MPIP1_HUMAN
ID MPIP1_HUMAN Reviewed; 524 AA.
AC P30304; Q8IZH5; Q96IL3; Q9H2F2;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT 19-JUL-2004, sequence version 2.
DT 03-AUG-2022, entry version 205.
DE RecName: Full=M-phase inducer phosphatase 1;
DE EC=3.1.3.48;
DE AltName: Full=Dual specificity phosphatase Cdc25A;
GN Name=CDC25A;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT GLY-182.
RX PubMed=1836978; DOI=10.1016/0092-8674(91)90294-9;
RA Galaktionov K.I., Beach D.;
RT "Specific activation of cdc25 tyrosine phosphatases by B-type cyclins:
RT evidence for multiple roles of mitotic cyclins.";
RL Cell 67:1181-1194(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA Varmeh-Ziaie S., Manfredi J.J.;
RL Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT PHE-88.
RG NIEHS SNPs program;
RL Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lymph;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 37-234 (ISOFORM 2).
RX PubMed=11139144; DOI=10.1078/0171-9335-00115;
RA Wegener S., Hampe W., Herrmann D., Schaller H.C.;
RT "Alternative splicing in the regulatory region of the human phosphatases
RT CDC25A and CDC25C.";
RL Eur. J. Cell Biol. 79:810-815(2000).
RN [6]
RP INTERACTION WITH CHEK2, PHOSPHORYLATION AT SER-124 BY CHEK2, AND
RP MUTAGENESIS OF SER-124.
RX PubMed=11298456; DOI=10.1038/35071124;
RA Falck J., Mailand N., Syljuaasen R.G., Bartek J., Lukas J.;
RT "The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA
RT synthesis.";
RL Nature 410:842-847(2001).
RN [7]
RP UBIQUITINATION BY THE APC/C UBIQUITIN LIGASE COMPLEX, DOMAIN KEN BOX MOTIF,
RP AND MUTAGENESIS OF 141-LYS--ASN-143.
RX PubMed=12234927; DOI=10.1093/emboj/cdf491;
RA Donzelli M., Squatrito M., Ganoth D., Hershko A., Pagano M., Draetta G.F.;
RT "Dual mode of degradation of Cdc25 A phosphatase.";
RL EMBO J. 21:4875-4884(2002).
RN [8]
RP PHOSPHORYLATION AT SER-124, AND MUTAGENESIS OF SER-124.
RX PubMed=12399544; DOI=10.1073/pnas.182557299;
RA Zhao H., Watkins J.L., Piwnica-Worms H.;
RT "Disruption of the checkpoint kinase 1/cell division cycle 25A pathway
RT abrogates ionizing radiation-induced S and G2 checkpoints.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:14795-14800(2002).
RN [9]
RP PHOSPHORYLATION AT SER-124; SER-178; SER-279 AND SER-293, AND MUTAGENESIS
RP OF SER-124; SER-178; SER-279 AND SER-293.
RX PubMed=12676583; DOI=10.1016/s1535-6108(03)00048-5;
RA Soerensen C.S., Syljuaesen R.G., Falck J., Schroeder T., Roennstrand L.,
RA Khanna K.K., Zhou B.-B., Bartek J., Lukas J.;
RT "Chk1 regulates the S phase checkpoint by coupling the physiological
RT turnover and ionizing radiation-induced accelerated proteolysis of
RT Cdc25A.";
RL Cancer Cell 3:247-258(2003).
RN [10]
RP INTERACTION WITH BTRC; CUL1 AND FBXW11, PHOSPHODEGRON MOTIF,
RP PHOSPHORYLATION AT SER-76 AND SER-124, UBIQUITINATION, AND MUTAGENESIS OF
RP SER-76; SER-79; ASP-81 AND SER-82.
RX PubMed=14681206; DOI=10.1101/gad.1157503;
RA Jin J., Shirogane T., Xu L., Nalepa G., Qin J., Elledge S.J., Harper J.W.;
RT "SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein
RT phosphatase.";
RL Genes Dev. 17:3062-3074(2003).
RN [11]
RP PHOSPHORYLATION, AND MUTAGENESIS OF CYS-431.
RX PubMed=12676925; DOI=10.1074/jbc.m300229200;
RA Xiao Z., Chen Z., Gunasekera A.H., Sowin T.J., Rosenberg S.H., Fesik S.,
RA Zhang H.;
RT "Chk1 mediates S and G2 arrests through Cdc25A degradation in response to
RT DNA-damaging agents.";
RL J. Biol. Chem. 278:21767-21773(2003).
RN [12]
RP PHOSPHORYLATION AT SER-76; SER-124 AND SER-178, AND MUTAGENESIS OF SER-76;
RP SER-124 AND SER-178.
RX PubMed=12759351; DOI=10.1074/jbc.m302704200;
RA Hassepass I., Voit R., Hoffmann I.;
RT "Phosphorylation at serine 75 is required for UV-mediated degradation of
RT human Cdc25A phosphatase at the S-phase checkpoint.";
RL J. Biol. Chem. 278:29824-29829(2003).
RN [13]
RP INTERACTION WITH CCNB1 AND YWHAE, PHOSPHORYLATION AT SER-178 AND THR-507,
RP AND MUTAGENESIS OF SER-178; CYS-431; THR-507; LYS-514 AND ARG-520.
RX PubMed=14559997; DOI=10.1128/mcb.23.21.7488-7497.2003;
RA Chen M.-S., Ryan C.E., Piwnica-Worms H.;
RT "Chk1 kinase negatively regulates mitotic function of Cdc25A phosphatase
RT through 14-3-3 binding.";
RL Mol. Cell. Biol. 23:7488-7497(2003).
RN [14]
RP INTERACTION WITH PIM1.
RX PubMed=16356754; DOI=10.1016/j.biocel.2005.10.010;
RA Bachmann M., Kosan C., Xing P.X., Montenarh M., Hoffmann I., Moroy T.;
RT "The oncogenic serine/threonine kinase Pim-1 directly phosphorylates and
RT activates the G2/M specific phosphatase Cdc25C.";
RL Int. J. Biochem. Cell Biol. 38:430-443(2006).
RN [15]
RP PHOSPHORYLATION AT SER-79; SER-82 AND SER-88.
RX PubMed=19734889; DOI=10.1038/ncb1969;
RA Melixetian M., Klein D.K., Soerensen C.S., Helin K.;
RT "NEK11 regulates CDC25A degradation and the IR-induced G2/M checkpoint.";
RL Nat. Cell Biol. 11:1247-1253(2009).
RN [16]
RP PHOSPHORYLATION AT SER-82 AND SER-88.
RX PubMed=20090422; DOI=10.4161/cc.9.3.10513;
RA Soerensen C.S., Melixetian M., Klein D.K., Helin K.;
RT "NEK11: linking CHK1 and CDC25A in DNA damage checkpoint signaling.";
RL Cell Cycle 9:450-455(2010).
RN [17]
RP DEUBIQUITINATION BY USP17L2.
RX PubMed=20228808; DOI=10.1038/ncb2041;
RA Pereg Y., Liu B.Y., O'Rourke K.M., Sagolla M., Dey A., Komuves L.,
RA French D.M., Dixit V.M.;
RT "Ubiquitin hydrolase Dub3 promotes oncogenic transformation by stabilizing
RT Cdc25A.";
RL Nat. Cell Biol. 12:400-406(2010).
RN [18]
RP PHOSPHORYLATION AT SER-513 AND SER-519 BY PLK3, UBIQUITINATION, AND
RP MUTAGENESIS OF SER-513 AND SER-519.
RX PubMed=21376736; DOI=10.1016/j.mrfmmm.2011.02.006;
RA Myer D.L., Robbins S.B., Yin M., Boivin G.P., Liu Y., Greis K.D.,
RA Bahassi el M., Stambrook P.J.;
RT "Absence of polo-like kinase 3 in mice stabilizes Cdc25A after DNA damage
RT but is not sufficient to produce tumors.";
RL Mutat. Res. 714:1-10(2011).
RN [19]
RP INTERACTION WITH HSP90AB1.
RX PubMed=22843495; DOI=10.1093/hmg/dds303;
RA Giessrigl B., Krieger S., Rosner M., Huttary N., Saiko P., Alami M.,
RA Messaoudi S., Peyrat J.F., Maciuk A., Gollinger M., Kopf S., Kazlauskas E.,
RA Mazal P., Szekeres T., Hengstschlaeger M., Matulis D., Jaeger W.,
RA Krupitza G.;
RT "Hsp90 stabilizes Cdc25A and counteracts heat shock-mediated Cdc25A
RT degradation and cell-cycle attenuation in pancreatic carcinoma cells.";
RL Hum. Mol. Genet. 21:4615-4627(2012).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-107 AND SER-321, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 336-496.
RX PubMed=9604936; DOI=10.1016/s0092-8674(00)81190-3;
RA Fauman E.B., Cogswell J.P., Lovejoy B., Rocque W.J., Holmes W.,
RA Montana V.G., Piwnica-Worms H., Rink M.J., Saper M.A.;
RT "Crystal structure of the catalytic domain of the human cell cycle control
RT phosphatase, Cdc25A.";
RL Cell 93:617-625(1998).
CC -!- FUNCTION: Tyrosine protein phosphatase which functions as a dosage-
CC dependent inducer of mitotic progression. Directly dephosphorylates
CC CDK1 and stimulates its kinase activity. Also dephosphorylates CDK2 in
CC complex with cyclin E, in vitro.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + O-phospho-L-tyrosyl-[protein] = L-tyrosyl-[protein] +
CC phosphate; Xref=Rhea:RHEA:10684, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620; EC=3.1.3.48;
CC -!- ACTIVITY REGULATION: Stimulated by B-type cyclins. Stimulated by PIM1-
CC mediated phosphorylation.
CC -!- SUBUNIT: Interacts with CCNB1/cyclin B1. Interacts with YWHAE/14-3-3
CC epsilon when phosphorylated. Interacts with CUL1 specifically when CUL1
CC is neddylated and active. Interacts with BTRC/BTRCP1 and FBXW11/BTRCP2.
CC Interactions with CUL1, BTRC and FBXW11 are enhanced upon DNA damage.
CC Interacts with PIM1. Interacts with CHEK2; mediates CDC25A
CC phosphorylation and degradation in response to infrared-induced DNA
CC damages. Interacts with HSP90AB1; prevents heat shock-mediated CDC25A
CC degradation and contributes to cell cycle progression
CC (PubMed:22843495). {ECO:0000269|PubMed:11298456,
CC ECO:0000269|PubMed:14559997, ECO:0000269|PubMed:14681206,
CC ECO:0000269|PubMed:16356754, ECO:0000269|PubMed:22843495}.
CC -!- INTERACTION:
CC P30304; Q9BSU3: NAA11; NbExp=3; IntAct=EBI-747671, EBI-2585120;
CC P30304; P04049: RAF1; NbExp=4; IntAct=EBI-747671, EBI-365996;
CC P30304; P31946: YWHAB; NbExp=10; IntAct=EBI-747671, EBI-359815;
CC P30304; P27348: YWHAQ; NbExp=3; IntAct=EBI-747671, EBI-359854;
CC P30304; P63104: YWHAZ; NbExp=2; IntAct=EBI-747671, EBI-347088;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=CDC25A1;
CC IsoId=P30304-1; Sequence=Displayed;
CC Name=2; Synonyms=CDC25A2;
CC IsoId=P30304-2; Sequence=VSP_000860;
CC -!- DOMAIN: The phosphodegron motif mediates interaction with specific F-
CC box proteins when phosphorylated. Putative phosphorylation sites at
CC Ser-79 and Ser-82 appear to be essential for this interaction.
CC {ECO:0000269|PubMed:12234927}.
CC -!- PTM: Phosphorylated by CHEK1 on Ser-76, Ser-124, Ser-178, Ser-279, Ser-
CC 293 and Thr-507 during checkpoint mediated cell cycle arrest. Also
CC phosphorylated by CHEK2 on Ser-124, Ser-279, and Ser-293 during
CC checkpoint mediated cell cycle arrest. Phosphorylation on Ser-178 and
CC Thr-507 creates binding sites for YWHAE/14-3-3 epsilon which inhibits
CC CDC25A. Phosphorylation on Ser-76, Ser-124, Ser-178, Ser-279 and Ser-
CC 293 may also promote ubiquitin-dependent proteolysis of CDC25A by the
CC SCF complex. Phosphorylation of CDC25A at Ser-76 by CHEK1 primes it for
CC subsequent phosphorylation at Ser-79, Ser-82 and Ser-88 by NEK11.
CC Phosphorylation by NEK11 is required for BTRC-mediated
CC polyubiquitination and degradation. Phosphorylation by PIM1 leads to an
CC increase in phosphatase activity. Phosphorylated by PLK3 following DNA
CC damage, leading to promote its ubiquitination and degradation.
CC {ECO:0000269|PubMed:11298456, ECO:0000269|PubMed:12399544,
CC ECO:0000269|PubMed:12676583, ECO:0000269|PubMed:12676925,
CC ECO:0000269|PubMed:12759351, ECO:0000269|PubMed:14559997,
CC ECO:0000269|PubMed:14681206, ECO:0000269|PubMed:19734889,
CC ECO:0000269|PubMed:20090422, ECO:0000269|PubMed:20228808,
CC ECO:0000269|PubMed:21376736}.
CC -!- PTM: Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C)
CC ubiquitin ligase complex that contains FZR1/CDH1 during G1 phase
CC leading to its degradation by the proteasome. Ubiquitinated by a SCF
CC complex containing BTRC and FBXW11 during S phase leading to its
CC degradation by the proteasome. Deubiquitination by USP17L2/DUB3 leads
CC to its stabilization. {ECO:0000269|PubMed:20228808}.
CC -!- SIMILARITY: Belongs to the MPI phosphatase family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/CDC25AID40004ch3p21.html";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/cdc25a/";
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DR EMBL; M81933; AAA58415.1; -; mRNA.
DR EMBL; AY137580; AAN11305.1; -; mRNA.
DR EMBL; AF527417; AAM77917.1; -; Genomic_DNA.
DR EMBL; BC007401; AAH07401.1; -; mRNA.
DR EMBL; BC018642; AAH18642.1; -; mRNA.
DR EMBL; AF277722; AAG41884.1; -; mRNA.
DR CCDS; CCDS2760.1; -. [P30304-1]
DR CCDS; CCDS2761.1; -. [P30304-2]
DR PIR; A41648; A41648.
DR RefSeq; NP_001780.2; NM_001789.2. [P30304-1]
DR RefSeq; NP_963861.1; NM_201567.1. [P30304-2]
DR RefSeq; XP_011532618.1; XM_011534316.1.
DR PDB; 1C25; X-ray; 2.30 A; A=337-496.
DR PDBsum; 1C25; -.
DR AlphaFoldDB; P30304; -.
DR SMR; P30304; -.
DR BioGRID; 107428; 137.
DR DIP; DIP-166N; -.
DR ELM; P30304; -.
DR IntAct; P30304; 46.
DR MINT; P30304; -.
DR STRING; 9606.ENSP00000303706; -.
DR BindingDB; P30304; -.
DR ChEMBL; CHEMBL3775; -.
DR DrugCentral; P30304; -.
DR DEPOD; CDC25A; -.
DR GlyGen; P30304; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P30304; -.
DR PhosphoSitePlus; P30304; -.
DR BioMuta; CDC25A; -.
DR DMDM; 50403734; -.
DR EPD; P30304; -.
DR jPOST; P30304; -.
DR MassIVE; P30304; -.
DR MaxQB; P30304; -.
DR PaxDb; P30304; -.
DR PeptideAtlas; P30304; -.
DR PRIDE; P30304; -.
DR ProteomicsDB; 54652; -. [P30304-1]
DR ProteomicsDB; 54653; -. [P30304-2]
DR Antibodypedia; 1619; 1755 antibodies from 47 providers.
DR DNASU; 993; -.
DR Ensembl; ENST00000302506.8; ENSP00000303706.3; ENSG00000164045.12. [P30304-1]
DR Ensembl; ENST00000351231.7; ENSP00000343166.3; ENSG00000164045.12. [P30304-2]
DR GeneID; 993; -.
DR KEGG; hsa:993; -.
DR MANE-Select; ENST00000302506.8; ENSP00000303706.3; NM_001789.3; NP_001780.2.
DR UCSC; uc003csh.2; human. [P30304-1]
DR CTD; 993; -.
DR DisGeNET; 993; -.
DR GeneCards; CDC25A; -.
DR HGNC; HGNC:1725; CDC25A.
DR HPA; ENSG00000164045; Tissue enhanced (bone marrow, lymphoid tissue, testis).
DR MIM; 116947; gene.
DR neXtProt; NX_P30304; -.
DR OpenTargets; ENSG00000164045; -.
DR PharmGKB; PA26259; -.
DR VEuPathDB; HostDB:ENSG00000164045; -.
DR eggNOG; KOG3772; Eukaryota.
DR GeneTree; ENSGT00940000160737; -.
DR HOGENOM; CLU_014464_0_1_1; -.
DR InParanoid; P30304; -.
DR OMA; ECEQPLE; -.
DR PhylomeDB; P30304; -.
DR TreeFam; TF101056; -.
DR BRENDA; 3.1.3.48; 2681.
DR PathwayCommons; P30304; -.
DR Reactome; R-HSA-1362277; Transcription of E2F targets under negative control by DREAM complex.
DR Reactome; R-HSA-156711; Polo-like kinase mediated events.
DR Reactome; R-HSA-176187; Activation of ATR in response to replication stress.
DR Reactome; R-HSA-5689880; Ub-specific processing proteases.
DR Reactome; R-HSA-69202; Cyclin E associated events during G1/S transition.
DR Reactome; R-HSA-69273; Cyclin A/B1/B2 associated events during G2/M transition.
DR Reactome; R-HSA-69601; Ubiquitin Mediated Degradation of Phosphorylated Cdc25A.
DR Reactome; R-HSA-69656; Cyclin A:Cdk2-associated events at S phase entry.
DR Reactome; R-HSA-8862803; Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models.
DR SignaLink; P30304; -.
DR SIGNOR; P30304; -.
DR BioGRID-ORCS; 993; 62 hits in 1092 CRISPR screens.
DR ChiTaRS; CDC25A; human.
DR EvolutionaryTrace; P30304; -.
DR GeneWiki; CDC25A; -.
DR GenomeRNAi; 993; -.
DR Pharos; P30304; Tchem.
DR PRO; PR:P30304; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; P30304; protein.
DR Bgee; ENSG00000164045; Expressed in secondary oocyte and 134 other tissues.
DR ExpressionAtlas; P30304; baseline and differential.
DR Genevisible; P30304; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0051087; F:chaperone binding; IPI:UniProtKB.
DR GO; GO:0004721; F:phosphoprotein phosphatase activity; TAS:Reactome.
DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR GO; GO:0004725; F:protein tyrosine phosphatase activity; IBA:GO_Central.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0008283; P:cell population proliferation; TAS:UniProtKB.
DR GO; GO:0034644; P:cellular response to UV; IDA:UniProtKB.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; TAS:Reactome.
DR GO; GO:0000086; P:G2/M transition of mitotic cell cycle; IBA:GO_Central.
DR GO; GO:0010971; P:positive regulation of G2/M transition of mitotic cell cycle; IBA:GO_Central.
DR GO; GO:0110032; P:positive regulation of G2/MI transition of meiotic cell cycle; IBA:GO_Central.
DR GO; GO:0006470; P:protein dephosphorylation; IEA:InterPro.
DR GO; GO:0000079; P:regulation of cyclin-dependent protein serine/threonine kinase activity; TAS:ProtInc.
DR GO; GO:0009314; P:response to radiation; IDA:UniProtKB.
DR CDD; cd01530; Cdc25; 1.
DR Gene3D; 3.40.250.10; -; 1.
DR InterPro; IPR000751; MPI_Phosphatase.
DR InterPro; IPR001763; Rhodanese-like_dom.
DR InterPro; IPR036873; Rhodanese-like_dom_sf.
DR Pfam; PF06617; M-inducer_phosp; 1.
DR Pfam; PF00581; Rhodanese; 1.
DR PRINTS; PR00716; MPIPHPHTASE.
DR SMART; SM00450; RHOD; 1.
DR SUPFAM; SSF52821; SSF52821; 1.
DR PROSITE; PS50206; RHODANESE_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell cycle; Cell division; Hydrolase;
KW Mitosis; Phosphoprotein; Protein phosphatase; Reference proteome;
KW Ubl conjugation.
FT CHAIN 1..524
FT /note="M-phase inducer phosphatase 1"
FT /id="PRO_0000198641"
FT DOMAIN 376..482
FT /note="Rhodanese"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00173"
FT REGION 264..317
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 74..84
FT /note="Phosphodegron"
FT MOTIF 141..143
FT /note="KEN box"
FT COMPBIAS 274..288
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 431
FT MOD_RES 76
FT /note="Phosphoserine; by CHEK1"
FT /evidence="ECO:0000269|PubMed:12759351,
FT ECO:0000269|PubMed:14681206"
FT MOD_RES 79
FT /note="Phosphoserine; by NEK11"
FT /evidence="ECO:0000269|PubMed:19734889"
FT MOD_RES 82
FT /note="Phosphoserine; by NEK11"
FT /evidence="ECO:0000269|PubMed:19734889,
FT ECO:0000269|PubMed:20090422"
FT MOD_RES 88
FT /note="Phosphoserine; by NEK11"
FT /evidence="ECO:0000269|PubMed:19734889,
FT ECO:0000269|PubMed:20090422"
FT MOD_RES 107
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 124
FT /note="Phosphoserine; by CHEK1 and CHEK2"
FT /evidence="ECO:0000269|PubMed:11298456,
FT ECO:0000269|PubMed:12399544, ECO:0000269|PubMed:12676583,
FT ECO:0000269|PubMed:12759351, ECO:0000269|PubMed:14681206"
FT MOD_RES 178
FT /note="Phosphoserine; by CHEK1"
FT /evidence="ECO:0000269|PubMed:12676583,
FT ECO:0000269|PubMed:12759351, ECO:0000269|PubMed:14559997"
FT MOD_RES 279
FT /note="Phosphoserine; by CHEK1 and CHEK2"
FT /evidence="ECO:0000269|PubMed:12676583"
FT MOD_RES 293
FT /note="Phosphoserine; by CHEK1 and CHEK2"
FT /evidence="ECO:0000269|PubMed:12676583"
FT MOD_RES 321
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 507
FT /note="Phosphothreonine; by CHEK1"
FT /evidence="ECO:0000269|PubMed:14559997"
FT MOD_RES 513
FT /note="Phosphoserine; by PLK3"
FT /evidence="ECO:0000269|PubMed:21376736"
FT MOD_RES 519
FT /note="Phosphoserine; by PLK3"
FT /evidence="ECO:0000269|PubMed:21376736"
FT VAR_SEQ 144..183
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11139144, ECO:0000303|Ref.2"
FT /id="VSP_000860"
FT VARIANT 88
FT /note="S -> F (in dbSNP:rs3731499)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_020932"
FT VARIANT 182
FT /note="R -> G (in dbSNP:rs6771386)"
FT /evidence="ECO:0000269|PubMed:1836978"
FT /id="VAR_023532"
FT VARIANT 182
FT /note="R -> W (in dbSNP:rs6771386)"
FT /id="VAR_023533"
FT MUTAGEN 76
FT /note="S->A: Abolishes ubiquitination and impairs CHEK1-
FT dependent degradation following checkpoint activation."
FT /evidence="ECO:0000269|PubMed:12759351,
FT ECO:0000269|PubMed:14681206"
FT MUTAGEN 79
FT /note="S->A: Abrogates interactions with BTRC and FBXW11
FT and prevents ubiquitination."
FT /evidence="ECO:0000269|PubMed:14681206"
FT MUTAGEN 81
FT /note="D->A: Abrogates interactions with BTRC and FBXW11
FT and prevents ubiquitination."
FT /evidence="ECO:0000269|PubMed:14681206"
FT MUTAGEN 82
FT /note="S->A: Abrogates interactions with BTRC and FBXW11
FT and prevents ubiquitination."
FT /evidence="ECO:0000269|PubMed:14681206"
FT MUTAGEN 124
FT /note="S->A: Abrogates phosphorylation by CHEK2 and
FT infrared-induced degradation. Increases basal stability and
FT impairs CHEK1-dependent degradation following checkpoint
FT activation; when associated with A-178; A-279 and A-293."
FT /evidence="ECO:0000269|PubMed:11298456,
FT ECO:0000269|PubMed:12399544, ECO:0000269|PubMed:12676583,
FT ECO:0000269|PubMed:12759351"
FT MUTAGEN 141..143
FT /note="KEN->AAA: Prevents ubiquitination and subsequent
FT degradation by the APC/C ubiquitin ligase complex."
FT /evidence="ECO:0000269|PubMed:12234927"
FT MUTAGEN 178
FT /note="S->A: Increases basal stability and impairs CHEK1-
FT dependent degradation following checkpoint activation; when
FT associated with A-124; A-279 and A-293. Abrogates 14-3-3
FT protein binding."
FT /evidence="ECO:0000269|PubMed:12676583,
FT ECO:0000269|PubMed:12759351, ECO:0000269|PubMed:14559997"
FT MUTAGEN 279
FT /note="S->A: Increases basal stability and impairs CHEK1-
FT dependent degradation following checkpoint activation; when
FT associated with A-124; A-178 and A-293."
FT /evidence="ECO:0000269|PubMed:12676583"
FT MUTAGEN 293
FT /note="S->A: Increases basal stability and impairs CHEK1-
FT dependent degradation following checkpoint activation; when
FT associated with A-124; A-178 and A-279."
FT /evidence="ECO:0000269|PubMed:12676583"
FT MUTAGEN 431
FT /note="C->S: Abolishes phosphatase activity."
FT /evidence="ECO:0000269|PubMed:12676925,
FT ECO:0000269|PubMed:14559997"
FT MUTAGEN 507
FT /note="T->A: Abrogates 14-3-3 protein binding; increases
FT binding to cyclin B1."
FT /evidence="ECO:0000269|PubMed:14559997"
FT MUTAGEN 513
FT /note="S->A: Increased stability following IR treatment."
FT /evidence="ECO:0000269|PubMed:21376736"
FT MUTAGEN 513
FT /note="S->D: Mimicks phosphorylation state, leading to
FT promote degradation following IR treatment."
FT /evidence="ECO:0000269|PubMed:21376736"
FT MUTAGEN 514
FT /note="K->L: Abrogates binding to CCNB1; when associated
FT with L-520."
FT /evidence="ECO:0000269|PubMed:14559997"
FT MUTAGEN 519
FT /note="S->A: Increased stability following IR treatment."
FT /evidence="ECO:0000269|PubMed:21376736"
FT MUTAGEN 519
FT /note="S->D: Mimicks phosphorylation state, leading to
FT promote degradation following IR treatment."
FT /evidence="ECO:0000269|PubMed:21376736"
FT MUTAGEN 520
FT /note="R->L: Abrogates binding to CCNB1; when associated
FT with L-514."
FT /evidence="ECO:0000269|PubMed:14559997"
FT CONFLICT 6..10
FT /note="EPPHR -> SPAP (in Ref. 1; AAA58415)"
FT /evidence="ECO:0000305"
FT CONFLICT 180..181
FT /note="PA -> QL (in Ref. 1; AAA58415)"
FT /evidence="ECO:0000305"
FT STRAND 341..344
FT /evidence="ECO:0007829|PDB:1C25"
FT HELIX 362..369
FT /evidence="ECO:0007829|PDB:1C25"
FT TURN 370..376
FT /evidence="ECO:0007829|PDB:1C25"
FT STRAND 377..384
FT /evidence="ECO:0007829|PDB:1C25"
FT HELIX 388..392
FT /evidence="ECO:0007829|PDB:1C25"
FT HELIX 405..411
FT /evidence="ECO:0007829|PDB:1C25"
FT TURN 412..414
FT /evidence="ECO:0007829|PDB:1C25"
FT STRAND 423..430
FT /evidence="ECO:0007829|PDB:1C25"
FT STRAND 432..436
FT /evidence="ECO:0007829|PDB:1C25"
FT HELIX 437..451
FT /evidence="ECO:0007829|PDB:1C25"
FT STRAND 463..466
FT /evidence="ECO:0007829|PDB:1C25"
FT HELIX 469..477
FT /evidence="ECO:0007829|PDB:1C25"
FT HELIX 478..480
FT /evidence="ECO:0007829|PDB:1C25"
FT STRAND 481..484
FT /evidence="ECO:0007829|PDB:1C25"
SQ SEQUENCE 524 AA; 59087 MW; B2F6B792D4E6122B CRC64;
MELGPEPPHR RRLLFACSPP PASQPVVKAL FGASAAGGLS PVTNLTVTMD QLQGLGSDYE
QPLEVKNNSN LQRMGSSEST DSGFCLDSPG PLDSKENLEN PMRRIHSLPQ KLLGCSPALK
RSHSDSLDHD IFQLIDPDEN KENEAFEFKK PVRPVSRGCL HSHGLQEGKD LFTQRQNSAP
ARMLSSNERD SSEPGNFIPL FTPQSPVTAT LSDEDDGFVD LLDGENLKNE EETPSCMASL
WTAPLVMRTT NLDNRCKLFD SPSLCSSSTR SVLKRPERSQ EESPPGSTKR RKSMSGASPK
ESTNPEKAHE TLHQSLSLAS SPKGTIENIL DNDPRDLIGD FSKGYLFHTV AGKHQDLKYI
SPEIMASVLN GKFANLIKEF VIIDCRYPYE YEGGHIKGAV NLHMEEEVED FLLKKPIVPT
DGKRVIVVFH CEFSSERGPR MCRYVRERDR LGNEYPKLHY PELYVLKGGY KEFFMKCQSY
CEPPSYRPMH HEDFKEDLKK FRTKSRTWAG EKSKREMYSR LKKL
