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P30304 (MPIP1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 139. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
M-phase inducer phosphatase 1

EC=3.1.3.48
Alternative name(s):
Dual specificity phosphatase Cdc25A
Gene names
Name:CDC25A
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length524 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Tyrosine protein phosphatase which functions as a dosage-dependent inducer of mitotic progression. Directly dephosphorylates CDK1 and stimulates its kinase activity. Also dephosphorylates CDK2 in complex with cyclin E, in vitro.

Catalytic activity

Protein tyrosine phosphate + H2O = protein tyrosine + phosphate.

Enzyme regulation

Stimulated by B-type cyclins. Stimulated by PIM1-mediated phosphorylation.

Subunit structure

Interacts with CCNB1/cyclin B1. Interacts with YWHAE/14-3-3 epsilon when phosphorylated. Interacts with CUL1 specifically when CUL1 is neddylated and active. Interacts with BTRC/BTRCP1 and FBXW11/BTRCP2. Interactions with CUL1, BTRC and FBXW11 are enhanced upon DNA damage. Interacts with PIM1. Interacts with CHEK2; mediates CDC25A phosphorylation and degradation in response to infrared-induced DNA damages. Ref.6 Ref.10 Ref.13 Ref.14

Domain

The phosphodegron motif mediates interaction with specific F-box proteins when phosphorylated. Putative phosphorylation sites at Ser-79 and Ser-82 appear to be essential for this interaction. Ref.7

Post-translational modification

Phosphorylated by CHEK1 on Ser-76, Ser-124, Ser-178, Ser-279, Ser-293 and Thr-507 during checkpoint mediated cell cycle arrest. Also phosphorylated by CHEK2 on Ser-124, Ser-279, and Ser-293 during checkpoint mediated cell cycle arrest. Phosphorylation on Ser-178 and Thr-507 creates binding sites for YWHAE/14-3-3 epsilon which inhibits CDC25A. Phosphorylation on Ser-76, Ser-124, Ser-178, Ser-279 and Ser-293 may also promote ubiquitin-dependent proteolysis of CDC25A by the SCF complex. Phosphorylation of CDC25A at Ser-76 by CHEK1 primes it for subsequent phosphorylation at Ser-79, Ser-82 and Ser-88 by NEK11. Phosphorylation by NEK11 is required for BTRC-mediated polyubiquitination and degradation. Phosphorylation by PIM1 leads to an increase in phosphatase activity. Phosphorylated by PLK3 following DNA damage, leading to promote its ubiquitination and degradation. Ref.6 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.15 Ref.16 Ref.18

Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase complex that contains FZR1/CDH1 during G1 phase leading to its degradation by the proteasome. Ubiquitinated by a SCF complex containing BTRC and FBXW11 during S phase leading to its degradation by the proteasome. Deubiquitination by USP17L2/DUB3 leads to its stabilization. Ref.7 Ref.10 Ref.17 Ref.18

Sequence similarities

Belongs to the MPI phosphatase family.

Contains 1 rhodanese domain.

Binary interactions

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P30304-1)

Also known as: CDC25A1;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: P30304-2)

Also known as: CDC25A2;

The sequence of this isoform differs from the canonical sequence as follows:
     144-183: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 524524M-phase inducer phosphatase 1
PRO_0000198641

Regions

Domain376 – 482107Rhodanese
Motif74 – 8411Phosphodegron
Motif141 – 1433KEN box

Sites

Active site4311

Amino acid modifications

Modified residue761Phosphoserine; by CHEK1 Ref.10 Ref.12
Modified residue791Phosphoserine; by NEK11 Ref.15
Modified residue821Phosphoserine; by NEK11 Ref.15 Ref.16
Modified residue881Phosphoserine; by NEK11 Ref.15 Ref.16
Modified residue1241Phosphoserine; by CHEK1 and CHEK2 Ref.6 Ref.8 Ref.9 Ref.10 Ref.12
Modified residue1781Phosphoserine; by CHEK1 Ref.9 Ref.12 Ref.13
Modified residue2791Phosphoserine; by CHEK1 and CHEK2 Ref.9
Modified residue2931Phosphoserine; by CHEK1 and CHEK2 Ref.9
Modified residue5071Phosphothreonine; by CHEK1 Ref.13
Modified residue5131Phosphoserine; by PLK3 Ref.18
Modified residue5191Phosphoserine; by PLK3 Ref.18

Natural variations

Alternative sequence144 – 18340Missing in isoform 2.
VSP_000860
Natural variant881S → F. Ref.3
Corresponds to variant rs3731499 [ dbSNP | Ensembl ].
VAR_020932
Natural variant1821R → G. Ref.1
Corresponds to variant rs6771386 [ dbSNP | Ensembl ].
VAR_023532
Natural variant1821R → W.
Corresponds to variant rs6771386 [ dbSNP | Ensembl ].
VAR_023533

Experimental info

Mutagenesis761S → A: Abolishes ubiquitination and impairs CHEK1-dependent degradation following checkpoint activation. Ref.10 Ref.12
Mutagenesis791S → A: Abrogates interactions with BTRC and FBXW11 and prevents ubiquitination. Ref.10
Mutagenesis811D → A: Abrogates interactions with BTRC and FBXW11 and prevents ubiquitination. Ref.10
Mutagenesis821S → A: Abrogates interactions with BTRC and FBXW11 and prevents ubiquitination. Ref.10
Mutagenesis1241S → A: Abrogates phosphorylation by CHEK2 and infrared-induced degradation. Increases basal stability and impairs CHEK1-dependent degradation following checkpoint activation; when associated with A-178; A-279 and A-293. Ref.6 Ref.8 Ref.9 Ref.12
Mutagenesis141 – 1433KEN → AAA: Prevents ubiquitination and subsequent degradation by the APC/C ubiquitin ligase complex. Ref.7
Mutagenesis1781S → A: Increases basal stability and impairs CHEK1-dependent degradation following checkpoint activation; when associated with A-124; A-279 and A-293. Abrogates 14-3-3 protein binding. Ref.9 Ref.12 Ref.13
Mutagenesis2791S → A: Increases basal stability and impairs CHEK1-dependent degradation following checkpoint activation; when associated with A-124; A-178 and A-293. Ref.9
Mutagenesis2931S → A: Increases basal stability and impairs CHEK1-dependent degradation following checkpoint activation; when associated with A-124; A-178 and A-279. Ref.9
Mutagenesis4311C → S: Abolishes phosphatase activity. Ref.11 Ref.13
Mutagenesis5071T → A: Abrogates 14-3-3 protein binding; increases binding to cyclin B1. Ref.13
Mutagenesis5131S → A: Increased stability following IR treatment. Ref.18
Mutagenesis5131S → D: Mimicks phosphorylation state, leading to promote degradation following IR treatment. Ref.18
Mutagenesis5141K → L: Abrogates binding to CCNB1; when associated with L-520. Ref.13
Mutagenesis5191S → A: Increased stability following IR treatment. Ref.18
Mutagenesis5191S → D: Mimicks phosphorylation state, leading to promote degradation following IR treatment. Ref.18
Mutagenesis5201R → L: Abrogates binding to CCNB1; when associated with L-514. Ref.13
Sequence conflict6 – 105EPPHR → SPAP in AAA58415. Ref.1
Sequence conflict180 – 1812PA → QL in AAA58415. Ref.1

Secondary structure

....................... 524
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (CDC25A1) [UniParc].

Last modified July 19, 2004. Version 2.
Checksum: B2F6B792D4E6122B

FASTA52459,087
        10         20         30         40         50         60 
MELGPEPPHR RRLLFACSPP PASQPVVKAL FGASAAGGLS PVTNLTVTMD QLQGLGSDYE 

        70         80         90        100        110        120 
QPLEVKNNSN LQRMGSSEST DSGFCLDSPG PLDSKENLEN PMRRIHSLPQ KLLGCSPALK 

       130        140        150        160        170        180 
RSHSDSLDHD IFQLIDPDEN KENEAFEFKK PVRPVSRGCL HSHGLQEGKD LFTQRQNSAP 

       190        200        210        220        230        240 
ARMLSSNERD SSEPGNFIPL FTPQSPVTAT LSDEDDGFVD LLDGENLKNE EETPSCMASL 

       250        260        270        280        290        300 
WTAPLVMRTT NLDNRCKLFD SPSLCSSSTR SVLKRPERSQ EESPPGSTKR RKSMSGASPK 

       310        320        330        340        350        360 
ESTNPEKAHE TLHQSLSLAS SPKGTIENIL DNDPRDLIGD FSKGYLFHTV AGKHQDLKYI 

       370        380        390        400        410        420 
SPEIMASVLN GKFANLIKEF VIIDCRYPYE YEGGHIKGAV NLHMEEEVED FLLKKPIVPT 

       430        440        450        460        470        480 
DGKRVIVVFH CEFSSERGPR MCRYVRERDR LGNEYPKLHY PELYVLKGGY KEFFMKCQSY 

       490        500        510        520 
CEPPSYRPMH HEDFKEDLKK FRTKSRTWAG EKSKREMYSR LKKL 

« Hide

Isoform 2 (CDC25A2) [UniParc].

Checksum: AE6326F34B704D4B
Show »

FASTA48454,551

References

« Hide 'large scale' references
[1]"Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: evidence for multiple roles of mitotic cyclins."
Galaktionov K.I., Beach D.
Cell 67:1181-1194(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT GLY-182.
[2]Varmeh-Ziaie S., Manfredi J.J.
Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[3]NIEHS SNPs program
Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT PHE-88.
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Lymph.
[5]"Alternative splicing in the regulatory region of the human phosphatases CDC25A and CDC25C."
Wegener S., Hampe W., Herrmann D., Schaller H.C.
Eur. J. Cell Biol. 79:810-815(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 37-234 (ISOFORM 2).
[6]"The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis."
Falck J., Mailand N., Syljuaasen R.G., Bartek J., Lukas J.
Nature 410:842-847(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CHEK2, PHOSPHORYLATION AT SER-124 BY CHEK2, MUTAGENESIS OF SER-124.
[7]"Dual mode of degradation of Cdc25 A phosphatase."
Donzelli M., Squatrito M., Ganoth D., Hershko A., Pagano M., Draetta G.F.
EMBO J. 21:4875-4884(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION BY THE APC/C UBIQUITIN LIGASE COMPLEX, DOMAIN KEN BOX MOTIF, MUTAGENESIS OF 141-LYS--ASN-143.
[8]"Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints."
Zhao H., Watkins J.L., Piwnica-Worms H.
Proc. Natl. Acad. Sci. U.S.A. 99:14795-14800(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-124, MUTAGENESIS OF SER-124.
[9]"Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A."
Soerensen C.S., Syljuaesen R.G., Falck J., Schroeder T., Roennstrand L., Khanna K.K., Zhou B.-B., Bartek J., Lukas J.
Cancer Cell 3:247-258(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-124; SER-178; SER-279 AND SER-293, MUTAGENESIS OF SER-124; SER-178; SER-279 AND SER-293.
[10]"SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase."
Jin J., Shirogane T., Xu L., Nalepa G., Qin J., Elledge S.J., Harper J.W.
Genes Dev. 17:3062-3074(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH BTRC; CUL1 AND FBXW11, PHOSPHODEGRON MOTIF, PHOSPHORYLATION AT SER-76 AND SER-124, UBIQUITINATION, MUTAGENESIS OF SER-76; SER-79; ASP-81 AND SER-82.
[11]"Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents."
Xiao Z., Chen Z., Gunasekera A.H., Sowin T.J., Rosenberg S.H., Fesik S., Zhang H.
J. Biol. Chem. 278:21767-21773(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION, MUTAGENESIS OF CYS-431.
[12]"Phosphorylation at serine 75 is required for UV-mediated degradation of human Cdc25A phosphatase at the S-phase checkpoint."
Hassepass I., Voit R., Hoffmann I.
J. Biol. Chem. 278:29824-29829(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-76; SER-124 AND SER-178, MUTAGENESIS OF SER-76; SER-124 AND SER-178.
[13]"Chk1 kinase negatively regulates mitotic function of Cdc25A phosphatase through 14-3-3 binding."
Chen M.-S., Ryan C.E., Piwnica-Worms H.
Mol. Cell. Biol. 23:7488-7497(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CCNB1 AND YWHAE, PHOSPHORYLATION AT SER-178 AND THR-507, MUTAGENESIS OF SER-178; CYS-431; THR-507; LYS-514 AND ARG-520.
[14]"The oncogenic serine/threonine kinase Pim-1 directly phosphorylates and activates the G2/M specific phosphatase Cdc25C."
Bachmann M., Kosan C., Xing P.X., Montenarh M., Hoffmann I., Moroy T.
Int. J. Biochem. Cell Biol. 38:430-443(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PIM1.
[15]"NEK11 regulates CDC25A degradation and the IR-induced G2/M checkpoint."
Melixetian M., Klein D.K., Soerensen C.S., Helin K.
Nat. Cell Biol. 11:1247-1253(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-79; SER-82 AND SER-88.
[16]"NEK11: linking CHK1 and CDC25A in DNA damage checkpoint signaling."
Soerensen C.S., Melixetian M., Klein D.K., Helin K.
Cell Cycle 9:450-455(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-82 AND SER-88.
[17]"Ubiquitin hydrolase Dub3 promotes oncogenic transformation by stabilizing Cdc25A."
Pereg Y., Liu B.Y., O'Rourke K.M., Sagolla M., Dey A., Komuves L., French D.M., Dixit V.M.
Nat. Cell Biol. 12:400-406(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: DEUBIQUITINATION BY USP17L2.
[18]"Absence of polo-like kinase 3 in mice stabilizes Cdc25A after DNA damage but is not sufficient to produce tumors."
Myer D.L., Robbins S.B., Yin M., Boivin G.P., Liu Y., Greis K.D., Bahassi el M., Stambrook P.J.
Mutat. Res. 714:1-10(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-513 AND SER-519 BY PLK3, UBIQUITINATION, MUTAGENESIS OF SER-513 AND SER-519.
[19]"Crystal structure of the catalytic domain of the human cell cycle control phosphatase, Cdc25A."
Fauman E.B., Cogswell J.P., Lovejoy B., Rocque W.J., Holmes W., Montana V.G., Piwnica-Worms H., Rink M.J., Saper M.A.
Cell 93:617-625(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 336-496.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M81933 mRNA. Translation: AAA58415.1.
AY137580 mRNA. Translation: AAN11305.1.
AF527417 Genomic DNA. Translation: AAM77917.1.
BC007401 mRNA. Translation: AAH07401.1.
BC018642 mRNA. Translation: AAH18642.1.
AF277722 mRNA. Translation: AAG41884.1.
PIRA41648.
RefSeqNP_001780.2. NM_001789.2.
NP_963861.1. NM_201567.1.
UniGeneHs.437705.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1C25X-ray2.30A337-496[»]
ProteinModelPortalP30304.
SMRP30304. Positions 337-496.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid107428. 49 interactions.
DIPDIP-166N.
IntActP30304. 33 interactions.
MINTMINT-124723.
STRING9606.ENSP00000303706.

Chemistry

BindingDBP30304.
ChEMBLCHEMBL3775.

PTM databases

PhosphoSiteP30304.

Polymorphism databases

DMDM50403734.

Proteomic databases

PaxDbP30304.
PRIDEP30304.

Protocols and materials databases

DNASU993.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000302506; ENSP00000303706; ENSG00000164045. [P30304-1]
ENST00000351231; ENSP00000343166; ENSG00000164045. [P30304-2]
GeneID993.
KEGGhsa:993.
UCSCuc003csh.1. human. [P30304-1]
uc003csi.1. human. [P30304-2]

Organism-specific databases

CTD993.
GeneCardsGC03M048173.
HGNCHGNC:1725. CDC25A.
HPAHPA005855.
MIM116947. gene.
neXtProtNX_P30304.
PharmGKBPA26259.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG5105.
HOGENOMHOG000082672.
HOVERGENHBG052501.
InParanoidP30304.
KOK06645.
OMANLTVTMD.
OrthoDBEOG7288R1.
PhylomeDBP30304.
TreeFamTF101056.

Enzyme and pathway databases

BRENDA3.1.3.48. 2681.
ReactomeREACT_115566. Cell Cycle.

Gene expression databases

ArrayExpressP30304.
BgeeP30304.
CleanExHS_CDC25A.
GenevestigatorP30304.

Family and domain databases

Gene3D3.40.250.10. 1 hit.
InterProIPR000751. MPI_Phosphatase.
IPR001763. Rhodanese-like_dom.
[Graphical view]
PfamPF06617. M-inducer_phosp. 1 hit.
PF00581. Rhodanese. 1 hit.
[Graphical view]
PRINTSPR00716. MPIPHPHTASE.
SMARTSM00450. RHOD. 1 hit.
[Graphical view]
SUPFAMSSF52821. SSF52821. 1 hit.
PROSITEPS50206. RHODANESE_3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP30304.
GeneWikiCDC25A.
GenomeRNAi993.
NextBio4164.
PROP30304.
SOURCESearch...

Entry information

Entry nameMPIP1_HUMAN
AccessionPrimary (citable) accession number: P30304
Secondary accession number(s): Q8IZH5, Q96IL3, Q9H2F2
Entry history
Integrated into UniProtKB/Swiss-Prot: April 1, 1993
Last sequence update: July 19, 2004
Last modified: April 16, 2014
This is version 139 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 3

Human chromosome 3: entries, gene names and cross-references to MIM