PIAS3

E3 SUMO-protein ligase PIAS3 is an enzyme that in humans is encoded by the PIAS3 gene.[5][6]

PIAS3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4MVT
Identifiers
Aliases	PIAS3, ZMIZ5, protein inhibitor of activated STAT 3
External IDs	OMIM: 605987 MGI: 1913126 HomoloGene: 4447 GeneCards: PIAS3
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q21.1 Start 145,848,522 bp[1] End 145,859,836 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3|3 F2.1 Start 96,696,384 bp[2] End 96,706,070 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • protein N-terminus binding • zinc ion binding • metal ion binding • potassium channel regulator activity • protein C-terminus binding • GO:0001948 protein binding • enzyme binding • SUMO transferase activity • transferase activity Cellular component • cytoplasm • nuclear speck • synapse • nucleoplasm • dendrite • cell nucleus Biological process • negative regulation of protein sumoylation • regulation of transcription, DNA-templated • positive regulation of protein sumoylation • protein sumoylation • transcription, DNA-templated • positive regulation of gene expression • response to hormone • positive regulation of membrane potential • negative regulation of transcription from RNA polymerase II promoter • negative regulation of gene expression • negative regulation of osteoclast differentiation • negative regulation of transcription, DNA-templated • TNFSF11-mediated signaling pathway Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	10401	229615
Ensembl	ENSG00000131788	ENSMUSG00000028101
UniProt	Q9Y6X2	O54714
RefSeq (mRNA)	NM_006099	NM_001165949 NM_018812 NM_146135
RefSeq (protein)	NP_006090	NP_001159421 NP_061282 NP_666247
Location (UCSC)	Chr 1: 145.85 – 145.86 Mb	Chr 3: 96.7 – 96.71 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

PIAS family

The mammalian PIAS family consists of four members: PIAS1, PIAS2, PIAS3 and PIAS4. In Drosophila, a single PIAS homologue named dPIAS/Zimp has been identified.[7] In yeast, two PIAS-related proteins were identified namely SIZ1 and SIZ2.[8] The PIAS family contains more than 60 proteins, most of them transcription factors that can be either positively or negatively regulated through multiple mechanisms.

Discovery

IAS proteins were originally identified in studies that were aimed to decipher the Janus Kinase (JAK)/STAT signaling pathway. Originally, PIAS3 was found to interact specifically with phosphorylated STAT3 in Interleukin -6 (IL-6) activated murine myeloblast M1 cells.[9] This interaction is mediated via PIAS3 binding to the STAT3 DNA binding domain. Hence, STAT3 transcriptional activity is inhibited by the physical prevention of its binding to target genes. Subsequently, PIAS3 was also found to be a regulator protein of other key transcription factors, including MITF,[10] NFκB,[11] SMAD[12] and estrogen receptor.[13]

Function

PIAS3 protein also functions as a SUMO (small ubiquitin-like modifier)-E3 ligase which catalyzes the covalent attachment of a SUMO protein to specific target substrates. It directly binds to several transcription factors and either blocks or enhances their activity. Alternatively spliced transcript variants of this gene have been identified, but the full-length nature of some of these variants has not been determined.[6]

Domains

The SAF-A/B, Acinus and PIAS (SAP) domain is located at the N-terminal of PIAS proteins.[14] This evolutionarily conserved domain is found in proteins ranging from yeast to human and is shared by other chromatin-binding proteins, such as scaffold attachment factor A and B.[15] The SAP domain can recognize and bind to AT-rich DNA sequences present in scaffold-attachment regions/matrix-attachment regions.[16] These elements are frequently found near gene enhancers and interact with nuclear matrix proteins to provide a unique nuclear microenvironment for transcriptional regulation. An LXXLL signature motif is present within the SAP domain of all PIAS proteins. This signature motif has been shown to mediate interactions between nuclear receptors and their co-regulators.[17] It is also essential for the binding of PIAS3 to androgen receptor. The LXXLL motif represents the minimal requirement for the interaction with the NFκB p65 subunit and for the inhibition of NFκB transcriptional activity.[11] It was previously described that the LXXLL motif is also responsible for the retention of PIAS3 in the nucleus.

The Pro-Ile-Asn-Ile-Thr (PINIT) motif represents a highly conserved region of PIAS proteins, which was shown to be involved in the nuclear retention of PIAS3.[18] Within the PINIT domain, the PIAS382-132 region was isolated and characterized as an inhibitory domain that binds and inhibits both the MITF and STAT3 transcription factors.[19] The RING-finger-like zinc-binding domain (RLD) is one of the most conserved domains of the PIAS family and has been shown to be important for PIAS3 activity as a SUMO-E3 ligase.[20] The RLD domain is also involved in the positive regulation of SMAD3 by PIAS3.[21]

Interactions

PIAS3 has been shown to interact with:

• GFI1,[22]
• HMGA2[23]
• MITF,[10][24]
• SMAD2,[25]
• SMAD3,[25] and
• RELA.[11]

Related gene problems

• TAR syndrome[26]
• 1q21.1 deletion syndrome
• 1q21.1 duplication syndrome

References

1. GRCh38: Ensembl release 89: ENSG00000131788 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000028101 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Ueki N, Seki N, Yano K, Saito T, Masuho Y, Muramatsu M (June 1999). "Isolation and chromosomal assignment of a human gene encoding protein inhibitor of activated STAT3 (PIAS3)". Journal of Human Genetics. 44 (3): 193–6. doi:10.1007/s100380050141. PMID 10319586. S2CID 12454718.
6. "Entrez Gene: PIAS3 protein inhibitor of activated STAT, 3".
7. Mohr SE, Boswell RE (Mar 1999). "Zimp encodes a homologue of mouse Miz1 and PIAS3 and is an essential gene in Drosophila melanogaster". Gene. 229 (1–2): 109–16. doi:10.1016/s0378-1119(99)00033-5. PMID 10095110.
8. Islam HK, Fujioka Y, Tomidokoro T, Sugiura H, Takahashi T, Kondo S, Katoh H (2001). "Immunohistochemical study of genetic alterations in intraductal and invasive ductal tumors of the pancreas". Hepato-Gastroenterology. 48 (39): 879–83. PMID 11462947.
9. Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, Shuai K (Dec 1997). "Specific inhibition of Stat3 signal transduction by PIAS3". Science. 278 (5344): 1803–5. Bibcode:1997Sci...278.1803C. doi:10.1126/science.278.5344.1803. PMID 9388184.
10. Levy C, Nechushtan H, Razin E (Jan 2002). "A new role for the STAT3 inhibitor, PIAS3: a repressor of microphthalmia transcription factor". The Journal of Biological Chemistry. 277 (3): 1962–6. doi:10.1074/jbc.m109236200. PMID 11709556. S2CID 25141003.
11. Jang HD, Yoon K, Shin YJ, Kim J, Lee SY (Jun 2004). "PIAS3 suppresses NF-kappaB-mediated transcription by interacting with the p65/RelA subunit". The Journal of Biological Chemistry. 279 (23): 24873–80. doi:10.1074/jbc.m313018200. PMID 15140884. S2CID 20036187.
12. Bava KA, Gromiha MM, Uedaira H, Kitajima K, Sarai A (2004). "ProTherm, version 4.0: thermodynamic database for proteins and mutants". Nucleic Acids Research. 32 (Database issue): D120–1. doi:10.1093/nar/gkh082. PMC 308816. PMID 14681373.
13. Sentis S, Le Romancer M, Bianchin C, Rostan MC, Corbo L (2005). "Sumoylation of the estrogen receptor alpha hinge region regulates its transcriptional activity". Molecular Endocrinology (Baltimore, Md.). 19 (11): 2671–84. doi:10.1210/me.2005-0042. PMID 15961505.
14. Shuai K (Feb 2006). "Regulation of cytokine signaling pathways by PIAS proteins". Cell Research. 16 (2): 196–202. doi:10.1038/sj.cr.7310027. PMID 16474434. S2CID 755228.
15. Aravind L, Koonin EV (2000). "SAP - a putative DNA-binding motif involved in chromosomal organization". Trends in Biochemical Sciences. 25 (3): 112–4. doi:10.1016/s0968-0004(99)01537-6. PMID 10694879.
16. Kipp, M.; et al. (2000). "SAF-Box, a conserved protein domain that specifically recognizes scaffold attachment region DNA". Mol Cell Biol. 20 (20): 7480–7489. doi:10.1128/mcb.20.20.7480-7489.2000. PMC 86301. PMID 11003645.
17. Glass CK, Rosenfeld MG (Jan 2000). "The coregulator exchange in transcriptional functions of nuclear receptors". Genes & Development. 14 (2): 121–41. doi:10.1101/gad.14.2.121 (inactive 2021-01-14). PMID 10652267.CS1 maint: DOI inactive as of January 2021 (link)
18. Duval D, Duval G, Kedinger C, Poch O, Boeuf H (Nov 2003). "The 'PINIT' motif, of a newly identified conserved domain of the PIAS protein family, is essential for nuclear retention of PIAS3L". FEBS Letters. 554 (1–2): 111–8. doi:10.1016/s0014-5793(03)01116-5. PMID 14596924. S2CID 23261716.
19. Levy C, Khaled M, Fisher DE (Sep 2006). "MITF: master regulator of melanocyte development and melanoma oncogene". Trends in Molecular Medicine. 12 (9): 406–14. doi:10.1016/j.molmed.2006.07.008. PMID 16899407.
20. Nakagawa, K.; Yokosawa, H. (2002). "PIAS3 induces SUMO-1 modification and transcriptional repression of IRF-1". FEBS Lett. 530 (1–3): 204–208. doi:10.1016/s0014-5793(02)03486-5. PMID 12387893. S2CID 38456991.
21. Long J, Wang G, Matsuura I, He D, Liu F (Jan 2004). "Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3)". Proceedings of the National Academy of Sciences of the United States of America. 101 (1): 99–104. Bibcode:2004PNAS..101...99L. doi:10.1073/pnas.0307598100. PMC 314145. PMID 14691252.
22. Rödel B, Tavassoli K, Karsunky H, Schmidt T, Bachmann M, Schaper F, Heinrich P, Shuai K, Elsässer HP, Möröy T (Nov 2000). "The zinc finger protein Gfi-1 can enhance STAT3 signaling by interacting with the STAT3 inhibitor PIAS3". EMBO J. 19 (21): 5845–55. doi:10.1093/emboj/19.21.5845. PMC 305799. PMID 11060035.
23. Zentner MD, Lin HH, Deng HT, Kim KJ, Shih HM, Ann DK (Aug 2001). "Requirement for high mobility group protein HMGI-C interaction with STAT3 inhibitor PIAS3 in repression of alpha-subunit of epithelial Na+ channel (alpha-ENaC) transcription by Ras activation in salivary epithelial cells". J. Biol. Chem. 276 (32): 29805–14. doi:10.1074/jbc.M103153200. PMID 11390395. S2CID 33084417.
24. Yagil Z, Nechushtan H, Kay G, Yang CM, Kemeny DM, Razin E (May 2010). "The enigma of the role of protein inhibitor of activated STAT3 (PIAS3) in the immune response". Trends Immunol. 31 (5): 199–204. doi:10.1016/j.it.2010.01.005. PMID 20181527.
25. Long J, Wang G, Matsuura I, He D, Liu F (Jan 2004). "Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3)". Proc. Natl. Acad. Sci. U.S.A. 101 (1): 99–104. Bibcode:2004PNAS..101...99L. doi:10.1073/pnas.0307598100. PMC 314145. PMID 14691252.
26. Klopocki E, Schulze H, Strauss G, Ott CE, Hall J, Trotier F, Fleischhauer S, Greenhalgh L, Newbury-Ecob RA, Neumann LM, Habenicht R, König R, Seemanova E, Megarbane A, Ropers HH, Ullmann R, Horn D, Mundlos S (Feb 2007). "Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome". American Journal of Human Genetics. 80 (2): 232–40. doi:10.1086/510919. PMC 1785342. PMID 17236129.

Further reading

• Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, Shuai K (Dec 1997). "Specific inhibition of Stat3 signal transduction by PIAS3". Science. 278 (5344): 1803–5. Bibcode:1997Sci...278.1803C. doi:10.1126/science.278.5344.1803. PMID 9388184.
• Rödel B, Tavassoli K, Karsunky H, Schmidt T, Bachmann M, Schaper F, Heinrich P, Shuai K, Elsässer HP, Möröy T (Nov 2000). "The zinc finger protein Gfi-1 can enhance STAT3 signaling by interacting with the STAT3 inhibitor PIAS3". The EMBO Journal. 19 (21): 5845–55. doi:10.1093/emboj/19.21.5845. PMC 305799. PMID 11060035.
• Junicho A, Matsuda T, Yamamoto T, Kishi H, Korkmaz K, Saatcioglu F, Fuse H, Muraguchi A (Nov 2000). "Protein inhibitor of activated STAT3 regulates androgen receptor signaling in prostate carcinoma cells". Biochemical and Biophysical Research Communications. 278 (1): 9–13. doi:10.1006/bbrc.2000.3753. PMID 11071847.
• Kotaja N, Aittomäki S, Silvennoinen O, Palvimo JJ, Jänne OA (Dec 2000). "ARIP3 (androgen receptor-interacting protein 3) and other PIAS (protein inhibitor of activated STAT) proteins differ in their ability to modulate steroid receptor-dependent transcriptional activation". Molecular Endocrinology. 14 (12): 1986–2000. doi:10.1210/mend.14.12.0569. PMID 11117529.
• Zentner MD, Lin HH, Deng HT, Kim KJ, Shih HM, Ann DK (Aug 2001). "Requirement for high mobility group protein HMGI-C interaction with STAT3 inhibitor PIAS3 in repression of alpha-subunit of epithelial Na+ channel (alpha-ENaC) transcription by Ras activation in salivary epithelial cells". The Journal of Biological Chemistry. 276 (32): 29805–14. doi:10.1074/jbc.M103153200. PMID 11390395. S2CID 33084417.
• Wang LH, Yang XY, Mihalic K, Xiao W, Li D, Farrar WL (Aug 2001). "Activation of estrogen receptor blocks interleukin-6-inducible cell growth of human multiple myeloma involving molecular cross-talk between estrogen receptor and STAT3 mediated by co-regulator PIAS3". The Journal of Biological Chemistry. 276 (34): 31839–44. doi:10.1074/jbc.M105185200. PMID 11429412. S2CID 24912586.
• Jiménez-Lara AM, Heine MJ, Gronemeyer H (Aug 2002). "PIAS3 (protein inhibitor of activated STAT-3) modulates the transcriptional activation mediated by the nuclear receptor coactivator TIF2". FEBS Letters. 526 (1–3): 142–6. doi:10.1016/S0014-5793(02)03154-X. PMID 12208521. S2CID 2934712.
• Nakagawa K, Yokosawa H (Oct 2002). "PIAS3 induces SUMO-1 modification and transcriptional repression of IRF-1". FEBS Letters. 530 (1–3): 204–8. doi:10.1016/S0014-5793(02)03486-5. PMID 12387893. S2CID 38456991.
• Yamamoto T, Sato N, Sekine Y, Yumioka T, Imoto S, Junicho A, Fuse H, Matsuda T (Jun 2003). "Molecular interactions between STAT3 and protein inhibitor of activated STAT3, and androgen receptor". Biochemical and Biophysical Research Communications. 306 (2): 610–5. doi:10.1016/S0006-291X(03)01026-X. hdl:2115/28119. PMID 12804609.
• Di Y, Li J, Zhang Y, He X, Lu H, Xu D, Ling J, Huo K, Wan D, Li YY, Gu J (Jun 2003). "HCC-associated protein HCAP1, a variant of GEMIN4, interacts with zinc-finger proteins". Journal of Biochemistry. 133 (6): 713–8. doi:10.1093/jb/mvg091. PMID 12869526.
• Cheng J, Zhang D, Zhou C, Marasco WA (Jan 2004). "Down-regulation of SHP1 and up-regulation of negative regulators of JAK/STAT signaling in HTLV-1 transformed cell lines and freshly transformed human peripheral blood CD4+ T-cells". Leukemia Research. 28 (1): 71–82. doi:10.1016/S0145-2126(03)00158-9. PMID 14630083.
• Long J, Wang G, Matsuura I, He D, Liu F (Jan 2004). "Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3)". Proceedings of the National Academy of Sciences of the United States of America. 101 (1): 99–104. Bibcode:2004PNAS..101...99L. doi:10.1073/pnas.0307598100. PMC 314145. PMID 14691252.
• Nojiri S, Joh T, Miura Y, Sakata N, Nomura T, Nakao H, Sobue S, Ohara H, Asai K, Ito M (Jan 2004). "ATBF1 enhances the suppression of STAT3 signaling by interaction with PIAS3". Biochemical and Biophysical Research Communications. 314 (1): 97–103. doi:10.1016/j.bbrc.2003.12.054. PMID 14715251.
• Wang L, Banerjee S (Jun 2004). "Differential PIAS3 expression in human malignancy". Oncology Reports. 11 (6): 1319–24. doi:10.3892/or.11.6.1319. PMID 15138572.
• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM (Jul 2004). "Functional proteomics mapping of a human signaling pathway". Genome Research. 14 (7): 1324–32. doi:10.1101/gr.2334104. PMC 442148. PMID 15231748.

External links

• Overview of all the structural information available in the PDB for UniProt: Q9Y6X2 (E3 SUMO-protein ligase PIAS3) at the PDBe-KB.