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PTPA ( protein phosphatase 2 phosphatase activator)

Written2009-02Veerle Janssens
Protein Phosphorylation, Proteomics Group, Department of Molecular Cell Biology, Faculty of Medicine, University of Leuven, Campus GHB O&N1, Herestraat 49, box 901, B-3000 Leuven, Belgium

(Note : for Links provided by Atlas : click)

Identity

Alias_namesPPP2R4
protein phosphatase 2A, regulatory subunit B' (PR 53)
protein phosphatase 2A activator, regulatory subunit 4
protein phosphatase 2 regulatory subunit 4
Alias_symbol (synonym)PR53
Other aliasPPP2R4 (protein phosphatase 2A activator, regulatory subunit 4)
MGC2184
OTTHUMP00000022333
PP2A
PTPA
HGNC (Hugo) PTPA
LocusID (NCBI) 5524
Atlas_Id 41817
Location 9q34.11  [Link to chromosome band 9q34]
Location_base_pair Starts at 129111688 and ends at 129148946 bp from pter ( according to hg19-Feb_2009)  [Mapping PTPA.png]
Local_order From centromere to telomere: DOLPP1 (dolichyl pyrophosphate phosphatase 1), CRAT (carnitine acetyltransferase), PPP2R4, IER5L (immediate early response 5-like), C9orf106.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
DPH7 (9q34.3) / PTPA (9q34)DPH7 (9q34.3) / PTPA (9q34.11)PTPA (9q34) / MIGA2 (9Q34.13)
PTPA (9q34) / NEK6 (9q33.3)PTPA (9q34) / NUP188 (9q34.11)PTPA (9q34.11) / NEK6 (9q33.3)
PTPA (9q34.11) / NUP188 (9q34.11)TMEM104 (17q25.1) / PTPA (9q34)
Note In fact the gene name would be better: 'protein phosphatase 2A, regulatory subunit 4' or 'protein phosphatase 2A activator', and not a mixture of the two.

DNA/RNA

 
  Figure 1. Schematic representation of PPP2R4 splice variants.
The top line represents the PPP2R4 gene. Exons are boxed (5' and 3' UTR are speckled). Introns and the 3' UTR are not drawn to scale. PTPA alpha and beta are the major transcripts/proteins; PTPA gamma, zeta and eta do not encode functional proteins and probably result from splicing errors.
Gene promoter has been analyzed and resides in a non-methylated CpG island. No TATA or CAAT box. Two functional yin-yang-1 (YY1) binding sites direct basal promoter expression. Tumor suppressor p53 represses transcription through a mechanism involving YY1 inhibition.
Figure 2. Schematic structure of the PPP2R4 promoter.
Two YY1 sites are required for basal PPP2R4 promoter activity and reside within the minimal promoter (nt -67/+38 relative to the start of transcription which is at +1). Upstream of this minimal promoter a GC-rich Sp1-cluster is present (nt -670/-470) of which the functionality has not yet been proven. The PPP2R4 promoter resides within an unmethylated CpG island.
Description The gene encompasses around 40 kb; 11 exons.
Transcription Several transcripts have been identified, resulting from alternative splicing; two transcripts in Northern blot of human placental RNA with probe encompassing exons 1-10: 4.1 kb and 2.8 kb (likely resulting from the use of different polyadenylation signals).
  • Alpha isoform: encompasses exons 1,2,3,5-11.
  • Beta isoform: encompasses exons 1-11.
  • Gamma isoform: encompasses exons 1,3-11.
  • Delta isoform: encompasses exons 1,2,5-11.
  • Epsilon isoform: encompasses exons 1,2,3,6-11.
  • Zeta isoform: encompasses exons 1,3,5-11.
  • Eta isoform: encompasses exons 1,5-11.
    Alpha, beta, delta, epsilon isoforms can be translated into functional proteins in vitro; gamma, zeta, eta, are probably the result of splicing errors.
  • Pseudogene None has been described.

    Protein

    Description Two isoforms detectable in Western blot of human placenta and several human cell lines: PTPA alpha, 323 amino acids, 36.8 kDa; PTPA beta, 358 amino acids, 40.7 kDa. pI around 5.8; trypsin-resistant.
    Expression Both isoforms are widely expressed. In a given cell line, PTPA alpha is about 10x more abundant than PTPA beta. Very high expression in p53-negative cell lines (for instance the osteosarcoma cell line Saos-2).
    Localisation Predominantly cytoplasmic.
    Function
  • Stimulates the phosphotyrosyl phosphatase activity of the PP2A core heterodimer in the presence of ATP/Mg2+ (in vitro).
  • Reactivates the phosphoserine/threonine phosphatase activity of an inactive PP2A form in the presence of ATP/Mg2+. This inactive PP2A is associated with the PP2A methylesterase (PME-1).
  • ATP/Mg2+-dependent peptidyl prolyl cis/trans isomerase acting on Pro190 in the PP2A catalytic subunit.
  • Binds to the PP2A heterodimeric core enzyme (A and C subunit).
  • Required for the biogenesis of active PP2A.
  • Reported to be pro- as well as anti-apoptotic.
  • In Saccharomyces cerevisiae: two orthologues found. Involved in protection against oxidative damage, G1 progression, G2/M transition, Target of Rapamycin (TOR) pathway.
  •  
      Figure 3. PTPA protein structure.
    PTPA is an all alpha-helical polypeptide, organized into two domains separated by a groove. Here the ribbon structure of human PTPA is displayed (derived from PDB code: 2IXM, Leulliot et al., 2006).
    Homology No other human homologues known. Defines a new family of peptidyl prolyl cis/trans isomerases (PPIases) with all alpha-helical structure, organized into two domains separated by a groove.

    To be noted

    Although there is a huge and accumulating literature implicating PP2A in cancer etiology, PP2A enzymes represent a large and diverse family of holoenzymes, and the functional implications of specific complexes are only beginning to emerge. As such, it is clear that some PP2A holoenzymes may act as tumor suppressors, whereas others may on the contrary rather promote tumorigenesis.
    As for PPP2R4, one of the many cellular regulators/subunits of PP2A, there is as yet no direct evidence that this gene product is directly involved in these pathological processes.

    Bibliography

    A comparative study of the phosphotyrosyl phosphatase specificity of protein phosphatase type 2A and phosphotyrosyl phosphatase type 1B using phosphopeptides and the phosphoproteins p50/HS1, c-Fgr and Lyn.
    Agostinis P, Donella-Deana A, Van Hoof C, Cesaro L, Brunati AM, Ruzzene M, Merlevede W, Pinna LA, Goris J.
    Eur J Biochem. 1996 Mar 1;236(2):548-57.
    PMID 8612628
     
    Overexpression of the cis/trans isomerase PTPA triggers caspase 3-dependent apoptosis.
    Azam S, Drobetsky E, Ramotar D.
    Apoptosis. 2007 Jul;12(7):1243-55.
    PMID 17333320
     
    Isolation and characterization of a tyrosyl phosphatase activator from rabbit skeletal muscle and Xenopus laevis oocytes.
    Cayla X, Goris J, Hermann J, Hendrix P, Ozon R, Merlevede W.
    Biochemistry. 1990 Jan 23;29(3):658-67.
    PMID 2159785
     
    Molecular cloning, expression, and characterization of PTPA, a protein that activates the tyrosyl phosphatase activity of protein phosphatase 2A.
    Cayla X, Van Hoof C, Bosch M, Waelkens E, Vandekerckhove J, Peeters B, Merlevede W, Goris J.
    J Biol Chem. 1994 Jun 3;269(22):15668-75.
    PMID 8195217
     
    Structure and mechanism of the phosphotyrosyl phosphatase activator.
    Chao Y, Xing Y, Chen Y, Xu Y, Lin Z, Li Z, Jeffrey PD, Stock JB, Shi Y.
    Mol Cell. 2006 Aug;23(4):535-46.
    PMID 16916641
     
    A novel and essential mechanism determining specificity and activity of protein phosphatase 2A (PP2A) in vivo.
    Fellner T, Lackner DH, Hombauer H, Piribauer P, Mudrak I, Zaragoza K, Juno C, Ogris E.
    Genes Dev. 2003 Sep 1;17(17):2138-50.
    PMID 12952889
     
    Generation of active protein phosphatase 2A is coupled to holoenzyme assembly.
    Hombauer H, Weismann D, Mudrak I, Stanzel C, Fellner T, Lackner DH, Ogris E.
    PLoS Biol. 2007 Jun;5(6):e155.
    PMID 17550305
     
    Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling.
    Janssens V, Goris J.
    Biochem J. 2001 Feb 1;353(Pt 3):417-39. (Review)
    PMID 11171037
     
    The protein phosphatase 2A phosphatase activator is a novel peptidyl-prolyl cis/trans-isomerase.
    Jordens J, Janssens V, Longin S, Stevens I, Martens E, Bultynck G, Engelborghs Y, Lescrinier E, Waelkens E, Goris J, Van Hoof C.
    J Biol Chem. 2006 Mar 10;281(10):6349-57. Epub 2005 Dec 27.
    PMID 16380387
     
    Crystal structure of the PP2A phosphatase activator: implications for its PP2A-specific PPIase activity.
    Leulliot N, Vicentini G, Jordens J, Quevillon-Cheruel S, Schiltz M, Barford D, van Tilbeurgh H, Goris J.
    Mol Cell. 2006 Aug 4;23(3):413-24.
    PMID 16885030
     
    An inactive protein phosphatase 2A population is associated with methylesterase and can be re-activated by the phosphotyrosyl phosphatase activator.
    Longin S, Jordens J, Martens E, Stevens I, Janssens V, Rondelez E, De Baere I, Derua R, Waelkens E, Goris J, Van Hoof C.
    Biochem J. 2004 May 15;380(Pt 1):111-9.
    PMID 14748741
     
    Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance.
    MacKeigan JP, Murphy LO, Blenis J.
    Nat Cell Biol. 2005 Jun;7(6):591-600. Epub 2005 May 1.
    PMID 15864305
     
    The crystal structure of a human PP2A phosphatase activator reveals a novel fold and highly conserved cleft implicated in protein-protein interactions.
    Magnusdottir A, Stenmark P, Flodin S, Nyman T, Hammarstrom M, Ehn M, Bakali H MA, Berglund H, Nordlund P.
    J Biol Chem. 2006 Aug 11;281(32):22434-8. Epub 2006 Jun 16.
    PMID 16782712
     
    The phosphotyrosyl phosphatase activator, Ncs1p (Rrd1p), functions with Cla4p to regulate the G(2)/M transition in Saccharomyces cerevisiae.
    Mitchell DA, Sprague GF Jr.
    Mol Cell Biol. 2001 Jan;21(2):488-500.
    PMID 11134337
     
    A yeast homologue of the human phosphotyrosyl phosphatase activator PTPA is implicated in protection against oxidative DNA damage induced by the model carcinogen 4-nitroquinoline 1-oxide.
    Ramotar D, Belanger E, Brodeur I, Masson JY, Drobetsky EA.
    J Biol Chem. 1998 Aug 21;273(34):21489-96.
    PMID 9705277
     
    Anaerobic growth of Saccharomyces cerevisiae alleviates the lethal effect of phosphotyrosyl phosphatase activators depletion.
    Rempola B, Kaniak A, di Rago JP, Rytka J.
    Acta Biochim Pol. 2001;48(4):1043-9.
    PMID 11995966
     
    Specific interactions of PP2A and PP2A-like phosphatases with the yeast PTPA homologues, Ypa1 and Ypa2.
    Van Hoof C, Martens E, Longin S, Jordens J, Stevens I, Janssens V, Goris J.
    Biochem J. 2005 Feb 15;386(Pt 1):93-102.
    PMID 15447631
     
    The yeast phosphotyrosyl phosphatase activator is part of the Tap42-phosphatase complexes.
    Zheng Y, Jiang Y.
    Mol Biol Cell. 2005 Apr;16(4):2119-27. Epub 2005 Feb 2.
    PMID 15689491
     

    Citation

    This paper should be referenced as such :
    Janssens, V
    PPP2R4 (protein phosphatase 2A activator, regulatory subunit 4)
    Atlas Genet Cytogenet Oncol Haematol. 2010;14(1):48-51.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Genes/PPP2R4ID41817ch9q34.html


    Other Leukemias implicated (Data extracted from papers in the Atlas) [ 2 ]
      Chronic myelogenous leukaemia (CML)
    t(11;18)(p15;q12) NUP98/SETBP1


    External links

    Nomenclature
    HGNC (Hugo)PTPA   9308
    Cards
    AtlasPPP2R4ID41817ch9q34
    Entrez_Gene (NCBI)PTPA  5524  protein phosphatase 2 phosphatase activator
    AliasesPP2A; PPP2R4; PR53
    GeneCards (Weizmann)PTPA
    Ensembl hg19 (Hinxton)ENSG00000119383 [Gene_View]
    Ensembl hg38 (Hinxton)ENSG00000119383 [Gene_View]  chr9:129111688-129148946 [Contig_View]  PTPA [Vega]
    ICGC DataPortalENSG00000119383
    TCGA cBioPortalPTPA
    AceView (NCBI)PTPA
    Genatlas (Paris)PTPA
    WikiGenes5524
    SOURCE (Princeton)PTPA
    Genetics Home Reference (NIH)PTPA
    Genomic and cartography
    GoldenPath hg38 (UCSC)PTPA  -     chr9:129111688-129148946 +  9q34.11   [Description]    (hg38-Dec_2013)
    GoldenPath hg19 (UCSC)PTPA  -     9q34.11   [Description]    (hg19-Feb_2009)
    EnsemblPTPA - 9q34.11 [CytoView hg19]  PTPA - 9q34.11 [CytoView hg38]
    Mapping of homologs : NCBIPTPA [Mapview hg19]  PTPA [Mapview hg38]
    OMIM600756   
    Gene and transcription
    Genbank (Entrez)###############################################################################################################################################################################################################################################################
    RefSeq transcript (Entrez)NM_001193397 NM_001271832 NM_021131 NM_178000 NM_178001 NM_178002 NM_178003
    RefSeq genomic (Entrez)
    Consensus coding sequences : CCDS (NCBI)PTPA
    Cluster EST : UnigeneHs.400740 [ NCBI ]
    CGAP (NCI)Hs.400740
    Alternative Splicing GalleryENSG00000119383
    Gene ExpressionPTPA [ NCBI-GEO ]   PTPA [ EBI - ARRAY_EXPRESS ]   PTPA [ SEEK ]   PTPA [ MEM ]
    Gene Expression Viewer (FireBrowse)PTPA [ Firebrowse - Broad ]
    SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)5524
    GTEX Portal (Tissue expression)PTPA
    Human Protein AtlasENSG00000119383-PTPA [pathology]   [cell]   [tissue]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtQ15257   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
    NextProtQ15257  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProQ15257
    Splice isoforms : SwissVarQ15257
    Catalytic activity : Enzyme5.2.1.8 [ Enzyme-Expasy ]   5.2.1.85.2.1.8 [ IntEnz-EBI ]   5.2.1.8 [ BRENDA ]   5.2.1.8 [ KEGG ]   
    PhosPhoSitePlusQ15257
    Domains : Interpro (EBI)Phstyr_phstse_ac   
    Domain families : Pfam (Sanger)PTPA (PF03095)   
    Domain families : Pfam (NCBI)pfam03095   
    Conserved Domain (NCBI)PTPA
    DMDM Disease mutations5524
    Blocks (Seattle)PTPA
    PDB (SRS)2G62    2HV6    2HV7    2IXM    4LAC    4NY3   
    PDB (PDBSum)2G62    2HV6    2HV7    2IXM    4LAC    4NY3   
    PDB (IMB)2G62    2HV6    2HV7    2IXM    4LAC    4NY3   
    PDB (RSDB)2G62    2HV6    2HV7    2IXM    4LAC    4NY3   
    Structural Biology KnowledgeBase2G62    2HV6    2HV7    2IXM    4LAC    4NY3   
    SCOP (Structural Classification of Proteins)2G62    2HV6    2HV7    2IXM    4LAC    4NY3   
    CATH (Classification of proteins structures)2G62    2HV6    2HV7    2IXM    4LAC    4NY3   
    SuperfamilyQ15257
    Human Protein Atlas [tissue]ENSG00000119383-PTPA [tissue]
    Peptide AtlasQ15257
    HPRD02858
    IPIIPI00293102   IPI00217296   IPI00217297   IPI00852637   IPI00910771   IPI00941236   IPI00893197   IPI00748668   IPI00640101   IPI00470813   IPI00853207   IPI00935879   IPI00853351   IPI00853294   IPI00880122   IPI00893753   IPI00925818   IPI00927771   IPI00925006   
    Protein Interaction databases
    DIP (DOE-UCLA)Q15257
    IntAct (EBI)Q15257
    FunCoupENSG00000119383
    BioGRIDPTPA
    STRING (EMBL)PTPA
    ZODIACPTPA
    Ontologies - Pathways
    QuickGOQ15257
    Ontology : AmiGOprotein phosphatase type 2A complex  protein peptidyl-prolyl isomerization  peptidyl-prolyl cis-trans isomerase activity  receptor binding  protein binding  ATP binding  nucleus  nucleoplasm  cytoplasm  protein tyrosine phosphatase activator activity  ATPase activity  protein phosphatase regulator activity  protein phosphatase regulator activity  mitotic spindle organization in nucleus  negative regulation of phosphoprotein phosphatase activity  positive regulation of phosphoprotein phosphatase activity  calcium channel complex  positive regulation of protein dephosphorylation  negative regulation of protein dephosphorylation  protein homodimerization activity  positive regulation of apoptotic process  regulation of phosphoprotein phosphatase activity  protein heterodimerization activity  protein phosphatase 2A binding  extracellular exosome  
    Ontology : EGO-EBIprotein phosphatase type 2A complex  protein peptidyl-prolyl isomerization  peptidyl-prolyl cis-trans isomerase activity  receptor binding  protein binding  ATP binding  nucleus  nucleoplasm  cytoplasm  protein tyrosine phosphatase activator activity  ATPase activity  protein phosphatase regulator activity  protein phosphatase regulator activity  mitotic spindle organization in nucleus  negative regulation of phosphoprotein phosphatase activity  positive regulation of phosphoprotein phosphatase activity  calcium channel complex  positive regulation of protein dephosphorylation  negative regulation of protein dephosphorylation  protein homodimerization activity  positive regulation of apoptotic process  regulation of phosphoprotein phosphatase activity  protein heterodimerization activity  protein phosphatase 2A binding  extracellular exosome  
    NDEx NetworkPTPA
    Atlas of Cancer Signalling NetworkPTPA
    Wikipedia pathwaysPTPA
    Orthology - Evolution
    OrthoDB5524
    GeneTree (enSembl)ENSG00000119383
    Phylogenetic Trees/Animal Genes : TreeFamPTPA
    HOVERGENQ15257
    HOGENOMQ15257
    Homologs : HomoloGenePTPA
    Homology/Alignments : Family Browser (UCSC)PTPA
    Gene fusions - Rearrangements
    Fusion : MitelmanDPH7/PPP2R4 [9q34.3/9q34.11]  [t(9;9)(q34;q34)]  
    Fusion : MitelmanPPP2R4/FAM73B [9q34.11/9q34.11]  [t(9;9)(q34;q34)]  
    Fusion : MitelmanPPP2R4/NEK6 [9q34.11/9q33.3]  [t(9;9)(q33;q34)]  
    Fusion : MitelmanPPP2R4/NUP188 [9q34.11/9q34.11]  [t(9;9)(q34;q34)]  
    Fusion: TCGA_MDACCPPP2R4 9q34.11 FAM73B 9q34.11 BRCA
    Fusion: TCGA_MDACCPPP2R4 9q34.11 NEK6 9q33.3 LUAD
    Fusion: TCGA_MDACCPPP2R4 9q34.11 NUP188 9q34.11 BRCA
    Fusion: TCGA_MDACCWDR85 PPP2R4 9q34.11 BRCA
    Tumor Fusion PortalPTPA
    Polymorphisms : SNP and Copy number variants
    NCBI Variation ViewerPTPA [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)PTPA
    dbVarPTPA
    ClinVarPTPA
    1000_GenomesPTPA 
    Exome Variant ServerPTPA
    ExAC (Exome Aggregation Consortium)ENSG00000119383
    GNOMAD BrowserENSG00000119383
    Genetic variants : HAPMAP5524
    Genomic Variants (DGV)PTPA [DGVbeta]
    DECIPHERPTPA [patients]   [syndromes]   [variants]   [genes]  
    CONAN: Copy Number AnalysisPTPA 
    Mutations
    ICGC Data PortalPTPA 
    TCGA Data PortalPTPA 
    Broad Tumor PortalPTPA
    OASIS PortalPTPA [ Somatic mutations - Copy number]
    Mutations and Diseases : HGMDPTPA
    BioMutasearch PTPA
    DgiDB (Drug Gene Interaction Database)PTPA
    DoCM (Curated mutations)PTPA (select the gene name)
    CIViC (Clinical Interpretations of Variants in Cancer)PTPA (select a term)
    intoGenPTPA
    NCG5 (London)PTPA
    Cancer3DPTPA(select the gene name)
    Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
    Diseases
    OMIM600756   
    Orphanet
    DisGeNETPTPA
    MedgenPTPA
    Genetic Testing Registry PTPA
    NextProtQ15257 [Medical]
    TSGene5524
    GENETestsPTPA
    Target ValidationPTPA
    Huge Navigator PTPA [HugePedia]
    snp3D : Map Gene to Disease5524
    BioCentury BCIQPTPA
    ClinGenPTPA
    Clinical trials, drugs, therapy
    Chemical/Protein Interactions : CTD5524
    Chemical/Pharm GKB GenePA33671
    Clinical trialPTPA
    Miscellaneous
    canSAR (ICR)PTPA (select the gene name)
    Probes
    Litterature
    PubMed150 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    CoreMinePTPA
    EVEXPTPA
    GoPubMedPTPA
    iHOPPTPA
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    indexed on : Wed Nov 15 12:31:51 CET 2017

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