PIAS3

Summary

PIAS3 (protein inhibitor of activated STAT 3, HGNC:16861) is a protein-coding gene on chromosome 1q21.1, encoding E3 SUMO-protein ligase PIAS3 (Q9Y6X2). 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.

This gene encodes a member of the PIAS [protein inhibitor of activated STAT (signal transducer and activator of transcription)] family of transcriptional modulators. The protein 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.

Source: NCBI Gene 10401 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 70 total
• MANE Select transcript: NM_006099

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16861
Approved symbol	PIAS3
Name	protein inhibitor of activated STAT 3
Location	1q21.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ14651, ZMIZ5
Ensembl gene	ENSG00000131788
Ensembl biotype	protein_coding
OMIM	605987
Entrez	10401

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 5 retained_intron

ENST00000369298, ENST00000369299, ENST00000393045, ENST00000393046, ENST00000463514, ENST00000472114, ENST00000475261, ENST00000484423, ENST00000498436, ENST00000867627, ENST00000867628, ENST00000948928, ENST00000948929

RefSeq mRNA: 1 — MANE Select: NM_006099 NM_006099

CCDS: CCDS72866

Canonical transcript exons

ENST00000393045 — 14 exons

Exon	Start	End
ENSE00000903022	145856347	145856431
ENSE00000903026	145854458	145854563
ENSE00000903027	145853813	145853886
ENSE00001951436	145858967	145859081
ENSE00003467622	145856068	145856118
ENSE00003471916	145856589	145857006
ENSE00003478209	145850453	145850586
ENSE00003502733	145853504	145853664
ENSE00003521903	145850771	145850939
ENSE00003541194	145850232	145850269
ENSE00003543238	145855736	145855826
ENSE00003583253	145848522	145849712
ENSE00003634561	145851020	145851153
ENSE00003786896	145854746	145854880

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 98.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.2692 / max 194.1812, expressed in 1798 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14146	18.8735	1771
14142	4.1670	1608
14144	3.9177	1514
14143	1.7186	1089
14145	0.4642	270
14139	0.1282	43

Top tissues by expression

286 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	98.28	gold quality
endocervix	UBERON:0000458	96.54	gold quality
descending thoracic aorta	UBERON:0002345	96.31	gold quality
right coronary artery	UBERON:0001625	95.96	gold quality
ectocervix	UBERON:0012249	95.68	gold quality
body of uterus	UBERON:0009853	95.60	gold quality
thoracic aorta	UBERON:0001515	95.45	gold quality
ascending aorta	UBERON:0001496	95.40	gold quality
left uterine tube	UBERON:0001303	95.30	gold quality
lower esophagus mucosa	UBERON:0035834	95.30	gold quality
mucosa of stomach	UBERON:0001199	95.28	gold quality
aorta	UBERON:0000947	95.08	gold quality
popliteal artery	UBERON:0002250	95.05	gold quality
tibial artery	UBERON:0007610	95.05	gold quality
right ovary	UBERON:0002118	94.97	gold quality
minor salivary gland	UBERON:0001830	94.91	gold quality
skin of leg	UBERON:0001511	94.66	gold quality
vagina	UBERON:0000996	94.60	gold quality
left coronary artery	UBERON:0001626	94.40	gold quality
esophagus mucosa	UBERON:0002469	94.24	gold quality
tibial nerve	UBERON:0001323	94.14	gold quality
skin of abdomen	UBERON:0001416	94.04	gold quality
left ovary	UBERON:0002119	94.04	gold quality
esophagus	UBERON:0001043	93.71	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.68	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.42	gold quality
lower esophagus	UBERON:0013473	93.41	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.40	gold quality
body of stomach	UBERON:0001161	93.28	gold quality
coronary artery	UBERON:0001621	92.98	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.92
E-MTAB-4850	no	487.10

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
ATF1	Activation
ESR1	Unknown
MUC1	Repression
STAT3	Unknown

Upstream regulators (CollecTRI, top): ESR1, MITF, NR1I2, NR2E3, NRL, RORA, RXRG, STAT3, STAT5A, THRB, TP53

miRNA regulators (miRDB)

81 targeting PIAS3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 40)

• AR and PIAS3 regulate the STAT3-mediated transcriptional activity by their physical protein-protein competition on STAT3 (PMID:12804609)
• Up-regulation of protein inhibitor of activated STAT3 protein is associated with adult T-cell leukemia (PMID:14630083)
• PIAS3 and Smad3 interact with each other at the endogenous protein level in mammalian cells and also in vitro, and the association occurs through the C-terminal domain of Smad3. (PMID:14691252)
• In conclusion, ATBF1 can suppress the IL-6-mediated cellular response by acting together with PIAS3. (PMID:14715251)
• Increased PIAS3 expression is associated with human cancers including lung, breast, prostate, colon-rectum, and brain tumors (PMID:15138572)
• PIAS3 may function in vivo as a modulator in suppressing the transcriptional activity of p65 (PMID:15140884)
• End-stage hepatitis c and alcoholic liver cirrhosis is characterized by impaired Stat3 DNA-binding possibly through up-regulation of Pias3. (PMID:16098628)
• Mechanisms of PIAS3 activity could pave the way toward the formulation of an antioncogenic agent for the inhibition of both STAT3 and MITF. (PMID:16368885)
• overexpression of PIAS3 in lung cancer cells contributed to growth suppression and restored the drug sensitivity of the cells (PMID:17032498)
• PIAS3 is a new regulator of ATF1 that regulates the ARE-mediated transcription of the ferritin H gene (PMID:17565989)
• Both SUMO E2 conjugating enzyme Ubc9 and E3 ligase protein inhibitor of activated STAT3 (Pias3) are targets for S-nitrosation (PMID:17987106)
• Pias3 associates and colocalizes with Trim32, a Ubiquitin E3 ligase. (PMID:17987106)
• PIAS3 binds to Tel and stimulates sumoylation of K11 in the nucleus.PIAS3 may have a dual, context-dependent influence on Tel; it mediates Tel sumoylation, but it also augments Tel’s repressive function in a sumoylation-independent fashion. (PMID:18212042)
• parvovirus B19 NS1 protein modulates inflammatory signaling by activation of STAT3/PIAS3 in human endothelial cells (PMID:18550668)
• This study suggests a link between PIAS3 and nuclear pyruvate kinase. (PMID:19308990)
• PIAS3 is expressed in NSCLC cell lines and its over-expression decreased STAT3 transcriptional activity, decreased proliferation of NSCLC cells and when used in conjunction with EGFR inhibitors, increased the anti-proliferative effects. (PMID:19569236)
• we selected one coding single nucleotide polymorphism in PIAS3 for association analyses in patients with breast cancer (PMID:19760037)
• data suggest an important role for the negative regulatory effect of PIAS3 on STAT3 in EGF-driven tumors (PMID:19903771)
• there is an interaction between Zimp7 and PIAS proteins with higher preference for PIAS3, in androgen receptor-mediated transcription (PMID:20159969)
• SOCS-3 and PIAS-3 upregulation impairs IL-12-mediated interferon-gamma response in CD56 T cells in HCV-infected heroin users (PMID:20231901)
• These findings indicate that TRIM8 enhances the STAT3-dependent signal pathway by inhibiting the function of PIAS3. (PMID:20516148)
• Identification of vimentin (vimentin354), a nuclear component in glioblastoma multiforme cells, as the main target of sumoylation promoted by PIAS3. (PMID:21317457)
• Squamous cell carcinoma of the lung commonly lacks PIAS3 protein expression. (PMID:21497567)
• novel transcription factor binding partners for PIAS3 including ETS, EGR1, NR1I2, and GATA1 were identified. (PMID:21532337)
• PIAS3 expression is closely related to the invasion properties of glioma TJ905 cells. (PMID:21733403)
• PIAS3 is a novel regulator of ErbB4 receptor tyrosine kinase, controlling its nuclear sequestration and function. (PMID:22584572)
• NF-kappaB is regulated through a novel negative feedback mechanism by SUMOylation, where the RelA subunit of NF-kappaB is SUMOylated by PIAS3. (PMID:22649547)
• Downregulation of PIAS3 is associated with gastric adenocarcinogenesis. (PMID:23322197)
• PIAS3 activates the intrinsic apoptotic pathway in non-small cell lung cancer cells independent of p53 status. (PMID:23959540)
• PIAS3 may be a potential biomarker target for early cancer detection and therapeutic of human colorectal cancer. (PMID:24120699)
• this newly identified p53PIAS3 interaction through the 1-52 amino acid region of p53, reduces p53MDM2 complex formation, which not only increases the half-life of p53, but also its transactivation of target genes. (PMID:24584189)
• Low PIAS3 expression in malignant mesothelioma is associated with increased STAT3 activation and poor patient survival. (PMID:25124686)
• Statistically significant positive correlation has been found between STAT5B and COX-2, and significant negative correlation between STAT5B and PIAS3. (PMID:25137041)
• PIAS3 expression in squamous cell lung cancer is low and predicts overall survival (PMID:25573684)
• Adenovirus E4-ORF3 targets PIAS3 and together with E1B-55K remodels SUMO2/SUMO3 Interactions in the nucleus and at virus genome replication domains. (PMID:26223632)
• PIAS3 primes ATR for checkpoint activation. (PMID:26565033)
• PIAS3 suppression may be protective against joint destruction in rheumatoid arthritis by regulating synoviocyte migration, invasion, and activation. (PMID:26667168)
• Taken together, these results suggest that PIAS3 functions as a positive regulator of HIF-1alpha-mediated transcription by increasing its protein stability. (PMID:26697750)
• PIAS3 may serve as a biomarker for predicting hormone therapy stratification, although it is limited to those breast cancer patients receiving hormone therapy. (PMID:26768588)
• Levels of PIAS3 are significantly lower, in contrast with phosphorylation of STAT3, in women with endometriosis compared to women without endometriosis. (PMID:27226311)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pias3	ENSMUSG00000028101
rattus_norvegicus	Pias3	ENSRNOG00000021218
drosophila_melanogaster	Su(var)2-10	FBGN0003612

Paralogs (5): PIAS1 (ENSG00000033800), PIAS2 (ENSG00000078043), PIAS4 (ENSG00000105229), ZMIZ1 (ENSG00000108175), ZMIZ2 (ENSG00000122515)

Protein

Protein identifiers

E3 SUMO-protein ligase PIAS3 — Q9Y6X2 (reviewed: Q9Y6X2)

Alternative names: E3 SUMO-protein transferase PIAS3, Protein inhibitor of activated STAT protein 3

All UniProt accessions (4): E7ESB4, E9PHH8, Q9Y6X2, U3KQV1

UniProt curated annotations — full annotation on UniProt →

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 coregulation in various cellular pathways, including the STAT pathway and the steroid hormone signaling pathway. Involved in regulating STAT3 signaling via inhibiting STAT3 DNA-binding and suppressing cell growth. Enhances the sumoylation of MTA1 and may participate in its paralog-selective sumoylation. Sumoylates CCAR2 which promotes its interaction with SIRT1. Diminishes the sumoylation of ZFHX3 by preventing the colocalization of ZFHX3 with SUMO1 in the nucleus.

Subunit / interactions. Monomer. Binds SUMO1 and UBE2I. Interacts with BCL11A, HMGA2, IRF1, MITF and NCOA2. Interacts with STAT5; the interaction occurs on stimulation by PRL. Interacts with GFI1; the interaction relieves the inhibitory effect of PIAS3 on STAT3-mediated transcriptional activity. Interacts with AR, PLAG1 and ZFHX3. Interacts with STAT3; the interaction occurs on stimulation by IL6, CNTF or OSM and inhibits the DNA binding activity of STAT3. Interacts with MTA1. Interacts with CCAR2 (via N-terminus). Interacts with TRIM8. Interacts with PRDM1/Blimp-1.

Subcellular location. Cytoplasm. Nucleus. Nucleus speckle.

Tissue specificity. Widely expressed.

Post-translational modifications. Sumoylated.

Domain organisation. The PINIT domain of PIAS3 is required for STAT3-PIAS3 interaction and for translocation to the nucleus. The LXXLL motif is a transcriptional coregulator signature.

Induction. By dihydrotestosterone (DHT) in prostate cancer cells.

Pathway. Protein modification; protein sumoylation.

Similarity. Belongs to the PIAS family.

RefSeq proteins (1): NP_006090* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003034	SAP_dom	Domain
IPR004181	Znf_MIZ	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR023321	PINIT	Domain
IPR036361	SAP_dom_sf	Homologous_superfamily
IPR038654	PINIT_sf	Homologous_superfamily

Pfam: PF02037, PF02891, PF14324

UniProt features (41 total): strand 13, helix 7, cross-link 6, binding site 4, region of interest 3, domain 2, turn 2, chain 1, sequence variant 1, zinc finger region 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4MVT	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6X2-F1	70.87	0.47

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 366; 369; 343; 345

Post-translational modifications (6): 46, 56, 230, 307, 466, 482

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-3232118	SUMOylation of transcription factors
R-HSA-3899300	SUMOylation of transcription cofactors
R-HSA-4090294	SUMOylation of intracellular receptors
R-HSA-4615885	SUMOylation of DNA replication proteins
R-HSA-4755510	SUMOylation of immune response proteins
R-HSA-5696395	Formation of Incision Complex in GG-NER

MSigDB gene sets: 261 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, REACTOME_FORMATION_OF_INCISION_COMPLEX_IN_GG_NER, GCACCTT_MIR18A_MIR18B, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_RESPONSE_TO_PEPTIDE, GOBP_REGULATION_OF_PROTEIN_SUMOYLATION, GOZGIT_ESR1_TARGETS_DN, MAZ_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, RIZ_ERYTHROID_DIFFERENTIATION_CCNE1, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION

GO Biological Process (10): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), negative regulation of gene expression (GO:0010629), regulation of tumor necrosis factor-mediated signaling pathway (GO:0010803), protein sumoylation (GO:0016925), negative regulation of protein sumoylation (GO:0033234), positive regulation of protein sumoylation (GO:0033235), negative regulation of osteoclast differentiation (GO:0045671), negative regulation of DNA-templated transcription (GO:0045892), regulation of macromolecule metabolic process (GO:0060255)

GO Molecular Function (7): transcription coregulator activity (GO:0003712), zinc ion binding (GO:0008270), SUMO transferase activity (GO:0019789), SUMO ligase activity (GO:0061665), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (8): chromatin (GO:0000785), nucleoplasm (GO:0005654), nuclear speck (GO:0016607), glutamatergic synapse (GO:0098978), presynaptic cytosol (GO:0099523), postsynaptic cytosol (GO:0099524), nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	5
Global Genome Nucleotide Excision Repair (GG-NER)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
protein sumoylation	2
regulation of protein sumoylation	2
cytosol	2
regulation of transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
regulation of cytokine-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
peptidyl-lysine modification	1
protein modification by small protein conjugation	1
negative regulation of protein modification by small protein conjugation or removal	1
positive regulation of protein modification by small protein conjugation or removal	1
negative regulation of myeloid leukocyte differentiation	1
osteoclast differentiation	1
regulation of osteoclast differentiation	1
DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
regulation of metabolic process	1
macromolecule metabolic process	1
transcription regulator activity	1
transition metal ion binding	1
ubiquitin-like protein transferase activity	1
SUMO transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
chromosome	1
nuclear lumen	1
nuclear ribonucleoprotein granule	1
synapse	1
presynapse	1
postsynapse	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1474 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIAS3	STAT3	P40763	988
PIAS3	STAT1	P42224	851
PIAS3	UBE2I	P50550	834
PIAS3	SUMO1	P55856	809
PIAS3	SENP1	Q9P0U3	778
PIAS3	UBA2	Q9UBT2	776
PIAS3	EP300	Q09472	742
PIAS3	ZFHX3	Q15911	712
PIAS3	SOCS3	O14543	705
PIAS3	GRIK2	Q13002	704
PIAS3	SAE1	Q9UBE0	679
PIAS3	TRIM8	Q9BZR9	678
PIAS3	CISH	Q9NSE2	657
PIAS3	SUMO2	P55855	645
PIAS3	NR2E3	Q9Y5X4	620

IntAct

89 interactions, top by confidence:

A	B	Type	Score
MBD1	PIAS3	psi-mi:“MI:0915”(physical association)	0.580
PIAS3	MBD1	psi-mi:“MI:0915”(physical association)	0.580
PLIN3	PIAS3	psi-mi:“MI:0915”(physical association)	0.560
PIAS3	PRKCA	psi-mi:“MI:0915”(physical association)	0.560
PIAS3	YWHAG	psi-mi:“MI:0915”(physical association)	0.560
PIAS3	SETDB1	psi-mi:“MI:0915”(physical association)	0.560
PIAS3	KAT5	psi-mi:“MI:0915”(physical association)	0.560
LMO3	PIAS3	psi-mi:“MI:0915”(physical association)	0.560
PIAS3	UBE2I	psi-mi:“MI:0915”(physical association)	0.550
PIAS3	SMAD4	psi-mi:“MI:0915”(physical association)	0.550
SMAD4	PIAS3	psi-mi:“MI:2364”(proximity)	0.550
SUMO1	PIAS3	psi-mi:“MI:0407”(direct interaction)	0.440
GFI1	PIAS3	psi-mi:“MI:0915”(physical association)	0.400
PIAS3	HNRNPK	psi-mi:“MI:0915”(physical association)	0.400
	PIAS3	psi-mi:“MI:0915”(physical association)	0.370
PIAS3		psi-mi:“MI:0915”(physical association)	0.370
PIAS3	NS	psi-mi:“MI:0915”(physical association)	0.370
NS1	PIAS3	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (132): PIAS3 (Two-hybrid), PIAS3 (Two-hybrid), HIC1 (Co-localization), PIAS3 (Two-hybrid), RELA (Biochemical Activity), BCL11A (Affinity Capture-Western), SMURF2 (Affinity Capture-Western), PIAS3 (Affinity Capture-Western), PIM1 (Affinity Capture-Western), PIAS3 (Two-hybrid), SNIP1 (Biochemical Activity), PIAS3 (Affinity Capture-MS), PIAS3 (Affinity Capture-Western), SMAD6 (Affinity Capture-Western), PIAS3 (Reconstituted Complex)

ESM2 similar proteins: A0JPN4, A2A288, A2ARK0, A6ND36, A6QQJ8, A7E316, E9Q0S6, E9Q2Z1, O15037, O54714, O54967, O70260, O70405, O75385, O94983, P42335, P48778, Q07912, Q0P4K8, Q17R13, Q1LVK9, Q32PJ7, Q4V8I3, Q5D1E7, Q5D1E8, Q5DTV4, Q5HYM0, Q5JV73, Q5SWY7, Q5SXM2, Q5U2X5, Q5XIS1, Q68CZ2, Q6A037, Q6IRU7, Q6P1H6, Q6S5L8, Q7TP65, Q7TSG2, Q80U38

Diamond homologs: F1R4C4, F4JYG0, O54714, O70260, O75925, O75928, O88907, Q04195, Q12216, Q680Q4, Q6ASW7, Q6AZ28, Q6L4L4, Q6P1E1, Q8C5D8, Q8CIE2, Q8N2W9, Q8NF64, Q94361, Q9JM05, Q9ULJ6, Q9Y6X2, A0A0A7EPL0, O94451

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
PIAS3	up-regulates	SMAD3	binding
PIAS3	down-regulates	STAT3	sumoylation
PIAS3	“up-regulates activity”	SMAD3	binding
PIAS3	“down-regulates activity”	STAT3	binding
PIAS3	“form complex”	SMAD3/PIAS3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 53 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	5	18.8×	2e-03
G2/M Checkpoints	5	17.2×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of miRNA transcription	5	32.3×	1e-04
protein stabilization	6	8.9×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

70 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	65
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2192 predictions. Top by Δscore:

Variant	Effect	Δscore
1:145850769:GGTA:G	donor_gain	1.0000
1:145850778:G:GT	donor_gain	1.0000
1:145850822:G:GT	donor_gain	1.0000
1:145851060:G:GT	donor_gain	1.0000
1:145851152:G:GG	acceptor_gain	1.0000
1:145851152:GTTT:G	acceptor_gain	1.0000
1:145851153:A:AG	acceptor_gain	1.0000
1:145853534:G:GT	donor_gain	1.0000
1:145854879:GG:G	acceptor_gain	1.0000
1:145854880:AG:A	acceptor_gain	1.0000
1:145856117:G:GG	acceptor_gain	1.0000
1:145856117:GA:G	acceptor_gain	1.0000
1:145856117:GAGA:G	acceptor_gain	1.0000
1:145856118:A:AG	acceptor_gain	1.0000
1:145856828:G:GT	donor_gain	1.0000
1:145856828:G:T	donor_gain	1.0000
1:145857005:G:GG	acceptor_gain	1.0000
1:145857005:GC:G	acceptor_gain	1.0000
1:145857005:GCA:G	acceptor_gain	1.0000
1:145857005:GCAC:G	acceptor_gain	1.0000
1:145857005:GCACA:G	acceptor_gain	1.0000
1:145857006:A:AG	acceptor_gain	1.0000
1:145858965:GG:G	donor_loss	1.0000
1:145858966:AG:A	donor_loss	1.0000
1:145850585:GA:G	acceptor_gain	0.9900
1:145850754:GC:G	donor_gain	0.9900
1:145850770:GG:G	donor_gain	0.9900
1:145850842:G:GT	donor_gain	0.9900
1:145850847:A:G	donor_gain	0.9900
1:145851057:GCATC:G	donor_gain	0.9900

AlphaMissense

4030 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:145851084:C:A	W405C	1.000
1:145851084:C:G	W405C	1.000
1:145851086:A:G	W405R	1.000
1:145851086:A:T	W405R	1.000
1:145851091:C:T	G403E	1.000
1:145851103:A:G	F399S	1.000
1:145851109:A:C	I397S	1.000
1:145851109:A:T	I397N	1.000
1:145853516:A:G	L378P	1.000
1:145853516:A:T	L378H	1.000
1:145853542:A:C	C369W	1.000
1:145853543:C:A	C369F	1.000
1:145853543:C:G	C369S	1.000
1:145853543:C:T	C369Y	1.000
1:145853544:A:G	C369R	1.000
1:145853544:A:T	C369S	1.000
1:145853551:A:C	C366W	1.000
1:145853552:C:A	C366F	1.000
1:145853552:C:G	C366S	1.000
1:145853552:C:T	C366Y	1.000
1:145853553:A:G	C366R	1.000
1:145853553:A:T	C366S	1.000
1:145853557:C:A	W364C	1.000
1:145853557:C:G	W364C	1.000
1:145853559:A:G	W364R	1.000
1:145853559:A:T	W364R	1.000
1:145853575:A:C	N358K	1.000
1:145853575:A:T	N358K	1.000
1:145853579:A:G	M357T	1.000
1:145853585:A:G	L355P	1.000

dbSNP variants (sampled 300 via entrez): RS1000988439 (1:145859234 G>T), RS1001131319 (1:145852874 A>T), RS1001518764 (1:145853116 A>T), RS1001578931 (1:145854257 A>G), RS1001917674 (1:145852247 G>A,C,T), RS1002501197 (1:145859057 C>T), RS1002780224 (1:145857774 A>C,G), RS1003593582 (1:145850408 G>A), RS1004808527 (1:145859899 C>T), RS1005147239 (1:145859033 C>T), RS1005295133 (1:145851751 C>T), RS1006630471 (1:145858212 G>A), RS1007227142 (1:145850813 G>C,T), RS1008374395 (1:145857160 G>A), RS1009084725 (1:145860984 A>C,G)

Disease associations

OMIM: gene MIM:605987 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

39 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	4
sodium arsenite	decreases expression, affects cotreatment, increases abundance	3
Resveratrol	affects localization, increases expression	3
Arsenic	affects cotreatment, decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	decreases expression	1
cobaltous chloride	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Vorinostat	decreases expression	1
Acrolein	increases oxidation, increases abundance, affects cotreatment	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Atrazine	increases expression	1
Carbamazepine	affects expression	1
Cisplatin	increases expression	1
Diazinon	increases methylation	1
Digitoxin	increases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Pentachlorophenol	decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D7X4	Ubigene A-549 PIAS3 KO	Cancer cell line	Male
CVCL_D8SI	Ubigene HCT 116 PIAS3 KO	Cancer cell line	Male
CVCL_D9N0	Ubigene HEK293 PIAS3 KO	Transformed cell line	Female
CVCL_E0KD	Ubigene HeLa PIAS3 KO	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.