ID   PP2AA_PIG               Reviewed;         309 AA.
AC   P67776; P05323; P13197;
DT   11-OCT-2004, integrated into UniProtKB/Swiss-Prot.
DT   11-OCT-2004, sequence version 1.
DT   27-MAR-2024, entry version 125.
DE   RecName: Full=Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform;
DE            Short=PP2A-alpha;
DE            EC=3.1.3.16 {ECO:0000250|UniProtKB:P67775};
GN   Name=PPP2CA;
OS   Sus scrofa (Pig).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX   NCBI_TaxID=9823;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Kidney;
RX   PubMed=2827745; DOI=10.1021/bi00397a003;
RA   Stone S.R., Hofsteenge J., Hemmings B.A.;
RT   "Molecular cloning of cDNAs encoding two isoforms of the catalytic subunit
RT   of protein phosphatase 2A.";
RL   Biochemistry 26:7215-7220(1987).
CC   -!- FUNCTION: PP2A is the major phosphatase for microtubule-associated
CC       proteins (MAPs) (By similarity). PP2A can modulate the activity of
CC       phosphorylase B kinase casein kinase 2, mitogen-stimulated S6 kinase,
CC       and MAP-2 kinase (By similarity). Cooperates with SGO2 to protect
CC       centromeric cohesin from separase-mediated cleavage in oocytes
CC       specifically during meiosis I (By similarity). Can dephosphorylate
CC       p53/TP53 (By similarity). Activates RAF1 by dephosphorylating it at
CC       'Ser-259' (By similarity). Mediates dephosphorylation of WEE1,
CC       preventing its ubiquitin-mediated proteolysis, increasing WEE1 protein
CC       levels, and promoting the G2/M checkpoint (By similarity). Mediates
CC       dephosphorylation of MYC; promoting its ubiquitin-mediated proteolysis:
CC       interaction with AMBRA1 enhances interaction between PPP2CA and MYC (By
CC       similarity). Mediates dephosphorylation of FOXO3; promoting its
CC       stabilization: interaction with AMBRA1 enhances interaction between
CC       PPP2CA and FOXO3 (By similarity). Catalyzes dephosphorylation of the
CC       pyrin domain of NLRP3, promoting assembly of the NLRP3 inflammasome (By
CC       similarity). {ECO:0000250|UniProtKB:P63330,
CC       ECO:0000250|UniProtKB:P67775}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=H2O + O-phospho-L-seryl-[protein] = L-seryl-[protein] +
CC         phosphate; Xref=Rhea:RHEA:20629, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC         COMP:11604, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999, ChEBI:CHEBI:43474,
CC         ChEBI:CHEBI:83421; EC=3.1.3.16;
CC         Evidence={ECO:0000250|UniProtKB:P67775};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=H2O + O-phospho-L-threonyl-[protein] = L-threonyl-[protein] +
CC         phosphate; Xref=Rhea:RHEA:47004, Rhea:RHEA-COMP:11060, Rhea:RHEA-
CC         COMP:11605, ChEBI:CHEBI:15377, ChEBI:CHEBI:30013, ChEBI:CHEBI:43474,
CC         ChEBI:CHEBI:61977; EC=3.1.3.16;
CC         Evidence={ECO:0000250|UniProtKB:P67775};
CC   -!- COFACTOR:
CC       Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC         Evidence={ECO:0000250|UniProtKB:P67775};
CC       Note=Binds 2 manganese ions per subunit.
CC       {ECO:0000250|UniProtKB:P67775};
CC   -!- SUBUNIT: PP2A consists of a common heterodimeric core enzyme, composed
CC       of PPP2CA a 36 kDa catalytic subunit (subunit C) and PPP2R1A a 65 kDa
CC       constant regulatory subunit (PR65 or subunit A), that associates with a
CC       variety of regulatory subunits. Proteins that associate with the core
CC       dimer include three families of regulatory subunits B (the
CC       R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48
CC       kDa variable regulatory subunit, viral proteins, and cell signaling
CC       molecules (By similarity). Interacts with the PP2A A subunit PPP2R1A
CC       (By similarity). Interacts with NXN; the interaction is direct (By
CC       similarity). Interacts with KCTD20 (By similarity). Interacts with
CC       BTBD10 (By similarity). Interacts with SGO1 and SGO2. Interacts with
CC       TP53. Interacts with AXIN1; the interaction dephosphorylates AXIN1.
CC       Interacts with PIM3; this interaction promotes dephosphorylation,
CC       ubiquitination and proteasomal degradation of PIM3. Interacts with
CC       RAF1. Interaction with IGBP1 protects unassembled PPP2CA from
CC       degradative ubiquitination. Interacts with GSK3B (via C2 domain).
CC       Interacts with MFHAS1; retains PPP2CA into the cytoplasm and excludes
CC       it from the nucleus. Interacts with PABIR1/FAM122A. Interacts with
CC       ADCY8; interaction is phosphatase activity-dependent; antagonizes
CC       interaction between ADCY8 and calmodulin. Interacts with CRTC3 (when
CC       phosphorylated at 'Ser-391'). Interacts with SPRY2; the interaction is
CC       inhibited by TESK1 interaction with SPRY2, possibly by vesicular
CC       sequestration of SPRY2. Interacts with TRAF3IP3. Interacts with AMBRA1
CC       (via PxP motifs); enhancing interaction between PPP2CA and MYC or FOXO3
CC       (By similarity). Forms a complex with AMBRA1 and BECN1; AMBRA1 and
CC       BECN1 components of the complex regulate MYC stability via different
CC       pathways (By similarity). {ECO:0000250|UniProtKB:P63330,
CC       ECO:0000250|UniProtKB:P67775}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P67775}. Nucleus
CC       {ECO:0000250|UniProtKB:P67775}. Chromosome, centromere
CC       {ECO:0000250|UniProtKB:P67775}. Cytoplasm, cytoskeleton, spindle pole
CC       {ECO:0000250|UniProtKB:P67775}. Note=In prometaphase cells, but not in
CC       anaphase cells, localizes at centromeres. During mitosis, also found at
CC       spindle poles (By similarity). Centromeric localization requires the
CC       presence of SGO2 (By similarity). {ECO:0000250|UniProtKB:P63330,
CC       ECO:0000250|UniProtKB:P67775}.
CC   -!- PTM: Reversibly methyl esterified on Leu-309 by leucine carboxyl
CC       methyltransferase 1 (LCMT1) and protein phosphatase methylesterase 1
CC       (PPME1). Carboxyl methylation influences the affinity of the catalytic
CC       subunit for the different regulatory subunits, thereby modulating the
CC       PP2A holoenzyme's substrate specificity, enzyme activity and cellular
CC       localization (By similarity). {ECO:0000250|UniProtKB:P67774}.
CC   -!- PTM: Phosphorylation of either threonine (by autophosphorylation-
CC       activated protein kinase) or tyrosine results in inactivation of the
CC       phosphatase. Auto-dephosphorylation has been suggested as a mechanism
CC       for reactivation (By similarity). {ECO:0000250|UniProtKB:P67774}.
CC   -!- PTM: Polyubiquitinated, leading to its degradation by the proteasome.
CC       {ECO:0000250|UniProtKB:P67775}.
CC   -!- SIMILARITY: Belongs to the PPP phosphatase family. PP-1 subfamily.
CC       {ECO:0000305}.
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DR   EMBL; M20192; AAA30981.1; -; mRNA.
DR   PIR; A27430; A27430.
DR   RefSeq; NP_999531.1; NM_214366.1.
DR   AlphaFoldDB; P67776; -.
DR   SMR; P67776; -.
DR   CORUM; P67776; -.
DR   STRING; 9823.ENSSSCP00000015208; -.
DR   iPTMnet; P67776; -.
DR   PeptideAtlas; P67776; -.
DR   Ensembl; ENSSSCT00000015621.5; ENSSSCP00000015208.3; ENSSSCG00000014298.5.
DR   Ensembl; ENSSSCT00015031907.1; ENSSSCP00015012660.1; ENSSSCG00015024027.1.
DR   Ensembl; ENSSSCT00025067102.1; ENSSSCP00025028701.1; ENSSSCG00025049272.1.
DR   Ensembl; ENSSSCT00030006853.1; ENSSSCP00030003069.1; ENSSSCG00030005027.1.
DR   Ensembl; ENSSSCT00035070097.1; ENSSSCP00035028434.1; ENSSSCG00035052570.1.
DR   Ensembl; ENSSSCT00040079016.1; ENSSSCP00040034100.1; ENSSSCG00040058228.1.
DR   Ensembl; ENSSSCT00045024477.1; ENSSSCP00045016913.1; ENSSSCG00045014363.1.
DR   Ensembl; ENSSSCT00050100322.1; ENSSSCP00050043515.1; ENSSSCG00050073394.1.
DR   Ensembl; ENSSSCT00055021387.1; ENSSSCP00055016941.1; ENSSSCG00055010854.1.
DR   Ensembl; ENSSSCT00055021414.1; ENSSSCP00055016964.1; ENSSSCG00055010854.1.
DR   Ensembl; ENSSSCT00060062308.1; ENSSSCP00060026688.1; ENSSSCG00060045924.1.
DR   Ensembl; ENSSSCT00065074223.1; ENSSSCP00065032333.1; ENSSSCG00065054140.1.
DR   Ensembl; ENSSSCT00065074230.1; ENSSSCP00065032339.1; ENSSSCG00065054140.1.
DR   Ensembl; ENSSSCT00070040758.1; ENSSSCP00070034202.1; ENSSSCG00070020508.1.
DR   GeneID; 397656; -.
DR   KEGG; ssc:397656; -.
DR   CTD; 5515; -.
DR   VGNC; VGNC:91745; PPP2CA.
DR   GeneTree; ENSGT00550000074618; -.
DR   InParanoid; P67776; -.
DR   OMA; CMKVRYP; -.
DR   OrthoDB; 19833at2759; -.
DR   Reactome; R-SSC-113501; Inhibition of replication initiation of damaged DNA by RB1/E2F1.
DR   Reactome; R-SSC-1295596; Spry regulation of FGF signaling.
DR   Reactome; R-SSC-141444; Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal.
DR   Reactome; R-SSC-180024; DARPP-32 events.
DR   Reactome; R-SSC-195253; Degradation of beta-catenin by the destruction complex.
DR   Reactome; R-SSC-196299; Beta-catenin phosphorylation cascade.
DR   Reactome; R-SSC-198753; ERK/MAPK targets.
DR   Reactome; R-SSC-202670; ERKs are inactivated.
DR   Reactome; R-SSC-2467813; Separation of Sister Chromatids.
DR   Reactome; R-SSC-2500257; Resolution of Sister Chromatid Cohesion.
DR   Reactome; R-SSC-2995383; Initiation of Nuclear Envelope (NE) Reformation.
DR   Reactome; R-SSC-389513; CTLA4 inhibitory signaling.
DR   Reactome; R-SSC-432142; Platelet sensitization by LDL.
DR   Reactome; R-SSC-4641262; Disassembly of the destruction complex and recruitment of AXIN to the membrane.
DR   Reactome; R-SSC-5663220; RHO GTPases Activate Formins.
DR   Reactome; R-SSC-5673000; RAF activation.
DR   Reactome; R-SSC-5675221; Negative regulation of MAPK pathway.
DR   Reactome; R-SSC-6804757; Regulation of TP53 Degradation.
DR   Reactome; R-SSC-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR   Reactome; R-SSC-68877; Mitotic Prometaphase.
DR   Reactome; R-SSC-69231; Cyclin D associated events in G1.
DR   Reactome; R-SSC-69273; Cyclin A/B1/B2 associated events during G2/M transition.
DR   Reactome; R-SSC-9648025; EML4 and NUDC in mitotic spindle formation.
DR   Reactome; R-SSC-975957; Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC).
DR   Reactome; R-SSC-9833482; PKR-mediated signaling.
DR   Proteomes; UP000008227; Chromosome 2.
DR   Proteomes; UP000314985; Chromosome 2.
DR   Proteomes; UP000694570; Unplaced.
DR   Proteomes; UP000694571; Unplaced.
DR   Proteomes; UP000694720; Unplaced.
DR   Proteomes; UP000694722; Unplaced.
DR   Proteomes; UP000694723; Unplaced.
DR   Proteomes; UP000694724; Unplaced.
DR   Proteomes; UP000694725; Unplaced.
DR   Proteomes; UP000694726; Unplaced.
DR   Proteomes; UP000694727; Unplaced.
DR   Proteomes; UP000694728; Unplaced.
DR   Bgee; ENSSSCG00000014298; Expressed in Ammon's horn and 42 other cell types or tissues.
DR   ExpressionAtlas; P67776; baseline and differential.
DR   GO; GO:0000775; C:chromosome, centromeric region; IEA:UniProtKB-SubCell.
DR   GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR   GO; GO:0045121; C:membrane raft; ISS:UniProtKB.
DR   GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0005886; C:plasma membrane; IEA:Ensembl.
DR   GO; GO:0000159; C:protein phosphatase type 2A complex; IEA:Ensembl.
DR   GO; GO:0000922; C:spindle pole; IEA:UniProtKB-SubCell.
DR   GO; GO:0045202; C:synapse; IEA:Ensembl.
DR   GO; GO:0050811; F:GABA receptor binding; IEA:Ensembl.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0017018; F:myosin phosphatase activity; IEA:UniProtKB-EC.
DR   GO; GO:0046982; F:protein heterodimerization activity; ISS:UniProtKB.
DR   GO; GO:0004722; F:protein serine/threonine phosphatase activity; ISS:UniProtKB.
DR   GO; GO:0004725; F:protein tyrosine phosphatase activity; IEA:Ensembl.
DR   GO; GO:0051321; P:meiotic cell cycle; IEA:UniProtKB-KW.
DR   GO; GO:0007498; P:mesoderm development; IEA:Ensembl.
DR   GO; GO:0000278; P:mitotic cell cycle; IBA:GO_Central.
DR   GO; GO:0010719; P:negative regulation of epithelial to mesenchymal transition; IEA:Ensembl.
DR   GO; GO:1904539; P:negative regulation of glycolytic process through fructose-6-phosphate; IEA:Ensembl.
DR   GO; GO:0051898; P:negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; ISS:UniProtKB.
DR   GO; GO:1900227; P:positive regulation of NLRP3 inflammasome complex assembly; ISS:UniProtKB.
DR   GO; GO:0006470; P:protein dephosphorylation; ISS:UniProtKB.
DR   GO; GO:2000045; P:regulation of G1/S transition of mitotic cell cycle; IEA:Ensembl.
DR   GO; GO:0043029; P:T cell homeostasis; ISS:UniProtKB.
DR   CDD; cd07415; MPP_PP2A_PP4_PP6; 1.
DR   Gene3D; 3.60.21.10; -; 1.
DR   InterPro; IPR004843; Calcineurin-like_PHP_ApaH.
DR   InterPro; IPR029052; Metallo-depent_PP-like.
DR   InterPro; IPR047129; PPA2-like.
DR   InterPro; IPR006186; Ser/Thr-sp_prot-phosphatase.
DR   PANTHER; PTHR45619; SERINE/THREONINE-PROTEIN PHOSPHATASE PP2A-RELATED; 1.
DR   PANTHER; PTHR45619:SF42; SERINE_THREONINE-PROTEIN PHOSPHATASE 2A CATALYTIC SUBUNIT ALPHA ISOFORM; 1.
DR   Pfam; PF00149; Metallophos; 1.
DR   PRINTS; PR00114; STPHPHTASE.
DR   SMART; SM00156; PP2Ac; 1.
DR   SUPFAM; SSF56300; Metallo-dependent phosphatases; 1.
DR   PROSITE; PS00125; SER_THR_PHOSPHATASE; 1.
PE   2: Evidence at transcript level;
KW   Centromere; Chromosome; Cytoplasm; Cytoskeleton; Hydrolase; Manganese;
KW   Meiosis; Metal-binding; Methylation; Nucleus; Phosphoprotein;
KW   Protein phosphatase; Reference proteome; Ubl conjugation.
FT   CHAIN           1..309
FT                   /note="Serine/threonine-protein phosphatase 2A catalytic
FT                   subunit alpha isoform"
FT                   /id="PRO_0000058841"
FT   ACT_SITE        118
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000250|UniProtKB:P36873"
FT   BINDING         57
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250|UniProtKB:P67775"
FT   BINDING         59
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250|UniProtKB:P67775"
FT   BINDING         85
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250|UniProtKB:P67775"
FT   BINDING         85
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250|UniProtKB:P67775"
FT   BINDING         117
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250|UniProtKB:P67775"
FT   BINDING         167
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250|UniProtKB:P67775"
FT   BINDING         241
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250|UniProtKB:P67775"
FT   MOD_RES         307
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:P67774"
FT   MOD_RES         309
FT                   /note="Leucine methyl ester"
FT                   /evidence="ECO:0000250|UniProtKB:P67774"
SQ   SEQUENCE   309 AA;  35594 MW;  C602291F78F34555 CRC64;
     MDEKVFTKEL DQWIEQLNEC KQLSESQVKS LCEKAKEILT KESNVQEVRC PVTVCGDVHG
     QFHDLMELFR IGGKSPDTNY LFMGDYVDRG YYSVETVTLL VALKVRYRER ITILRGNHES
     RQITQVYGFY DECLRKYGNA NVWKYFTDLF DYLPLTALVD GQIFCLHGGL SPSIDTLDHI
     RALDRLQEVP HEGPMCDLLW SDPDDRGGWG ISPRGAGYTF GQDISETFNH ANGLTLVSRA
     HQLVMEGYNW CHDRNVVTIF SAPNYCYRCG NQAAIMELDD TLKYSFLQFD PAPRRGEPHV
     TRRTPDYFL
//