205) and impaired dephosphorylation of vimentin, but no neurodegeneration [49].”
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    • cites [49] source

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  • May combine two claims.

    Premisecitation

    Additional research in neuronal progenitor cells identified upregulation of Hippo signaling, witnessed by increased phosphorylation of MST1/2 (Ser180/183), LATS1 (Ser909) and YAP (Ser127), and inhibited nuclear translocation of YAP.

    “Additional research in neuronal progenitor cells (NPCs) identified an upregulation of Hippo signaling, witnessed by an increased phosphorylation of MST1/2 (Ser180/183), LATS1 (Ser909) and YAP (Ser127), and inhibited nuclear translocation of YAP.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] source

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  • May combine two claims.

    Premisecitation

    Brain-specific α4 knockout mice showed impaired learning and memory (measured through spatial learning and shuttle box avoidance tests), but no sensorimotor or motivational deficiencies.

    “Nevertheless, the brain-specific α4 KO mice did show impaired learning and memory (measured through spatial learning and shuttle box avoidance tests), but no sensorimotor or motivational deficiencies.”
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    • cites [48] source

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  • May combine two claims.

    Premisecitation

    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].”
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    • cites [25] source

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    • cites [44] source

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  • May combine two claims.

    Premisecitation

    Crossbreeding of these mice with P301L mutant tau transgenic pR5 mice intensified tau pathology, further increasing tau Ser422 phosphorylation and neurofibrillary tangle formation in hippocampus and amygdala.

    “Interestingly, crossbreeding of these mice with P301L mutant tau transgenic pR5 mice intensified the tau pathology, further increasing tau Ser422 phosphorylation and neurofibrillary tangle (NFT) formation in hippocampus and amygdala [50].”
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    • cites [50] source

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  • May combine two claims.

    Premisecitation

    NOSIP is a ubiquitin E3 ligase that post-translationally modifies PP2A-C.

    “Another protein that has been shown to post-translationally modify PP2A-C, is nitric oxide synthase interacting protein (NOSIP), a ubiquitin E3 ligase [46].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] source

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  • May combine two claims.

    Premisecitation

    Conditional knockout of α4 in neurons did not result in any gross abnormalities in brain development, despite clearly decreased overall PP2A activity in hippocampal extracts.

    “In contrast, conditional KO of α4 in neurons did not result in any gross abnormalities in brain development, despite clearly decreased overall PP2A activity in hippocampal extracts [48].”
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    • cites [48] source

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  • May combine two claims.

    Premisecitation

    Neuron-specific expression of the dominant negative L199P Cα mutant induced tau hyperphosphorylation at the physiological AT8 (Ser202/205) and pathological pS422 (Ser422) epitopes, accompanied by formation of ubiquitin-containing tau aggregates in somatodendritic neuronal compartments.

    “Neuron-specific expression of the dominant negative L199P Cα mutant also induced tau hyperphosphorylation at the physiological AT8 (Ser202/205) and pathological pS 422 (Ser422) epitopes, accompanied by the formation of ubiquitin-containing tau aggregates in the somatodendritic neuronal compartments [51].”
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    • cites [51] source

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  • May combine two claims.

    Interpretationcitation

    The PME-1 and LCMT-1 transgenic models provide further evidence that PP2A-B55 trimers dephosphorylate tau and regulate APP phosphorylation.

    “the PME-1 and LCMT-1 transgenic models provide nevertheless further evidence for a role of these PP2A trimers in tau dephosphorylation, and additionally, in the regulation of APP phosphorylation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] source

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  • May combine two claims.

    Premisecitation

    The Cα mutant is catalytically inactive but binds the A subunit normally, and likely interferes with PP2A function by titrating B subunits.

    “This Cα mutant is catalytically inactive, while showing normal A subunit binding, and thus presumably interferes with PP2A function through titration of B subunits [52].”
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    • cites [52] source

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  • May combine two claims.

    Premisecitation

    The AΔ5 mutant cannot bind any B subunit class and would therefore act as a dominant-negative mutant toward several different PP2A trimers.

    “The AΔ5 mutant is incapable of binding any B subunit class [66] and would therefore behave as a dominantnegative mutant towards several different PP2A trimers.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] source

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  • May combine two claims.

    Interpretationcitation

    Chronic myocardial infarction in Cα transgenic mice increased left ventricle infarct size, suggesting impaired post-myocardial infarction remodeling capacity.

    “an increased left ventricle infarct size was observed, suggestive for impaired post-myocardial infarction remodeling capacity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] source

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

    Premisecitation

    RyR2 augments Ca2+ flux from the sarcoplasmic reticulum into the cytosol during contraction, while SERCA is important for restoring resting Ca2+ concentration.

    “While RyR 2 augments Ca 2+ flux from the SR into the cytosol during contraction, SERCA is important for restoring resting [Ca 2+ ] [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69]

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  • May combine two claims.

    Interpretationcitation

    Early cardiac Cα knockout showed decreased glucose transport and glycolysis, increased aerobic glucose metabolism, and increased fatty acid transport and metabolism, suggesting a role for PP2A in regulating cardiomyocyte carbohydrate and lipid metabolism.

    “In the early (at P6.5) conditional KO model of Cα in heart, evidence was obtained for decreased glucose transport and glycolysis, increased aerobic glucose metabolism, and increased fatty acid transport and metabolism [62], suggesting a role for PP2A in the regulation of carbohydrate and lipid metabolism in cardiomyocytes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] source

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  • May combine two claims.

    Interpretationreasoning

    Although in vivo PP2A dysregulation causes various cardiac phenotypes, a common impairment of the Ca2+ response pathway may underlie the heart failure phenotypes.

    “although in vivo PP2A dysregulation results in a variety of cardiac phenotypes, a common impairment of the Ca 2+ response pathway might serve as the underlying cause of the heart failure phenotypes observed”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These data reveal an undeniable role of PP2A in regulating carbohydrate and lipid metabolism homeostasis, which is highly dependent on the particular holoenzyme, as distinct and even opposite phenotypes are seen upon deficiency of different regulatory B subunits.

    “Overall, these data revealed an undeniable role of PP2A in the regulation of carbohydrate and lipid metabolism homeostasis, which is however highly dependent on the particular holoenzyme involved, as distinct and even opposite phenotypes are seen upon deficiency of different regulatory B subunits.”
    Quote in the paperSubstantial claim

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    Interpretationcitation

    This phenotype was not caused by effects on gluconeogenesis or insulin-induced AKT or GSK-3β phosphorylation, but rather by increased glucose uptake by hepatocytes.

    “this phenotype was not caused by any effects on gluconeogenesis or insulin-induced AKT or GSK-3β phosphorylation, but rather by increased glucose uptake by the hepatocytes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] source

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  • May combine two claims.

    Interpretationreasoning

    PP2A plays a major role in the adaptive immune response and in preventing autoimmunity.

    “PP2A also plays a major role in the adaptive immune response and in preventing autoimmunity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    B56γ knockdown livers had increased triglyceride levels, suggesting increased de novo lipogenesis.

    “increased triglyceride levels were found in the B56γ KD livers, suggestive for increased de novo lipogenesis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] source

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  • May combine two claims.

    Interpretationreasoning

    Enhanced liver mass, elevated VLDL secretion, and decreased glycogen breakdown upon fasting infer a more detrimental effect on lipid metabolism than on carbohydrate metabolism.

    “Together with an enhanced liver mass, elevated VLDL secretion in blood and decreased glycogen breakdown upon fasting, these phenotypes infer a more detrimental effect on lipid metabolism than on carbohydrate metabolism.”
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    • cites [73] source

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  • May combine two claims.

    Interpretationcitation

    Overexpression of catalase rescued cell death, implicating reactive oxygen species in the cell death mechanism.

    “Overexpression of catalase rescued cell death, inferring the involvement of Reactive Oxygen Species (ROS) in the cell death mechanism.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] source

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  • May combine two claims.

    Premisecitation

    G5PR is a regulatory subunit of the B′′ family known to interact with both PP2A and PP5.

    “G5PR is a regulatory subunit of the B″ family known to interact with both PP2A and PP5 [77].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] source

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  • May combine two claims.

    Interpretationcitation

    Upon aging, nonimmunized G5PR transgenic mice showed increased peritoneal B-1a cells that were not caused by increased proliferation, but attributed to prevention of BCR-activation-induced apoptosis.

    “Upon aging (> 40 weeks), nonimmunized mice showed increased numbers of peritoneal B-1a cells that were not caused by increased proliferation of B-1a or B-2 cells, but attributed to prevention of BCR-activation-induced apoptosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] source

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  • May combine two claims.

    Interpretationcitation

    Prolonged JNK activation and increased FasL expression explained the considerable reduction in double positive thymocytes and the nearly complete loss of single positive T-cells in the thymus.

    “Together with a prolonged JNK activation and increased FasL expression, this explained the considerable reduction in DP thymocytes and the nearly complete loss of single positive T-cells in the thymus [79].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] source

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  • May combine two claims.

    Interpretationcitation

    In wild-type T-cells, CIP2A expression was induced after anti-CD3/anti-CD28 stimulation, implying a role for CIP2A in T-cell activation, particularly of effector CD8+ T-cells.

    “In WT T-cells, CIP2A expression was induced after anti-CD3/anti-CD28 stimulation, further implying a role of CIP2A in T-cell activation, particularly of effector CD8 + T-cells [83].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • May combine two claims.

    Interpretationcitation

    These data are consistent with a direct role for PP2A in IRF3 dephosphorylation, a process that appears to be mediated by the RACK1 adaptor protein.

    “These data are thus consistent with a direct role for PP2A in IRF3 dephosphorylation, a process that appears to be mediated by the RACK1 adaptor protein [84].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] source

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  • May combine two claims.

    Premisecitation

    The Harderian gland in L309A Cα transgenic mice shows reduced E-cadherin and β-catenin levels and a spatial shift of their expression from the membrane to the cytosol.

    “the Harderian gland showed reduced E-cadherin and β-catenin levels and their expression was spatially shifted from the membrane to the cytosol.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] source

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  • May combine two claims.

    Premisecitation

    Injured Cα knockout livers show fewer activated stellate cells and reduced hepatocyte proliferation, partially correlated with a slight increase in apoptotic hepatocytes.

    “Histologically, injured Cα KO livers showed less activated stellate cells, and clearly reduced hepatocyte proliferation, which partially correlated with a slight increase in number of apoptotic hepatocytes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] source

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  • May combine two claims.

    Premisecitation

    In a constitutive total-body Ppp2r5a knockout mouse model, B56α expression is significantly reduced but not completely absent, with 0.01-0.2% of control levels remaining in all tissues tested.

    “In these mice, B56α expression was significantly decreased but not entirely null, with 0.01-0.2% of control levels remaining in all tissues tested.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] source

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  • May combine two claims.

    Premisecitation

    Moderate transgenic expression of the dominant-negative L309A Cα mutant in the Harderian gland causes delayed development and hypoplasia of this gland, accompanied by enophthalmos in a significant number of mice.

    “Moderate transgenic expression of the dominant negative L309A Cα mutant in the Harderian gland caused a delayed development and hypoplasia of this gland, accompanied by a slit-eye phenotype (enophthalmos) in a significant number of mice [91].”
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    • cites [91] source

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  • May combine two claims.

    Premisecitation

    Cα knockout livers have 50% fewer fibrotic lesions than wild-type, with decreased collagen deposition and reduced serum ALT and AST levels.

    “Compared with WT mice, 50% less fibrotic lesions were found in Cα KO livers, accompanied by decreased collagen deposition, as well as reduced serum levels of Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] source

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  • May combine two claims.

    Premisecitation

    B56α knockout mice have increased numbers of skin and bone marrow stem cells.

    “Notably, an increased number of skin (and bone marrow) stem cells was found”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] source

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  • May combine two claims.

    Premisecitation

    In hepatocyte-specific Ppp2ca knockout mice, Cα expression is severely decreased but not completely absent, resulting in a 30% reduction in PP2A activity.

    “Although severely decreased, Cα expression was not completely absent in this model, resulting in a 30% reduction in PP2A activity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] source

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  • May combine two claims.

    Premisecitation

    Hepatocyte-specific knockout of Ppp2ca results in a metabolic phenotype and appears protective against chronic liver injury induced by repeated intraperitoneal CCl4 injections.

    “In the liver, hepatocyte-specific KO of Ppp2ca expression did not only result in a metabolic phenotype (see Section 6), but also appeared protective against chronic liver injury, as induced upon repeated i.p. injections with CCl 4 [95].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • May combine two claims.

    Premisecitation

    In the E64G Aα knockin model, phosphorylation of PP2A substrates PKCα and mTOR is enhanced, and this effect can also be induced under light-adapted conditions.

    “Nevertheless, an enhanced phosphorylation of PP2A substrates PKCα and mTOR was observed, an effect that could also be induced under light-adapted conditions [94].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] source

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  • May combine two claims.

    Premisecitation

    Osteoblast-specific overexpression of the dominant-negative L199P Cα mutant causes a 50% overall decrease in PP2A activity and is associated with larger and heavier mice.

    “In bone, osteoblast-specific overexpression of the dominant-negative L199P Cα mutant, caused a 50% overall decrease in PP2A activity, associated with larger and heavier mice [96].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] source

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  • May combine two claims.

    Premisecitation

    The blood pressure effects in STRN-deficient mice are in part due to changes in vascular contraction and relaxation, with increased aortic contraction upon phenylephrine or KCl and reduced relaxation upon acetylcholine.

    “Additionally, the BP effects were in part due to changes in vascular contraction/relaxation, as an increased aortic contraction was observed upon phenylephrine or KCl addition, and a reduced aortic relaxation upon acetylcholine addition.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] source

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  • May combine two claims.

    Premisecitation

    α4 knockout mice have impaired epithelial barrier function, with increased gut permeability and decreased expression of junction proteins claudin-1/3, ZO-1, and E-cadherin.

    “An impaired epithelial barrier function was also apparent, characterized by increased gut permeability and decreased expression of several epithelial junction proteins (e.g.claudin-1/3, ZO-1 and E-cadherin).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] source

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  • May combine two claims.

    Premisecitation

    α4 knockout mice are smaller, weigh less, and have a shorter and thinner gastrointestinal tract.

    “The α4 KO mice were smaller, weighed less, and contained a shorter and thinner gastrointestinal tract.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] source

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  • May combine two claims.

    Premisecitation

    The small intestinal mucosal epithelium of α4 knockout mice is abnormally structured, with inhibited mucosal maturation, villous shrinkages, crypt hyperplasia, and displacement of Paneth cells.

    “The mucosal epithelium of the small intestine was abnormally structured, showing inhibited mucosal maturation, villous shrinkages, crypt hyperplasia and displacement of the Paneth cells from the bases to the tops of the crypts or the villous areas.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] source

      Not checked in the free run.

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

    Interpretationcitation

    The increased bone marrow adipogenesis in L199P Cα mice is suspected to be caused by a paracrine mechanism.

    “In addition, in the bone marrow, increased adipogenesis was observed, suspected to be caused by a paracrine mechanism.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aα E64G and E64D mutants, discovered in breast and lung carcinoma, are defective in B56α and B56δ binding in vivo and B56γ binding in vitro.

    “For instance, the Aα E64G and E64D mutants, respectively discovered in breast and lung carcinoma [104], were found to be defective in B56α and B56δ binding in vivo [10], and B56γ binding in vitro [93].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [104] source

      Not checked in the free run.

    • cites [10] source

      Not checked in the free run.

    • cites [93] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Compared with wild-type, STRN-deficient mice show enhanced salt sensitivity of blood pressure, with a higher increase upon liberal salt intake and a higher decrease upon salt restriction.

    “Compared with WT mice, STRN-deficient mice showed an enhanced salt sensitivity of their blood pressure (BP), characterized by a higher increase in BP upon liberal salt intake, and a higher decrease in BP upon salt restriction.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [97] source

      Not checked in the free run.

    • cites [98] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In these mice, bone mineral density and thickness are significantly increased, while cartilage thickness is not affected.

    “In the animals, bone mineral density and thickness were significantly increased, while cartilage thickness was not affected.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In α4 knockout mice, crypt cell proliferation is enhanced, crypt-to-villus migration rates are decreased, and apoptosis in the mucosal epithelium is increased.

    “Overall, proliferation of crypt cells was enhanced, crypt-to-villus migration rates were decreased, and apoptosis in the mucosal epithelium was increased.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In α4 knockout intestinal mucosa, α4 mRNA and protein are undetectable, correlating with 40% decreased PP2A-C levels.

    “Alpha4 mRNA and protein levels in the intestinal mucosa were undetectable, and this correlated with 40% decreased levels of PP2A-C, consistent with several other α4 KO models.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Loss of B56α increases initiation of carcinogenesis without affecting progression.

    “indicating that loss of B56α increases the initiation of carcinogenesis, without affecting progression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Global PP2A inhibition is detrimental and underscores the importance of PP2A as a major homeostatic factor.

    “In other words, global PP2A inhibition is detrimental and underscores the importance of PP2A as a major homeostatic factor.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    A substantial part of PP2A's physiologic functions remains unclear, largely because of its complex structure and regulation, with 19 PP2A subunit encoding genes in mice not all studied in vivo.

    “Nevertheless, a substantial part of its physiologic functions remains unclear.This is mostly due to the highly complex structure and regulation of PP2A, stemming from the presence of no less than 19 different PP2A subunit encoding genes in mice, which have not all been studied in vivo to date.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In PTPA-deficient mouse tumors, no common signaling defects are revealed, although sporadic activation of Wnt, Hedgehog, and c-Myc signaling is present in some tumor tissues.

    “In this case, no common signaling defects could be revealed, although sporadic activation of Wnt signaling (increased β-catenin expression), Hedgehog signaling (increased Gli1 expression) and c-Myc activation (Ser62 phosphorylation) were present in some of the tumor tissues analyzed [43].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The B56α knockout skin phenotype is likely connected to induced stemness potential of skin cells, which may relate to increased phosphorylated c-Myc at Ser62.

    “This phenotype is likely connectable to the induced stemness potential of skin cells in these mice, which on its turn could be related to increased expression of phosphorylated c-Myc (Ser62).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Data from PP2A cancer strains specifically highlight the tumor suppressive role of PP2A-B56-type complexes in vivo, particularly B56α and B56δ isoforms, which prevent tumorigenesis in a context- and tissue-dependent manner.

    “Together, the data from the above PP2A cancer strains seem to specifically highlight the tumor suppressive role of the PP2A-B56-type of complexes in vivo, particularly of the B56α and B56δ isoforms, which seem to be able to prevent tumorigenesis in a context-and tissue-dependent manner.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Specific PP2A subunits can be functionally redundant in specific contexts, complicating interpretation of certain phenotypes or lack of phenotypes.

    “Moreover, it became evident from several of the PP2A subunit strains, that specific PP2A subunits can be functionally redundant in specific contexts, further complicating the interpretation of certain phenotypes (or lack of phenotypes)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A prominent spontaneous cancer phenotype is observed in total-body constitutive B56δ knockout mice and in homozygous and heterozygous hypomorphic Ptpa mice.

    “A very prominent spontaneous cancer phenotype was indeed observed in the total-body, constitutive KO model of the B56δ subunit [110] and in both homozygous and heterozygous mice of a hypomorphic Ptpa allele [43].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [110] source

      Not checked in the free run.

    • cites [43] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    B56δ knockout mice show a high incidence of hepatocellular carcinomas, up to 60% in the oldest age category, while HCC does not occur in aging wild-type mice.

    “More surprisingly, a high incidence of hepatocellular carcinomas (HCCs) was observed as well, in up to 60% of mice in the oldest age category, while HCC did not occur at all in aging WT mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [110] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    PP2A phosphatases are essential enzymes for maintaining homeostasis of targeted tissues and for organismal survival.

    “it became clear that PP2A phosphatases are essential enzymes, not only for maintaining homeostasis of the particular targeted tissue, but also for organismal survival as a whole.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Some PP2A functions are well-defined and mechanistically underbuilt in vivo, including modulation of Wnt, Nodal (TGF-β), and likely Hedgehog signaling during embryonic development, mediated by different PP2A trimers with B subunits from different families.

    “Some of these PP2A functions are quite well-defined and mechanistically underbuilt in vivo, such as e.g. the general modulation of Wnt, Nodal (TGF-β) and, likely, Hedgehog signaling during (embryonic) development, which is mediated by different PP2A trimers, harboring B subunits from different families.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The spontaneous tumor phenotype in PTPA-deficient mice upon aging is less penetrant and mainly characterized by hematologic malignancies, less commonly HCC.

    “The spontaneous tumor phenotype observed in PTPA-deficient mice upon aging, was somewhat less penetrant, and mainly characterized by the development of hematologic malignancies, and less commonly, of HCC.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In B56α knockout mice, DMBA/TPA treatment accelerates skin papilloma formation, although endpoint levels are similar to wild-type.

    “In this model, accelerated skin papilloma formation was observed upon DMBA/TPA treatment of the skin, although endpoint levels were similar to those in WT mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Knockin mice with cancer-associated Aα variants E64D/E64D, E64D/+, E64G/E64G, E64G/+, Δ5-6/E64G, Δ5-6/E64D, and Δ5-6/+ are viable and fertile with no discernible phenotypes.

    “E64D/E64D, E64D/+, E64G/E64G, E64G/+, Δ5-6/E64G, Δ5-6/E64D and Δ5-6/+ mice all turned out to be viable and fertile, with no discernable phenotypes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Unbiased transcriptome data reveal commonly upregulated c-Myc activity in B56δ knockout HCCs, corroborated by increased c-Myc phosphorylation at Ser62 and enhanced CIP2A expression in all HCCs examined.

    “Unbiased transcriptome data revealed a commonly upregulated c-Myc activity in the HCCs, further corroborated by increased c-Myc phosphorylation (Ser62) and enhanced CIP2A expression (a Myc target gene) in all HCCs examined.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [110] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Important insights were derived from strains in which PP2A regulators were manipulated, highlighting particular PP2A functions in brain, immune system, and tumor development, and underscoring the therapeutic potential of indirect PP2A targeting.

    “important insights were derived from the strains in which these regulators were manipulated, for instance, by highlighting particular PP2A functions in brain, the immune system and tumor development, but also by underscoring the therapeutic potential of indirect PP2A targeting, through these inhibitors or activators, for the improved treatment of certain diseases.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Premisecitation

    In mice with inducible neuronal expression of FLAG-tagged PME-1, FLAG-PME-1 overexpression reaches 350%.

    “-FLAG-PME-1 overexpression: 350% [55]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    In mice with B-cell-specific conditional knockout of Igbp1 (CD19-Cre), the spleen shows a B-cell maturation defect.

    “-In spleen, B-cell maturation defect [87]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Premisecitation

    In mice with inducible neuronal expression of FLAG-tagged LCMT-1, FLAG-LCMT-1 overexpression reaches 150%.

    “-FLAG-LCMT-1 overexpression: 150% [55]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Ppme1 knockout mice, embryonic development is normal, but perinatal death occurs at P1.

    “Normal embryonic development, but perinatal death at P1; neonatal [56] | mice showed breathing and suckling difficulties”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] source

      Not checked in the free run.

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

    Premisecitation

    In mice with a gene-trap insertion in the first intron of Lcmt1 (German Gene Trap consortium clone), embryonic lethality occurs between E14.5 and E16.5, with 5% dying before E12.5.

    “-Embryonic lethality between E14.5 and E16.5 (5% die before E12.5) [26,39,41]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [26] source

      Not checked in the free run.

    • cites [39] source

      Not checked in the free run.

    • cites [41] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [25] source

      Not checked in the free run.

    • cites [44] source

      Not checked in the free run.

    • cites [45] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Igbp1 -/- adipocytes, apoptosis occurs, with c-jun, p53 and caspase-3 activation.

    “-In -/-adipocytes: apoptosis (c-jun, p53, caspase-3 activation)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [25] source

      Not checked in the free run.

    • cites [44] source

      Not checked in the free run.

    • cites [45] source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    In mice with T-cell-specific conditional knockout of Igbp1 (Lck-Cre), early T-cell development is impaired.

    “-Impaired early T-cell development [88]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice with T-cell-specific expression of FLAG-tagged α4 (CD2 promoter/enhancer), T-cell viability, proliferation and development are unaffected.

    “No effects on T-cell viability, proliferation or development; enhanced [45] | T-cell migration in transwell assay; increased levels of activated Rac1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] source

      Not checked in the free run.

199 of 199

  • The paper relies on this without support.

    Findings from genetically modified mouse models about PP2A functions are informative about PP2A physiology and disease in humans or mammals.

    “Mouse models have proven useful tools for research on physiologic functions of proteins, but also on disease and underlying pathology.”
    “the therapeutic potential of PP2A targeting in human disease”

  • The paper relies on this without support.

    Findings from genetically modified mouse models can be used to infer the physiologic functions of PP2A in humans and to support clinical development of PP2A-targeting therapies.

    “In conclusion, the 63 PP2A-related mouse models discussed here, have certainly represented a significant aid in elucidating PP2A's in vivo mechanisms, its intense modulation and its impact on (patho)physiology.”
    “provide some of the missing clues for the full clinical development of PP2A as a promising therapeutic target in human disease.”
2 of 2

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.

  • Liver B56γ knockdown vector is identified two ways

    Minor

    The liver-specific B56γ knockdown is described as using an adenovirus in the text, but Table 3 specifies an AAV (adeno-associated virus) vector for the same model.

  • Basal AKT response differs between text and table

    Minor

    For the digenic Ppp2r2a/insulin-receptor model, the text reports increased basal AKT phosphorylation, whereas Table 3 describes basal AKT signaling as normal.

  • Second IL-17 gene differs between table and text

    Minor

    For the Cα-overexpressing T-cell model, Table 1 names Il17f alongside Il17a, while the text names Il17b alongside Il17a.

3 of 3

Cites

1 retracted

Flagged first, then by citations

3 of the 118 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Reynhout, S., & Janssens, V.
Affiliations
KU Leuven (BE)
Corresponding author
Janssens, Veerle
ORCID
Janssens, Veerle
Venue
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Publisher
Elsevier BV
Published
2019-01
Volume
1866
Issue
1
Pages
31-50
ISSN
0167-4889 (ISSN-L)
DOI
10.1016/j.bbamcr.2018.07.010
OpenAlex
W2883486552
Semantic Scholar
29296c58e3e94571ca50797d2cf5afd26f704be5
Cited by
124
References
118
Citations by year
2026: 7 · 2025: 7 · 2024: 21 · 2023: 16 · 2022: 20 · 2021: 15 · 2020: 23 · 2019: 13 · 2018: 2
FWCI
1.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
  • PubMed (publishedVersion)
  • Lirias (KU Leuven) (submittedVersion, other-oa)
Funders
  • Belgian Foundation against Cancer (FAC-F/2016/822)
  • Fund for Scientific Research-Flanders (G.0B01.16N)
  • KU Leuven (C24/17/073)
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 inhibitors, germ cell maturation, embryonic development, metabolic regulation, tumor suppression, tissue-specific function
MeSH terms
Animals, Germ Cells, Homeostasis, Humans, Metabolism, Phosphoprotein Phosphatases, Genes, Tumor Suppressor, Holoenzymes, Protein Subunits, Models, Animal, Embryonic Development, Intracellular Signaling Peptides and Proteins, Mice, 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.

Statistics and arithmetic are recomputed, not judged.

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