Reviewed, UniProtKB/Swiss-Prot O75928 (PIAS2_HUMAN)

Names and origin

Protein names

Recommended name:
    E3 SUMO-protein ligase PIAS2
Alternative name(s):
    Protein inhibitor of activated STAT2
    Protein inhibitor of activated STAT x
    Msx-interacting zinc finger protein
    Miz1
    DAB2-interacting protein
      Short name=DIP
    Androgen receptor-interacting protein 3
      Short name=ARIP3
    PIAS-NY protein

Gene names

Name:	PIAS2
Synonyms:	PIASX

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	621 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Functions as an E3-type small ubiquitin-like modifier (SUMO) ligase, stabilizing the interaction between UBE2I and the substrate, and as a SUMO-tethering factor. Plays a crucial role as a transcriptional coregulator in various cellular pathways, including the STAT pathway, the p53 pathway and the steroid hormone signaling pathway. The effects of this transcriptional coregulation, transactivation or silencing may vary depending upon the biological context and the PIAS2 isoform studied. However, it seems to be mostly involved in gene silencing. Binds to sumoylated ELK1 and enhances its transcriptional activity by preventing recruitment of HDAC2 by ELK1, thus reversing SUMO-mediated repression of ELK1 transactivation activity. Isoform PIAS2-beta, but not isoform PIAS2-alpha, promotes MDM2 sumoylation. Isoform PIAS2-alpha promotes PARK7 sumoylation. Isoform PIAS2-beta promotes NCOA2 sumoylation more efficiently than isoform PIAS2-alpha. Ref.13 Ref.14
Pathway	Protein modification; protein sumoylation.
Subunit structure	Binds SUMO1 and UBE2I. Interacts with JUN, MDM2, PARK7, TP53 and TP73 isoform alpha, but not TP73 isoform beta. Interacts with STAT4 following IL12 and IFN-alpha stimulation of T-cells. Interacts also with GTF2I, GTF2IRD1, DAB2 and MSX2, as well as with several steroid receptors, including ESR1, ESR2, NR3C1, PGR, AR, and with NCOA2 By similarity. Sumoylation of a target protein seems to enhance the interaction. Binds to sumoylated ELK1. Binds DNA, such as CDKN1A promoter, in a sequence-specific manner. Interacts with PLAG1. Interacts with KLF8; the interaction results in SUMO ligation and repression of KLF8 transcriptional activity and of its cell cycle progression into G1 phase.
Subcellular location	Nucleus speckle. Note: Colocalizes at least partially with promyelocytic leukemia nuclear bodies (PML NBs). Ref.7 Ref.9 Ref.11
Tissue specificity	Mainly testis. Isoform 3 is expressed predominantly in adult testis, weakly in pancreas, embryonic testis and sperm, and at very low levels in other organs. Ref.2 Ref.5 Ref.8
Developmental stage	Expression of isoform 3 in adult testis is 14.2-fold stronger than in embryonic testis. Ref.2
Induction	Up-regulated transiently during myeloid differentiation in various cells lines, such as HL-60, U-937, K-562, induced by either phorbol ester (TPA) or retinoic acid.
Domain	The LXXLL motif is a transcriptional coregulator signature.
Post-translational modification	Sumoylated. Ref.14 Ref.9 Ref.10
Sequence similarities	Belongs to the PIAS family. Contains 1 SAP domain. Contains 1 SP-RING-type zinc finger.

Ontologies

Keywords
Biological process	Transcription Transcription regulation Ubl conjugation pathway
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Zinc-finger
Ligand	DNA-binding Metal-binding Zinc
PTM	Ubl conjugation
Technical term	3D-structure
Gene Ontology (GO)
Biological process	androgen receptor signaling pathway Non-traceable author statement. Source: UniProtKB modification-dependent protein catabolic process Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of transcription, DNA-dependent Non-traceable author statement. Source: UniProtKB transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	nuclear speck Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	DNA binding Inferred from electronic annotation. Source: UniProtKB-KW SUMO ligase activity Inferred from direct assay. Source: UniProtKB androgen receptor binding Non-traceable author statement. Source: UniProtKB transcription coactivator activity Non-traceable author statement. Source: UniProtKB zinc ion binding Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
BAT1	Q13838	1	EBI-348555,EBI-348622
Ikzf1	Q03267	1	EBI-348567,EBI-908572	From a different organism.
MYC	P01106	2	EBI-348555,EBI-447544

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform PIAS2-beta (identifier: O75928-1)

Also known as: PIASx-beta; Miz1;

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 PIAS2-alpha (identifier: O75928-2)

Also known as: PIASx-alpha; ARIP3;

The sequence of this isoform differs from the canonical sequence as follows:
     551-572: LDFLSLIPVDPQYCPPMFLDSL → EQRRNDINNELKLGTSSDTVQQ
     573-621: Missing.

Isoform 3 (identifier: O75928-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-8: MADFEELR → MNAGKQLQRTLH
     402-621: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 621

621

E3 SUMO-protein ligase PIAS2

PRO_0000218976

Regions

Domain

11 – 45

35

SAP

Zinc finger

331 – 408

78

SP-RING-type

Region

467 – 473

7

SUMO1-binding

Motif

19 – 23

5

LXXLL motif

Motif

484 – 492

9

Nuclear localization signal By similarity

Compositional bias

571 – 612

42

Ser-rich

Compositional bias

596 – 602

7

Poly-Ser

Natural variations

Alternative sequence

1 – 8

8

MADFEELR → MNAGKQLQRTLH in isoform 3.

VSP_012196

Alternative sequence

402 – 621

220

Missing in isoform 3.

VSP_012197

Alternative sequence

551 – 572

22

LDFLS…FLDSL → EQRRNDINNELKLGTSSDTV QQ in isoform PIAS2-alpha.

VSP_050008

Alternative sequence

573 – 621

49

Missing in isoform PIAS2-alpha.

VSP_050009

Natural variant

207

1

V → A: dbSNP rs16940108.

VAR_056693

Experimental info

Mutagenesis

362

1

C → S or A: Loss of MDM2 and TP53 sumoylation and of autosumoylation; no loss of JUN-and TP53-binding. Ref.9 Ref.10

Mutagenesis

467

1

V → A: Reduces affinity for SUMO1. Ref.16

Mutagenesis

469

1

V → A: Abolishes binding to SUMO1. Ref.16

Mutagenesis

470

1

I → A: Abolishes binding to SUMO1. Ref.16

Mutagenesis

472

1

L → A: Abolishes binding to SUMO1. Ref.16

Mutagenesis

473

1

T → A: Reduces affinity for SUMO1. Ref.16

Sequence conflict

144

1

P → L in AAK48938. Ref.2

Sequence conflict

616

1

D → E in AAC36705. Ref.1

Secondary structure

1

.

.

.

621

Helix Strand Turn

Details...

Beta strand

469 – 471

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform PIAS2-beta (PIASx-beta) (Miz1) [UniParc]. Last modified May 5, 2009. Version 3. Checksum: 6422B383345AD883	FASTA	621	68,240
	10 20 30 40 50 60 MADFEELRNM VSSFRVSELQ VLLGFAGRNK SGRKHDLLMR ALHLLKSGCS PAVQIKIREL 70 80 90 100 110 120 YRRRYPRTLE GLSDLSTIKS SVFSLDGGSS PVEPDLAVAG IHSLPSTSVT PHSPSSPVGS 130 140 150 160 170 180 VLLQDTKPTF EMQQPSPPIP PVHPDVQLKN LPFYDVLDVL IKPTSLVQSS IQRFQEKFFI 190 200 210 220 230 240 FALTPQQVRE ICISRDFLPG GRRDYTVQVQ LRLCLAETSC PQEDNYPNSL CIKVNGKLFP 250 260 270 280 290 300 LPGYAPPPKN GIEQKRPGRP LNITSLVRLS SAVPNQISIS WASEIGKNYS MSVYLVRQLT 310 320 330 340 350 360 SAMLLQRLKM KGIRNPDHSR ALIKEKLTAD PDSEIATTSL RVSLMCPLGK MRLTIPCRAV 370 380 390 400 410 420 TCTHLQCFDA ALYLQMNEKK PTWICPVCDK KAAYESLILD GLFMEILNDC SDVDEIKFQE 430 440 450 460 470 480 DGSWCPMRPK KEAMKVSSQP CTKIESSSVL SKPCSVTVAS EASKKKVDVI DLTIESSSDE 490 500 510 520 530 540 EEDPPAKRKC IFMSETQSSP TKGVLMYQPS SVRVPSVTSV DPAAIPPSLT DYSVPFHHTP 550 560 570 580 590 600 ISSMSSDLPG LDFLSLIPVD PQYCPPMFLD SLTSPLTASS TSVTTTSSHE SSTHVSSSSS 610 620 RSETGVITSS GSNIPDIISL D
	Isoform PIAS2-alpha (PIASx-alpha) (ARIP3). Checksum: 63106D68C585F0ED	FASTA	572	63,396
	10 20 30 40 50 60 MADFEELRNM VSSFRVSELQ VLLGFAGRNK SGRKHDLLMR ALHLLKSGCS PAVQIKIREL 70 80 90 100 110 120 YRRRYPRTLE GLSDLSTIKS SVFSLDGGSS PVEPDLAVAG IHSLPSTSVT PHSPSSPVGS 130 140 150 160 170 180 VLLQDTKPTF EMQQPSPPIP PVHPDVQLKN LPFYDVLDVL IKPTSLVQSS IQRFQEKFFI 190 200 210 220 230 240 FALTPQQVRE ICISRDFLPG GRRDYTVQVQ LRLCLAETSC PQEDNYPNSL CIKVNGKLFP 250 260 270 280 290 300 LPGYAPPPKN GIEQKRPGRP LNITSLVRLS SAVPNQISIS WASEIGKNYS MSVYLVRQLT 310 320 330 340 350 360 SAMLLQRLKM KGIRNPDHSR ALIKEKLTAD PDSEIATTSL RVSLMCPLGK MRLTIPCRAV 370 380 390 400 410 420 TCTHLQCFDA ALYLQMNEKK PTWICPVCDK KAAYESLILD GLFMEILNDC SDVDEIKFQE 430 440 450 460 470 480 DGSWCPMRPK KEAMKVSSQP CTKIESSSVL SKPCSVTVAS EASKKKVDVI DLTIESSSDE 490 500 510 520 530 540 EEDPPAKRKC IFMSETQSSP TKGVLMYQPS SVRVPSVTSV DPAAIPPSLT DYSVPFHHTP 550 560 570 ISSMSSDLPG EQRRNDINNE LKLGTSSDTV QQ
	Isoform 3. Checksum: 6C16003BCDB6384E	FASTA	405	45,057
	10 20 30 40 50 60 MNAGKQLQRT LHNMVSSFRV SELQVLLGFA GRNKSGRKHD LLMRALHLLK SGCSPAVQIK 70 80 90 100 110 120 IRELYRRRYP RTLEGLSDLS TIKSSVFSLD GGSSPVEPDL AVAGIHSLPS TSVTPHSPSS 130 140 150 160 170 180 PVGSVLLQDT KPTFEMQQPS PPIPPVHPDV QLKNLPFYDV LDVLIKPTSL VQSSIQRFQE 190 200 210 220 230 240 KFFIFALTPQ QVREICISRD FLPGGRRDYT VQVQLRLCLA ETSCPQEDNY PNSLCIKVNG 250 260 270 280 290 300 KLFPLPGYAP PPKNGIEQKR PGRPLNITSL VRLSSAVPNQ ISISWASEIG KNYSMSVYLV 310 320 330 340 350 360 RQLTSAMLLQ RLKMKGIRNP DHSRALIKEK LTADPDSEIA TTSLRVSLMC PLGKMRLTIP 370 380 390 400 CRAVTCTHLQ CFDAALYLQM NEKKPTWICP VCDKKAAYES LILDG

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Inhibition of Stat1-mediated gene activation by PIAS1." Liu B., Liao J., Rao X., Kushner S.A., Chung C.D., Chang D.D., Shuai K. Proc. Natl. Acad. Sci. U.S.A. 95:10626-10631(1998) [PubMed: 9724754] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS PIAS2-ALPHA AND PIAS2-BETA). Tissue: B-cell.
[2]	"Molecular cloning and characterization of a novel splicing variant of PIASx." Zheng Y., Zhou Z.-M., Yin L.-L., Li J.-M., Sha J.-H. Acta Pharmacol. Sin. 25:1058-1064(2004) [PubMed: 15301740] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), TISSUE SPECIFICITY, DEVELOPMENTAL STAGE. Tissue: Testis.
[3]	"DNA sequence and analysis of human chromosome 18." Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D., Taylor T.D., Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Abouelleil A., Allen N.R., Anderson S., Bloom T., Bugalter B., Butler J. , Cook A., DeCaprio D., Engels R., Garber M., Gnirke A., Hafez N., Hall J.L., Norman C.H., Itoh T., Jaffe D.B., Kuroki Y., Lehoczky J., Lui A., Macdonald P., Mauceli E., Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C., Noguchi H., O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K., Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R., Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S. Nature 437:551-555(2005) [PubMed: 16177791] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM PIAS2-ALPHA). Tissue: Brain.
[5]	"A testis-specific androgen receptor coregulator that belongs to a novel family of nuclear proteins." Moilanen A.-M., Karvonen U., Poukka H., Yan W., Toppari J., Jaenne O.A., Palvimo J.J. J. Biol. Chem. 274:3700-3704(1999) [PubMed: 9920921] [Abstract] Cited for: TISSUE SPECIFICITY.
[6]	"Covalent modification of p73alpha by SUMO-1. Two-hybrid screening with p73 identifies novel SUMO-1-interacting proteins and a SUMO-1 interaction motif." Minty A., Dumont X., Kaghad M., Caput D. J. Biol. Chem. 275:36316-36323(2000) [PubMed: 10961991] [Abstract] Cited for: INTERACTION WITH SUMO1; TP73 AND TP53.
[7]	"DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx alpha to the receptor." Takahashi K., Taira T., Niki T., Seino C., Iguchi-Ariga S.M.M., Ariga H. J. Biol. Chem. 276:37556-37563(2001) [PubMed: 11477070] [Abstract] Cited for: INTERACTION WITH PARK7, SUBCELLULAR LOCATION.
[8]	"Distinct effects of PIAS proteins on androgen-mediated gene activation in prostate cancer cells." Gross M., Liu B., Tan J.-A., French F.S., Carey M., Shuai K. Oncogene 20:3880-3887(2001) [PubMed: 11439351] [Abstract] Cited for: TISSUE SPECIFICITY.
[9]	"Sumoylation of Mdm2 by protein inhibitor of activated STAT (PIAS) and RanBP2 enzymes." Miyauchi Y., Yogosawa S., Honda R., Nishida T., Yasuda H. J. Biol. Chem. 277:50131-50136(2002) [PubMed: 12393906] [Abstract] Cited for: SUMOYLATION OF MDM2, SUBCELLULAR LOCATION, MUTAGENESIS OF CYS-362.
[10]	"Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity." Schmidt D., Mueller S. Proc. Natl. Acad. Sci. U.S.A. 99:2872-2877(2002) [PubMed: 11867732] [Abstract] Cited for: INTERACTION WITH JUN; TP53 AND UBE2I, SUMOYLATION, MUTAGENESIS OF CYS-362.
[11]	"PIASx is a transcriptional co-repressor of signal transducer and activator of transcription 4." Arora T., Liu B., He H., Kim J., Murphy T.L., Murphy K.M., Modlin R.L., Shuai K. J. Biol. Chem. 278:21327-21330(2003) [PubMed: 12716907] [Abstract] Cited for: INTERACTION WITH STAT4, SUBCELLULAR LOCATION.
[12]	"Repression of the transactivating capacity of the oncoprotein PLAG1 by SUMOylation." Van Dyck F., Delvaux E.L.D., Van de Ven W.J.M., Chavez M.V. J. Biol. Chem. 279:36121-36131(2004) [PubMed: 15208321] [Abstract] Cited for: INTERACTION WITH PLAG1.
[13]	"PIASx acts as an Elk-1 coactivator by facilitating derepression." Yang S.-H., Sharrocks A.D. EMBO J. 24:2161-2171(2005) [PubMed: 15920481] [Abstract] Cited for: FUNCTION, INTERACTION WITH ELK1.
[14]	"Proper SUMO-1 conjugation is essential to DJ-1 to exert its full activities." Shinbo Y., Niki T., Taira T., Ooe H., Takahashi-Niki K., Maita C., Seino C., Iguchi-Ariga S.M.M., Ariga H. Cell Death Differ. 13:96-108(2006) [PubMed: 15976810] [Abstract] Cited for: FUNCTION IN PARK7 SUMOYLATION.
[15]	"Sumoylation delimits KLF8 transcriptional activity associated with the cell cycle regulation." Wei H., Wang X., Gan B., Urvalek A.M., Melkoumian Z.K., Guan J.-L., Zhao J. J. Biol. Chem. 281:16664-16671(2006) [PubMed: 16617055] [Abstract] Cited for: INTERACTION WITH KLF8.
[16]	"Small ubiquitin-like modifier (SUMO) recognition of a SUMO binding motif: a reversal of the bound orientation." Song J., Zhang Z., Hu W., Chen Y. J. Biol. Chem. 280:40122-40129(2005) [PubMed: 16204249] [Abstract] Cited for: STRUCTURE BY NMR OF 466-488 IN COMPLEX WITH SUMO1, MUTAGENESIS OF VAL-467; VAL-469; ILE-470; LEU-472 AND THR-473.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

AF077953 mRNA. Translation: AAC36704.1.
AF077954 mRNA. Translation: AAC36705.1.
AF361054 mRNA. Translation: AAK48938.1.
AC090241 Genomic DNA. No translation available.
AC090373 Genomic DNA. No translation available.
BC015190 mRNA. Translation: AAH15190.1.

IPI

IPI00005836.
IPI00244407.
IPI00477352.

RefSeq

NP_004662.2.
NP_775298.1.

UniGene

Hs.658013

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2ASQ	NMR	-	B	466-488	[»]

SMR

O75928. Positions 1-65.

ModBase

Search...

Protein-protein interaction databases

IntAct

O75928. 6 interactions.

PTM databases

PhosphoSite

O75928.

Genome annotation databases

Ensembl

ENSG00000078043. Homo sapiens. [Contig view]

GeneID

9063.

KEGG

hsa:9063.

Organism-specific databases

GeneCards

GC18M042646.

HGNC

HGNC:17311. PIAS2.

MIM

603567. gene.

PharmGKB

PA134933292.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

O75928.

HOVERGEN

O75928.

Enzyme and pathway databases

Pathway_Interaction_DB

il12_stat4pathway. IL12 signaling mediated by STAT4.
ranbp2pathway. Sumoylation by RanBP2 regulates transcriptional repression.

Gene expression databases

ArrayExpress

O75928.

Bgee

O75928.

CleanEx

HS_PIAS2.

GermOnline

ENSG00000078043. Homo sapiens.

Family and domain databases

InterPro

IPR003034. SAP_DNA_bd.
IPR004181. Znf_MIZ.
[Graphical view]

Pfam

PF02037. SAP. 1 hit.
PF02891. zf-MIZ. 1 hit.
[Graphical view]

SMART

SM00513. SAP. 1 hit.
[Graphical view]

PROSITE

PS50800. SAP. 1 hit.
PS51044. ZF_SP_RING. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

33959.

SOURCE

Search...

Entry information

Entry name

PIAS2_HUMAN

Accession

Primary (citable) accession number: O75928
Secondary accession number(s): O75927, Q96BT5, Q96KE3

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 7, 2004
Last sequence update:	May 5, 2009
Last modified:	June 16, 2009
This is version 80 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)