PTTG1_HUMAN
ID PTTG1_HUMAN Reviewed; 202 AA.
AC O95997;
DT 25-MAR-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 03-AUG-2022, entry version 175.
DE RecName: Full=Securin;
DE AltName: Full=Esp1-associated protein;
DE AltName: Full=Pituitary tumor-transforming gene 1 protein;
DE Short=Tumor-transforming protein 1;
DE Short=hPTTG;
GN Name=PTTG1; Synonyms=EAP1, PTTG, TUTR1;
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], AND TISSUE SPECIFICITY.
RC TISSUE=Thymus;
RX PubMed=9811450; DOI=10.1038/sj.onc.1202140;
RA Dominguez A., Ramos-Morales F., Romero F., Rios R.M., Dreyfus F.,
RA Tortolero M., Pintor-Toro J.A.;
RT "hPTTG, a human homologue of rat PTTG, is overexpressed in hematopoietic
RT neoplasms. Evidence for a transcriptional activation function of hPTTG.";
RL Oncogene 17:2187-2193(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Pituitary adenoma;
RA Mu Y.;
RL Submitted (SEP-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND DISEASE.
RC TISSUE=Testis;
RX PubMed=10393434; DOI=10.1159/000015261;
RA Kakar S.S., Jennes L.;
RT "Molecular cloning and characterization of the tumor transforming gene
RT (TUTR1): a novel gene in human tumorigenesis.";
RL Cytogenet. Cell Genet. 84:211-216(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=10580151; DOI=10.1016/s0378-1119(99)00446-1;
RA Kakar S.S.;
RT "Molecular cloning, genomic organization, and identification of the
RT promoter for the human pituitary tumor transforming gene (PTTG).";
RL Gene 240:317-324(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA], DISEASE, AND MUTAGENESIS OF PRO-163 AND
RP 170-PRO--PRO-173.
RC TISSUE=Fetal liver;
RX PubMed=9892021; DOI=10.1210/mend.13.1.0225;
RA Zhang X., Horwitz G.A., Prezant T.R., Valentini A., Nakashima M.,
RA Bronstein M.D., Melmed S.;
RT "Structure, expression, and function of human pituitary tumor-transforming
RT gene (PTTG).";
RL Mol. Endocrinol. 13:156-166(1999).
RN [6]
RP DISEASE.
RX PubMed=10022450; DOI=10.1210/jcem.84.2.5432;
RA Zhang X., Horwitz G.A., Heaney A.P., Nakashima M., Prezant T.R.,
RA Bronstein M.D., Melmed S.;
RT "Pituitary tumor transforming gene (PTTG) expression in pituitary
RT adenomas.";
RL J. Clin. Endocrinol. Metab. 84:761-767(1999).
RN [7]
RP FUNCTION, INTERACTION WITH ESPL1, UBIQUITINATION, AND MUTAGENESIS OF ARG-61
RP AND LEU-64.
RX PubMed=10411507; DOI=10.1126/science.285.5426.418;
RA Zou H., McGarry T.J., Bernal T., Kirschner M.W.;
RT "Identification of a vertebrate sister-chromatid separation inhibitor
RT involved in transformation and tumorigenesis.";
RL Science 285:418-422(1999).
RN [8]
RP INTERACTION WITH PTTG1IP.
RX PubMed=10781616; DOI=10.1074/jbc.m910105199;
RA Chien W., Pei L.;
RT "A novel binding factor facilitates nuclear translocation and
RT transcriptional activation function of the pituitary tumor-transforming
RT gene product.";
RL J. Biol. Chem. 275:19422-19427(2000).
RN [9]
RP FUNCTION, AND INTERACTION WITH KU.
RX PubMed=11238996; DOI=10.1093/nar/29.6.1300;
RA Romero F., Multon M.C., Ramos-Morales F., Dominguez A., Bernal J.A.,
RA Pintor-Toro J.A., Tortolero M.;
RT "Human securin, hPTTG, is associated with Ku heterodimer, the regulatory
RT subunit of the DNA-dependent protein kinase.";
RL Nucleic Acids Res. 29:1300-1307(2001).
RN [10]
RP FUNCTION.
RX PubMed=11371342; DOI=10.1016/s0092-8674(01)00340-3;
RA Jallepalli P.V., Waizenegger I.C., Bunz F., Langer S., Speicher M.R.,
RA Peters J.-M., Kinzler K.W., Vogelstein B., Lengauer C.;
RT "Securin is required for chromosomal stability in human cells.";
RL Cell 105:445-457(2001).
RN [11]
RP DISEASE.
RX PubMed=11158059; DOI=10.1210/jcem.86.2.7184;
RA Ishikawa H., Heaney A.P., Yu R., Horwitz G.A., Melmed S.;
RT "Human pituitary tumor-transforming gene induces angiogenesis.";
RL J. Clin. Endocrinol. Metab. 86:867-874(2001).
RN [12]
RP INTERACTION WITH TP53, AND FUNCTION IN TP53 PATHWAY.
RX PubMed=12355087; DOI=10.1038/ng997;
RA Bernal J.A., Luna R., Espina A., Lazaro I., Ramos-Morales F., Romero F.,
RA Arias C., Silva A., Tortolero M., Pintor-Toro J.A.;
RT "Human securin interacts with p53 and modulates p53-mediated
RT transcriptional activity and apoptosis.";
RL Nat. Genet. 32:306-311(2002).
RN [13]
RP PHOSPHORYLATION AT SER-165, AND MUTAGENESIS OF SER-165.
RX PubMed=10656688; DOI=10.1038/sj.onc.1203320;
RA Ramos-Morales F., Dominguez A., Romero F., Luna R., Multon M.-C.,
RA Pintor-Toro J.A., Tortolero M.;
RT "Cell cycle regulated expression and phosphorylation of hpttg proto-
RT oncogene product.";
RL Oncogene 19:403-409(2000).
RN [14]
RP UBIQUITINATION, AND DOMAIN TEK-BOX.
RX PubMed=18485873; DOI=10.1016/j.cell.2008.04.012;
RA Jin L., Williamson A., Banerjee S., Philipp I., Rape M.;
RT "Mechanism of ubiquitin-chain formation by the human anaphase-promoting
RT complex.";
RL Cell 133:653-665(2008).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
CC -!- FUNCTION: Regulatory protein, which plays a central role in chromosome
CC stability, in the p53/TP53 pathway, and DNA repair. Probably acts by
CC blocking the action of key proteins. During the mitosis, it blocks
CC Separase/ESPL1 function, preventing the proteolysis of the cohesin
CC complex and the subsequent segregation of the chromosomes. At the onset
CC of anaphase, it is ubiquitinated, conducting to its destruction and to
CC the liberation of ESPL1. Its function is however not limited to a
CC blocking activity, since it is required to activate ESPL1. Negatively
CC regulates the transcriptional activity and related apoptosis activity
CC of TP53. The negative regulation of TP53 may explain the strong
CC transforming capability of the protein when it is overexpressed. May
CC also play a role in DNA repair via its interaction with Ku, possibly by
CC connecting DNA damage-response pathways with sister chromatid
CC separation. {ECO:0000269|PubMed:10411507, ECO:0000269|PubMed:11238996,
CC ECO:0000269|PubMed:11371342, ECO:0000269|PubMed:12355087}.
CC -!- SUBUNIT: Interacts with RPS10 and DNAJA1 (By similarity). Interacts
CC with the caspase-like ESPL1, and prevents its protease activity
CC probably by covering its active site. Interacts with TP53 and blocks
CC its activity probably by blocking its binding to DNA. Interacts with
CC the Ku 70 kDa subunit of ds-DNA kinase. Interacts with PTTG1IP.
CC {ECO:0000250, ECO:0000269|PubMed:10411507, ECO:0000269|PubMed:10781616,
CC ECO:0000269|PubMed:11238996, ECO:0000269|PubMed:12355087}.
CC -!- INTERACTION:
CC O95997; Q14145: KEAP1; NbExp=2; IntAct=EBI-2551072, EBI-751001;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus.
CC -!- TISSUE SPECIFICITY: Expressed at low level in most tissues, except in
CC adult testis, where it is highly expressed. Overexpressed in many
CC patients suffering from pituitary adenomas, primary epithelial
CC neoplasias, and esophageal cancer. {ECO:0000269|PubMed:9811450}.
CC -!- DEVELOPMENTAL STAGE: Low level during G1 and S phases. Peaks at M
CC phase. During anaphase, it is degraded.
CC -!- DOMAIN: The N-terminal destruction box (D-box) acts as a recognition
CC signal for degradation via the ubiquitin-proteasome pathway.
CC {ECO:0000250}.
CC -!- DOMAIN: The TEK-boxes are required for 'Lys-11'-linked ubiquitination
CC and facilitate the transfer of the first ubiquitin and ubiquitin chain
CC nucleation. TEK-boxes may direct a catalytically competent orientation
CC of the UBE2C/UBCH10-ubiquitin thioester with the acceptor lysine
CC residue. {ECO:0000269|PubMed:18485873}.
CC -!- PTM: Phosphorylated at Ser-165 by CDK1 during mitosis.
CC {ECO:0000269|PubMed:10656688}.
CC -!- PTM: Phosphorylated in vitro by ds-DNA kinase.
CC {ECO:0000269|PubMed:10656688}.
CC -!- PTM: Ubiquitinated through 'Lys-11' linkage of ubiquitin moieties by
CC the anaphase promoting complex (APC) at the onset of anaphase,
CC conducting to its degradation. 'Lys-11'-linked ubiquitination is
CC mediated by the E2 ligase UBE2C/UBCH10. {ECO:0000269|PubMed:10411507,
CC ECO:0000269|PubMed:18485873}.
CC -!- SIMILARITY: Belongs to the securin family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/PTTG1ID41943ch5q35.html";
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DR EMBL; AJ223953; CAA11683.1; -; mRNA.
DR EMBL; AF095287; AAC64409.1; -; mRNA.
DR EMBL; AF075242; AAD19335.1; -; mRNA.
DR EMBL; AF167564; AAF06995.1; -; Genomic_DNA.
DR EMBL; AF167560; AAF06995.1; JOINED; Genomic_DNA.
DR EMBL; AF167561; AAF06995.1; JOINED; Genomic_DNA.
DR EMBL; AF167562; AAF06995.1; JOINED; Genomic_DNA.
DR EMBL; AF167563; AAF06995.1; JOINED; Genomic_DNA.
DR CCDS; CCDS4353.1; -.
DR RefSeq; NP_001269311.1; NM_001282382.1.
DR RefSeq; NP_001269312.1; NM_001282383.1.
DR RefSeq; NP_004210.1; NM_004219.3.
DR PDB; 7NJ0; EM; 3.60 A; A=159-202.
DR PDB; 7NJ1; EM; 2.90 A; B=1-202.
DR PDBsum; 7NJ0; -.
DR PDBsum; 7NJ1; -.
DR AlphaFoldDB; O95997; -.
DR SMR; O95997; -.
DR BioGRID; 114663; 111.
DR CORUM; O95997; -.
DR DIP; DIP-56460N; -.
DR ELM; O95997; -.
DR IntAct; O95997; 20.
DR MINT; O95997; -.
DR STRING; 9606.ENSP00000377536; -.
DR iPTMnet; O95997; -.
DR PhosphoSitePlus; O95997; -.
DR BioMuta; PTTG1; -.
DR EPD; O95997; -.
DR jPOST; O95997; -.
DR MassIVE; O95997; -.
DR PaxDb; O95997; -.
DR PeptideAtlas; O95997; -.
DR PRIDE; O95997; -.
DR ProteomicsDB; 51174; -.
DR Antibodypedia; 1853; 434 antibodies from 38 providers.
DR DNASU; 9232; -.
DR Ensembl; ENST00000352433.10; ENSP00000344936.5; ENSG00000164611.13.
DR Ensembl; ENST00000393964.1; ENSP00000377536.1; ENSG00000164611.13.
DR Ensembl; ENST00000520452.5; ENSP00000430642.1; ENSG00000164611.13.
DR GeneID; 9232; -.
DR KEGG; hsa:9232; -.
DR MANE-Select; ENST00000352433.10; ENSP00000344936.5; NM_004219.4; NP_004210.1.
DR CTD; 9232; -.
DR DisGeNET; 9232; -.
DR GeneCards; PTTG1; -.
DR HGNC; HGNC:9690; PTTG1.
DR HPA; ENSG00000164611; Tissue enhanced (bone marrow, lymphoid tissue, testis).
DR MIM; 604147; gene.
DR neXtProt; NX_O95997; -.
DR OpenTargets; ENSG00000164611; -.
DR PharmGKB; PA34033; -.
DR VEuPathDB; HostDB:ENSG00000164611; -.
DR eggNOG; ENOG502S2GG; Eukaryota.
DR GeneTree; ENSGT00390000009693; -.
DR HOGENOM; CLU_1363209_0_0_1; -.
DR InParanoid; O95997; -.
DR OMA; SWESNLL; -.
DR OrthoDB; 1296347at2759; -.
DR PhylomeDB; O95997; -.
DR TreeFam; TF330797; -.
DR PathwayCommons; O95997; -.
DR Reactome; R-HSA-174154; APC/C:Cdc20 mediated degradation of Securin.
DR Reactome; R-HSA-174178; APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1.
DR Reactome; R-HSA-2467813; Separation of Sister Chromatids.
DR SignaLink; O95997; -.
DR SIGNOR; O95997; -.
DR BioGRID-ORCS; 9232; 294 hits in 1084 CRISPR screens.
DR ChiTaRS; PTTG1; human.
DR GeneWiki; PTTG1; -.
DR GenomeRNAi; 9232; -.
DR Pharos; O95997; Tbio.
DR PRO; PR:O95997; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; O95997; protein.
DR Bgee; ENSG00000164611; Expressed in secondary oocyte and 168 other tissues.
DR ExpressionAtlas; O95997; baseline and differential.
DR Genevisible; O95997; HS.
DR GO; GO:0005737; C:cytoplasm; TAS:ProtInc.
DR GO; GO:0005829; C:cytosol; IDA:CAFA.
DR GO; GO:0005634; C:nucleus; IDA:CAFA.
DR GO; GO:0004869; F:cysteine-type endopeptidase inhibitor activity; NAS:UniProtKB.
DR GO; GO:0017124; F:SH3 domain binding; IEA:UniProtKB-KW.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0051276; P:chromosome organization; IEA:InterPro.
DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR GO; GO:0045143; P:homologous chromosome segregation; IBA:GO_Central.
DR GO; GO:2000816; P:negative regulation of mitotic sister chromatid separation; IBA:GO_Central.
DR GO; GO:0007283; P:spermatogenesis; TAS:ProtInc.
DR DisProt; DP00521; -.
DR InterPro; IPR006940; Securin_separation_inhibitor.
DR PANTHER; PTHR10418; PTHR10418; 1.
DR Pfam; PF04856; Securin; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cell cycle; Cell division; Chromosome partition;
KW Cytoplasm; DNA damage; DNA repair; Mitosis; Nucleus; Phosphoprotein;
KW Proto-oncogene; Reference proteome; Repeat; SH3-binding; Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:22814378"
FT CHAIN 2..202
FT /note="Securin"
FT /id="PRO_0000206361"
FT REGION 35..90
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 61..64
FT /note="D-box"
FT MOTIF 71..73
FT /note="TEK-box 1"
FT MOTIF 94..96
FT /note="TEK-box 2"
FT MOTIF 163..173
FT /note="SH3-binding"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:22814378"
FT MOD_RES 165
FT /note="Phosphoserine; by CDK1"
FT /evidence="ECO:0000269|PubMed:10656688"
FT MUTAGEN 61
FT /note="R->A: Abolishes ubiquitination and subsequent
FT degradation; when associated with A-64."
FT /evidence="ECO:0000269|PubMed:10411507"
FT MUTAGEN 64
FT /note="L->A: Abolishes ubiquitination and subsequent
FT degradation; when associated with A-61."
FT /evidence="ECO:0000269|PubMed:10411507"
FT MUTAGEN 163
FT /note="P->A: Strongly reduces transforming capability; when
FT associated with L-170; A-172 and L-173."
FT /evidence="ECO:0000269|PubMed:9892021"
FT MUTAGEN 165
FT /note="S->A: Abolishes phosphorylation."
FT /evidence="ECO:0000269|PubMed:10656688"
FT MUTAGEN 170..173
FT /note="PSPP->LSAL: Strongly reduces transforming
FT capability; when associated with A-163."
FT /evidence="ECO:0000269|PubMed:9892021"
FT HELIX 122..125
FT /evidence="ECO:0007829|PDB:7NJ1"
FT STRAND 132..134
FT /evidence="ECO:0007829|PDB:7NJ1"
SQ SEQUENCE 202 AA; 22024 MW; 5F4740619AB8856F CRC64;
MATLIYVDKE NGEPGTRVVA KDGLKLGSGP SIKALDGRSQ VSTPRFGKTF DAPPALPKAT
RKALGTVNRA TEKSVKTKGP LKQKQPSFSA KKMTEKTVKA KSSVPASDDA YPEIEKFFPF
NPLDFESFDL PEEHQIAHLP LSGVPLMILD EERELEKLFQ LGPPSPVKMP SPPWESNLLQ
SPSSILSTLD VELPPVCCDI DI
