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Protein inhibitor of activated STAT, 3
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols PIAS3 ; ZMIZ5
External IDs OMIM605987 MGI1913126 HomoloGene4447 GeneCards: PIAS3 Gene
RNA expression pattern
PBB GE PIAS3 203035 s at tn.png
More reference expression data
Species Human Mouse
Entrez 10401 229615
Ensembl ENSG00000131788 ENSMUSG00000028101
UniProt Q9Y6X2 O54714
RefSeq (mRNA) NM_006099 NM_001165949
RefSeq (protein) NP_006090 NP_001159421
Location (UCSC) Chr 1:
145.58 – 145.59 Mb
Chr 3:
96.7 – 96.71 Mb
PubMed search [1] [2]

E3 SUMO-protein ligase PIAS3 is an enzyme that in humans is encoded by the PIAS3 gene.[1][2] PIAS proteins were originally identified in studies that were aimed to decipher the Janus Kinase (JAK)/STAT signaling pathway. 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.[3] In yeast, two PIAS-related proteins were identified namely SIZ1 and SIZ2.[4] Studies by different research groups have now identified a rapidly growing list of more than 60 proteins, most of them transcription factors that can be either positively or negatively regulated by members of the PIAS family through multiple mechanisms. Originally, PIAS3 was found to interact specifically with phosphorylated STAT3 in Interleukin -6 (IL-6) activated murine myeloblast M1 cells.[5] 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,[6] NFκB,[7] SMAD [8] and estrogen receptor.[9]

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.[2]


The SAF-A/B, Acinus and PIAS (SAP) domain is located at the N-terminal of PIAS proteins.[10] 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.[11] The SAP domain can recognize and bind to AT-rich DNA sequences present in scaffold-attachment regions/matrix-attachment regions.[12] 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.[13] 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.[14] 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.[15] 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.[16] 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.[17] The RLD domain is also involved in the positive regulation of SMAD3 by PIAS3.[18]


PIAS3 has been shown to interact with GFI1,[19] RELA,[20] Mothers against decapentaplegic homolog 3,[21] Microphthalmia-associated transcription factor,[22][23] HMGA2[24] and Mothers against decapentaplegic homolog 2.[21]

Related gene problems[edit]


  1. ^ 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)". J Hum Genet 44 (3): 193–6. doi:10.1007/s100380050141. PMID 10319586. 
  2. ^ a b "Entrez Gene: PIAS3 protein inhibitor of activated STAT, 3". 
  3. ^ Mohr, S. E.; Boswell, R. E. (1999). "Zimp encodes a homologue of mouse Miz1 and PIAS3 and is an essential gene in Drosophila melanogaster". Gene 229: 109–116. doi:10.1016/s0378-1119(99)00033-5. PMID 10095110. 
  4. ^ Slam, H. K. et al. (2001). "Immunohistochemical study of genetic alterations in intraductal and invasive ductal tumors of the pancreas". Hepatogastroenterology 48: 879–883. 
  5. ^ Chung, C. D. et al. (1997). "Specific inhibition of Stat3 signal transduction by PIAS3". Science 278: 1803–1805. doi:10.1126/science.278.5344.1803. PMID 9388184. 
  6. ^ Levy, C.; Nechushtan, H.; Razin, E. (2002). "A new role for the STAT3 inhibitor, PIAS3: a repressor of microphthalmia transcription factor". J Biol Chem 277: 1962–1966. doi:10.1074/jbc.m109236200. 
  7. ^ Jang, H. D.; Yoon, K.; Shin, Y. J.; Kim, J.; Lee, S. Y. (2004). "PIAS3 suppresses NF-kappaB-mediated transcription by interacting with the p65/RelA subunit". J Biol Chem 279: 24873–24880. doi:10.1074/jbc.m313018200. 
  8. ^ Bava, K. A., Gromiha, M. M., Uedaira, H., Kitajima, K. & Sarai, A. "ProTherm, version 4.0: thermodynamic database for proteins and mutants. Nucleic Acids Res 32: D120-121 (2004)
  9. ^ Sentis, S., Le Romancer, M., Bianchin, C., Rostan, M. C. & Corbo, L. SUMOylation of the Estrogen receptor {alpha} hinge region by SUMO-E3 ligases PIAS1 and PIAS3 regulates ER{alpha} transcriptional activity. Mol Endocrinol (2005).
  10. ^ Shuai, K (2006). "Regulation of cytokine signaling pathways by PIAS proteins". Cell Res 16: 196–202. doi:10.1038/sj.cr.7310027. PMID 16474434. 
  11. ^ Aravind, L. & Koonin, E. V. SAP - a putative DNA-binding motif involved in chromosomal organization. Trends Biochem Sci 2000; 25, 112-114
  12. ^ Kipp, M. et al. (2000). "SAF-Box, a conserved protein domain that specifically recognizes scaffold attachment region DNA". Mol Cell Biol 20: 7480–7489. doi:10.1128/mcb.20.20.7480-7489.2000. 
  13. ^ Glass, C. K.; Rosenfeld, M. G. (2000). "The coregulator exchange in transcriptional functions of nuclear receptors". Genes Dev 14: 121–141. 
  14. ^ Jang H. D., Yoon, K., Shin, Y. J., Kim, J. & Lee, S. Y. PIAS3 suppresses NF-kappaB-mediated transcription by interacting with the p65/RelA subunit. J Biol Chem 2004; 279, 24873-24880
  15. ^ Duval, D.; Duval, G.; Kedinger, C.; Poch, O.; Boeuf, H. (2003). "The 'PINIT' motif, of a newly identified conserved domain of the PIAS protein family, is essential for nuclear retention of PIAS3L". FEBS Lett 554: 111–118. doi:10.1016/s0014-5793(03)01116-5. PMID 14596924. 
  16. ^ Levy, C.; Khaled, M.; Fisher, D. E. (2006). "MITF: master regulator of melanocyte development and melanoma oncogene". Trends Mol Med 12: 406–414. doi:10.1016/j.molmed.2006.07.008. 
  17. ^ Nakagawa, K.; Yokosawa, H. (2002). "PIAS3 induces SUMO-1 modification and transcriptional repression of IRF-1". FEBS Lett 530: 204–208. doi:10.1016/s0014-5793(02)03486-5. 
  18. ^ Long, J.; Wang, G.; Matsuura, I.; He, D.; Liu, F. (2004). "Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3)". Proc Natl Acad Sci U S A 101: 99–104. doi:10.1073/pnas.0307598100. PMC 314145. PMID 14691252. 
  19. ^ Rödel, B; Tavassoli K; Karsunky H; Schmidt T; Bachmann M; Schaper F; Heinrich P; Shuai K; Elsässer H P; Möröy T (November 2000). "The zinc finger protein Gfi-1 can enhance STAT3 signaling by interacting with the STAT3 inhibitor PIAS3". EMBO J. (ENGLAND) 19 (21): 5845–55. doi:10.1093/emboj/19.21.5845. ISSN 0261-4189. PMC 305799. PMID 11060035. 
  20. ^ Jang, Hyun Duk; Yoon Kwiyeom; Shin Young Joo; Kim Jaesang; Lee Soo Young (June 2004). "PIAS3 suppresses NF-kappaB-mediated transcription by interacting with the p65/RelA subunit". J. Biol. Chem. (United States) 279 (23): 24873–80. doi:10.1074/jbc.M313018200. ISSN 0021-9258. PMID 15140884. 
  21. ^ a b Long, Jianyin; Wang Guannan; Matsuura Isao; He Dongming; Liu Fang (January 2004). "Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3)". Proc. Natl. Acad. Sci. U.S.A. (United States) 101 (1): 99–104. doi:10.1073/pnas.0307598100. ISSN 0027-8424. PMC 314145. PMID 14691252. 
  22. ^ Levy, Carmit; Nechushtan Hovav; Razin Ehud (January 2002). "A new role for the STAT3 inhibitor, PIAS3: a repressor of microphthalmia transcription factor". J. Biol. Chem. (United States) 277 (3): 1962–6. doi:10.1074/jbc.M109236200. ISSN 0021-9258. PMID 11709556. 
  23. ^ Yagil Z, Nechushtan H, Kay G, Yang CM, Kemeny DM, Razin E, (February 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. 
  24. ^ Zentner, M D; Lin H H; Deng H T; Kim K J; Shih H M; Ann D K (August 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. (United States) 276 (32): 29805–14. doi:10.1074/jbc.M103153200. ISSN 0021-9258. PMID 11390395. 
  25. ^ Klopocki E; Schulze H; Strauss G et al. (February 2007). "Complex Inheritance Pattern Resembling Autosomal Recessive Inheritance Involving a Microdeletion in Thrombocytopenia–Absent Radius Syndrome". Am. J. Hum. Genet. 80 (2): 232–40. doi:10.1086/510919. PMC 1785342. PMID 17236129. 

Further reading[edit]