Full text data of PPP2CA
PPP2CA
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform; PP2A-alpha; 3.1.3.16 (Replication protein C; RP-C)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform; PP2A-alpha; 3.1.3.16 (Replication protein C; RP-C)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00008380
IPI00008380 Serine/threonine protein phosphatase 2A, PP2A can modulate the activity of casein kinase, A phosphoprotein + H2O = a protein + phosphate, protein heterodimerization activity, ceramide metabolism, inactivation of MAPK, protein amino acid dephosphorylation, regulation of cell adhesion, regulation of Wnt receptor signaling pathway, response to organic substance, second-messenger-mediated signaling soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a expected molecular weight found in band at molecular weight
IPI00008380 Serine/threonine protein phosphatase 2A, PP2A can modulate the activity of casein kinase, A phosphoprotein + H2O = a protein + phosphate, protein heterodimerization activity, ceramide metabolism, inactivation of MAPK, protein amino acid dephosphorylation, regulation of cell adhesion, regulation of Wnt receptor signaling pathway, response to organic substance, second-messenger-mediated signaling soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a expected molecular weight found in band at molecular weight
UniProt
P67775
ID PP2AA_HUMAN Reviewed; 309 AA.
AC P67775; P05323; P13197;
DT 11-OCT-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 11-OCT-2004, sequence version 1.
DT 22-JAN-2014, entry version 103.
DE RecName: Full=Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform;
DE Short=PP2A-alpha;
DE EC=3.1.3.16;
DE AltName: Full=Replication protein C;
DE Short=RP-C;
GN Name=PPP2CA;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Fibroblast;
RX PubMed=2849764; DOI=10.1093/nar/16.23.11365;
RA Stone S.R., Mayer R., Wernet W., Maurer F., Hofsteenge J.,
RA Hemmings B.A.;
RT "The nucleotide sequence of the cDNA encoding the human lung protein
RT phosphatase 2A alpha catalytic subunit.";
RL Nucleic Acids Res. 16:11365-11365(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=2837763; DOI=10.1073/pnas.85.12.4252;
RA Arino J., Woon C.W., Brautigan D.L., Miller T.B. Jr., Johnson G.L.;
RT "Human liver phosphatase 2A: cDNA and amino acid sequence of two
RT catalytic subunit isotypes.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:4252-4256(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1846293; DOI=10.1021/bi00215a014;
RA Khew-Goodall Y., Mayer R.E., Maurer F., Stone S.R., Hemmings B.A.;
RT "Structure and transcriptional regulation of protein phosphatase 2A
RT catalytic subunit genes.";
RL Biochemistry 30:89-97(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung, Placenta, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP DEPHOSPHORYLATION OF SV40 LARGE-T ANTIGEN AND P53 PROTEIN.
RX PubMed=1848668;
RA Scheidtmann K.H., Mumby M.C., Rundell K., Walter G.;
RT "Dephosphorylation of simian virus 40 large-T antigen and p53 protein
RT by protein phosphatase 2A: inhibition by small-t antigen.";
RL Mol. Cell. Biol. 11:1996-2003(1991).
RN [6]
RP METHYLATION AT LEU-309.
RX PubMed=8206937;
RA Favre B., Zolnierowicz S., Turowski P., Hemmings B.A.;
RT "The catalytic subunit of protein phosphatase 2A is carboxyl-
RT methylated in vivo.";
RL J. Biol. Chem. 269:16311-16317(1994).
RN [7]
RP INTERACTION WITH IGBP1.
RX PubMed=9647778; DOI=10.1006/bbrc.1998.8792;
RA Chen J., Peterson R.T., Schreiber S.L.;
RT "Alpha 4 associates with protein phosphatases 2A, 4, and 6.";
RL Biochem. Biophys. Res. Commun. 247:827-832(1998).
RN [8]
RP MUTAGENESIS OF LEU-309.
RX PubMed=10191253; DOI=10.1042/0264-6021:3390241;
RA Bryant J.C., Westphal R.S., Wadzinski B.E.;
RT "Methylated C-terminal leucine residue of PP2A catalytic subunit is
RT important for binding of regulatory Balpha subunit.";
RL Biochem. J. 339:241-246(1999).
RN [9]
RP PARTIAL PROTEIN SEQUENCE, AND ACTIVATION OF SV40 REPLICATION.
RX PubMed=2555176;
RA Virshup D.M., Kauffman M.G., Kelly T.J.;
RT "Activation of SV40 DNA replication in vitro by cellular protein
RT phosphatase 2A.";
RL EMBO J. 8:3891-3898(1989).
RN [10]
RP INTERACTION WITH AXIN1, AND FUNCTION.
RX PubMed=9920888; DOI=10.1074/jbc.274.6.3439;
RA Hsu W., Zeng L., Costantini F.;
RT "Identification of a domain of Axin that binds to the serine/threonine
RT protein phosphatase 2A and a self-binding domain.";
RL J. Biol. Chem. 274:3439-3445(1999).
RN [11]
RP FUNCTION, AND INTERACTION WITH RAF1.
RX PubMed=10801873; DOI=10.1074/jbc.M003259200;
RA Abraham D., Podar K., Pacher M., Kubicek M., Welzel N., Hemmings B.A.,
RA Dilworth S.M., Mischak H., Kolch W., Baccarini M.;
RT "Raf-1-associated protein phosphatase 2A as a positive regulator of
RT kinase activation.";
RL J. Biol. Chem. 275:22300-22304(2000).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY, AND INTERACTION WITH SGOL1.
RX PubMed=16580887; DOI=10.1016/j.devcel.2006.03.010;
RA Tang Z., Shu H., Qi W., Mahmood N.A., Mumby M.C., Yu H.;
RT "PP2A is required for centromeric localization of Sgo1 and proper
RT chromosome segregation.";
RL Dev. Cell 10:575-585(2006).
RN [13]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH SGOL1.
RX PubMed=16541025; DOI=10.1038/nature04663;
RA Kitajima T.S., Sakuno T., Ishiguro K., Iemura S., Natsume T.,
RA Kawashima S.A., Watanabe Y.;
RT "Shugoshin collaborates with protein phosphatase 2A to protect
RT cohesin.";
RL Nature 441:46-52(2006).
RN [14]
RP INTERACTION WITH PIM3.
RX PubMed=12473674; DOI=10.1074/jbc.M208246200;
RA Losman J.A., Chen X.P., Vuong B.Q., Fay S., Rothman P.B.;
RT "Protein phosphatase 2A regulates the stability of Pim protein
RT kinases.";
RL J. Biol. Chem. 278:4800-4805(2003).
RN [15]
RP INTERACTION WITH TP53.
RX PubMed=17245430; DOI=10.1038/sj.emboj.7601519;
RA Li H.H., Cai X., Shouse G.P., Piluso L.G., Liu X.;
RT "A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-
RT induced dephosphorylation of p53 at Thr55.";
RL EMBO J. 26:402-411(2007).
RN [16]
RP INTERACTION WITH SGOL2.
RX PubMed=17485487; DOI=10.1083/jcb.200701122;
RA Huang H., Feng J., Famulski J., Rattner J.B., Liu S.T., Kao G.D.,
RA Muschel R., Chan G.K., Yen T.J.;
RT "Tripin/hSgo2 recruits MCAK to the inner centromere to correct
RT defective kinetochore attachments.";
RL J. Cell Biol. 177:413-424(2007).
RN [17]
RP INTERACTION WITH IGBP1.
RX PubMed=19818709; DOI=10.1016/j.molcel.2009.09.025;
RA Kong M., Ditsworth D., Lindsten T., Thompson C.B.;
RT "Alpha4 is an essential regulator of PP2A phosphatase activity.";
RL Mol. Cell 36:51-60(2009).
RN [18]
RP INTERACTION WITH IGBP1.
RX PubMed=20092282; DOI=10.1021/bi901837h;
RA McConnell J.L., Watkins G.R., Soss S.E., Franz H.S., McCorvey L.R.,
RA Spiller B.W., Chazin W.J., Wadzinski B.E.;
RT "Alpha4 is a ubiquitin-binding protein that regulates protein
RT serine/threonine phosphatase 2A ubiquitination.";
RL Biochemistry 49:1713-1718(2010).
RN [19]
RP INTERACTION WITH GSK3B.
RX PubMed=20080667; DOI=10.1073/pnas.0908133107;
RA Xie D., Gore C., Liu J., Pong R.C., Mason R., Hao G., Long M.,
RA Kabbani W., Yu L., Zhang H., Chen H., Sun X., Boothman D.A., Min W.,
RA Hsieh J.T.;
RT "Role of DAB2IP in modulating epithelial-to-mesenchymal transition and
RT prostate cancer metastasis.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:2485-2490(2010).
RN [20]
RP ALTERNATIVE SPLICING (ISOFORM 2).
RX PubMed=22167190; DOI=10.1074/jbc.M111.283341;
RA Migueleti D.L., Smetana J.H., Nunes H.F., Kobarg J., Zanchin N.I.;
RT "Identification and characterization of an alternatively spliced
RT isoform of the human protein phosphatase 2Aalpha catalytic subunit.";
RL J. Biol. Chem. 287:4853-4862(2012).
RN [21]
RP FUNCTION.
RX PubMed=22613722; DOI=10.1074/jbc.M112.368613;
RA Watkins G.R., Wang N., Mazalouskas M.D., Gomez R.J., Guthrie C.R.,
RA Kraemer B.C., Schweiger S., Spiller B.W., Wadzinski B.E.;
RT "Monoubiquitination promotes calpain cleavage of the protein
RT phosphatase 2A (PP2A) regulatory subunit alpha4, altering PP2A
RT stability and microtubule-associated protein phosphorylation.";
RL J. Biol. Chem. 287:24207-24215(2012).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) IN COMPLEX WITH PPP2R1A AND
RP PPME1.
RX PubMed=18394995; DOI=10.1016/j.cell.2008.02.041;
RA Xing Y., Li Z., Chen Y., Stock J.B., Jeffrey P.D., Shi Y.;
RT "Structural mechanism of demethylation and inactivation of protein
RT phosphatase 2A.";
RL Cell 133:154-163(2008).
CC -!- FUNCTION: PP2A is the major phosphatase for microtubule-associated
CC proteins (MAPs). PP2A can modulate the activity of phosphorylase B
CC kinase casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2
CC kinase. Cooperates with SGOL2 to protect centromeric cohesin from
CC separase-mediated cleavage in oocytes specifically during meiosis
CC I (By similarity). Can dephosphorylate SV40 large T antigen and
CC p53/TP53. Activates RAF1 by dephosphorylating it at 'Ser-259'.
CC -!- CATALYTIC ACTIVITY: A phosphoprotein + H(2)O = a protein +
CC phosphate.
CC -!- COFACTOR: Binds 1 iron ion per subunit (By similarity).
CC -!- COFACTOR: Binds 1 manganese ion per subunit (By similarity).
CC -!- SUBUNIT: PP2A consists of a common heterodimeric core enzyme,
CC composed of PPP2CA a 36 kDa catalytic subunit (subunit C) and
CC PPP2R1A a 65 kDa constant regulatory subunit (PR65 or subunit A),
CC that associates with a variety of regulatory subunits. Proteins
CC that associate with the core dimer include three families of
CC regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59
CC and R5/B'/B56 families), the 48 kDa variable regulatory subunit,
CC viral proteins, and cell signaling molecules. Interacts with NXN;
CC the interaction is direct (By similarity). Interacts with TP53,
CC SGOL1 and SGOL2. Interacts with AXIN1; the interaction
CC dephosphorylates AXIN1. Interacts with PIM3; this interaction
CC promotes dephosphorylation, ubiquitination and proteasomal
CC degradation of PIM3. Interacts with RAF1. Interaction with IGBP1
CC protects unassembled PPP2CA from degradative ubiquitination.
CC Interacts with GSK3B (via C2 domain).
CC -!- INTERACTION:
CC P31749:AKT1; NbExp=5; IntAct=EBI-712311, EBI-296087;
CC P39687:ANP32A; NbExp=2; IntAct=EBI-712311, EBI-359234;
CC P03129:E7 (xeno); NbExp=3; IntAct=EBI-712311, EBI-866453;
CC P04020:E7 (xeno); NbExp=2; IntAct=EBI-712311, EBI-7005254;
CC P16104:H2AFX; NbExp=2; IntAct=EBI-712311, EBI-494830;
CC P46695:IER3; NbExp=2; IntAct=EBI-712311, EBI-1748945;
CC P78318:IGBP1; NbExp=10; IntAct=EBI-712311, EBI-1055954;
CC Q61249:Igbp1 (xeno); NbExp=3; IntAct=EBI-712311, EBI-7002233;
CC O14920:IKBKB; NbExp=3; IntAct=EBI-712311, EBI-81266;
CC Q9Y6K9:IKBKG; NbExp=4; IntAct=EBI-712311, EBI-81279;
CC Q969F8:KISS1R; NbExp=3; IntAct=EBI-712311, EBI-8481408;
CC P97346:Nxn (xeno); NbExp=2; IntAct=EBI-712311, EBI-309684;
CC P30153:PPP2R1A; NbExp=14; IntAct=EBI-712311, EBI-302388;
CC P30154:PPP2R1B; NbExp=7; IntAct=EBI-712311, EBI-357094;
CC Q9Y2T4:PPP2R2C; NbExp=3; IntAct=EBI-712311, EBI-1774058;
CC Q15172:PPP2R5A; NbExp=3; IntAct=EBI-712311, EBI-641666;
CC Q15173:PPP2R5B; NbExp=4; IntAct=EBI-712311, EBI-1369497;
CC Q13362:PPP2R5C; NbExp=7; IntAct=EBI-712311, EBI-1266156;
CC P28749:RBL1; NbExp=2; IntAct=EBI-712311, EBI-971402;
CC Q08999:RBL2; NbExp=2; IntAct=EBI-712311, EBI-971439;
CC Q04206:RELA; NbExp=4; IntAct=EBI-712311, EBI-73886;
CC O43815:STRN; NbExp=3; IntAct=EBI-712311, EBI-1046642;
CC O75663:TIPRL; NbExp=3; IntAct=EBI-712311, EBI-1054735;
CC Q15645:TRIP13; NbExp=3; IntAct=EBI-712311, EBI-358993;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Chromosome, centromere.
CC Cytoplasm, cytoskeleton, spindle pole. Note=In prometaphase cells,
CC but not in anaphase cells, localizes at centromeres. During
CC mitosis, also found at spindle poles. Centromeric localization
CC requires the presence of SGOL2 (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=PP2Acalpha1;
CC IsoId=P67775-1; Sequence=Displayed;
CC Name=2; Synonyms=PP2Acalpha2;
CC IsoId=P67775-2; Sequence=VSP_044320;
CC Note=Catalytically inactive, shows enhanced binding to IGBP1,
CC and does not interact with the scaffolding subunit PPP2R1A;
CC -!- PTM: Reversibly methyl esterified on Leu-309. Carboxyl methylation
CC may play a role in holoenzyme assembly, enhancing the affinity of
CC the PP2A core enzyme for some, but not all, regulatory subunits.
CC It varies during the cell cycle.
CC -!- PTM: Phosphorylation of either threonine (by autophosphorylation-
CC activated protein kinase) or tyrosine results in inactivation of
CC the phosphatase. Auto-dephosphorylation has been suggested as a
CC mechanism for reactivation.
CC -!- SIMILARITY: Belongs to the PPP phosphatase family. PP-1 subfamily.
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DR EMBL; X12646; CAA31176.1; -; mRNA.
DR EMBL; J03804; AAB38019.1; -; mRNA.
DR EMBL; M60483; AAA36466.1; -; Genomic_DNA.
DR EMBL; BC000400; AAH00400.1; -; mRNA.
DR EMBL; BC002657; AAH02657.1; -; mRNA.
DR EMBL; BC019275; AAH19275.1; -; mRNA.
DR EMBL; BC031696; AAH31696.1; -; mRNA.
DR PIR; S01986; PAHU2A.
DR RefSeq; NP_002706.1; NM_002715.2.
DR UniGene; Hs.105818; -.
DR PDB; 2IAE; X-ray; 3.50 A; C/F=1-309.
DR PDB; 2IE3; X-ray; 2.80 A; C=1-309.
DR PDB; 2IE4; X-ray; 2.60 A; C=1-309.
DR PDB; 2NPP; X-ray; 3.30 A; C/F=1-309.
DR PDB; 2NYL; X-ray; 3.80 A; C/F=2-294.
DR PDB; 2NYM; X-ray; 3.60 A; C/F=2-294.
DR PDB; 3C5W; X-ray; 2.80 A; C=1-309.
DR PDB; 3DW8; X-ray; 2.85 A; C/F=1-309.
DR PDB; 3FGA; X-ray; 2.70 A; C=1-309.
DR PDB; 3K7V; X-ray; 2.85 A; C=1-309.
DR PDB; 3K7W; X-ray; 2.96 A; C=1-309.
DR PDB; 3P71; X-ray; 2.70 A; C=1-309.
DR PDB; 4I5L; X-ray; 2.43 A; C/F=1-309.
DR PDB; 4I5N; X-ray; 2.80 A; C/F=1-309.
DR PDB; 4IYP; X-ray; 2.80 A; C=6-153.
DR PDB; 4LAC; X-ray; 2.82 A; C=1-309.
DR PDBsum; 2IAE; -.
DR PDBsum; 2IE3; -.
DR PDBsum; 2IE4; -.
DR PDBsum; 2NPP; -.
DR PDBsum; 2NYL; -.
DR PDBsum; 2NYM; -.
DR PDBsum; 3C5W; -.
DR PDBsum; 3DW8; -.
DR PDBsum; 3FGA; -.
DR PDBsum; 3K7V; -.
DR PDBsum; 3K7W; -.
DR PDBsum; 3P71; -.
DR PDBsum; 4I5L; -.
DR PDBsum; 4I5N; -.
DR PDBsum; 4IYP; -.
DR PDBsum; 4LAC; -.
DR ProteinModelPortal; P67775; -.
DR SMR; P67775; 2-296.
DR DIP; DIP-29395N; -.
DR IntAct; P67775; 115.
DR MINT; MINT-215645; -.
DR STRING; 9606.ENSP00000418447; -.
DR BindingDB; P67775; -.
DR ChEMBL; CHEMBL4703; -.
DR DrugBank; DB00163; Vitamin E.
DR PhosphoSite; P67775; -.
DR DMDM; 54038809; -.
DR PaxDb; P67775; -.
DR PRIDE; P67775; -.
DR DNASU; 5515; -.
DR Ensembl; ENST00000481195; ENSP00000418447; ENSG00000113575.
DR GeneID; 5515; -.
DR KEGG; hsa:5515; -.
DR UCSC; uc003kze.3; human.
DR CTD; 5515; -.
DR GeneCards; GC05M133530; -.
DR HGNC; HGNC:9299; PPP2CA.
DR HPA; CAB003848; -.
DR MIM; 176915; gene.
DR neXtProt; NX_P67775; -.
DR PharmGKB; PA33663; -.
DR eggNOG; COG0639; -.
DR HOGENOM; HOG000172696; -.
DR HOVERGEN; HBG000216; -.
DR InParanoid; P67775; -.
DR KO; K04382; -.
DR OMA; LMACKQL; -.
DR OrthoDB; EOG74N5H2; -.
DR PhylomeDB; P67775; -.
DR BioCyc; MetaCyc:HS03696-MONOMER; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_21257; Metabolism of RNA.
DR Reactome; REACT_21300; Mitotic M-M/G1 phases.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6900; Immune System.
DR Reactome; REACT_71; Gene Expression.
DR SignaLink; P67775; -.
DR EvolutionaryTrace; P67775; -.
DR GeneWiki; PPP2CA; -.
DR GenomeRNAi; 5515; -.
DR NextBio; 21330; -.
DR PRO; PR:P67775; -.
DR ArrayExpress; P67775; -.
DR Bgee; P67775; -.
DR CleanEx; HS_PPP2CA; -.
DR Genevestigator; P67775; -.
DR GO; GO:0000775; C:chromosome, centromeric region; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; TAS:UniProtKB.
DR GO; GO:0016020; C:membrane; NAS:UniProtKB.
DR GO; GO:0015630; C:microtubule cytoskeleton; NAS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; NAS:UniProtKB.
DR GO; GO:0005634; C:nucleus; NAS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:Ensembl.
DR GO; GO:0000159; C:protein phosphatase type 2A complex; IDA:UniProtKB.
DR GO; GO:0000922; C:spindle pole; IEA:UniProtKB-SubCell.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; IEA:Ensembl.
DR GO; GO:0006915; P:apoptotic process; TAS:UniProtKB.
DR GO; GO:0006672; P:ceramide metabolic process; NAS:UniProtKB.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0000188; P:inactivation of MAPK activity; NAS:UniProtKB.
DR GO; GO:0007126; P:meiosis; IEA:UniProtKB-KW.
DR GO; GO:0007498; P:mesoderm development; IEA:Ensembl.
DR GO; GO:0007084; P:mitotic nuclear envelope reassembly; TAS:Reactome.
DR GO; GO:0030308; P:negative regulation of cell growth; NAS:UniProtKB.
DR GO; GO:0010719; P:negative regulation of epithelial to mesenchymal transition; IMP:BHF-UCL.
DR GO; GO:0042518; P:negative regulation of tyrosine phosphorylation of Stat3 protein; NAS:UniProtKB.
DR GO; GO:0000184; P:nuclear-transcribed mRNA catabolic process, nonsense-mediated decay; TAS:Reactome.
DR GO; GO:0071902; P:positive regulation of protein serine/threonine kinase activity; IMP:BHF-UCL.
DR GO; GO:0006470; P:protein dephosphorylation; TAS:UniProtKB.
DR GO; GO:0070208; P:protein heterotrimerization; IEA:Ensembl.
DR GO; GO:0030155; P:regulation of cell adhesion; NAS:UniProtKB.
DR GO; GO:0006275; P:regulation of DNA replication; NAS:UniProtKB.
DR GO; GO:0031952; P:regulation of protein autophosphorylation; IEA:Ensembl.
DR GO; GO:0042176; P:regulation of protein catabolic process; IEA:Ensembl.
DR GO; GO:0010469; P:regulation of receptor activity; IEA:Ensembl.
DR GO; GO:0006355; P:regulation of transcription, DNA-dependent; NAS:UniProtKB.
DR GO; GO:0030111; P:regulation of Wnt receptor signaling pathway; NAS:UniProtKB.
DR GO; GO:0008380; P:RNA splicing; NAS:UniProtKB.
DR GO; GO:0019932; P:second-messenger-mediated signaling; NAS:UniProtKB.
DR InterPro; IPR004843; PEstase_dom.
DR InterPro; IPR006186; Ser/Thr-sp_prot-phosphatase.
DR Pfam; PF00149; Metallophos; 1.
DR PRINTS; PR00114; STPHPHTASE.
DR SMART; SM00156; PP2Ac; 1.
DR PROSITE; PS00125; SER_THR_PHOSPHATASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Centromere; Chromosome;
KW Complete proteome; Cytoplasm; Cytoskeleton; Direct protein sequencing;
KW Hydrolase; Iron; Manganese; Meiosis; Metal-binding; Methylation;
KW Nucleus; Phosphoprotein; Polymorphism; Protein phosphatase;
KW Reference proteome.
FT CHAIN 1 309 Serine/threonine-protein phosphatase 2A
FT catalytic subunit alpha isoform.
FT /FTId=PRO_0000058839.
FT ACT_SITE 118 118 Proton donor (By similarity).
FT METAL 57 57 Iron (By similarity).
FT METAL 59 59 Iron (By similarity).
FT METAL 85 85 Iron (By similarity).
FT METAL 85 85 Manganese (By similarity).
FT METAL 117 117 Manganese (By similarity).
FT METAL 167 167 Manganese (By similarity).
FT METAL 241 241 Manganese (By similarity).
FT MOD_RES 307 307 Phosphotyrosine.
FT MOD_RES 309 309 Leucine methyl ester.
FT VAR_SEQ 193 246 Missing (in isoform 2).
FT /FTId=VSP_044320.
FT VARIANT 52 52 V -> A (in dbSNP:rs11552681).
FT /FTId=VAR_051735.
FT MUTAGEN 309 309 L->A: Loss of binding to PP2A B-alpha
FT regulatory subunit.
FT HELIX 3 18
FT HELIX 25 39
FT STRAND 44 48
FT STRAND 50 55
FT HELIX 62 72
FT TURN 75 77
FT STRAND 80 82
FT STRAND 87 91
FT HELIX 93 106
FT TURN 108 110
FT STRAND 111 113
FT HELIX 121 127
FT HELIX 129 137
FT STRAND 138 140
FT HELIX 141 150
FT STRAND 155 159
FT TURN 160 162
FT STRAND 163 168
FT HELIX 177 182
FT STRAND 186 188
FT STRAND 191 193
FT HELIX 194 200
FT STRAND 205 211
FT STRAND 215 220
FT HELIX 222 232
FT STRAND 235 239
FT STRAND 247 251
FT TURN 252 255
FT STRAND 256 259
FT HELIX 265 267
FT STRAND 273 278
FT STRAND 284 289
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
//
ID PP2AA_HUMAN Reviewed; 309 AA.
AC P67775; P05323; P13197;
DT 11-OCT-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 11-OCT-2004, sequence version 1.
DT 22-JAN-2014, entry version 103.
DE RecName: Full=Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform;
DE Short=PP2A-alpha;
DE EC=3.1.3.16;
DE AltName: Full=Replication protein C;
DE Short=RP-C;
GN Name=PPP2CA;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Fibroblast;
RX PubMed=2849764; DOI=10.1093/nar/16.23.11365;
RA Stone S.R., Mayer R., Wernet W., Maurer F., Hofsteenge J.,
RA Hemmings B.A.;
RT "The nucleotide sequence of the cDNA encoding the human lung protein
RT phosphatase 2A alpha catalytic subunit.";
RL Nucleic Acids Res. 16:11365-11365(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=2837763; DOI=10.1073/pnas.85.12.4252;
RA Arino J., Woon C.W., Brautigan D.L., Miller T.B. Jr., Johnson G.L.;
RT "Human liver phosphatase 2A: cDNA and amino acid sequence of two
RT catalytic subunit isotypes.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:4252-4256(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1846293; DOI=10.1021/bi00215a014;
RA Khew-Goodall Y., Mayer R.E., Maurer F., Stone S.R., Hemmings B.A.;
RT "Structure and transcriptional regulation of protein phosphatase 2A
RT catalytic subunit genes.";
RL Biochemistry 30:89-97(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung, Placenta, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP DEPHOSPHORYLATION OF SV40 LARGE-T ANTIGEN AND P53 PROTEIN.
RX PubMed=1848668;
RA Scheidtmann K.H., Mumby M.C., Rundell K., Walter G.;
RT "Dephosphorylation of simian virus 40 large-T antigen and p53 protein
RT by protein phosphatase 2A: inhibition by small-t antigen.";
RL Mol. Cell. Biol. 11:1996-2003(1991).
RN [6]
RP METHYLATION AT LEU-309.
RX PubMed=8206937;
RA Favre B., Zolnierowicz S., Turowski P., Hemmings B.A.;
RT "The catalytic subunit of protein phosphatase 2A is carboxyl-
RT methylated in vivo.";
RL J. Biol. Chem. 269:16311-16317(1994).
RN [7]
RP INTERACTION WITH IGBP1.
RX PubMed=9647778; DOI=10.1006/bbrc.1998.8792;
RA Chen J., Peterson R.T., Schreiber S.L.;
RT "Alpha 4 associates with protein phosphatases 2A, 4, and 6.";
RL Biochem. Biophys. Res. Commun. 247:827-832(1998).
RN [8]
RP MUTAGENESIS OF LEU-309.
RX PubMed=10191253; DOI=10.1042/0264-6021:3390241;
RA Bryant J.C., Westphal R.S., Wadzinski B.E.;
RT "Methylated C-terminal leucine residue of PP2A catalytic subunit is
RT important for binding of regulatory Balpha subunit.";
RL Biochem. J. 339:241-246(1999).
RN [9]
RP PARTIAL PROTEIN SEQUENCE, AND ACTIVATION OF SV40 REPLICATION.
RX PubMed=2555176;
RA Virshup D.M., Kauffman M.G., Kelly T.J.;
RT "Activation of SV40 DNA replication in vitro by cellular protein
RT phosphatase 2A.";
RL EMBO J. 8:3891-3898(1989).
RN [10]
RP INTERACTION WITH AXIN1, AND FUNCTION.
RX PubMed=9920888; DOI=10.1074/jbc.274.6.3439;
RA Hsu W., Zeng L., Costantini F.;
RT "Identification of a domain of Axin that binds to the serine/threonine
RT protein phosphatase 2A and a self-binding domain.";
RL J. Biol. Chem. 274:3439-3445(1999).
RN [11]
RP FUNCTION, AND INTERACTION WITH RAF1.
RX PubMed=10801873; DOI=10.1074/jbc.M003259200;
RA Abraham D., Podar K., Pacher M., Kubicek M., Welzel N., Hemmings B.A.,
RA Dilworth S.M., Mischak H., Kolch W., Baccarini M.;
RT "Raf-1-associated protein phosphatase 2A as a positive regulator of
RT kinase activation.";
RL J. Biol. Chem. 275:22300-22304(2000).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY, AND INTERACTION WITH SGOL1.
RX PubMed=16580887; DOI=10.1016/j.devcel.2006.03.010;
RA Tang Z., Shu H., Qi W., Mahmood N.A., Mumby M.C., Yu H.;
RT "PP2A is required for centromeric localization of Sgo1 and proper
RT chromosome segregation.";
RL Dev. Cell 10:575-585(2006).
RN [13]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH SGOL1.
RX PubMed=16541025; DOI=10.1038/nature04663;
RA Kitajima T.S., Sakuno T., Ishiguro K., Iemura S., Natsume T.,
RA Kawashima S.A., Watanabe Y.;
RT "Shugoshin collaborates with protein phosphatase 2A to protect
RT cohesin.";
RL Nature 441:46-52(2006).
RN [14]
RP INTERACTION WITH PIM3.
RX PubMed=12473674; DOI=10.1074/jbc.M208246200;
RA Losman J.A., Chen X.P., Vuong B.Q., Fay S., Rothman P.B.;
RT "Protein phosphatase 2A regulates the stability of Pim protein
RT kinases.";
RL J. Biol. Chem. 278:4800-4805(2003).
RN [15]
RP INTERACTION WITH TP53.
RX PubMed=17245430; DOI=10.1038/sj.emboj.7601519;
RA Li H.H., Cai X., Shouse G.P., Piluso L.G., Liu X.;
RT "A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-
RT induced dephosphorylation of p53 at Thr55.";
RL EMBO J. 26:402-411(2007).
RN [16]
RP INTERACTION WITH SGOL2.
RX PubMed=17485487; DOI=10.1083/jcb.200701122;
RA Huang H., Feng J., Famulski J., Rattner J.B., Liu S.T., Kao G.D.,
RA Muschel R., Chan G.K., Yen T.J.;
RT "Tripin/hSgo2 recruits MCAK to the inner centromere to correct
RT defective kinetochore attachments.";
RL J. Cell Biol. 177:413-424(2007).
RN [17]
RP INTERACTION WITH IGBP1.
RX PubMed=19818709; DOI=10.1016/j.molcel.2009.09.025;
RA Kong M., Ditsworth D., Lindsten T., Thompson C.B.;
RT "Alpha4 is an essential regulator of PP2A phosphatase activity.";
RL Mol. Cell 36:51-60(2009).
RN [18]
RP INTERACTION WITH IGBP1.
RX PubMed=20092282; DOI=10.1021/bi901837h;
RA McConnell J.L., Watkins G.R., Soss S.E., Franz H.S., McCorvey L.R.,
RA Spiller B.W., Chazin W.J., Wadzinski B.E.;
RT "Alpha4 is a ubiquitin-binding protein that regulates protein
RT serine/threonine phosphatase 2A ubiquitination.";
RL Biochemistry 49:1713-1718(2010).
RN [19]
RP INTERACTION WITH GSK3B.
RX PubMed=20080667; DOI=10.1073/pnas.0908133107;
RA Xie D., Gore C., Liu J., Pong R.C., Mason R., Hao G., Long M.,
RA Kabbani W., Yu L., Zhang H., Chen H., Sun X., Boothman D.A., Min W.,
RA Hsieh J.T.;
RT "Role of DAB2IP in modulating epithelial-to-mesenchymal transition and
RT prostate cancer metastasis.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:2485-2490(2010).
RN [20]
RP ALTERNATIVE SPLICING (ISOFORM 2).
RX PubMed=22167190; DOI=10.1074/jbc.M111.283341;
RA Migueleti D.L., Smetana J.H., Nunes H.F., Kobarg J., Zanchin N.I.;
RT "Identification and characterization of an alternatively spliced
RT isoform of the human protein phosphatase 2Aalpha catalytic subunit.";
RL J. Biol. Chem. 287:4853-4862(2012).
RN [21]
RP FUNCTION.
RX PubMed=22613722; DOI=10.1074/jbc.M112.368613;
RA Watkins G.R., Wang N., Mazalouskas M.D., Gomez R.J., Guthrie C.R.,
RA Kraemer B.C., Schweiger S., Spiller B.W., Wadzinski B.E.;
RT "Monoubiquitination promotes calpain cleavage of the protein
RT phosphatase 2A (PP2A) regulatory subunit alpha4, altering PP2A
RT stability and microtubule-associated protein phosphorylation.";
RL J. Biol. Chem. 287:24207-24215(2012).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) IN COMPLEX WITH PPP2R1A AND
RP PPME1.
RX PubMed=18394995; DOI=10.1016/j.cell.2008.02.041;
RA Xing Y., Li Z., Chen Y., Stock J.B., Jeffrey P.D., Shi Y.;
RT "Structural mechanism of demethylation and inactivation of protein
RT phosphatase 2A.";
RL Cell 133:154-163(2008).
CC -!- FUNCTION: PP2A is the major phosphatase for microtubule-associated
CC proteins (MAPs). PP2A can modulate the activity of phosphorylase B
CC kinase casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2
CC kinase. Cooperates with SGOL2 to protect centromeric cohesin from
CC separase-mediated cleavage in oocytes specifically during meiosis
CC I (By similarity). Can dephosphorylate SV40 large T antigen and
CC p53/TP53. Activates RAF1 by dephosphorylating it at 'Ser-259'.
CC -!- CATALYTIC ACTIVITY: A phosphoprotein + H(2)O = a protein +
CC phosphate.
CC -!- COFACTOR: Binds 1 iron ion per subunit (By similarity).
CC -!- COFACTOR: Binds 1 manganese ion per subunit (By similarity).
CC -!- SUBUNIT: PP2A consists of a common heterodimeric core enzyme,
CC composed of PPP2CA a 36 kDa catalytic subunit (subunit C) and
CC PPP2R1A a 65 kDa constant regulatory subunit (PR65 or subunit A),
CC that associates with a variety of regulatory subunits. Proteins
CC that associate with the core dimer include three families of
CC regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59
CC and R5/B'/B56 families), the 48 kDa variable regulatory subunit,
CC viral proteins, and cell signaling molecules. Interacts with NXN;
CC the interaction is direct (By similarity). Interacts with TP53,
CC SGOL1 and SGOL2. Interacts with AXIN1; the interaction
CC dephosphorylates AXIN1. Interacts with PIM3; this interaction
CC promotes dephosphorylation, ubiquitination and proteasomal
CC degradation of PIM3. Interacts with RAF1. Interaction with IGBP1
CC protects unassembled PPP2CA from degradative ubiquitination.
CC Interacts with GSK3B (via C2 domain).
CC -!- INTERACTION:
CC P31749:AKT1; NbExp=5; IntAct=EBI-712311, EBI-296087;
CC P39687:ANP32A; NbExp=2; IntAct=EBI-712311, EBI-359234;
CC P03129:E7 (xeno); NbExp=3; IntAct=EBI-712311, EBI-866453;
CC P04020:E7 (xeno); NbExp=2; IntAct=EBI-712311, EBI-7005254;
CC P16104:H2AFX; NbExp=2; IntAct=EBI-712311, EBI-494830;
CC P46695:IER3; NbExp=2; IntAct=EBI-712311, EBI-1748945;
CC P78318:IGBP1; NbExp=10; IntAct=EBI-712311, EBI-1055954;
CC Q61249:Igbp1 (xeno); NbExp=3; IntAct=EBI-712311, EBI-7002233;
CC O14920:IKBKB; NbExp=3; IntAct=EBI-712311, EBI-81266;
CC Q9Y6K9:IKBKG; NbExp=4; IntAct=EBI-712311, EBI-81279;
CC Q969F8:KISS1R; NbExp=3; IntAct=EBI-712311, EBI-8481408;
CC P97346:Nxn (xeno); NbExp=2; IntAct=EBI-712311, EBI-309684;
CC P30153:PPP2R1A; NbExp=14; IntAct=EBI-712311, EBI-302388;
CC P30154:PPP2R1B; NbExp=7; IntAct=EBI-712311, EBI-357094;
CC Q9Y2T4:PPP2R2C; NbExp=3; IntAct=EBI-712311, EBI-1774058;
CC Q15172:PPP2R5A; NbExp=3; IntAct=EBI-712311, EBI-641666;
CC Q15173:PPP2R5B; NbExp=4; IntAct=EBI-712311, EBI-1369497;
CC Q13362:PPP2R5C; NbExp=7; IntAct=EBI-712311, EBI-1266156;
CC P28749:RBL1; NbExp=2; IntAct=EBI-712311, EBI-971402;
CC Q08999:RBL2; NbExp=2; IntAct=EBI-712311, EBI-971439;
CC Q04206:RELA; NbExp=4; IntAct=EBI-712311, EBI-73886;
CC O43815:STRN; NbExp=3; IntAct=EBI-712311, EBI-1046642;
CC O75663:TIPRL; NbExp=3; IntAct=EBI-712311, EBI-1054735;
CC Q15645:TRIP13; NbExp=3; IntAct=EBI-712311, EBI-358993;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Chromosome, centromere.
CC Cytoplasm, cytoskeleton, spindle pole. Note=In prometaphase cells,
CC but not in anaphase cells, localizes at centromeres. During
CC mitosis, also found at spindle poles. Centromeric localization
CC requires the presence of SGOL2 (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=PP2Acalpha1;
CC IsoId=P67775-1; Sequence=Displayed;
CC Name=2; Synonyms=PP2Acalpha2;
CC IsoId=P67775-2; Sequence=VSP_044320;
CC Note=Catalytically inactive, shows enhanced binding to IGBP1,
CC and does not interact with the scaffolding subunit PPP2R1A;
CC -!- PTM: Reversibly methyl esterified on Leu-309. Carboxyl methylation
CC may play a role in holoenzyme assembly, enhancing the affinity of
CC the PP2A core enzyme for some, but not all, regulatory subunits.
CC It varies during the cell cycle.
CC -!- PTM: Phosphorylation of either threonine (by autophosphorylation-
CC activated protein kinase) or tyrosine results in inactivation of
CC the phosphatase. Auto-dephosphorylation has been suggested as a
CC mechanism for reactivation.
CC -!- SIMILARITY: Belongs to the PPP phosphatase family. PP-1 subfamily.
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DR EMBL; X12646; CAA31176.1; -; mRNA.
DR EMBL; J03804; AAB38019.1; -; mRNA.
DR EMBL; M60483; AAA36466.1; -; Genomic_DNA.
DR EMBL; BC000400; AAH00400.1; -; mRNA.
DR EMBL; BC002657; AAH02657.1; -; mRNA.
DR EMBL; BC019275; AAH19275.1; -; mRNA.
DR EMBL; BC031696; AAH31696.1; -; mRNA.
DR PIR; S01986; PAHU2A.
DR RefSeq; NP_002706.1; NM_002715.2.
DR UniGene; Hs.105818; -.
DR PDB; 2IAE; X-ray; 3.50 A; C/F=1-309.
DR PDB; 2IE3; X-ray; 2.80 A; C=1-309.
DR PDB; 2IE4; X-ray; 2.60 A; C=1-309.
DR PDB; 2NPP; X-ray; 3.30 A; C/F=1-309.
DR PDB; 2NYL; X-ray; 3.80 A; C/F=2-294.
DR PDB; 2NYM; X-ray; 3.60 A; C/F=2-294.
DR PDB; 3C5W; X-ray; 2.80 A; C=1-309.
DR PDB; 3DW8; X-ray; 2.85 A; C/F=1-309.
DR PDB; 3FGA; X-ray; 2.70 A; C=1-309.
DR PDB; 3K7V; X-ray; 2.85 A; C=1-309.
DR PDB; 3K7W; X-ray; 2.96 A; C=1-309.
DR PDB; 3P71; X-ray; 2.70 A; C=1-309.
DR PDB; 4I5L; X-ray; 2.43 A; C/F=1-309.
DR PDB; 4I5N; X-ray; 2.80 A; C/F=1-309.
DR PDB; 4IYP; X-ray; 2.80 A; C=6-153.
DR PDB; 4LAC; X-ray; 2.82 A; C=1-309.
DR PDBsum; 2IAE; -.
DR PDBsum; 2IE3; -.
DR PDBsum; 2IE4; -.
DR PDBsum; 2NPP; -.
DR PDBsum; 2NYL; -.
DR PDBsum; 2NYM; -.
DR PDBsum; 3C5W; -.
DR PDBsum; 3DW8; -.
DR PDBsum; 3FGA; -.
DR PDBsum; 3K7V; -.
DR PDBsum; 3K7W; -.
DR PDBsum; 3P71; -.
DR PDBsum; 4I5L; -.
DR PDBsum; 4I5N; -.
DR PDBsum; 4IYP; -.
DR PDBsum; 4LAC; -.
DR ProteinModelPortal; P67775; -.
DR SMR; P67775; 2-296.
DR DIP; DIP-29395N; -.
DR IntAct; P67775; 115.
DR MINT; MINT-215645; -.
DR STRING; 9606.ENSP00000418447; -.
DR BindingDB; P67775; -.
DR ChEMBL; CHEMBL4703; -.
DR DrugBank; DB00163; Vitamin E.
DR PhosphoSite; P67775; -.
DR DMDM; 54038809; -.
DR PaxDb; P67775; -.
DR PRIDE; P67775; -.
DR DNASU; 5515; -.
DR Ensembl; ENST00000481195; ENSP00000418447; ENSG00000113575.
DR GeneID; 5515; -.
DR KEGG; hsa:5515; -.
DR UCSC; uc003kze.3; human.
DR CTD; 5515; -.
DR GeneCards; GC05M133530; -.
DR HGNC; HGNC:9299; PPP2CA.
DR HPA; CAB003848; -.
DR MIM; 176915; gene.
DR neXtProt; NX_P67775; -.
DR PharmGKB; PA33663; -.
DR eggNOG; COG0639; -.
DR HOGENOM; HOG000172696; -.
DR HOVERGEN; HBG000216; -.
DR InParanoid; P67775; -.
DR KO; K04382; -.
DR OMA; LMACKQL; -.
DR OrthoDB; EOG74N5H2; -.
DR PhylomeDB; P67775; -.
DR BioCyc; MetaCyc:HS03696-MONOMER; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_21257; Metabolism of RNA.
DR Reactome; REACT_21300; Mitotic M-M/G1 phases.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6900; Immune System.
DR Reactome; REACT_71; Gene Expression.
DR SignaLink; P67775; -.
DR EvolutionaryTrace; P67775; -.
DR GeneWiki; PPP2CA; -.
DR GenomeRNAi; 5515; -.
DR NextBio; 21330; -.
DR PRO; PR:P67775; -.
DR ArrayExpress; P67775; -.
DR Bgee; P67775; -.
DR CleanEx; HS_PPP2CA; -.
DR Genevestigator; P67775; -.
DR GO; GO:0000775; C:chromosome, centromeric region; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; TAS:UniProtKB.
DR GO; GO:0016020; C:membrane; NAS:UniProtKB.
DR GO; GO:0015630; C:microtubule cytoskeleton; NAS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; NAS:UniProtKB.
DR GO; GO:0005634; C:nucleus; NAS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:Ensembl.
DR GO; GO:0000159; C:protein phosphatase type 2A complex; IDA:UniProtKB.
DR GO; GO:0000922; C:spindle pole; IEA:UniProtKB-SubCell.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; IEA:Ensembl.
DR GO; GO:0006915; P:apoptotic process; TAS:UniProtKB.
DR GO; GO:0006672; P:ceramide metabolic process; NAS:UniProtKB.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0000188; P:inactivation of MAPK activity; NAS:UniProtKB.
DR GO; GO:0007126; P:meiosis; IEA:UniProtKB-KW.
DR GO; GO:0007498; P:mesoderm development; IEA:Ensembl.
DR GO; GO:0007084; P:mitotic nuclear envelope reassembly; TAS:Reactome.
DR GO; GO:0030308; P:negative regulation of cell growth; NAS:UniProtKB.
DR GO; GO:0010719; P:negative regulation of epithelial to mesenchymal transition; IMP:BHF-UCL.
DR GO; GO:0042518; P:negative regulation of tyrosine phosphorylation of Stat3 protein; NAS:UniProtKB.
DR GO; GO:0000184; P:nuclear-transcribed mRNA catabolic process, nonsense-mediated decay; TAS:Reactome.
DR GO; GO:0071902; P:positive regulation of protein serine/threonine kinase activity; IMP:BHF-UCL.
DR GO; GO:0006470; P:protein dephosphorylation; TAS:UniProtKB.
DR GO; GO:0070208; P:protein heterotrimerization; IEA:Ensembl.
DR GO; GO:0030155; P:regulation of cell adhesion; NAS:UniProtKB.
DR GO; GO:0006275; P:regulation of DNA replication; NAS:UniProtKB.
DR GO; GO:0031952; P:regulation of protein autophosphorylation; IEA:Ensembl.
DR GO; GO:0042176; P:regulation of protein catabolic process; IEA:Ensembl.
DR GO; GO:0010469; P:regulation of receptor activity; IEA:Ensembl.
DR GO; GO:0006355; P:regulation of transcription, DNA-dependent; NAS:UniProtKB.
DR GO; GO:0030111; P:regulation of Wnt receptor signaling pathway; NAS:UniProtKB.
DR GO; GO:0008380; P:RNA splicing; NAS:UniProtKB.
DR GO; GO:0019932; P:second-messenger-mediated signaling; NAS:UniProtKB.
DR InterPro; IPR004843; PEstase_dom.
DR InterPro; IPR006186; Ser/Thr-sp_prot-phosphatase.
DR Pfam; PF00149; Metallophos; 1.
DR PRINTS; PR00114; STPHPHTASE.
DR SMART; SM00156; PP2Ac; 1.
DR PROSITE; PS00125; SER_THR_PHOSPHATASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Centromere; Chromosome;
KW Complete proteome; Cytoplasm; Cytoskeleton; Direct protein sequencing;
KW Hydrolase; Iron; Manganese; Meiosis; Metal-binding; Methylation;
KW Nucleus; Phosphoprotein; Polymorphism; Protein phosphatase;
KW Reference proteome.
FT CHAIN 1 309 Serine/threonine-protein phosphatase 2A
FT catalytic subunit alpha isoform.
FT /FTId=PRO_0000058839.
FT ACT_SITE 118 118 Proton donor (By similarity).
FT METAL 57 57 Iron (By similarity).
FT METAL 59 59 Iron (By similarity).
FT METAL 85 85 Iron (By similarity).
FT METAL 85 85 Manganese (By similarity).
FT METAL 117 117 Manganese (By similarity).
FT METAL 167 167 Manganese (By similarity).
FT METAL 241 241 Manganese (By similarity).
FT MOD_RES 307 307 Phosphotyrosine.
FT MOD_RES 309 309 Leucine methyl ester.
FT VAR_SEQ 193 246 Missing (in isoform 2).
FT /FTId=VSP_044320.
FT VARIANT 52 52 V -> A (in dbSNP:rs11552681).
FT /FTId=VAR_051735.
FT MUTAGEN 309 309 L->A: Loss of binding to PP2A B-alpha
FT regulatory subunit.
FT HELIX 3 18
FT HELIX 25 39
FT STRAND 44 48
FT STRAND 50 55
FT HELIX 62 72
FT TURN 75 77
FT STRAND 80 82
FT STRAND 87 91
FT HELIX 93 106
FT TURN 108 110
FT STRAND 111 113
FT HELIX 121 127
FT HELIX 129 137
FT STRAND 138 140
FT HELIX 141 150
FT STRAND 155 159
FT TURN 160 162
FT STRAND 163 168
FT HELIX 177 182
FT STRAND 186 188
FT STRAND 191 193
FT HELIX 194 200
FT STRAND 205 211
FT STRAND 215 220
FT HELIX 222 232
FT STRAND 235 239
FT STRAND 247 251
FT TURN 252 255
FT STRAND 256 259
FT HELIX 265 267
FT STRAND 273 278
FT STRAND 284 289
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
//
MIM
176915
*RECORD*
*FIELD* NO
176915
*FIELD* TI
*176915 PROTEIN PHOSPHATASE 2, CATALYTIC SUBUNIT, ALPHA ISOFORM; PPP2CA
;;PROTEIN PHOSPHATASE 2A, CATALYTIC SUBUNIT, ALPHA ISOFORM; PP2CA
read more*FIELD* TX
DESCRIPTION
Protein phosphorylation, a crucial posttranslational modification step
controlling many diverse cellular functions, is dependent on the
opposing actions of protein kinases and protein phosphatases. The enzyme
protein phosphatase 2A is 1 of 4 major protein phosphatases identified
in the cytosol of eukaryotic cells which are responsible for the
dephosphorylation of serine and threonine residues in proteins. Although
all 4 protein phosphatases, PP1, PP2A, PP2B, and PP2C, have overlapping
substrate specificities in vitro, they can be distinguished by the use
of inhibitor proteins and by their dependence on metal ions. PP1 is
inhibited by nanomolar concentrations of 2 thermostable proteins,
inhibitor 1 and inhibitor 2, whereas the type 2 phosphatases are
unaffected by these inhibitors. The type 2 phosphatases can be
distinguished by how their activity is regulated: PP2A activity is
independent of metal ions, PP2B is activated by Ca(2+)/calmodulin, and
PP2C is activated by Mg(2+) (Cohen and Cohen, 1989). Protein phosphatase
2A appears to play a role in the regulation of most major metabolic
pathways, as well as translation, transcription, and control of
transition from G2 to the M phase of the cell cycle. PP2A may function
as either a tumor promoter or tumor suppressor, depending on the cell
type or the transforming agent. The mammalian enzyme can be isolated as
a catalytic subunit of 36 kD complexed to 1 regulatory subunit of 65 kD
and to another regulatory subunit of varying molecular mass, depending
on the tissue and the separation technique used. Two isoforms of the
catalytic subunit of PP2A, alpha and beta (176916), are demonstrable in
many mammalian species. The structures of these catalytic subunits show
the highest evolutionary conservation of all known enzymes, supporting
the idea that they may serve crucial functions.
CLONING
Stone et al. (1988) isolated the human cDNA for the PPP2CA subunit from
lung and lung fibroblast libraries. The cDNA encodes a 309-amino acid
polypeptide.
MAPPING
Jones et al. (1993) mapped the PPP2CA gene to human chromosome 5 by
somatic cell hybridization and refined the mapping to 5q23-q31 by in
situ hybridization.
BIOCHEMICAL FEATURES
- Crystal Structure
Herzog et al. (2012) gained distance restraints on a modular interaction
network of protein complexes affinity-purified from human cells by
applying an adapted crosslinking and mass spectrometry (XL-MS) protocol.
Systematic analysis of human protein phosphatase 2A (PP2A) complexes
identified 176 interprotein and 570 intraprotein crosslinks that link
specific trimeric PP2A complexes to a multitude of adaptor proteins that
control their cellular functions. Spatial restraints guided molecular
modeling of the binding interface between immunoglobulin binding
protein-1 (IGBP1; 300139) and PP2A and revealed the topology of TCP1
(186980) ring complex (TRiC) chaperonin (see 605139) interacting with
the PP2A regulatory subunit 2ABG. Herzog et al. (2012) concluded that
this study established XL-MS as an integral part of hybrid structural
biology approaches for the analysis of endogenous protein complexes.
GENE FUNCTION
Veech (2003) pointed out that most modern biologists and contemporary
textbooks of biochemistry present the glycolytic pathway and the
synthesis of fats as history, all the relevant facts being known. He
pointed to the report by Kabashima et al. (2003), combining new insights
into the regulation of lipogenesis with 'heroic protein chemistry and an
elegant combination of enzymology and molecular biology.' He described
how a small and ignored metabolite of the hexose monophosphate pathway,
xylulose 5-phosphate, activates protein phosphatase-2A to mediate the
acute effects of carbohydrate feeding on the glycolytic pathway, as well
as the coordinate long-term control of the enzymes required for fatty
acid and triglyceride synthesis.
Gergs et al. (2004) generated transgenic mice that overexpress the
catalytic subunit alpha of PP2A in the heart. The phosphorylation states
of phospholamban (PLN; 172405), troponin I (TNNI3; 191044), and
eukaryotic elongation factor-2 (EEF2; 130610) were reduced
significantly, but the expression of junctional and free sarcoplasmic
reticulum proteins was not altered. The transgenic mice showed islands
of necrosis and fibrosis in the myocardium and developed cardiac
hypertrophy, dilatation, and reduced contractility, although no increase
in morbidity or mortality was seen. Gergs et al. (2004) concluded that
PP2A has a fundamental role in cardiac function, and suggested that
disturbances in protein phosphatase expression and activity may cause or
exacerbate the course of cardiac diseases.
Chowdhury et al. (2005) found that PP2A is involved in removing
phosphorylated H2AX (601772), or gamma-H2AX, from DNA foci during
double-stranded break repair. PPP2CA and gamma-H2AX coimmunoprecipitated
from human cell lines and colocalized in DNA damage foci, and PP2A
dephosphorylated gamma-H2AX in vitro. Recruitment of PPP2CA to DNA
damage foci was H2AX dependent. Inhibition of PPP2CA by RNA interference
led to the persistence of gamma-H2AX foci, inefficient DNA repair, and
cells that were hypersensitive to DNA damage.
Riedel et al. (2006) showed in both fission and budding yeast that Sgo1
(SGOL1; 609168) recruited to centromeres a specific form of PP2A. Its
inactivation caused loss of centromeric cohesin (see RAD21; 606462) at
anaphase I and random segregation of sister centromeres at the second
meiotic division. Artificial recruitment of PP2A to chromosome arms
prevented Rec8 (608193) phosphorylation and hindered resolution of
chiasmata. Riedel et al. (2006) concluded that their data were
consistent with the notion that efficient cleavage of Rec8 requires
phosphorylation of cohesin and that this is blocked by PP2A at meiosis I
centromeres.
In mitotic cells, phosphorylation of cohesin promotes its dissociation
from chromosomes, but centromeric cohesin is protected from
phosphorylation until kinetochores are properly captured by the spindle
microtubules. Kitajima et al. (2006) found that a shugoshin complex made
up of SGO1, SGO2 (SGOL2; 612425), and a specific subtype of PP2A
containing the regulatory B56 subunit (see 601643) was required for
protection of centromeric cohesin in HeLa cells. The shugoshin-PP2A
complex protected cohesin by reversing phosphorylation of the cohesin
subunit SA2 (STAG2; 300826). Both SGO1 and SGO2 bound PP2A directly,
although SGO1 appeared to bind the regulatory subunit PP2A-B56, while
SGO2 appeared to bind the core subunit PP2A-A (see 605983). Knockdown
studies showed that SGO2 tethered PP2A to the centromere, whereas SGO1
had the more important role in centromere protection and appeared to
facilitate PP2A function at centromeres.
By yeast 2-hybrid screening, in vitro binding analysis, and
coimmunoprecipitation analysis, Gil-Bernabe et al. (2006) found that
securin (PTTG1; 604147) interacted with the B55-delta regulatory subunit
(PPP2R2D; 613992) and the alpha catalytic subunit of PP2A. Securin was a
PP2A substrate in vivo and in vitro. Treatment of cells with a chemical
PP2A inhibitor resulted in hyperphosphorylated forms of securin that
were unstable due to degradation through the ubiquitin pathway.
Gil-Bernabe et al. (2006) proposed that PP2A stabilizes and regulates
securin levels by counteracting its phosphorylation.
Stipanovich et al. (2008) demonstrated that drugs of abuse, as well as
food reinforcement learning, promote the nuclear accumulation of 32-kD
dopamine- and cAMP-regulated phosphoprotein (DARPP32; 604399). This
accumulation is mediated through a signaling cascade involving dopamine
D1 receptors (see 126449), cAMP-dependent activation of protein
phosphatase-2A, and dephosphorylation of DARPP32 at ser97 and inhibition
of its nuclear export. The nuclear accumulation of DARPP32, a potent
inhibitor of protein phosphatase-1 (see 176875), increased the
phosphorylation of histone H3 (see 602810), an important component of
nucleosomal response. Mutation of ser97 profoundly altered behavioral
effects of drugs of abuse and decreased motivation for food, underlining
the functional importance of this signaling cascade.
Initiation and maintenance of mitosis require the inhibition of PP2A,
which dephosphorylates mitotic substrates. The protein kinase Greatwall
(MASTL; 608221) is required to maintain mitosis through PP2A inhibition.
Gharbi-Ayachi et al. (2010) described how Greatwall (Gwl) activation
results in PP2A inhibition. They identified Arpp19 (605487) and Ensa
(603061) as 2 substrates of Gwl that, when phosphorylated by this
kinase, associate with and inhibit PP2, thus promoting mitotic entry.
Conversely, in the absence of Gwl activity, Arpp19 and Ensa are
dephosphorylated and lose their capacity to bind and inhibit PP2A.
Gharbi-Ayachi et al. (2010) stated that although both proteins can
inhibit PP2A, endogenous Arpp19, but not Ensa, is responsible for PP2A
inhibition and mitotic entry in Xenopus egg extracts.
Using isoelectric focusing in combination with suitable inhibitors in
lymphoblastoid cell lines (LCLs) from patients with monoclonal
gammopathy of undetermined significance (MGUS), multiple myeloma (see
254500), or Waldenstrom macroglobulinemia (see 153600), whose
paraprotein targeted paratarg-7 (STOML2; 608292) and who were carriers
of hyperphosphorylated paratarg-7 (615121), Preuss et al. (2011)
demonstrated that PRKCZ (176982) is the active kinase responsible for
phosphorylation at ser17 of paratarg-7. Analysis of LCLs from patients
and controls showed that phosphorylation of paratarg-7 occurred in both,
but dephosphorylation was inhibited in patients carrying
hyperphosphorylated paratarg-7. Protease inhibitor experiments with LCLs
revealed that PPP2CA is responsible for the dephosphorylation of the
hyperphosphorylated form of paratarg-7. Although the total amount of
PPP2CA did not differ between patients and controls, the ratio of
phosphorylated to nonphosphorylated PPP2CA differed strikingly: in
patients, the phosphorylated form of catalytic subunit C of PPP2CA (with
phosphorylation at tyr307, which inactivates the enzyme) was abundant,
whereas in healthy donors the nonphosphorylated, active form prevailed.
Preuss et al. (2011) concluded that the genetic defect underlying
autosomal dominantly inherited hyperphosphorylation of paratarg-7 is not
in PPP2CA itself, but in genes or proteins controlling PPP2CA activity
by phosphorylation of its catalytic subunit.
*FIELD* RF
1. Chowdhury, D.; Keogh, M.-C.; Ishii, H.; Peterson, C. L.; Buratowski,
S.; Lieberman, J.: Gamma-H2AX dephosphorylation by protein phosphatase
2A facilitates DNA double-strand break repair. Molec. Cell 20: 801-809,
2005.
2. Cohen, P.; Cohen, P. T. W.: Protein phosphatases come of age. J.
Biol. Chem. 264: 21435-21438, 1989.
3. Gergs, U.; Boknik, P.; Buchwalow, I.; Fabritz, L.; Matus, M.; Justus,
I.; Hanske, G.; Schmitz, W.; Neumann, J.: Overexpression of the catalytic
subunit of protein phosphatase 2A impairs cardiac function. J. Biol.
Chem. 279: 40827-40834, 2004.
4. Gharbi-Ayachi, A.; Labbe, J.-C.; Burgess, A.; Vigneron, S.; Strub,
J.-M.; Brioudes, E.; Van-Dorsselaer, A.; Castro, A.; Lorca, T.: The
substrate of Greatwall kinase, Arpp19, controls mitosis by inhibiting
protein phosphatase 2A. Science 330: 1673-1677, 2010.
5. Gil-Bernabe, A. M.; Romero, F.; Limon-Mortes, M. C.; Tortolero,
M.: Protein phosphatase 2A stabilizes human securin, whose phosphorylated
forms are degraded via the SCF ubiquitin ligase. Molec. Cell. Biol. 26:
4017-4027, 2006.
6. Herzog, F.; Kahraman, A.; Boehringer, D.; Mak, R.; Bracher, A.;
Walzthoeni, T.; Leitner, A.; Beck, M.; Hartl, F.-U.; Ban, N.; Malmstrom,
L.; Aebersold, R.: Structural probing of a protein phosphatase 2A
network by chemical cross-linking and mass spectrometry. Science 337:
1348-1352, 2012.
7. Jones, T. A.; Barker, H. M.; da Cruz e Silva, E. F.; Mayer-Jaekel,
R. E.; Hemmings, B. A.; Spurr, N. K.; Sheer, D.; Cohen, P. T. W.:
Localization of the genes encoding the catalytic subunits of protein
phosphatase 2A to human chromosome bands 5q23-q31 and 8p12-p11.2,
respectively. Cytogenet. Cell Genet. 63: 35-41, 1993.
8. Kabashima, T.; Kawaguchi, T.; Wadzinski, B. E.; Uyeda, K.: Xylulose
5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated
protein phosphatase in rat liver. Proc. Nat. Acad. Sci. 100: 5107-5112,
2003.
9. Kitajima, T. S.; Sakuno, T.; Ishiguro, K.; Iemura, S.; Natsume,
T.; Kawashima, S. A.; Watanabe, Y.: Shugoshin collaborates with protein
phosphatase 2A to protect cohesin. Nature 441: 46-52, 2006.
10. Preuss, K.-D.; Pfeundschuh, M.; Fadle, N.; Regitz, E.; Raudies,
S.; Murwaski, N.; Ahlgrimm, M.; Bittenbring, J.; Klotz, M.; Schafer,
K.-H.; Held, G.; Neumann, F.; Grass, S.: Hyperphosphorylation of
autoantigenic targets of paraproteins is due to inactivation of PP2A. Blood 118:
3340-3346, 2011.
11. Riedel, C. G.; Katis, V. L.; Katou, Y.; Mori, S.; Itoh, T.; Helmhart,
W.; Galova, M.; Petronczki, M.; Gregan, J.; Cetin, B.; Mudrak, I.;
Ogris, E.; Mechtler, K.; Pelletier, L.; Buchholz, F.; Shirahige, K.;
Nasmyth, K.: Protein phosphatase 2A protects centromeric sister chromatid
cohesion during meiosis I. Nature 441: 53-61, 2006.
12. Stipanovich, A.; Valjent, E.; Matamales, M.; Nishi, A.; Ahn, J.-H.;
Maroteaux, M.; Bertran-Gonzalez, J.; Brami-Cherrier, K.; Enslen, H.;
Corbille, A.-G.; Filhol, O.; Nairn, A. C.; Greengard, P.; Herve, D.;
Girault, J.-A.: A phosphatase cascade by which rewarding stimuli
control nucleosomal response. Nature 453: 879-884, 2008.
13. Stone, S. R.; Mayer, R.; Wernet, W.; Maurer, F.; Hofsteenge, J.;
Hemmings, B. A.: The nucleotide sequence of the cDNA encoding the
human lung protein phosphatase 2A alpha catalytic subunit. Nucleic
Acids Res. 16: 11365 only, 1988.
14. Veech, R. L.: A humble hexose monophosphate pathway metabolite
regulates short- and long-term control of lipogenesis. (Commentary) Proc.
Nat. Acad. Sci. 100: 5578-5580, 2003.
*FIELD* CN
Marla J. F. O'Neill - updated: 3/15/2013
Ada Hamosh - updated: 10/31/2012
Ada Hamosh - updated: 1/28/2011
Patricia A. Hartz - updated: 11/20/2008
Ada Hamosh - updated: 7/11/2008
Patricia A. Hartz - updated: 10/19/2006
Ada Hamosh - updated: 6/1/2006
Patricia A. Hartz - updated: 2/2/2006
Marla J. F. O'Neill - updated: 12/3/2004
Jennifer P. Macke - updated: 3/12/1999
Stylianos E. Antonarakis - updated: 2/3/1999
*FIELD* CD
Victor A. McKusick: 5/26/1993
*FIELD* ED
carol: 03/15/2013
mgross: 2/4/2013
alopez: 11/2/2012
terry: 10/31/2012
mgross: 5/23/2011
alopez: 2/1/2011
terry: 1/28/2011
carol: 11/8/2010
mgross: 10/2/2009
mgross: 11/20/2008
alopez: 7/14/2008
terry: 7/11/2008
wwang: 4/30/2008
terry: 4/25/2008
mgross: 10/19/2006
alopez: 6/4/2006
terry: 6/1/2006
mgross: 3/15/2006
mgross: 2/2/2006
mgross: 3/1/2005
carol: 12/3/2004
carol: 5/3/2000
mgross: 3/12/1999
carol: 2/3/1999
mark: 8/21/1995
warfield: 3/31/1994
carol: 11/18/1993
carol: 5/28/1993
carol: 5/26/1993
*RECORD*
*FIELD* NO
176915
*FIELD* TI
*176915 PROTEIN PHOSPHATASE 2, CATALYTIC SUBUNIT, ALPHA ISOFORM; PPP2CA
;;PROTEIN PHOSPHATASE 2A, CATALYTIC SUBUNIT, ALPHA ISOFORM; PP2CA
read more*FIELD* TX
DESCRIPTION
Protein phosphorylation, a crucial posttranslational modification step
controlling many diverse cellular functions, is dependent on the
opposing actions of protein kinases and protein phosphatases. The enzyme
protein phosphatase 2A is 1 of 4 major protein phosphatases identified
in the cytosol of eukaryotic cells which are responsible for the
dephosphorylation of serine and threonine residues in proteins. Although
all 4 protein phosphatases, PP1, PP2A, PP2B, and PP2C, have overlapping
substrate specificities in vitro, they can be distinguished by the use
of inhibitor proteins and by their dependence on metal ions. PP1 is
inhibited by nanomolar concentrations of 2 thermostable proteins,
inhibitor 1 and inhibitor 2, whereas the type 2 phosphatases are
unaffected by these inhibitors. The type 2 phosphatases can be
distinguished by how their activity is regulated: PP2A activity is
independent of metal ions, PP2B is activated by Ca(2+)/calmodulin, and
PP2C is activated by Mg(2+) (Cohen and Cohen, 1989). Protein phosphatase
2A appears to play a role in the regulation of most major metabolic
pathways, as well as translation, transcription, and control of
transition from G2 to the M phase of the cell cycle. PP2A may function
as either a tumor promoter or tumor suppressor, depending on the cell
type or the transforming agent. The mammalian enzyme can be isolated as
a catalytic subunit of 36 kD complexed to 1 regulatory subunit of 65 kD
and to another regulatory subunit of varying molecular mass, depending
on the tissue and the separation technique used. Two isoforms of the
catalytic subunit of PP2A, alpha and beta (176916), are demonstrable in
many mammalian species. The structures of these catalytic subunits show
the highest evolutionary conservation of all known enzymes, supporting
the idea that they may serve crucial functions.
CLONING
Stone et al. (1988) isolated the human cDNA for the PPP2CA subunit from
lung and lung fibroblast libraries. The cDNA encodes a 309-amino acid
polypeptide.
MAPPING
Jones et al. (1993) mapped the PPP2CA gene to human chromosome 5 by
somatic cell hybridization and refined the mapping to 5q23-q31 by in
situ hybridization.
BIOCHEMICAL FEATURES
- Crystal Structure
Herzog et al. (2012) gained distance restraints on a modular interaction
network of protein complexes affinity-purified from human cells by
applying an adapted crosslinking and mass spectrometry (XL-MS) protocol.
Systematic analysis of human protein phosphatase 2A (PP2A) complexes
identified 176 interprotein and 570 intraprotein crosslinks that link
specific trimeric PP2A complexes to a multitude of adaptor proteins that
control their cellular functions. Spatial restraints guided molecular
modeling of the binding interface between immunoglobulin binding
protein-1 (IGBP1; 300139) and PP2A and revealed the topology of TCP1
(186980) ring complex (TRiC) chaperonin (see 605139) interacting with
the PP2A regulatory subunit 2ABG. Herzog et al. (2012) concluded that
this study established XL-MS as an integral part of hybrid structural
biology approaches for the analysis of endogenous protein complexes.
GENE FUNCTION
Veech (2003) pointed out that most modern biologists and contemporary
textbooks of biochemistry present the glycolytic pathway and the
synthesis of fats as history, all the relevant facts being known. He
pointed to the report by Kabashima et al. (2003), combining new insights
into the regulation of lipogenesis with 'heroic protein chemistry and an
elegant combination of enzymology and molecular biology.' He described
how a small and ignored metabolite of the hexose monophosphate pathway,
xylulose 5-phosphate, activates protein phosphatase-2A to mediate the
acute effects of carbohydrate feeding on the glycolytic pathway, as well
as the coordinate long-term control of the enzymes required for fatty
acid and triglyceride synthesis.
Gergs et al. (2004) generated transgenic mice that overexpress the
catalytic subunit alpha of PP2A in the heart. The phosphorylation states
of phospholamban (PLN; 172405), troponin I (TNNI3; 191044), and
eukaryotic elongation factor-2 (EEF2; 130610) were reduced
significantly, but the expression of junctional and free sarcoplasmic
reticulum proteins was not altered. The transgenic mice showed islands
of necrosis and fibrosis in the myocardium and developed cardiac
hypertrophy, dilatation, and reduced contractility, although no increase
in morbidity or mortality was seen. Gergs et al. (2004) concluded that
PP2A has a fundamental role in cardiac function, and suggested that
disturbances in protein phosphatase expression and activity may cause or
exacerbate the course of cardiac diseases.
Chowdhury et al. (2005) found that PP2A is involved in removing
phosphorylated H2AX (601772), or gamma-H2AX, from DNA foci during
double-stranded break repair. PPP2CA and gamma-H2AX coimmunoprecipitated
from human cell lines and colocalized in DNA damage foci, and PP2A
dephosphorylated gamma-H2AX in vitro. Recruitment of PPP2CA to DNA
damage foci was H2AX dependent. Inhibition of PPP2CA by RNA interference
led to the persistence of gamma-H2AX foci, inefficient DNA repair, and
cells that were hypersensitive to DNA damage.
Riedel et al. (2006) showed in both fission and budding yeast that Sgo1
(SGOL1; 609168) recruited to centromeres a specific form of PP2A. Its
inactivation caused loss of centromeric cohesin (see RAD21; 606462) at
anaphase I and random segregation of sister centromeres at the second
meiotic division. Artificial recruitment of PP2A to chromosome arms
prevented Rec8 (608193) phosphorylation and hindered resolution of
chiasmata. Riedel et al. (2006) concluded that their data were
consistent with the notion that efficient cleavage of Rec8 requires
phosphorylation of cohesin and that this is blocked by PP2A at meiosis I
centromeres.
In mitotic cells, phosphorylation of cohesin promotes its dissociation
from chromosomes, but centromeric cohesin is protected from
phosphorylation until kinetochores are properly captured by the spindle
microtubules. Kitajima et al. (2006) found that a shugoshin complex made
up of SGO1, SGO2 (SGOL2; 612425), and a specific subtype of PP2A
containing the regulatory B56 subunit (see 601643) was required for
protection of centromeric cohesin in HeLa cells. The shugoshin-PP2A
complex protected cohesin by reversing phosphorylation of the cohesin
subunit SA2 (STAG2; 300826). Both SGO1 and SGO2 bound PP2A directly,
although SGO1 appeared to bind the regulatory subunit PP2A-B56, while
SGO2 appeared to bind the core subunit PP2A-A (see 605983). Knockdown
studies showed that SGO2 tethered PP2A to the centromere, whereas SGO1
had the more important role in centromere protection and appeared to
facilitate PP2A function at centromeres.
By yeast 2-hybrid screening, in vitro binding analysis, and
coimmunoprecipitation analysis, Gil-Bernabe et al. (2006) found that
securin (PTTG1; 604147) interacted with the B55-delta regulatory subunit
(PPP2R2D; 613992) and the alpha catalytic subunit of PP2A. Securin was a
PP2A substrate in vivo and in vitro. Treatment of cells with a chemical
PP2A inhibitor resulted in hyperphosphorylated forms of securin that
were unstable due to degradation through the ubiquitin pathway.
Gil-Bernabe et al. (2006) proposed that PP2A stabilizes and regulates
securin levels by counteracting its phosphorylation.
Stipanovich et al. (2008) demonstrated that drugs of abuse, as well as
food reinforcement learning, promote the nuclear accumulation of 32-kD
dopamine- and cAMP-regulated phosphoprotein (DARPP32; 604399). This
accumulation is mediated through a signaling cascade involving dopamine
D1 receptors (see 126449), cAMP-dependent activation of protein
phosphatase-2A, and dephosphorylation of DARPP32 at ser97 and inhibition
of its nuclear export. The nuclear accumulation of DARPP32, a potent
inhibitor of protein phosphatase-1 (see 176875), increased the
phosphorylation of histone H3 (see 602810), an important component of
nucleosomal response. Mutation of ser97 profoundly altered behavioral
effects of drugs of abuse and decreased motivation for food, underlining
the functional importance of this signaling cascade.
Initiation and maintenance of mitosis require the inhibition of PP2A,
which dephosphorylates mitotic substrates. The protein kinase Greatwall
(MASTL; 608221) is required to maintain mitosis through PP2A inhibition.
Gharbi-Ayachi et al. (2010) described how Greatwall (Gwl) activation
results in PP2A inhibition. They identified Arpp19 (605487) and Ensa
(603061) as 2 substrates of Gwl that, when phosphorylated by this
kinase, associate with and inhibit PP2, thus promoting mitotic entry.
Conversely, in the absence of Gwl activity, Arpp19 and Ensa are
dephosphorylated and lose their capacity to bind and inhibit PP2A.
Gharbi-Ayachi et al. (2010) stated that although both proteins can
inhibit PP2A, endogenous Arpp19, but not Ensa, is responsible for PP2A
inhibition and mitotic entry in Xenopus egg extracts.
Using isoelectric focusing in combination with suitable inhibitors in
lymphoblastoid cell lines (LCLs) from patients with monoclonal
gammopathy of undetermined significance (MGUS), multiple myeloma (see
254500), or Waldenstrom macroglobulinemia (see 153600), whose
paraprotein targeted paratarg-7 (STOML2; 608292) and who were carriers
of hyperphosphorylated paratarg-7 (615121), Preuss et al. (2011)
demonstrated that PRKCZ (176982) is the active kinase responsible for
phosphorylation at ser17 of paratarg-7. Analysis of LCLs from patients
and controls showed that phosphorylation of paratarg-7 occurred in both,
but dephosphorylation was inhibited in patients carrying
hyperphosphorylated paratarg-7. Protease inhibitor experiments with LCLs
revealed that PPP2CA is responsible for the dephosphorylation of the
hyperphosphorylated form of paratarg-7. Although the total amount of
PPP2CA did not differ between patients and controls, the ratio of
phosphorylated to nonphosphorylated PPP2CA differed strikingly: in
patients, the phosphorylated form of catalytic subunit C of PPP2CA (with
phosphorylation at tyr307, which inactivates the enzyme) was abundant,
whereas in healthy donors the nonphosphorylated, active form prevailed.
Preuss et al. (2011) concluded that the genetic defect underlying
autosomal dominantly inherited hyperphosphorylation of paratarg-7 is not
in PPP2CA itself, but in genes or proteins controlling PPP2CA activity
by phosphorylation of its catalytic subunit.
*FIELD* RF
1. Chowdhury, D.; Keogh, M.-C.; Ishii, H.; Peterson, C. L.; Buratowski,
S.; Lieberman, J.: Gamma-H2AX dephosphorylation by protein phosphatase
2A facilitates DNA double-strand break repair. Molec. Cell 20: 801-809,
2005.
2. Cohen, P.; Cohen, P. T. W.: Protein phosphatases come of age. J.
Biol. Chem. 264: 21435-21438, 1989.
3. Gergs, U.; Boknik, P.; Buchwalow, I.; Fabritz, L.; Matus, M.; Justus,
I.; Hanske, G.; Schmitz, W.; Neumann, J.: Overexpression of the catalytic
subunit of protein phosphatase 2A impairs cardiac function. J. Biol.
Chem. 279: 40827-40834, 2004.
4. Gharbi-Ayachi, A.; Labbe, J.-C.; Burgess, A.; Vigneron, S.; Strub,
J.-M.; Brioudes, E.; Van-Dorsselaer, A.; Castro, A.; Lorca, T.: The
substrate of Greatwall kinase, Arpp19, controls mitosis by inhibiting
protein phosphatase 2A. Science 330: 1673-1677, 2010.
5. Gil-Bernabe, A. M.; Romero, F.; Limon-Mortes, M. C.; Tortolero,
M.: Protein phosphatase 2A stabilizes human securin, whose phosphorylated
forms are degraded via the SCF ubiquitin ligase. Molec. Cell. Biol. 26:
4017-4027, 2006.
6. Herzog, F.; Kahraman, A.; Boehringer, D.; Mak, R.; Bracher, A.;
Walzthoeni, T.; Leitner, A.; Beck, M.; Hartl, F.-U.; Ban, N.; Malmstrom,
L.; Aebersold, R.: Structural probing of a protein phosphatase 2A
network by chemical cross-linking and mass spectrometry. Science 337:
1348-1352, 2012.
7. Jones, T. A.; Barker, H. M.; da Cruz e Silva, E. F.; Mayer-Jaekel,
R. E.; Hemmings, B. A.; Spurr, N. K.; Sheer, D.; Cohen, P. T. W.:
Localization of the genes encoding the catalytic subunits of protein
phosphatase 2A to human chromosome bands 5q23-q31 and 8p12-p11.2,
respectively. Cytogenet. Cell Genet. 63: 35-41, 1993.
8. Kabashima, T.; Kawaguchi, T.; Wadzinski, B. E.; Uyeda, K.: Xylulose
5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated
protein phosphatase in rat liver. Proc. Nat. Acad. Sci. 100: 5107-5112,
2003.
9. Kitajima, T. S.; Sakuno, T.; Ishiguro, K.; Iemura, S.; Natsume,
T.; Kawashima, S. A.; Watanabe, Y.: Shugoshin collaborates with protein
phosphatase 2A to protect cohesin. Nature 441: 46-52, 2006.
10. Preuss, K.-D.; Pfeundschuh, M.; Fadle, N.; Regitz, E.; Raudies,
S.; Murwaski, N.; Ahlgrimm, M.; Bittenbring, J.; Klotz, M.; Schafer,
K.-H.; Held, G.; Neumann, F.; Grass, S.: Hyperphosphorylation of
autoantigenic targets of paraproteins is due to inactivation of PP2A. Blood 118:
3340-3346, 2011.
11. Riedel, C. G.; Katis, V. L.; Katou, Y.; Mori, S.; Itoh, T.; Helmhart,
W.; Galova, M.; Petronczki, M.; Gregan, J.; Cetin, B.; Mudrak, I.;
Ogris, E.; Mechtler, K.; Pelletier, L.; Buchholz, F.; Shirahige, K.;
Nasmyth, K.: Protein phosphatase 2A protects centromeric sister chromatid
cohesion during meiosis I. Nature 441: 53-61, 2006.
12. Stipanovich, A.; Valjent, E.; Matamales, M.; Nishi, A.; Ahn, J.-H.;
Maroteaux, M.; Bertran-Gonzalez, J.; Brami-Cherrier, K.; Enslen, H.;
Corbille, A.-G.; Filhol, O.; Nairn, A. C.; Greengard, P.; Herve, D.;
Girault, J.-A.: A phosphatase cascade by which rewarding stimuli
control nucleosomal response. Nature 453: 879-884, 2008.
13. Stone, S. R.; Mayer, R.; Wernet, W.; Maurer, F.; Hofsteenge, J.;
Hemmings, B. A.: The nucleotide sequence of the cDNA encoding the
human lung protein phosphatase 2A alpha catalytic subunit. Nucleic
Acids Res. 16: 11365 only, 1988.
14. Veech, R. L.: A humble hexose monophosphate pathway metabolite
regulates short- and long-term control of lipogenesis. (Commentary) Proc.
Nat. Acad. Sci. 100: 5578-5580, 2003.
*FIELD* CN
Marla J. F. O'Neill - updated: 3/15/2013
Ada Hamosh - updated: 10/31/2012
Ada Hamosh - updated: 1/28/2011
Patricia A. Hartz - updated: 11/20/2008
Ada Hamosh - updated: 7/11/2008
Patricia A. Hartz - updated: 10/19/2006
Ada Hamosh - updated: 6/1/2006
Patricia A. Hartz - updated: 2/2/2006
Marla J. F. O'Neill - updated: 12/3/2004
Jennifer P. Macke - updated: 3/12/1999
Stylianos E. Antonarakis - updated: 2/3/1999
*FIELD* CD
Victor A. McKusick: 5/26/1993
*FIELD* ED
carol: 03/15/2013
mgross: 2/4/2013
alopez: 11/2/2012
terry: 10/31/2012
mgross: 5/23/2011
alopez: 2/1/2011
terry: 1/28/2011
carol: 11/8/2010
mgross: 10/2/2009
mgross: 11/20/2008
alopez: 7/14/2008
terry: 7/11/2008
wwang: 4/30/2008
terry: 4/25/2008
mgross: 10/19/2006
alopez: 6/4/2006
terry: 6/1/2006
mgross: 3/15/2006
mgross: 2/2/2006
mgross: 3/1/2005
carol: 12/3/2004
carol: 5/3/2000
mgross: 3/12/1999
carol: 2/3/1999
mark: 8/21/1995
warfield: 3/31/1994
carol: 11/18/1993
carol: 5/28/1993
carol: 5/26/1993