PPP2R1A (protein phosphatase 2 regulatory subunit A, alpha)

2016-03-01   Razia Sultana , Kentaro Nakayama , Kohei Nakamura , Satoru Kyo 

Department of Gynecology\\\/Obstetrics Shimane University Hospital kn88@med.shimane-u.ac.jp

Identity

HGNC
LOCATION
19q13.41
IMAGE
Atlas Image
LEGEND
PPP2R1A gene is located on the long (q) arm of chromosome 19 at position 13.41
LOCUSID
ALIAS
MRD36,PP2A-Aalpha,PP2AA,PP2AAALPHA,PR65A
FUSION GENES

Abstract

Review on PPP2R1A, with data on DNA, on the protein encoded, and where the gene is implicated.

DNA/RNA

Atlas Image

Description

PPP2R1A gene is encoded by 15 exons located on chromosome 19q13. The genomic size is 36624 bp.

Transcription

mRNA size: 2509 bp; coding sequence from 296bp-1770 bp.

Mutations

Somatic

Recently, somatic mutations in PPP2R1A have been reported in certain types of ovarian and uterine carcinoma. PPP2R1A mutations were demonstrated in 10 of 110 type I ovarian tumors (9.1%) including low grade serous, low-grade endometrioid, clear-cell, and mucinous carcinomas. Moreover, PPP2R1A mutations were observed in 2 of 30 type I uterine (endometrioid) carcinomas (6.7%) and 5 of 26 type II uterine (serous) carcinomas (19.2%). All mutations were located in the alpha-helix repeats near the interface between the A subunit and the regulatory B subunit of the enzyme complex. All mutations identified were heterozygous missense mutations.

Implicated in

Entity name
Wilms tumorigenesis
Note
PP2A plays a role in the Wnt signaling pathway and has been shown to be present in the multiprotein complex containing the adenomatous polyposis coli (APC) protein, the serine/threonine kinase GSK3B, and AXIN1 (axin) (Fagotto et al., 1999; Hsu et al., 1999; Seeling et al., 1999; Ikeda et al., 2000), suggesting that PP2A has a role in regulating the activity of this complex. Overexpression of the PP2A B56 regulatory subunit has been shown to markedly reduce CTNNB1 levels in mammalian cells (Seeling et al., 1999), which suggests that increased levels of PP2A accelerate the phosphorylation-dependent proteolysis of CTNNB1. Interestingly, CTNNB1 mutations have recently been reported to occur in about 15% of Wilms tumors (Koesters et al., 1999; Maiti et al., 2000), suggesting that the APC/CTNNB1/HNF4A (Tcf)- LEF1 pathway is involved in Wilms tumorigenesis. Since PP2A also plays a role in the Wnt signaling pathway, alterations in one or more of the PP2A subunits could plausibly affect this pathway and contribute to Wilms tumorigenesis.
Entity name
Mental retardation, autosomal dominant 36 (MRD36)
Note
A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associate with impairments in adaptive behavior and manifested during the developmental period. The disease is identified 2 different de novo heterozygous missense mutation in the PPP2R1A gene (Hougo et al., 2015). The mutation were found by parent-child trio exome sequencing and confirmed by Sanger sequencing. In vitro functional expression study showed that the patients with MRD36, PPP2R1A mutation affected PP2A holoenzyme formation by variably interfering with interaction of the A-alpha subunit with the C subunit. All mutation resulted in decreased phosphatase activity, consisting with a dominant negative effect.

Bibliography

Pubmed IDLast YearTitleAuthors
17186791991Pleiotropic effect of okadaic acid on maturing mouse oocytes.Alexandre H et al
107137072000Low frequency of alterations of the alpha (PPP2R1A) and beta (PPP2R1B) isoforms of the subunit A of the serine-threonine phosphatase 2A in human neoplasms.Calin GA et al
234342802013The PP2A inhibitor I2PP2A is essential for sister chromatid segregation in oocyte meiosis II.Chambon JP et al
21593271990alpha- and beta-forms of the 65-kDa subunit of protein phosphatase 2A have a similar 39 amino acid repeating structure.Hemmings BA et al
99208881999Identification of a domain of Axin that binds to the serine/threonine protein phosphatase 2A and a self-binding domain.Hsu W et al
106985232000GSK-3beta-dependent phosphorylation of adenomatous polyposis coli gene product can be modulated by beta-catenin and protein phosphatase 2A complexed with Axin.Ikeda S et al
104635741999Mutational activation of the beta-catenin proto-oncogene is a common event in the development of Wilms' tumors.Koesters R et al
90322961997Separation of PP2A core enzyme and holoenzyme with monoclonal antibodies against the regulatory A subunit: abundant expression of both forms in cells.Kremmer E et al
117512602002Regulation of spindle formation by active mitogen-activated protein kinase and protein phosphatase 2A during mouse oocyte meiosis.Lu Q et al
145160702003Okadaic acid, an inhibitor of protein phosphatase 1 and 2A, induces premature separation of sister chromatids during meiosis I and aneuploidy in mouse oocytes in vitro.Mailhes JB et al
111037852000Frequent association of beta-catenin and WT1 mutations in Wilms tumors.Maiti S et al
235982992013Impaired expression of protein phosphatase 2A subunits enhances metastatic potential of human prostate cancer cells through activation of AKT pathway.Pandey P et al
109857762000Effects of regulatory subunits on the kinetics of protein phosphatase 2A.Price NE et al
234443752013Overexpression of SETβ, a protein localizing to centromeres, causes precocious separation of chromatids during the first meiosis of mouse oocytes.Qi ST et al
217916162011Human cancer-associated mutations in the Aα subunit of protein phosphatase 2A increase lung cancer incidence in Aα knock-in and knockout mice.Ruediger R et al
175401762007The tumor suppressor PP2A Abeta regulates the RalA GTPase.Sablina AA et al
100922331999Regulation of beta-catenin signaling by the B56 subunit of protein phosphatase 2A.Seeling JM et al
224424842012MARF1 regulates essential oogenic processes in mice.Su YQ et al
118700612002Regulation of mitogen-activated protein kinase phosphorylation, microtubule organization, chromatin behavior, and cell cycle progression by protein phosphatases during pig oocyte maturation and fertilization in vitro.Sun QY et al
126586382003Specific inhibition of mouse oocyte nuclear protein phosphatase-1 stimulates germinal vesicle breakdown.Swain JE et al
123700812003Characterization of the Aalpha and Abeta subunit isoforms of protein phosphatase 2A: differences in expression, subunit interaction, and evolution.Zhou J et al

Other Information

Locus ID:

NCBI: 5518
MIM: 605983
HGNC: 9302
Ensembl: ENSG00000105568

Variants:

dbSNP: 5518
ClinVar: 5518
TCGA: ENSG00000105568
COSMIC: PPP2R1A

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000105568ENST00000322088P30153
ENSG00000105568ENST00000322088A8K7B7
ENSG00000105568ENST00000391791E9PH38
ENSG00000105568ENST00000454220C9J9C1
ENSG00000105568ENST00000462990B3KQV6
ENSG00000105568ENST00000477989M0R0K6
ENSG00000105568ENST00000490868M0QXG4
ENSG00000105568ENST00000628959M0QXG4

Expression (GTEx)

0
50
100
150
200

Pathways

PathwaySourceExternal ID
TGF-beta signaling pathwayKEGGko04350
Tight junctionKEGGko04530
Long-term depressionKEGGko04730
TGF-beta signaling pathwayKEGGhsa04350
Tight junctionKEGGhsa04530
Long-term depressionKEGGhsa04730
Oocyte meiosisKEGGko04114
Oocyte meiosisKEGGhsa04114
Chagas disease (American trypanosomiasis)KEGGko05142
Chagas disease (American trypanosomiasis)KEGGhsa05142
Hepatitis CKEGGko05160
Hepatitis CKEGGhsa05160
mRNA surveillance pathwayKEGGko03015
mRNA surveillance pathwayKEGGhsa03015
Dopaminergic synapseKEGGko04728
Dopaminergic synapseKEGGhsa04728
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Hippo signaling pathwayKEGGhsa04390
Hippo signaling pathwayKEGGko04390
Adrenergic signaling in cardiomyocytesKEGGhsa04261
Adrenergic signaling in cardiomyocytesKEGGko04261
AMPK signaling pathwayKEGGhsa04152
AMPK signaling pathwayKEGGko04152
Sphingolipid signaling pathwayKEGGhsa04071
Sphingolipid signaling pathwayKEGGko04071
Organelle biogenesis and maintenanceREACTOMER-HSA-1852241
Cilium AssemblyREACTOMER-HSA-5617833
Anchoring of the basal body to the plasma membraneREACTOMER-HSA-5620912
DiseaseREACTOMER-HSA-1643685
Diseases of signal transductionREACTOMER-HSA-5663202
Signaling by WNT in cancerREACTOMER-HSA-4791275
truncated APC mutants destabilize the destruction complexREACTOMER-HSA-4839744
APC truncation mutants have impaired AXIN bindingREACTOMER-HSA-5467337
AXIN mutants destabilize the destruction complex, activating WNT signalingREACTOMER-HSA-4839735
AXIN missense mutants destabilize the destruction complexREACTOMER-HSA-5467340
AMER1 mutants destabilize the destruction complexREACTOMER-HSA-4839748
Truncations of AMER1 destabilize the destruction complexREACTOMER-HSA-5467348
phosphorylation site mutants of CTNNB1 are not targeted to the proteasome by the destruction complexREACTOMER-HSA-4839743
S45 mutants of beta-catenin aren't phosphorylatedREACTOMER-HSA-5358751
T41 mutants of beta-catenin aren't phosphorylatedREACTOMER-HSA-5358752
S37 mutants of beta-catenin aren't phosphorylatedREACTOMER-HSA-5358749
S33 mutants of beta-catenin aren't phosphorylatedREACTOMER-HSA-5358747
Misspliced GSK3beta mutants stabilize beta-cateninREACTOMER-HSA-5339716
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Costimulation by the CD28 familyREACTOMER-HSA-388841
CTLA4 inhibitory signalingREACTOMER-HSA-389513
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
Innate Immune SystemREACTOMER-HSA-168249
Toll-Like Receptors CascadesREACTOMER-HSA-168898
Toll Like Receptor 10 (TLR10) CascadeREACTOMER-HSA-168142
MyD88 cascade initiated on plasma membraneREACTOMER-HSA-975871
MAP kinase activation in TLR cascadeREACTOMER-HSA-450294
MAPK targets/ Nuclear events mediated by MAP kinasesREACTOMER-HSA-450282
ERK/MAPK targetsREACTOMER-HSA-198753
ERKs are inactivatedREACTOMER-HSA-202670
Toll Like Receptor 3 (TLR3) CascadeREACTOMER-HSA-168164
MyD88-independent TLR3/TLR4 cascadeREACTOMER-HSA-166166
TRIF-mediated TLR3/TLR4 signalingREACTOMER-HSA-937061
Toll Like Receptor 5 (TLR5) CascadeREACTOMER-HSA-168176
Toll Like Receptor 7/8 (TLR7/8) CascadeREACTOMER-HSA-168181
MyD88 dependent cascade initiated on endosomeREACTOMER-HSA-975155
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activationREACTOMER-HSA-975138
Toll Like Receptor 9 (TLR9) CascadeREACTOMER-HSA-168138
Toll Like Receptor 4 (TLR4) CascadeREACTOMER-HSA-166016
Activated TLR4 signallingREACTOMER-HSA-166054
MyD88:Mal cascade initiated on plasma membraneREACTOMER-HSA-166058
Toll Like Receptor 2 (TLR2) CascadeREACTOMER-HSA-181438
Toll Like Receptor TLR1:TLR2 CascadeREACTOMER-HSA-168179
Toll Like Receptor TLR6:TLR2 CascadeREACTOMER-HSA-168188
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
RAF activationREACTOMER-HSA-5673000
Negative regulation of MAPK pathwayREACTOMER-HSA-5675221
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
HemostasisREACTOMER-HSA-109582
Platelet homeostasisREACTOMER-HSA-418346
Platelet sensitization by LDLREACTOMER-HSA-432142
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
GAB1 signalosomeREACTOMER-HSA-180292
Signaling by FGFRREACTOMER-HSA-190236
Signaling by FGFR1REACTOMER-HSA-5654736
Negative regulation of FGFR1 signalingREACTOMER-HSA-5654726
Spry regulation of FGF signalingREACTOMER-HSA-1295596
Signaling by FGFR2REACTOMER-HSA-5654738
Negative regulation of FGFR2 signalingREACTOMER-HSA-5654727
Signaling by FGFR3REACTOMER-HSA-5654741
Negative regulation of FGFR3 signalingREACTOMER-HSA-5654732
Signaling by FGFR4REACTOMER-HSA-5654743
Negative regulation of FGFR4 signalingREACTOMER-HSA-5654733
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
PI3K/AKT activationREACTOMER-HSA-198203
Nuclear Events (kinase and transcription factor activation)REACTOMER-HSA-198725
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFA-VEGFR2 PathwayREACTOMER-HSA-4420097
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by Rho GTPasesREACTOMER-HSA-194315
RHO GTPase EffectorsREACTOMER-HSA-195258
RHO GTPases Activate ForminsREACTOMER-HSA-5663220
Signaling by GPCRREACTOMER-HSA-372790
Opioid SignallingREACTOMER-HSA-111885
DARPP-32 eventsREACTOMER-HSA-180024
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by WntREACTOMER-HSA-195721
Degradation of beta-catenin by the destruction complexREACTOMER-HSA-195253
Beta-catenin phosphorylation cascadeREACTOMER-HSA-196299
TCF dependent signaling in response to WNTREACTOMER-HSA-201681
Disassembly of the destruction complex and recruitment of AXIN to the membraneREACTOMER-HSA-4641262
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Nonsense-Mediated Decay (NMD)REACTOMER-HSA-927802
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)REACTOMER-HSA-975957
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
Mitotic G1-G1/S phasesREACTOMER-HSA-453279
G1 PhaseREACTOMER-HSA-69236
Cyclin D associated events in G1REACTOMER-HSA-69231
G1/S TransitionREACTOMER-HSA-69206
E2F mediated regulation of DNA replicationREACTOMER-HSA-113510
Inhibition of replication initiation of damaged DNA by RB1/E2F1REACTOMER-HSA-113501
Mitotic G2-G2/M phasesREACTOMER-HSA-453274
G2/M TransitionREACTOMER-HSA-69275
Cyclin A/B1 associated events during G2/M transitionREACTOMER-HSA-69273
Regulation of PLK1 Activity at G2/M TransitionREACTOMER-HSA-2565942
Centrosome maturationREACTOMER-HSA-380287
Recruitment of mitotic centrosome proteins and complexesREACTOMER-HSA-380270
Loss of proteins required for interphase microtubule organization from the centrosomeREACTOMER-HSA-380284
Loss of Nlp from mitotic centrosomesREACTOMER-HSA-380259
M PhaseREACTOMER-HSA-68886
Mitotic ProphaseREACTOMER-HSA-68875
MASTL Facilitates Mitotic ProgressionREACTOMER-HSA-2465910
Mitotic PrometaphaseREACTOMER-HSA-68877
Resolution of Sister Chromatid CohesionREACTOMER-HSA-2500257
Mitotic Metaphase and AnaphaseREACTOMER-HSA-2555396
Mitotic AnaphaseREACTOMER-HSA-68882
Separation of Sister ChromatidsREACTOMER-HSA-2467813
Nuclear Envelope ReassemblyREACTOMER-HSA-2995410
Initiation of Nuclear Envelope ReformationREACTOMER-HSA-2995383
MetabolismREACTOMER-HSA-1430728
Metabolism of carbohydratesREACTOMER-HSA-71387
Glucose metabolismREACTOMER-HSA-70326
GlycolysisREACTOMER-HSA-70171
Integration of energy metabolismREACTOMER-HSA-163685
PP2A-mediated dephosphorylation of key metabolic factorsREACTOMER-HSA-163767
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
AURKA Activation by TPX2REACTOMER-HSA-8854518
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Expression and DegradationREACTOMER-HSA-6806003
Regulation of TP53 DegradationREACTOMER-HSA-6804757
RET signalingREACTOMER-HSA-8853659

References

Pubmed IDYearTitleCitations
208267642010Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma.420
207111812010Live-cell imaging RNAi screen identifies PP2A-B55alpha and importin-beta1 as key mitotic exit regulators in human cells.150
273482972016The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis.63
213810302011Subtype-specific mutation of PPP2R1A in endometrial and ovarian carcinomas.38
211574322011Dephosphorylation of Carma1 by PP2A negatively regulates T-cell activation.31
167170862006PP2A regulates BCL-2 phosphorylation and proteasome-mediated degradation at the endoplasmic reticulum.28
214354332011Somatic mutations of PPP2R1A in ovarian and uterine carcinomas.28
202374962010New genetic associations detected in a host response study to hepatitis B vaccine.27
197949602009A nonhomologous end-joining pathway is required for protein phosphatase 2A promotion of DNA double-strand break repair.25
172105762007Phosphatase type 2A-dependent and -independent pathways for ATR phosphorylation of Chk1.22

Citation

Razia Sultana ; Kentaro Nakayama ; Kohei Nakamura ; Satoru Kyo

PPP2R1A (protein phosphatase 2 regulatory subunit A, alpha)

Atlas Genet Cytogenet Oncol Haematol. 2016-03-01

Online version: http://atlasgeneticsoncology.org/gene/41814/ppp2r1a