PTPA ( protein phosphatase 2 phosphatase activator)

2009-02-01   Veerle 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

Identity

HGNC
LOCATION
9q34.11
LOCUSID
ALIAS
PP2A,PPP2R4,PR53
FUSION GENES

DNA/RNA

Atlas Image
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.

    Proteins

    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.
  • Atlas Image
    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.

    Implicated in

    Bibliography

    Pubmed IDLast YearTitleAuthors
    86126281996A 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 et al
    173333202007Overexpression of the cis/trans isomerase PTPA triggers caspase 3-dependent apoptosis.Azam S et al
    21597851990Isolation and characterization of a tyrosyl phosphatase activator from rabbit skeletal muscle and Xenopus laevis oocytes.Cayla X et al
    81952171994Molecular cloning, expression, and characterization of PTPA, a protein that activates the tyrosyl phosphatase activity of protein phosphatase 2A.Cayla X et al
    169166412006Structure and mechanism of the phosphotyrosyl phosphatase activator.Chao Y et al
    129528892003A novel and essential mechanism determining specificity and activity of protein phosphatase 2A (PP2A) in vivo.Fellner T et al
    175503052007Generation of active protein phosphatase 2A is coupled to holoenzyme assembly.Hombauer H et al
    111710372001Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling.Janssens V et al
    163803872006The protein phosphatase 2A phosphatase activator is a novel peptidyl-prolyl cis/trans-isomerase.Jordens J et al
    168850302006Crystal structure of the PP2A phosphatase activator: implications for its PP2A-specific PPIase activity.Leulliot N et al
    147487412004An inactive protein phosphatase 2A population is associated with methylesterase and can be re-activated by the phosphotyrosyl phosphatase activator.Longin S et al
    158643052005Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance.MacKeigan JP et al
    167827122006The crystal structure of a human PP2A phosphatase activator reveals a novel fold and highly conserved cleft implicated in protein-protein interactions.Magnusdottir A et al
    111343372001The phosphotyrosyl phosphatase activator, Ncs1p (Rrd1p), functions with Cla4p to regulate the G(2)/M transition in Saccharomyces cerevisiae.Mitchell DA et al
    97052771998A 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 et al
    119959662001Anaerobic growth of Saccharomyces cerevisiae alleviates the lethal effect of phosphotyrosyl phosphatase activators depletion.Rempola B et al
    154476312005Specific interactions of PP2A and PP2A-like phosphatases with the yeast PTPA homologues, Ypa1 and Ypa2.Van Hoof C et al
    156894912005The yeast phosphotyrosyl phosphatase activator is part of the Tap42-phosphatase complexes.Zheng Y et al

    Other Information

    Locus ID:

    NCBI: 5524
    MIM: 600756
    HGNC: 9308
    Ensembl: ENSG00000119383

    Variants:

    dbSNP: 5524
    ClinVar: 5524
    TCGA: ENSG00000119383
    COSMIC: PTPA

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000119383ENST00000337738Q15257
    ENSG00000119383ENST00000347048Q68CR8
    ENSG00000119383ENST00000348141A6PVN5
    ENSG00000119383ENST00000355007Q15257
    ENSG00000119383ENST00000357197Q15257
    ENSG00000119383ENST00000358994Q15257
    ENSG00000119383ENST00000393370Q15257
    ENSG00000119383ENST00000411917H0Y6E5
    ENSG00000119383ENST00000414331C9IZ76
    ENSG00000119383ENST00000414510B7ZBQ0
    ENSG00000119383ENST00000417504A6PVN6
    ENSG00000119383ENST00000417728A6PVN9
    ENSG00000119383ENST00000419582B7ZBQ0
    ENSG00000119383ENST00000423100B7ZBQ0
    ENSG00000119383ENST00000432124B7ZBP7
    ENSG00000119383ENST00000432651B7ZBQ0
    ENSG00000119383ENST00000434095B7ZBQ0
    ENSG00000119383ENST00000435132B7ZBQ0
    ENSG00000119383ENST00000435305B4DDQ6
    ENSG00000119383ENST00000436883B7ZBP9
    ENSG00000119383ENST00000440346A6PVN7
    ENSG00000119383ENST00000445241Q5T948
    ENSG00000119383ENST00000452489F6WIT2
    ENSG00000119383ENST00000453358A6PVN8
    ENSG00000119383ENST00000455240H0Y562
    ENSG00000119383ENST00000455292Q5T949

    Expression (GTEx)

    0
    50
    100
    150

    Pathways

    PathwaySourceExternal ID
    Insulin resistanceKEGGhsa04931

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    References

    Pubmed IDYearTitleCitations
    224436832013The biogenesis of active protein phosphatase 2A holoenzymes: a tightly regulated process creating phosphatase specificity.64
    269064532016PP2A as a master regulator of the cell cycle.59
    250568772014REDD1 enhances protein phosphatase 2A-mediated dephosphorylation of Akt to repress mTORC1 signaling.57
    212338402011PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect.56
    275510542016A PP2A-B55 recognition signal controls substrate dephosphorylation kinetics during mitotic exit.52
    201103482010Protein phosphatase 2A reactivates FOXO3a through a dynamic interplay with 14-3-3 and AKT.49
    180459922008PP2A regulates HDAC4 nuclear import.48
    192344872009Jak2 inhibition deactivates Lyn kinase through the SET-PP2A-SHP1 pathway, causing apoptosis in drug-resistant cells from chronic myelogenous leukemia patients.47
    189316622008The TBP-PP2A mitotic complex bookmarks genes by preventing condensin action.44
    203087882010PP2A regulates tau phosphorylation directly and also indirectly via activating GSK-3beta.43

    Citation

    Veerle Janssens

    PTPA ( protein phosphatase 2 phosphatase activator)

    Atlas Genet Cytogenet Oncol Haematol. 2009-02-01

    Online version: http://atlasgeneticsoncology.org/gene/41817/ppp2r4id41817ch9q34