Full text data of PPM1A
PPM1A
(PPPM1A)
[Confidence: low (only semi-automatic identification from reviews)]
Protein phosphatase 1A; 3.1.3.16 (Protein phosphatase 2C isoform alpha; PP2C-alpha; Protein phosphatase IA)
Protein phosphatase 1A; 3.1.3.16 (Protein phosphatase 2C isoform alpha; PP2C-alpha; Protein phosphatase IA)
UniProt
P35813
ID PPM1A_HUMAN Reviewed; 382 AA.
AC P35813; B5BU11; J3KNM0; O75551;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUN-1994, sequence version 1.
DT 22-JAN-2014, entry version 145.
DE RecName: Full=Protein phosphatase 1A;
DE EC=3.1.3.16;
DE AltName: Full=Protein phosphatase 2C isoform alpha;
DE Short=PP2C-alpha;
DE AltName: Full=Protein phosphatase IA;
GN Name=PPM1A; Synonyms=PPPM1A;
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 ALPHA-1).
RX PubMed=1311954; DOI=10.1016/0167-4781(92)90471-B;
RA Mann D.J., Campbell D.G., McGowan C.H., Cohen P.T.W.;
RT "Mammalian protein serine/threonine phosphatase 2C: cDNA cloning and
RT comparative analysis of amino acid sequences.";
RL Biochim. Biophys. Acta 1130:100-104(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ALPHA-2).
RX PubMed=9707433; DOI=10.1093/emboj/17.16.4744;
RA Takekawa M., Maeda T., Saito H.;
RT "Protein phosphatase 2Calpha inhibits the human stress-responsive p38
RT and JNK MAPK pathways.";
RL EMBO J. 17:4744-4752(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ALPHA-1).
RX PubMed=19054851; DOI=10.1038/nmeth.1273;
RA Goshima N., Kawamura Y., Fukumoto A., Miura A., Honma R., Satoh R.,
RA Wakamatsu A., Yamamoto J., Kimura K., Nishikawa T., Andoh T., Iida Y.,
RA Ishikawa K., Ito E., Kagawa N., Kaminaga C., Kanehori K., Kawakami B.,
RA Kenmochi K., Kimura R., Kobayashi M., Kuroita T., Kuwayama H.,
RA Maruyama Y., Matsuo K., Minami K., Mitsubori M., Mori M.,
RA Morishita R., Murase A., Nishikawa A., Nishikawa S., Okamoto T.,
RA Sakagami N., Sakamoto Y., Sasaki Y., Seki T., Sono S., Sugiyama A.,
RA Sumiya T., Takayama T., Takayama Y., Takeda H., Togashi T., Yahata K.,
RA Yamada H., Yanagisawa Y., Endo Y., Imamoto F., Kisu Y., Tanaka S.,
RA Isogai T., Imai J., Watanabe S., Nomura N.;
RT "Human protein factory for converting the transcriptome into an in
RT vitro-expressed proteome.";
RL Nat. Methods 5:1011-1017(2008).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S.,
RA Sun H., Du H., Pepin K., Artiguenave F., Robert C., Cruaud C.,
RA Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P.,
RA Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N.,
RA Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C.,
RA Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S.,
RA Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B.,
RA Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M.,
RA Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S.,
RA Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D.,
RA Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A.,
RA Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L.,
RA Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J.,
RA Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W.,
RA Quetier F., Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ALPHA-1).
RC TISSUE=Colon, and Lung;
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 [8]
RP INTERACTION WITH SMAD2 AND SMAD3, FUNCTION, SUBCELLULAR LOCATION, AND
RP MUTAGENESIS OF ASP-239.
RX PubMed=16751101; DOI=10.1016/j.cell.2006.03.044;
RA Lin X., Duan X., Liang Y.Y., Su Y., Wrighton K.H., Long J., Hu M.,
RA Davis C.M., Wang J., Brunicardi F.C., Shi Y., Chen Y.G., Meng A.,
RA Feng X.H.;
RT "PPM1A functions as a Smad phosphatase to terminate TGFbeta
RT signaling.";
RL Cell 125:915-928(2006).
RN [9]
RP FUNCTION, AND INTERACTION WITH IKBKB.
RX PubMed=18930133; DOI=10.1016/j.cellsig.2008.09.012;
RA Sun W., Yu Y., Dotti G., Shen T., Tan X., Savoldo B., Pass A.K.,
RA Chu M., Zhang D., Lu X., Fu S., Lin X., Yang J.;
RT "PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-
RT induced IKKbeta-NF-kappaB activation.";
RL Cell. Signal. 21:95-102(2009).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-375, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [11]
RP MYRISTOYLATION AT GLY-2.
RX PubMed=20213681; DOI=10.1002/pmic.200900783;
RA Suzuki T., Moriya K., Nagatoshi K., Ota Y., Ezure T., Ando E.,
RA Tsunasawa S., Utsumi T.;
RT "Strategy for comprehensive identification of human N-myristoylated
RT proteins using an insect cell-free protein synthesis system.";
RL Proteomics 10:1780-1793(2010).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [13]
RP SUBCELLULAR LOCATION.
RX PubMed=22781750; DOI=10.1016/j.cellsig.2012.07.003;
RA Bruce D.L., Macartney T., Yong W., Shou W., Sapkota G.P.;
RT "Protein phosphatase 5 modulates SMAD3 function in the transforming
RT growth factor-? pathway.";
RL Cell. Signal. 24:1999-2006(2012).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
RX PubMed=9003755;
RA Das A.K., Helps N.R., Cohen P.T.W., Barford D.;
RT "Crystal structure of the protein serine/threonine phosphatase 2C at
RT 2.0-A resolution.";
RL EMBO J. 15:6798-6809(1996).
CC -!- FUNCTION: Enzyme with a broad specificity. Negatively regulates
CC TGF-beta signaling through dephosphorylating SMAD2 and SMAD3,
CC resulting in their dissociation from SMAD4, nuclear export of the
CC SMADs and termination of the TGF-beta-mediated signaling.
CC Dephosphorylates PRKAA1 and PRKAA2. Plays an important role in the
CC termination of TNF-alpha-mediated NF-kappa-B activation through
CC dephosphorylating and inactivating IKBKB/IKKB.
CC -!- CATALYTIC ACTIVITY: A phosphoprotein + H(2)O = a protein +
CC phosphate.
CC -!- COFACTOR: Binds 2 magnesium or manganese ions per subunit.
CC -!- SUBUNIT: Monomer. Interacts with SMAD2; the interaction
CC dephosphorylates SMAD2 in its C-terminal SXS motif resulting in
CC disruption of the SMAD2/SMAD4 complex, SMAD2 nuclear export and
CC termination of the TGF-beta-mediated signaling. Interacts with
CC SMAD2; the interaction dephosphorylates SMAD2 in its C-terminal
CC SXS motif resulting in disruption of the SMAD2/SMAD4 complex,
CC SMAD2 nuclear export and termination of the TGF-beta-mediated
CC signaling. Interacts with the phosphorylated form of IKBKB/IKKB.
CC -!- INTERACTION:
CC P49407:ARRB1; NbExp=4; IntAct=EBI-989143, EBI-743313;
CC P32121:ARRB2; NbExp=3; IntAct=EBI-989143, EBI-714559;
CC O15169:AXIN1; NbExp=2; IntAct=EBI-989143, EBI-710484;
CC P28482:MAPK1; NbExp=19; IntAct=EBI-989143, EBI-959949;
CC Q16539:MAPK14; NbExp=2; IntAct=EBI-989143, EBI-73946;
CC Q9H6Z4:RANBP3; NbExp=4; IntAct=EBI-989143, EBI-992681;
CC Q15796:SMAD2; NbExp=2; IntAct=EBI-989143, EBI-1040141;
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm, cytosol. Membrane (By
CC similarity). Note=Weakly associates at the membrane and N-
CC myristoylation mediates the membrane localization (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=Alpha-1;
CC IsoId=P35813-1; Sequence=Displayed;
CC Name=Alpha-2;
CC IsoId=P35813-2; Sequence=VSP_005085, VSP_005086;
CC Name=3;
CC IsoId=P35813-3; Sequence=VSP_045687;
CC Note=No experimental confirmation available. Ref.3 (AK097843)
CC sequence is in conflict in position: 54:Q->R;
CC -!- PTM: N-myristoylation is essential for the recognition of its
CC substrates for dephosphorylation (By similarity).
CC -!- SIMILARITY: Belongs to the PP2C family.
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DR EMBL; S87759; AAB21784.1; -; mRNA.
DR EMBL; AF070670; AAC28354.1; -; mRNA.
DR EMBL; AK097843; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AB451247; BAG70061.1; -; mRNA.
DR EMBL; AL132778; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL157756; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471061; EAW80774.1; -; Genomic_DNA.
DR EMBL; BC026691; AAH26691.1; -; mRNA.
DR EMBL; BC063243; AAH63243.1; -; mRNA.
DR PIR; S22423; S22423.
DR RefSeq; NP_066283.1; NM_021003.4.
DR RefSeq; NP_808820.1; NM_177951.2.
DR RefSeq; NP_808821.2; NM_177952.2.
DR RefSeq; XP_005267834.1; XM_005267777.1.
DR RefSeq; XP_005267835.1; XM_005267778.1.
DR RefSeq; XP_005267836.1; XM_005267779.1.
DR RefSeq; XP_005267837.1; XM_005267780.1.
DR RefSeq; XP_005267838.1; XM_005267781.1.
DR UniGene; Hs.130036; -.
DR PDB; 1A6Q; X-ray; 2.00 A; A=1-382.
DR PDB; 3FXJ; X-ray; 2.50 A; A=1-382.
DR PDB; 3FXK; X-ray; 2.10 A; A=1-382.
DR PDB; 3FXL; X-ray; 2.30 A; A=1-382.
DR PDB; 3FXM; X-ray; 2.50 A; A=1-382.
DR PDB; 3FXO; X-ray; 2.50 A; A=1-382.
DR PDBsum; 1A6Q; -.
DR PDBsum; 3FXJ; -.
DR PDBsum; 3FXK; -.
DR PDBsum; 3FXL; -.
DR PDBsum; 3FXM; -.
DR PDBsum; 3FXO; -.
DR ProteinModelPortal; P35813; -.
DR SMR; P35813; 2-368.
DR IntAct; P35813; 20.
DR MINT; MINT-2802996; -.
DR STRING; 9606.ENSP00000327255; -.
DR BindingDB; P35813; -.
DR ChEMBL; CHEMBL2437; -.
DR PhosphoSite; P35813; -.
DR DMDM; 548442; -.
DR PaxDb; P35813; -.
DR PeptideAtlas; P35813; -.
DR PRIDE; P35813; -.
DR DNASU; 5494; -.
DR Ensembl; ENST00000325642; ENSP00000327255; ENSG00000100614.
DR Ensembl; ENST00000325658; ENSP00000314850; ENSG00000100614.
DR Ensembl; ENST00000395076; ENSP00000378514; ENSG00000100614.
DR Ensembl; ENST00000529574; ENSP00000432966; ENSG00000100614.
DR GeneID; 5494; -.
DR KEGG; hsa:5494; -.
DR UCSC; uc001xew.4; human.
DR CTD; 5494; -.
DR GeneCards; GC14P060712; -.
DR HGNC; HGNC:9275; PPM1A.
DR HPA; HPA029209; -.
DR MIM; 606108; gene.
DR neXtProt; NX_P35813; -.
DR PharmGKB; PA33603; -.
DR eggNOG; COG0631; -.
DR HOGENOM; HOG000233895; -.
DR HOVERGEN; HBG053647; -.
DR InParanoid; P35813; -.
DR KO; K04457; -.
DR OMA; EVYAIER; -.
DR OrthoDB; EOG7WMCJH; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_71; Gene Expression.
DR SignaLink; P35813; -.
DR ChiTaRS; PPM1A; human.
DR EvolutionaryTrace; P35813; -.
DR GeneWiki; PPM1A; -.
DR GenomeRNAi; 5494; -.
DR NextBio; 21242; -.
DR PRO; PR:P35813; -.
DR ArrayExpress; P35813; -.
DR Bgee; P35813; -.
DR CleanEx; HS_PPM1A; -.
DR Genevestigator; P35813; -.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR GO; GO:0043005; C:neuron projection; IEA:Ensembl.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005891; C:voltage-gated calcium channel complex; IEA:Ensembl.
DR GO; GO:0033192; F:calmodulin-dependent protein phosphatase activity; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR GO; GO:0030145; F:manganese ion binding; IEA:InterPro.
DR GO; GO:0004871; F:signal transducer activity; IMP:UniProtKB.
DR GO; GO:0007050; P:cell cycle arrest; TAS:Reactome.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0006499; P:N-terminal protein myristoylation; ISS:UniProtKB.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB cascade; IMP:UniProtKB.
DR GO; GO:0042347; P:negative regulation of NF-kappaB import into nucleus; IMP:UniProtKB.
DR GO; GO:0010991; P:negative regulation of SMAD protein complex assembly; IDA:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; TAS:Reactome.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0035970; P:peptidyl-threonine dephosphorylation; IDA:UniProtKB.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IMP:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-dependent; IDA:BHF-UCL.
DR GO; GO:0030177; P:positive regulation of Wnt receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0006367; P:transcription initiation from RNA polymerase II promoter; TAS:Reactome.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; TAS:Reactome.
DR GO; GO:0016055; P:Wnt receptor signaling pathway; IDA:BHF-UCL.
DR Gene3D; 1.10.10.430; -; 1.
DR Gene3D; 3.60.40.10; -; 1.
DR InterPro; IPR001932; PP2C-like_dom.
DR InterPro; IPR012911; PP2C_C.
DR InterPro; IPR000222; PP2C_Mn2_Asp60_BS.
DR InterPro; IPR015655; Protein_Pase_2C.
DR PANTHER; PTHR13832; PTHR13832; 1.
DR Pfam; PF00481; PP2C; 1.
DR Pfam; PF07830; PP2C_C; 1.
DR SMART; SM00331; PP2C_SIG; 1.
DR SMART; SM00332; PP2Cc; 1.
DR SUPFAM; SSF81601; SSF81601; 1.
DR SUPFAM; SSF81606; SSF81606; 1.
DR PROSITE; PS01032; PP2C; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytoplasm;
KW Hydrolase; Lipoprotein; Magnesium; Manganese; Membrane; Metal-binding;
KW Myristate; Nucleus; Phosphoprotein; Protein phosphatase;
KW Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 382 Protein phosphatase 1A.
FT /FTId=PRO_0000057741.
FT METAL 60 60 Manganese 1.
FT METAL 60 60 Manganese 2.
FT METAL 61 61 Manganese 1; via carbonyl oxygen.
FT METAL 239 239 Manganese 2.
FT METAL 282 282 Manganese 2.
FT MOD_RES 375 375 Phosphoserine.
FT LIPID 2 2 N-myristoyl glycine.
FT VAR_SEQ 1 1 M -> MFCSGRKWVAEATICTKLMKREKRRMGKRRAKKAKR
FT EEKKKGGERRRNEKRGNQMKRMCERKKYETDLEDQDIM
FT (in isoform 3).
FT /FTId=VSP_045687.
FT VAR_SEQ 318 324 EIIKKQG -> GGSFNKK (in isoform Alpha-2).
FT /FTId=VSP_005085.
FT VAR_SEQ 325 382 Missing (in isoform Alpha-2).
FT /FTId=VSP_005086.
FT MUTAGEN 239 239 D->N: No effect on binding SMAD2.
FT CONFLICT 342 342 I -> T (in Ref. 3; AK097843).
FT STRAND 9 19
FT STRAND 22 31
FT STRAND 33 35
FT STRAND 38 46
FT TURN 47 49
FT STRAND 50 63
FT HELIX 66 80
FT HELIX 83 86
FT STRAND 88 91
FT HELIX 94 118
FT STRAND 129 134
FT STRAND 136 146
FT STRAND 148 153
FT STRAND 156 160
FT HELIX 169 177
FT TURN 188 190
FT HELIX 200 202
FT HELIX 210 212
FT STRAND 213 216
FT STRAND 220 225
FT TURN 228 230
FT STRAND 231 237
FT HELIX 239 242
FT HELIX 247 258
FT HELIX 264 277
FT STRAND 284 290
FT HELIX 299 319
FT HELIX 330 339
FT TURN 347 349
FT HELIX 350 354
FT HELIX 355 365
SQ SEQUENCE 382 AA; 42448 MW; D48EF508B4A76687 CRC64;
MGAFLDKPKM EKHNAQGQGN GLRYGLSSMQ GWRVEMEDAH TAVIGLPSGL ESWSFFAVYD
GHAGSQVAKY CCEHLLDHIT NNQDFKGSAG APSVENVKNG IRTGFLEIDE HMRVMSEKKH
GADRSGSTAV GVLISPQHTY FINCGDSRGL LCRNRKVHFF TQDHKPSNPL EKERIQNAGG
SVMIQRVNGS LAVSRALGDF DYKCVHGKGP TEQLVSPEPE VHDIERSEED DQFIILACDG
IWDVMGNEEL CDFVRSRLEV TDDLEKVCNE VVDTCLYKGS RDNMSVILIC FPNAPKVSPE
AVKKEAELDK YLECRVEEII KKQGEGVPDL VHVMRTLASE NIPSLPPGGE LASKRNVIEA
VYNRLNPYKN DDTDSTSTDD MW
//
ID PPM1A_HUMAN Reviewed; 382 AA.
AC P35813; B5BU11; J3KNM0; O75551;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUN-1994, sequence version 1.
DT 22-JAN-2014, entry version 145.
DE RecName: Full=Protein phosphatase 1A;
DE EC=3.1.3.16;
DE AltName: Full=Protein phosphatase 2C isoform alpha;
DE Short=PP2C-alpha;
DE AltName: Full=Protein phosphatase IA;
GN Name=PPM1A; Synonyms=PPPM1A;
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 ALPHA-1).
RX PubMed=1311954; DOI=10.1016/0167-4781(92)90471-B;
RA Mann D.J., Campbell D.G., McGowan C.H., Cohen P.T.W.;
RT "Mammalian protein serine/threonine phosphatase 2C: cDNA cloning and
RT comparative analysis of amino acid sequences.";
RL Biochim. Biophys. Acta 1130:100-104(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ALPHA-2).
RX PubMed=9707433; DOI=10.1093/emboj/17.16.4744;
RA Takekawa M., Maeda T., Saito H.;
RT "Protein phosphatase 2Calpha inhibits the human stress-responsive p38
RT and JNK MAPK pathways.";
RL EMBO J. 17:4744-4752(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ALPHA-1).
RX PubMed=19054851; DOI=10.1038/nmeth.1273;
RA Goshima N., Kawamura Y., Fukumoto A., Miura A., Honma R., Satoh R.,
RA Wakamatsu A., Yamamoto J., Kimura K., Nishikawa T., Andoh T., Iida Y.,
RA Ishikawa K., Ito E., Kagawa N., Kaminaga C., Kanehori K., Kawakami B.,
RA Kenmochi K., Kimura R., Kobayashi M., Kuroita T., Kuwayama H.,
RA Maruyama Y., Matsuo K., Minami K., Mitsubori M., Mori M.,
RA Morishita R., Murase A., Nishikawa A., Nishikawa S., Okamoto T.,
RA Sakagami N., Sakamoto Y., Sasaki Y., Seki T., Sono S., Sugiyama A.,
RA Sumiya T., Takayama T., Takayama Y., Takeda H., Togashi T., Yahata K.,
RA Yamada H., Yanagisawa Y., Endo Y., Imamoto F., Kisu Y., Tanaka S.,
RA Isogai T., Imai J., Watanabe S., Nomura N.;
RT "Human protein factory for converting the transcriptome into an in
RT vitro-expressed proteome.";
RL Nat. Methods 5:1011-1017(2008).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S.,
RA Sun H., Du H., Pepin K., Artiguenave F., Robert C., Cruaud C.,
RA Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P.,
RA Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N.,
RA Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C.,
RA Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S.,
RA Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B.,
RA Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M.,
RA Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S.,
RA Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D.,
RA Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A.,
RA Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L.,
RA Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J.,
RA Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W.,
RA Quetier F., Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ALPHA-1).
RC TISSUE=Colon, and Lung;
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 [8]
RP INTERACTION WITH SMAD2 AND SMAD3, FUNCTION, SUBCELLULAR LOCATION, AND
RP MUTAGENESIS OF ASP-239.
RX PubMed=16751101; DOI=10.1016/j.cell.2006.03.044;
RA Lin X., Duan X., Liang Y.Y., Su Y., Wrighton K.H., Long J., Hu M.,
RA Davis C.M., Wang J., Brunicardi F.C., Shi Y., Chen Y.G., Meng A.,
RA Feng X.H.;
RT "PPM1A functions as a Smad phosphatase to terminate TGFbeta
RT signaling.";
RL Cell 125:915-928(2006).
RN [9]
RP FUNCTION, AND INTERACTION WITH IKBKB.
RX PubMed=18930133; DOI=10.1016/j.cellsig.2008.09.012;
RA Sun W., Yu Y., Dotti G., Shen T., Tan X., Savoldo B., Pass A.K.,
RA Chu M., Zhang D., Lu X., Fu S., Lin X., Yang J.;
RT "PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-
RT induced IKKbeta-NF-kappaB activation.";
RL Cell. Signal. 21:95-102(2009).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-375, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [11]
RP MYRISTOYLATION AT GLY-2.
RX PubMed=20213681; DOI=10.1002/pmic.200900783;
RA Suzuki T., Moriya K., Nagatoshi K., Ota Y., Ezure T., Ando E.,
RA Tsunasawa S., Utsumi T.;
RT "Strategy for comprehensive identification of human N-myristoylated
RT proteins using an insect cell-free protein synthesis system.";
RL Proteomics 10:1780-1793(2010).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [13]
RP SUBCELLULAR LOCATION.
RX PubMed=22781750; DOI=10.1016/j.cellsig.2012.07.003;
RA Bruce D.L., Macartney T., Yong W., Shou W., Sapkota G.P.;
RT "Protein phosphatase 5 modulates SMAD3 function in the transforming
RT growth factor-? pathway.";
RL Cell. Signal. 24:1999-2006(2012).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
RX PubMed=9003755;
RA Das A.K., Helps N.R., Cohen P.T.W., Barford D.;
RT "Crystal structure of the protein serine/threonine phosphatase 2C at
RT 2.0-A resolution.";
RL EMBO J. 15:6798-6809(1996).
CC -!- FUNCTION: Enzyme with a broad specificity. Negatively regulates
CC TGF-beta signaling through dephosphorylating SMAD2 and SMAD3,
CC resulting in their dissociation from SMAD4, nuclear export of the
CC SMADs and termination of the TGF-beta-mediated signaling.
CC Dephosphorylates PRKAA1 and PRKAA2. Plays an important role in the
CC termination of TNF-alpha-mediated NF-kappa-B activation through
CC dephosphorylating and inactivating IKBKB/IKKB.
CC -!- CATALYTIC ACTIVITY: A phosphoprotein + H(2)O = a protein +
CC phosphate.
CC -!- COFACTOR: Binds 2 magnesium or manganese ions per subunit.
CC -!- SUBUNIT: Monomer. Interacts with SMAD2; the interaction
CC dephosphorylates SMAD2 in its C-terminal SXS motif resulting in
CC disruption of the SMAD2/SMAD4 complex, SMAD2 nuclear export and
CC termination of the TGF-beta-mediated signaling. Interacts with
CC SMAD2; the interaction dephosphorylates SMAD2 in its C-terminal
CC SXS motif resulting in disruption of the SMAD2/SMAD4 complex,
CC SMAD2 nuclear export and termination of the TGF-beta-mediated
CC signaling. Interacts with the phosphorylated form of IKBKB/IKKB.
CC -!- INTERACTION:
CC P49407:ARRB1; NbExp=4; IntAct=EBI-989143, EBI-743313;
CC P32121:ARRB2; NbExp=3; IntAct=EBI-989143, EBI-714559;
CC O15169:AXIN1; NbExp=2; IntAct=EBI-989143, EBI-710484;
CC P28482:MAPK1; NbExp=19; IntAct=EBI-989143, EBI-959949;
CC Q16539:MAPK14; NbExp=2; IntAct=EBI-989143, EBI-73946;
CC Q9H6Z4:RANBP3; NbExp=4; IntAct=EBI-989143, EBI-992681;
CC Q15796:SMAD2; NbExp=2; IntAct=EBI-989143, EBI-1040141;
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm, cytosol. Membrane (By
CC similarity). Note=Weakly associates at the membrane and N-
CC myristoylation mediates the membrane localization (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=Alpha-1;
CC IsoId=P35813-1; Sequence=Displayed;
CC Name=Alpha-2;
CC IsoId=P35813-2; Sequence=VSP_005085, VSP_005086;
CC Name=3;
CC IsoId=P35813-3; Sequence=VSP_045687;
CC Note=No experimental confirmation available. Ref.3 (AK097843)
CC sequence is in conflict in position: 54:Q->R;
CC -!- PTM: N-myristoylation is essential for the recognition of its
CC substrates for dephosphorylation (By similarity).
CC -!- SIMILARITY: Belongs to the PP2C family.
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DR EMBL; S87759; AAB21784.1; -; mRNA.
DR EMBL; AF070670; AAC28354.1; -; mRNA.
DR EMBL; AK097843; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AB451247; BAG70061.1; -; mRNA.
DR EMBL; AL132778; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL157756; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471061; EAW80774.1; -; Genomic_DNA.
DR EMBL; BC026691; AAH26691.1; -; mRNA.
DR EMBL; BC063243; AAH63243.1; -; mRNA.
DR PIR; S22423; S22423.
DR RefSeq; NP_066283.1; NM_021003.4.
DR RefSeq; NP_808820.1; NM_177951.2.
DR RefSeq; NP_808821.2; NM_177952.2.
DR RefSeq; XP_005267834.1; XM_005267777.1.
DR RefSeq; XP_005267835.1; XM_005267778.1.
DR RefSeq; XP_005267836.1; XM_005267779.1.
DR RefSeq; XP_005267837.1; XM_005267780.1.
DR RefSeq; XP_005267838.1; XM_005267781.1.
DR UniGene; Hs.130036; -.
DR PDB; 1A6Q; X-ray; 2.00 A; A=1-382.
DR PDB; 3FXJ; X-ray; 2.50 A; A=1-382.
DR PDB; 3FXK; X-ray; 2.10 A; A=1-382.
DR PDB; 3FXL; X-ray; 2.30 A; A=1-382.
DR PDB; 3FXM; X-ray; 2.50 A; A=1-382.
DR PDB; 3FXO; X-ray; 2.50 A; A=1-382.
DR PDBsum; 1A6Q; -.
DR PDBsum; 3FXJ; -.
DR PDBsum; 3FXK; -.
DR PDBsum; 3FXL; -.
DR PDBsum; 3FXM; -.
DR PDBsum; 3FXO; -.
DR ProteinModelPortal; P35813; -.
DR SMR; P35813; 2-368.
DR IntAct; P35813; 20.
DR MINT; MINT-2802996; -.
DR STRING; 9606.ENSP00000327255; -.
DR BindingDB; P35813; -.
DR ChEMBL; CHEMBL2437; -.
DR PhosphoSite; P35813; -.
DR DMDM; 548442; -.
DR PaxDb; P35813; -.
DR PeptideAtlas; P35813; -.
DR PRIDE; P35813; -.
DR DNASU; 5494; -.
DR Ensembl; ENST00000325642; ENSP00000327255; ENSG00000100614.
DR Ensembl; ENST00000325658; ENSP00000314850; ENSG00000100614.
DR Ensembl; ENST00000395076; ENSP00000378514; ENSG00000100614.
DR Ensembl; ENST00000529574; ENSP00000432966; ENSG00000100614.
DR GeneID; 5494; -.
DR KEGG; hsa:5494; -.
DR UCSC; uc001xew.4; human.
DR CTD; 5494; -.
DR GeneCards; GC14P060712; -.
DR HGNC; HGNC:9275; PPM1A.
DR HPA; HPA029209; -.
DR MIM; 606108; gene.
DR neXtProt; NX_P35813; -.
DR PharmGKB; PA33603; -.
DR eggNOG; COG0631; -.
DR HOGENOM; HOG000233895; -.
DR HOVERGEN; HBG053647; -.
DR InParanoid; P35813; -.
DR KO; K04457; -.
DR OMA; EVYAIER; -.
DR OrthoDB; EOG7WMCJH; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_71; Gene Expression.
DR SignaLink; P35813; -.
DR ChiTaRS; PPM1A; human.
DR EvolutionaryTrace; P35813; -.
DR GeneWiki; PPM1A; -.
DR GenomeRNAi; 5494; -.
DR NextBio; 21242; -.
DR PRO; PR:P35813; -.
DR ArrayExpress; P35813; -.
DR Bgee; P35813; -.
DR CleanEx; HS_PPM1A; -.
DR Genevestigator; P35813; -.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR GO; GO:0043005; C:neuron projection; IEA:Ensembl.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005891; C:voltage-gated calcium channel complex; IEA:Ensembl.
DR GO; GO:0033192; F:calmodulin-dependent protein phosphatase activity; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR GO; GO:0030145; F:manganese ion binding; IEA:InterPro.
DR GO; GO:0004871; F:signal transducer activity; IMP:UniProtKB.
DR GO; GO:0007050; P:cell cycle arrest; TAS:Reactome.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0006499; P:N-terminal protein myristoylation; ISS:UniProtKB.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB cascade; IMP:UniProtKB.
DR GO; GO:0042347; P:negative regulation of NF-kappaB import into nucleus; IMP:UniProtKB.
DR GO; GO:0010991; P:negative regulation of SMAD protein complex assembly; IDA:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; TAS:Reactome.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0035970; P:peptidyl-threonine dephosphorylation; IDA:UniProtKB.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IMP:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-dependent; IDA:BHF-UCL.
DR GO; GO:0030177; P:positive regulation of Wnt receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0006367; P:transcription initiation from RNA polymerase II promoter; TAS:Reactome.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; TAS:Reactome.
DR GO; GO:0016055; P:Wnt receptor signaling pathway; IDA:BHF-UCL.
DR Gene3D; 1.10.10.430; -; 1.
DR Gene3D; 3.60.40.10; -; 1.
DR InterPro; IPR001932; PP2C-like_dom.
DR InterPro; IPR012911; PP2C_C.
DR InterPro; IPR000222; PP2C_Mn2_Asp60_BS.
DR InterPro; IPR015655; Protein_Pase_2C.
DR PANTHER; PTHR13832; PTHR13832; 1.
DR Pfam; PF00481; PP2C; 1.
DR Pfam; PF07830; PP2C_C; 1.
DR SMART; SM00331; PP2C_SIG; 1.
DR SMART; SM00332; PP2Cc; 1.
DR SUPFAM; SSF81601; SSF81601; 1.
DR SUPFAM; SSF81606; SSF81606; 1.
DR PROSITE; PS01032; PP2C; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytoplasm;
KW Hydrolase; Lipoprotein; Magnesium; Manganese; Membrane; Metal-binding;
KW Myristate; Nucleus; Phosphoprotein; Protein phosphatase;
KW Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 382 Protein phosphatase 1A.
FT /FTId=PRO_0000057741.
FT METAL 60 60 Manganese 1.
FT METAL 60 60 Manganese 2.
FT METAL 61 61 Manganese 1; via carbonyl oxygen.
FT METAL 239 239 Manganese 2.
FT METAL 282 282 Manganese 2.
FT MOD_RES 375 375 Phosphoserine.
FT LIPID 2 2 N-myristoyl glycine.
FT VAR_SEQ 1 1 M -> MFCSGRKWVAEATICTKLMKREKRRMGKRRAKKAKR
FT EEKKKGGERRRNEKRGNQMKRMCERKKYETDLEDQDIM
FT (in isoform 3).
FT /FTId=VSP_045687.
FT VAR_SEQ 318 324 EIIKKQG -> GGSFNKK (in isoform Alpha-2).
FT /FTId=VSP_005085.
FT VAR_SEQ 325 382 Missing (in isoform Alpha-2).
FT /FTId=VSP_005086.
FT MUTAGEN 239 239 D->N: No effect on binding SMAD2.
FT CONFLICT 342 342 I -> T (in Ref. 3; AK097843).
FT STRAND 9 19
FT STRAND 22 31
FT STRAND 33 35
FT STRAND 38 46
FT TURN 47 49
FT STRAND 50 63
FT HELIX 66 80
FT HELIX 83 86
FT STRAND 88 91
FT HELIX 94 118
FT STRAND 129 134
FT STRAND 136 146
FT STRAND 148 153
FT STRAND 156 160
FT HELIX 169 177
FT TURN 188 190
FT HELIX 200 202
FT HELIX 210 212
FT STRAND 213 216
FT STRAND 220 225
FT TURN 228 230
FT STRAND 231 237
FT HELIX 239 242
FT HELIX 247 258
FT HELIX 264 277
FT STRAND 284 290
FT HELIX 299 319
FT HELIX 330 339
FT TURN 347 349
FT HELIX 350 354
FT HELIX 355 365
SQ SEQUENCE 382 AA; 42448 MW; D48EF508B4A76687 CRC64;
MGAFLDKPKM EKHNAQGQGN GLRYGLSSMQ GWRVEMEDAH TAVIGLPSGL ESWSFFAVYD
GHAGSQVAKY CCEHLLDHIT NNQDFKGSAG APSVENVKNG IRTGFLEIDE HMRVMSEKKH
GADRSGSTAV GVLISPQHTY FINCGDSRGL LCRNRKVHFF TQDHKPSNPL EKERIQNAGG
SVMIQRVNGS LAVSRALGDF DYKCVHGKGP TEQLVSPEPE VHDIERSEED DQFIILACDG
IWDVMGNEEL CDFVRSRLEV TDDLEKVCNE VVDTCLYKGS RDNMSVILIC FPNAPKVSPE
AVKKEAELDK YLECRVEEII KKQGEGVPDL VHVMRTLASE NIPSLPPGGE LASKRNVIEA
VYNRLNPYKN DDTDSTSTDD MW
//
MIM
606108
*RECORD*
*FIELD* NO
606108
*FIELD* TI
*606108 PROTEIN PHOSPHATASE, MAGNESIUM-DEPENDENT, 1A; PPM1A
;;PROTEIN PHOSPHATASE, MAGNESIUM-DEPENDENT, 1, ALPHA ISOFORM;;
read morePROTEIN PHOSPHATASE 2C, ALPHA ISOFORM; PP2CA;;
PP2C-ALPHA
*FIELD* TX
DESCRIPTION
PPM1A is a serine/threonine protein phosphatase that is essential for
regulating cellular stress responses in eukaryotes. For further
background information on serine/threonine protein phosphatases, see
605119.
CLONING
By screening a human teratocarcinoma cDNA library with rat Pp2c-alpha as
the probe, Mann et al. (1992) cloned the human counterpart, PPM1A, which
they called PP2C-alpha. The PPM1A cDNA encodes a predicted 382-amino
acid peptide that shares 99.7% amino acid identity with rabbit
Pp2c-alpha.
In a genetic screen to identify protein phosphatases that negatively
regulate the p38 (600289) and JNK (see 601158) stress-activated MAPK
cascades, Takekawa et al. (1998) obtained a PP2C-alpha cDNA, which they
initially called MC4, that encodes a 324-amino acid peptide. The authors
hypothesized that MC4 is an alternative splicing product of PP2C-alpha.
The 2 proteins, which they termed PP2C-alpha-1 (382 amino acids) and
PP2C-alpha-2 (324 amino acids), differ at the C terminus. Northern blot
analysis detected 2.8- and 4.4-kb transcripts, which correspond to
PP2C-alpha-1 and PP2C-alpha-2, respectively. Both transcripts were
expressed at high levels in heart, placenta, skeletal muscle, and
pancreas, and the 4.4-kb transcript (PP2C-alpha-2) was detected in
brain.
GENE FUNCTION
Using immunohistochemical analysis, Das et al. (1996) detected PPM1A in
both the cytoplasm and nucleus of mammalian cells, consistent with a
role in dephosphorylating components of stress-activated pathways.
By expressing PPM1A in mammalian cells, Takekawa et al. (1998)
demonstrated that PPM1A inhibits the activation of the stress-responsive
p38 and JNK MAPK cascades. Their in vivo and in vitro observations
indicated that PPM1A dephosphorylates and inactivates MAPKKs (MKK6
(601254) and SEK1 (601335)) and a MAPK (p38) in the stress-responsive
MAPK cascades. Using coimmunoprecipitation assays, the authors
demonstrated that PPM1A directly interacts with p38.
A key step in TGF-beta (TGFB1; 190180) signaling is ligand-induced
phosphorylation of receptor-activated SMADs (see SMAD2; 601366). Using a
functional genomic approach, Lin et al. (2006) identified human PPM1A as
a SMAD phosphatase. PPM1A dephosphorylated and promoted nuclear export
of TGF-beta-activated SMAD2 and SMAD3 (603109) in human cells. Ectopic
expression of PPM1A abolished TGF-beta-induced antiproliferative and
transcriptional responses, whereas depletion of PPM1A enhanced TGF-beta
signaling in human and other mammalian cells. In zebrafish,
Smad-antagonizing activity of Ppm1a was observed during Nodal
(601265)-dependent early embryogenesis. Lin et al. (2006) concluded that
PPM1A plays a critical role in TGF-beta signaling through
dephosphorylation of SMAD2 and SMAD3.
BIOCHEMICAL FEATURES
Das et al. (1996) determined the crystal structure of PPM1A, which they
called PP2C. The structure revealed a novel protein fold with a
catalytic domain composed of a central beta sandwich that binds 2
manganese ions, which is surrounded by alpha helices. The authors stated
that the protein architecture and deduced catalytic mechanism are
similar to the PP1, PP2A, and PP2B family of protein ser/thr
phosphatases.
*FIELD* RF
1. Das, A. K.; Helps, N. R.; Cohen, P. T. W.; Barford, D.: Crystal
structure of the protein serine/threonine phosphatase 2C at 2.0 angstrom
resolution. EMBO J. 15: 6798-6809, 1996.
2. Lin, X.; Duan, X.; Liang, Y.-Y.; Su, Y.; Wrighton, K. H.; Long,
J.; Hu, M.; Davis, C. M.; Wang, J.; Brunicardi, F. C.; Shi, Y.; Chen,
Y.-G.; Meng, A.; Feng, X.-H.: PPM1A functions as a Smad phosphatase
to terminate TGF-beta signaling. Cell 125: 915-928, 2006.
3. Mann, D. J.; Campbell, D. G.; McGowan, C. H.; Cohen, P. T. W.:
Mammalian protein serine/threonine phosphatase 2C: cDNA cloning and
comparative analysis of amino acid sequences. Biochim. Biophys. Acta 1130:
100-104, 1992.
4. Takekawa, M.; Maeda, T.; Saito, H.: Protein phosphatase 2C-alpha
inhibits the human stress-responsive p38 and JNK MAPK pathways. EMBO
J. 17: 4744-4752, 1998.
*FIELD* CN
Matthew B. Gross - updated: 4/12/2010
*FIELD* CD
Dawn Watkins-Chow: 7/13/2001
*FIELD* ED
wwang: 04/16/2010
mgross: 4/12/2010
mgross: 3/15/2006
mgross: 7/13/2001
*RECORD*
*FIELD* NO
606108
*FIELD* TI
*606108 PROTEIN PHOSPHATASE, MAGNESIUM-DEPENDENT, 1A; PPM1A
;;PROTEIN PHOSPHATASE, MAGNESIUM-DEPENDENT, 1, ALPHA ISOFORM;;
read morePROTEIN PHOSPHATASE 2C, ALPHA ISOFORM; PP2CA;;
PP2C-ALPHA
*FIELD* TX
DESCRIPTION
PPM1A is a serine/threonine protein phosphatase that is essential for
regulating cellular stress responses in eukaryotes. For further
background information on serine/threonine protein phosphatases, see
605119.
CLONING
By screening a human teratocarcinoma cDNA library with rat Pp2c-alpha as
the probe, Mann et al. (1992) cloned the human counterpart, PPM1A, which
they called PP2C-alpha. The PPM1A cDNA encodes a predicted 382-amino
acid peptide that shares 99.7% amino acid identity with rabbit
Pp2c-alpha.
In a genetic screen to identify protein phosphatases that negatively
regulate the p38 (600289) and JNK (see 601158) stress-activated MAPK
cascades, Takekawa et al. (1998) obtained a PP2C-alpha cDNA, which they
initially called MC4, that encodes a 324-amino acid peptide. The authors
hypothesized that MC4 is an alternative splicing product of PP2C-alpha.
The 2 proteins, which they termed PP2C-alpha-1 (382 amino acids) and
PP2C-alpha-2 (324 amino acids), differ at the C terminus. Northern blot
analysis detected 2.8- and 4.4-kb transcripts, which correspond to
PP2C-alpha-1 and PP2C-alpha-2, respectively. Both transcripts were
expressed at high levels in heart, placenta, skeletal muscle, and
pancreas, and the 4.4-kb transcript (PP2C-alpha-2) was detected in
brain.
GENE FUNCTION
Using immunohistochemical analysis, Das et al. (1996) detected PPM1A in
both the cytoplasm and nucleus of mammalian cells, consistent with a
role in dephosphorylating components of stress-activated pathways.
By expressing PPM1A in mammalian cells, Takekawa et al. (1998)
demonstrated that PPM1A inhibits the activation of the stress-responsive
p38 and JNK MAPK cascades. Their in vivo and in vitro observations
indicated that PPM1A dephosphorylates and inactivates MAPKKs (MKK6
(601254) and SEK1 (601335)) and a MAPK (p38) in the stress-responsive
MAPK cascades. Using coimmunoprecipitation assays, the authors
demonstrated that PPM1A directly interacts with p38.
A key step in TGF-beta (TGFB1; 190180) signaling is ligand-induced
phosphorylation of receptor-activated SMADs (see SMAD2; 601366). Using a
functional genomic approach, Lin et al. (2006) identified human PPM1A as
a SMAD phosphatase. PPM1A dephosphorylated and promoted nuclear export
of TGF-beta-activated SMAD2 and SMAD3 (603109) in human cells. Ectopic
expression of PPM1A abolished TGF-beta-induced antiproliferative and
transcriptional responses, whereas depletion of PPM1A enhanced TGF-beta
signaling in human and other mammalian cells. In zebrafish,
Smad-antagonizing activity of Ppm1a was observed during Nodal
(601265)-dependent early embryogenesis. Lin et al. (2006) concluded that
PPM1A plays a critical role in TGF-beta signaling through
dephosphorylation of SMAD2 and SMAD3.
BIOCHEMICAL FEATURES
Das et al. (1996) determined the crystal structure of PPM1A, which they
called PP2C. The structure revealed a novel protein fold with a
catalytic domain composed of a central beta sandwich that binds 2
manganese ions, which is surrounded by alpha helices. The authors stated
that the protein architecture and deduced catalytic mechanism are
similar to the PP1, PP2A, and PP2B family of protein ser/thr
phosphatases.
*FIELD* RF
1. Das, A. K.; Helps, N. R.; Cohen, P. T. W.; Barford, D.: Crystal
structure of the protein serine/threonine phosphatase 2C at 2.0 angstrom
resolution. EMBO J. 15: 6798-6809, 1996.
2. Lin, X.; Duan, X.; Liang, Y.-Y.; Su, Y.; Wrighton, K. H.; Long,
J.; Hu, M.; Davis, C. M.; Wang, J.; Brunicardi, F. C.; Shi, Y.; Chen,
Y.-G.; Meng, A.; Feng, X.-H.: PPM1A functions as a Smad phosphatase
to terminate TGF-beta signaling. Cell 125: 915-928, 2006.
3. Mann, D. J.; Campbell, D. G.; McGowan, C. H.; Cohen, P. T. W.:
Mammalian protein serine/threonine phosphatase 2C: cDNA cloning and
comparative analysis of amino acid sequences. Biochim. Biophys. Acta 1130:
100-104, 1992.
4. Takekawa, M.; Maeda, T.; Saito, H.: Protein phosphatase 2C-alpha
inhibits the human stress-responsive p38 and JNK MAPK pathways. EMBO
J. 17: 4744-4752, 1998.
*FIELD* CN
Matthew B. Gross - updated: 4/12/2010
*FIELD* CD
Dawn Watkins-Chow: 7/13/2001
*FIELD* ED
wwang: 04/16/2010
mgross: 4/12/2010
mgross: 3/15/2006
mgross: 7/13/2001