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PPP2R4 (protein phosphatase 2A activator, regulatory subunit 4)

Identity

Other namesMGC2184
OTTHUMP00000022333
PP2A
PR53
PTPA
HGNC (Hugo) PPP2R4
LocusID (NCBI) 5524
Location 9q34.11
Location_base_pair Starts at 131873967 and ends at 131911225 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order From centromere to telomere: DOLPP1 (dolichyl pyrophosphate phosphatase 1), CRAT (carnitine acetyltransferase), PPP2R4, IER5L (immediate early response 5-like), C9orf106.
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.

    External links

    Nomenclature
    HGNC (Hugo)PPP2R4   9308
    Entrez_Gene (NCBI)PPP2R4  5524  protein phosphatase 2A activator, regulatory subunit 4
    Cards
    AtlasPPP2R4ID41817ch9q34
    GeneCards (Weizmann)PPP2R4
    Ensembl (Hinxton)ENSG00000119383 [Gene_View]  chr9:131873967-131911225 [Contig_View]  PPP2R4 [Vega]
    AceView (NCBI)PPP2R4
    Genatlas (Paris)PPP2R4
    euGene (Indiana)5524
    SOURCE (Stanford)NM_001193397 NM_021131 NM_178000 NM_178001 NM_178002 NM_178003
    Genomic and cartography
    GoldenPath (UCSC)PPP2R4  -  9q34.11   chr9:131873967-131911225 +  9q34   [Description]    (hg19-Feb_2009)
    EnsemblPPP2R4 - 9q34 [CytoView]
    Mapping of homologs : NCBIPPP2R4 [Mapview]
    OMIM600756   
    Gene and transcription
    Genbank (Entrez)AK222788 AK297202 AK302043 AK302897 AK307424
    RefSeq transcript (SRS)NM_001193397 NM_021131 NM_178000 NM_178001 NM_178002 NM_178003
    RefSeq transcript (Entrez)NM_001193397 NM_021131 NM_178000 NM_178001 NM_178002 NM_178003
    RefSeq genomic (SRS)AC_000141 NC_000009 NG_029370 NT_008470 NW_001839239
    RefSeq genomic (Entrez)AC_000141 NC_000009 NG_029370 NT_008470 NW_001839239
    Consensus coding sequences : CCDS (NCBI)PPP2R4
    Cluster EST : UnigeneHs.400740 [ SRS ] Hs.400740 [ NCBI ]
    Alternative Splicing : Fast-db (Paris)16142
    Alternative Splicing GalleryENSG00000119383
    Gene ExpressionPPP2R4 [ NCBI-GEO ]   PPP2R4 [ EBI - ARRAY_EXPRESS ]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtQ15257 (SRS) Q15257 (Uniprot)
    With graphics : InterProQ15257
    Splice isoforms : SwissVarQ15257(Swissvar)
    Domains : Interpro (SRS)Phstyr_phstse_ac   
    Domains : Interpro (EBI)Phstyr_phstse_ac   
    Related proteins : CluSTrQ15257
    Domain families : Pfam (SRS)PTPA (PF03095)   
    Domain families : Pfam (Sanger)PTPA (PF03095)   
    Domain families : Pfam (NCBI)pfam03095   
    Blocks (Seattle)Q15257
    PDB (SRS)2G62    2HV6    2HV7    2IXM   
    PDB (PDBSum)2G62    2HV6    2HV7    2IXM   
    PDB (IMB)2G62    2HV6    2HV7    2IXM   
    PDB (RSDB)2G62    2HV6    2HV7    2IXM   
    Human Protein AtlasENSG00000119383
    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
    REACTOMEPPP2R4
    BioGRIDPPP2R4
    InParanoidQ15257
    Interologous Interaction database Q15257
    Polymorphism : SNP, mutations, diseases
    SNP Single Nucleotide Polymorphism (NCBI)PPP2R4
    SNP (GeneSNP Utah)PPP2R4
    SNP : HGBasePPP2R4
    Genetic variants : HAPMAPPPP2R4
    Somatic Mutations in Cancer : COSMICPPP2R4 
    CONAN: Copy Number AnalysisPPP2R4 
    Mutations and Diseases : HGMDPPP2R4
    OMIM600756   
    GENETests600756   
    Disease Genetic AssociationPPP2R4
    Huge Navigator PPP2R4 [HugePedia]  PPP2R4 [HugeCancerGEM]
    Genomic VariantsPPP2R4
    snp3D : Map Gene to Disease5524
    General knowledge
    Homologs : HomoloGenePPP2R4
    Homology/Alignments : Family Browser (UCSC)PPP2R4
    Phylogenetic Trees/Animal Genes : TreeFamPPP2R4
    Catalytic activity : Enzyme5.2.1.8 [ Enzyme-Expasy ]   5.2.1.8 [ Enzyme-SRS ]   5.2.1.8 [ IntEnz-EBI ]   5.2.1.8 [ BRENDA ]   5.2.1.8 [ KEGG ]   
    Chemical/Protein Interactions : CTD5524
    Chemical/Pharm GKB GenePA33671
    Clinical trialPPP2R4
    Cancer Resource (Charite)ENSG00000119383
    Ontology : AmiGOprotein phosphatase type 2A complex  nucleotide binding  peptidyl-prolyl cis-trans isomerase activity  receptor binding  ATP binding  soluble fraction  nucleus  nucleolus  cytoplasm  ATP catabolic process  protein folding  protein tyrosine phosphatase activator activity  protein phosphatase type 2A regulator activity  protein phosphatase type 2A regulator activity  isomerase activity  ATPase activity  phosphatase activator activity  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  
    Ontology : EGO-EBIprotein phosphatase type 2A complex  nucleotide binding  peptidyl-prolyl cis-trans isomerase activity  receptor binding  ATP binding  soluble fraction  nucleus  nucleolus  cytoplasm  ATP catabolic process  protein folding  protein tyrosine phosphatase activator activity  protein phosphatase type 2A regulator activity  protein phosphatase type 2A regulator activity  isomerase activity  ATPase activity  phosphatase activator activity  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  
    Pathways : KEGGTight junction
    Other databases
    Probes
    Probes : ImagenesPPP2R4 Related clones (RZPD - Berlin)
    Litterature
    PubMed85 Pubmed reference(s) in Entrez
    PubGenePPP2R4
    iHOPPPP2R4

    Bibliography

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    Biochemistry. 1990 Jan 23;29(3):658-67.
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    Molecular cloning, expression, and characterization of PTPA, a protein that activates the tyrosyl phosphatase activity of protein phosphatase 2A.
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    The phosphotyrosyl phosphatase activator of protein phosphatase 2A. A novel purification method, immunological and enzymic characterization.
    Van Hoof C, Cayla X, Bosch M, Merlevede W, Goris J.
    Eur J Biochem. 1994 Dec 15;226(3):899-907.
    PMID 7813481
     
    Structure and chromosomal localization of the human gene of the phosphotyrosyl phosphatase activator (PTPA) of protein phosphatase 2A.
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    Genomics. 1995 Jul 20;28(2):261-72.
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    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.
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    PTPA regulating PP2A as a dual specificity phosphatase.
    Janssens V, Van Hoof C, Merlevede W, Goris J.
    Methods Mol Biol. 1998;93:103-15.
    PMID 9664530
     
    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
     
    Functional analysis of conserved domains in the phosphotyrosyl phosphatase activator. Molecular cloning of the homologues from Drosophila melanogaster and Saccharomyces cerevisiae.
    Van Hoof C, Janssens V, Dinishiotu A, Merlevede W, Goris J.
    Biochemistry. 1998 Sep 15;37(37):12899-908.
    PMID 9737869
     
    Functional analysis of the promoter region of the human phosphotyrosine phosphatase activator gene: Yin Yang 1 is essential for core promoter activity.
    Janssens V, Van Hoof C, De Baere I, Merlevede W, Goris J.
    Biochem J. 1999 Dec 15;344 Pt 3:755-63.
    PMID 10585862
     
    The phosphotyrosyl phosphatase activator gene is a novel p53 target gene.
    Janssens V, Van Hoof C, De Baere I, Merlevede W, Goris J.
    J Biol Chem. 2000 Jul 7;275(27):20488-95.
    PMID 10787423
     
    Identification and characterization of alternative splice products encoded by the human phosphotyrosyl phosphatase activator gene.
    Janssens V, van Hoof C, Martens E, de Baere I, Merlevede W, Goris J.
    Eur J Biochem. 2000 Jul;267(14):4406-13.
    PMID 10880964
     
    Functional analysis of RRD1 (YIL153w) and RRD2 (YPL152w), which encode two putative activators of the phosphotyrosyl phosphatase activity of PP2A in Saccharomyces cerevisiae.
    Rempola B, Kaniak A, Migdalski A, Rytka J, Slonimski PP, di Rago JP.
    Mol Gen Genet. 2000 Jan;262(6):1081-92.
    PMID 10660069
     
    The Saccharomyces cerevisiae homologue YPA1 of the mammalian phosphotyrosyl phosphatase activator of protein phosphatase 2A controls progression through the G1 phase of the yeast cell cycle.
    Van Hoof C, Janssens V, De Baere I, de Winde JH, Winderickx J, Dumortier F, Thevelein JM, Merlevede W, Goris J.
    J Mol Biol. 2000 Sep 8;302(1):103-20.
    PMID 10964564
     
    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 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
     
    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
     
    The Saccharomyces cerevisiae phosphotyrosyl phosphatase activator proteins are required for a subset of the functions disrupted by protein phosphatase 2A mutations.
    Van Hoof C, Janssens V, De Baere I, Stark MJ, de Winde JH, Winderickx J, Thevelein JM, Merlevede W, Goris J.
    Exp Cell Res. 2001 Apr 1;264(2):372-87.
    PMID 11262194
     
    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
     
    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
     
    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
     
    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
     
    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
     
    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
     
    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
     
    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
     
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    Contributor(s)

    Written02-2009Veerle Janssens
    Protein Phosphorylation and 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

    Citation

    This paper should be referenced as such :
    Janssens V . PPP2R4 (protein phosphatase 2A activator, regulatory subunit 4). Atlas Genet Cytogenet Oncol Haematol. February 2009 .
    URL : http://AtlasGeneticsOncology.org/Genes/PPP2R4ID41817ch9q34.html

    This paper is referenced by INIST as such :
    http://documents.irevues.inist.fr/bitstream/2042/44661/1/02-2009-PPP2R4ID41817ch9q34.pdf   [ Bibliographic record ]

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