SIAH2

Summary

SIAH2 (siah E3 ubiquitin protein ligase 2, HGNC:10858) is a protein-coding gene on chromosome 3q25.1, encoding E3 ubiquitin-protein ligase SIAH2 (O43255). E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins.

This gene encodes a protein that is a member of the seven in absentia homolog (SIAH) family. The protein is an E3 ligase and is involved in ubiquitination and proteasome-mediated degradation of specific proteins. The activity of this ubiquitin ligase has been implicated in regulating cellular response to hypoxia.

Source: NCBI Gene 6478 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 33 total
• MANE Select transcript: NM_005067

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10858
Approved symbol	SIAH2
Name	siah E3 ubiquitin protein ligase 2
Location	3q25.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000181788
Ensembl biotype	protein_coding
OMIM	602213
Entrez	6478

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000312960, ENST00000472885, ENST00000482706, ENST00000936558

RefSeq mRNA: 1 — MANE Select: NM_005067 NM_005067

CCDS: CCDS3152

Canonical transcript exons

ENST00000312960 — 2 exons

Exon	Start	End
ENSE00001231581	150741125	150742698
ENSE00001231588	150762433	150763169

Expression profiles

Bgee: expression breadth ubiquitous, 265 present calls, max score 95.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.9983 / max 420.3057, expressed in 1809 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45114	24.7467	1802
45120	1.4035	686
45115	0.5428	296
45116	0.5169	205
202978	0.3930	149
45118	0.2586	99
45117	0.1369	55

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	95.88	gold quality
right adrenal gland cortex	UBERON:0035827	95.80	gold quality
lower esophagus mucosa	UBERON:0035834	95.29	gold quality
right adrenal gland	UBERON:0001233	95.27	gold quality
left adrenal gland	UBERON:0001234	94.48	gold quality
adrenal gland	UBERON:0002369	94.35	gold quality
left adrenal gland cortex	UBERON:0035825	94.24	gold quality
adrenal cortex	UBERON:0001235	94.21	gold quality
monocyte	CL:0000576	93.62	gold quality
ectocervix	UBERON:0012249	93.57	gold quality
mononuclear cell	CL:0000842	93.40	gold quality
leukocyte	CL:0000738	93.22	gold quality
right lobe of liver	UBERON:0001114	93.01	gold quality
blood	UBERON:0000178	92.57	gold quality
esophagus mucosa	UBERON:0002469	91.64	gold quality
endocervix	UBERON:0000458	91.26	gold quality
bone marrow	UBERON:0002371	91.01	gold quality
liver	UBERON:0002107	90.92	gold quality
stromal cell of endometrium	CL:0002255	90.81	gold quality
placenta	UBERON:0001987	90.58	gold quality
endometrium epithelium	UBERON:0004811	90.40	gold quality
vagina	UBERON:0000996	90.21	gold quality
granulocyte	CL:0000094	90.20	gold quality
popliteal artery	UBERON:0002250	89.86	gold quality
tibial artery	UBERON:0007610	89.84	gold quality
body of uterus	UBERON:0009853	89.79	gold quality
left uterine tube	UBERON:0001303	89.67	gold quality
smooth muscle tissue	UBERON:0001135	89.52	gold quality
cartilage tissue	UBERON:0002418	89.17	gold quality
skin of leg	UBERON:0001511	89.12	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-6	yes	39.95
E-CURD-122	yes	4.75
E-MTAB-8060	no	203.83
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, NCOR1

miRNA regulators (miRDB)

74 targeting SIAH2, 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-188-3P	100.00	68.76	1240
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-8076	99.78	68.52	1170

Literature-anchored findings (GeneRIF, showing 40)

• SIAH2 regulates the expression of promyelocytic leukemia protein and other tripartite motif proteins (PMID:14645235)
• SIAH2 regulates stability of prolyl- hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia. (PMID:15210114)
• role of interaction with AF4 and AF4.MLL fusion protein in t(4,11) pathobiology (PMID:15221006)
• 2-oxoglutarate (alpha-ketoglutarate) dehydrogenase stability is regulated by the RING finger ubiquitin ligase Siah (PMID:15466852)
• mechanism by which the estrogen-ER complex markedly reduces the level of N-CoR through a process involving the up-regulation of Siah2 and the subsequent targeting of N-CoR for proteasomal degradation (PMID:16141343)
• Association of two isoforms Siah1 and Siah2 results in the regulation of Siah1 stability by Siah2 in the presence of a ring finger domain in HEK293 cells. (PMID:16899216)
• Mechanism underlying the regulation of PHD3 availability and activity in hypoxia by the E3 ligase Siah2. (PMID:16958618)
• The role of Siah2 phosphorylation in the regulation of its activity toward PHD3 is reported. (PMID:17003045)
• We provide evidences for hSiah2-dependent degradation of Pias as being a mechanism in the regulation of c-jun N-terminal kinase-activating pathways. (PMID:17533377)
• Data show that Siah2 is an important mediator of repp86 protein degradation. (PMID:17716627)
• monoubiquitylation by SIAH1 and SIAH2 represents a possible trigger event for alpha-synuclein aggregation and Lewy body formation (PMID:18070888)
• In primary breast tumor specimens as well as in vitro low SIAH2 levels associated with resistance to endocrine therapy. (PMID:18629630)
• Siah1 (human) reduced PHD3 protein levels similar to that observed with Siah2. PHDs may not interact directly with Siah2, but that the substrate-binding groove of Siah is nevertheless important. (PMID:18850011)
• SIAH-2 may be a viable target for novel anti-RAS and anticancer agents aimed at inhibiting EGFR and/or RAS-mediated tumorigenesis. (PMID:19001609)
• Hypoxic conditions allow a markedly increased HIPK2/Siah2 interaction and result in efficient polyubiquitylation and proteasomal degradation of the kinase. (PMID:19043406)
• The ability of myosin phosphatase to modulate myosin light chain might be regulated by the degradation of its targeting subunit MYPT1 through the SIAH2-ubiquitin-proteasomal pathway. (PMID:19744480)
• Review: Define the regulatory axis consisting of Siah2 and HIF-1alpha/FoxA2 cooperation and suggest novel therapeutic modalities to treat these most aggressive forms of prostate cancer. (PMID:21037926)
• SIAH2 expression is upregulated in basal-like breast cancers via copy number changes and/or transcriptional activation by p53. (PMID:21306611)
• The data presented here define POSH and Siah2 as important mediators of death receptor mediated apoptosis and suggest targeting the interaction of these two E3 ligases is a promising novel cancer therapeutic strategy. (PMID:21586138)
• study identifies a new layer of Siah2 regulation mediated by USP13 binding to ubiquitinated Siah2 protein with a concomitant inhibitory effect on its activity under normoxia (PMID:21659512)
• In sharp contrast to SIAH1/SIAH2 and UBCH8, TRIAD1 binding to PML-RARalpha has no effect on its turnover. (PMID:22037423)
• Src kinase activity downregulates C/EBP-delta protein but not mRNA levels through a SIAH2 E3 ligase-dependent mechanism. (PMID:22037769)
• Siah2 acts as an E3 ligase to directly ubiquitylate TIN2 in vitro. (PMID:22064479)
• SIAH-2 - as described for SIAH-1 - accumulates in nuclei of hepatocellular carcinoma cells where it supports tumor growth and tumor cell dissemination (PMID:22323152)
• SIAH2 knockdown increases DYRK2 stability, whereas SIAH2 expression facilitates DYRK2 polyubiquitination and degradation (PMID:22878263)
• Single Nucleotide Polymorphism in SIAH2 gene is associated with hormonal receptor-positive breast cancer. (PMID:22951594)
• the molecular mechanisms modulating ACK1 (PMID:23208506)
• USP19 interacts with the ubiquitin ligases SIAH1 and SIAH2, which promote USP19 ubiquitylation and degradation by the proteasome. (PMID:23500468)
• study found Siah2 enhances transcriptional activity of androgen receptor (AR) by degrading transcriptionally-inactive AR on select gene promoters/enhancers; Siah2 promotes expression of select AR target genes, leading to growth of castration-resistant prostate cancer cells under androgen-deprivation conditions (PMID:23518348)
• our studies demonstrate the role of Siah2 in regulation of tight junction integrity and cell polarity under hypoxia, through its regulation of ASPP2 stability. (PMID:23644657)
• Data suggest that Keap1 does not contribute to hypoxic Nrf2 suppression, and both HIF-1alpha and Siah2 are key regulators of hypoxic responses. (PMID:23645672)
• SIAH2 overexpression is associated with oral squamous cell carcinoma. (PMID:24222137)
• A common variant in the SIAH2 locus is associated with ER-positive breast cancer in the Chinese Han population. (PMID:24244489)
• the E3 ubiquitin ligase seven-in-absentia-2 (SIAH2) accelerates the proteasomal degradation of TYK which consequently suppresses the activation of STAT3 in non-small-cell lung cancer (PMID:24833526)
• molecular basis of Siah1 and Siah2 E3 ubiquitin ligase substrate specificity (PMID:25202994)
• the E3 ubiquitin ligase SIAH2 stimulates YAP by destabilizing LATS2, a critical component of the Hippo pathway, in response to hypoxia. (PMID:25438054)
• Data indicate that ubiquitin ligase Siah as a regulator of to Mesenchymal Transition (EMT) by controlling the abundance of the key transcription factor Zeb1, while Siah itself is subject to regulation by EMT-inducing factors. (PMID:25528765)
• The down-regulation of SIAH2 conferred sensitivity to anti-cancer drugs. The results of the study indicated that the miR-335/SIAH2/HDAC3 axis regulates the response to anti-cancer drugs. (PMID:25997740)
• A catalysis-independent role for AKR1C3 on AR activity via Siah2 has been identified. (PMID:26160177)
• Data show that ubiquitin E3 ligase Siah2 depletion delays circadian degradation of nuclear hormone receptor RevErbalpha (Nr1d1) and lengthens period length. (PMID:26392558)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	siah2l	ENSDARG00000044381
mus_musculus	Siah2	ENSMUSG00000036432
rattus_norvegicus	Siah2	ENSRNOG00000013703
drosophila_melanogaster	sina	FBGN0003410

Paralogs (3): ZSWIM9 (ENSG00000185453), SIAH1 (ENSG00000196470), SIAH3 (ENSG00000215475)

Protein

Protein identifiers

E3 ubiquitin-protein ligase SIAH2 — O43255 (reviewed: O43255)

Alternative names: RING-type E3 ubiquitin transferase SIAH2, Seven in absentia homolog 2

All UniProt accessions (2): C9J9D7, O43255

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Mediates E3 ubiquitin ligase activity either through direct binding to substrates or by functioning as the essential RING domain subunit of larger E3 complexes. Triggers the ubiquitin-mediated degradation of many substrates, including proteins involved in transcription regulation (GPS2, POU2AF1, PML, NCOR1), a cell surface receptor (DCC), an antiapoptotic protein (BAG1), and a protein involved in synaptic vesicle function in neurons (SYP). Mediates ubiquitination and proteasomal degradation of DYRK2 in response to hypoxia. It is thereby involved in apoptosis, tumor suppression, cell cycle, transcription and signaling processes. Has some overlapping function with SIAH1. Triggers the ubiquitin-mediated degradation of TRAF2, whereas SIAH1 does not. Promotes monoubiquitination of SNCA. Regulates cellular clock function via ubiquitination of the circadian transcriptional repressors NR1D1 and NR1D2 leading to their proteasomal degradation. Plays an important role in mediating the rhythmic degradation/clearance of NR1D1 and NR1D2 contributing to their circadian profile of protein abundance. Mediates ubiquitination and degradation of EGLN2 and EGLN3 in response to the unfolded protein response (UPR), leading to their degradation and subsequent stabilization of ATF4. Also part of the Wnt signaling pathway in which it mediates the Wnt-induced ubiquitin-mediated proteasomal degradation of AXIN1.

Subunit / interactions. Homodimer. Interacts with UBE2E2. Interacts with PEG3. Interacts with VAV1, without mediating its ubiquitin-mediated degradation. Interacts with CACYBP/SIP. Probable component of some large E3 complex possibly composed of UBE2D1, SIAH2, CACYBP/SIP, SKP1, APC and TBL1X. Interacts with PEG10, which may inhibit its activity. Interacts with EGLN2 and SNCAIP. Interacts with DYRK2. Interacts with NR1D1 and NR1D2. Interacts with DCC. Interacts with AXIN1.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed at low level.

Post-translational modifications. Phosphorylated at Ser-28 by MAPK14, which mediates the degradation by the proteasome of EGLN3. Phosphorylated at Ser-28 by DYRK2; this increases the ubiquitin ligase activity and promotes degradation of EGLN3.

Activity regulation. Inhibited by interaction with SNCAIP (isoform 2, but not isoform 1). May be inhibited by interaction with PEG10.

Domain organisation. The RING-type zinc finger domain is essential for ubiquitin ligase activity. The SBD domain (substrate-binding domain) mediates the homodimerization and the interaction with substrate proteins. It is related to the TRAF family.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the SINA (Seven in absentia) family.

RefSeq proteins (1): NP_005058* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR004162	SINA-like_animal	Family
IPR008974	TRAF-like	Homologous_superfamily
IPR013010	Znf_SIAH	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR018121	7-in-absentia-prot_TRAF-dom	Domain
IPR049548	Sina-like_RING	Domain

Pfam: PF03145, PF21361, PF21362

UniProt features (47 total): strand 10, binding site 8, helix 8, modified residue 6, mutagenesis site 5, compositionally biased region 3, zinc finger region 2, region of interest 2, chain 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5H9M	X-RAY DIFFRACTION	1.76

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43255-F1	85.03	0.74

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 (8): 157; 161; 168; 175; 187; 192; 138; 145

Post-translational modifications (6): 6, 16, 26, 28, 68, 119

Mutagenesis-validated functional residues (5):

Position	Phenotype
16	strongly reduced phosphorylation by dyrk2; when associated with a-26; a-28; a-68 and a-119.
26	strongly reduced phosphorylation by dyrk2; when associated with a-16; a-28; a-68 and a-119.
28	strongly reduced phosphorylation by dyrk2; when associated with a-16; a-26; a-68 and a-119.
68	strongly reduced phosphorylation by dyrk2; when associated with a-16; a-26; a-28 and a-119.
119	strongly reduced phosphorylation by dyrk2; when associated with a-16; a-26; a-28 and a-68.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-373752	Netrin-1 signaling
R-HSA-5689880	Ub-specific processing proteases
R-HSA-977225	Amyloid fiber formation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1266738	Developmental Biology
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-392499	Metabolism of proteins
R-HSA-422475	Axon guidance
R-HSA-5688426	Deubiquitination
R-HSA-597592	Post-translational protein modification
R-HSA-9675108	Nervous system development
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 272 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GOBP_CIRCADIAN_RHYTHM, LU_IL4_SIGNALING, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GENTILE_RESPONSE_CLUSTER_D3, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, WONG_PROTEASOME_GENE_MODULE, GOBP_REGULATION_OF_CIRCADIAN_RHYTHM, GOBP_NEGATIVE_REGULATION_OF_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, LINDSTEDT_DENDRITIC_CELL_MATURATION_B

GO Biological Process (16): ubiquitin-dependent protein catabolic process (GO:0006511), apoptotic process (GO:0006915), small GTPase-mediated signal transduction (GO:0007264), protein ubiquitination (GO:0016567), regulation of protein ubiquitination (GO:0031396), regulation of circadian rhythm (GO:0042752), negative regulation of apoptotic process (GO:0043066), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), rhythmic process (GO:0048511), canonical Wnt signaling pathway (GO:0060070), negative regulation of canonical Wnt signaling pathway (GO:0090090), amyloid fibril formation (GO:1990000), negative regulation of extrinsic apoptotic signaling pathway (GO:2001237), multicellular organism development (GO:0007275), negative regulation of DNA-templated transcription (GO:0045892), regulation of apoptotic signaling pathway (GO:2001233)

GO Molecular Function (8): transcription corepressor activity (GO:0003714), ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), ubiquitin conjugating enzyme binding (GO:0031624), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), early endosome (GO:0005769), cytosol (GO:0005829), neuronal cell body (GO:0043025), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Metabolism of proteins	2
Axon guidance	1
Deubiquitination	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Nervous system development	1
Post-translational protein modification	1
Developmental Biology	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein ubiquitination	2
apoptotic signaling pathway	2
regulation of apoptotic process	2
modification-dependent protein catabolic process	1
programmed cell death	1
execution phase of apoptosis	1
intracellular signaling cassette	1
protein modification by small protein conjugation	1
regulation of protein modification by small protein conjugation or removal	1
circadian rhythm	1
regulation of biological process	1
apoptotic process	1
negative regulation of programmed cell death	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
biological_process	1
Wnt signaling pathway	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
protein metabolic process	1
supramolecular fiber organization	1
extrinsic apoptotic signaling pathway	1
negative regulation of apoptotic signaling pathway	1
regulation of extrinsic apoptotic signaling pathway	1
multicellular organismal process	1
anatomical structure development	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
regulation of signal transduction	1
transcription coregulator activity	1
negative regulation of DNA-templated transcription	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
ubiquitin-like protein conjugating enzyme binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1

Protein interactions and networks

STRING

1384 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIAH2	EGLN3	Q9H6Z9	938
SIAH2	EGLN2	Q96KS0	920
SIAH2	LATS2	Q9NRM7	915
SIAH2	HIF1A	Q16665	858
SIAH2	VHL	P40337	732
SIAH2	EGLN1	Q9GZT9	728
SIAH2	AKAP1	Q92667	716
SIAH2	HIPK2	Q9H2X6	689
SIAH2	SYP	P08247	675
SIAH2	KHDRBS3	O75525	669
SIAH2	TINF2	Q9BSI4	666
SIAH2	NEDD4L	Q96PU5	567
SIAH2	AKR1C3	P42330	558
SIAH2	ARNT	P27540	547
SIAH2	CACYBP	Q9HB71	543

IntAct

57 interactions, top by confidence:

A	B	Type	Score
AR		psi-mi:“MI:0914”(association)	0.920
SIAH2	LATS2	psi-mi:“MI:0915”(physical association)	0.630
LATS2	SIAH2	psi-mi:“MI:0915”(physical association)	0.630
SIAH2	LATS2	psi-mi:“MI:0407”(direct interaction)	0.630
SIAH2	SH3RF1	psi-mi:“MI:0915”(physical association)	0.630
SH3RF1	SIAH2	psi-mi:“MI:0915”(physical association)	0.630
PRICKLE3	SIAH2	psi-mi:“MI:0914”(association)	0.530
PRR20E	SIAH2	psi-mi:“MI:0914”(association)	0.530
SIAH2	OPRM1	psi-mi:“MI:0915”(physical association)	0.510
SIAH2	MYD88	psi-mi:“MI:0915”(physical association)	0.440
MYD88	SIAH2	psi-mi:“MI:0403”(colocalization)	0.440
SIAH2	LATS1	psi-mi:“MI:0915”(physical association)	0.400
SIAH2	Oprd1	psi-mi:“MI:0915”(physical association)	0.400
SIAH2	OPRK1	psi-mi:“MI:0915”(physical association)	0.400
	SIAH2	psi-mi:“MI:0915”(physical association)	0.370
CCBE1	SIAH2	psi-mi:“MI:0915”(physical association)	0.370
SIAH2	EEF1D	psi-mi:“MI:0915”(physical association)	0.370
STAT3	SIAH2	psi-mi:“MI:0915”(physical association)	0.370
UBE2I	SIAH2	psi-mi:“MI:0915”(physical association)	0.370
SETD2	SIAH2	psi-mi:“MI:0915”(physical association)	0.370
SIAH2	HIPK3	psi-mi:“MI:0915”(physical association)	0.370
CACYBP	SIAH2	psi-mi:“MI:0915”(physical association)	0.370
SIAH2	Pou2af1	psi-mi:“MI:0915”(physical association)	0.370
KIE-2	SIAH2	psi-mi:“MI:0914”(association)	0.350

BioGRID (216): EGLN3 (Affinity Capture-Western), EGLN3 (Reconstituted Complex), HIPK2 (Affinity Capture-Western), XAF1 (Affinity Capture-Western), XAF1 (Phenotypic Suppression), SIAH2 (Two-hybrid), SIAH2 (Affinity Capture-Western), UBE2D1 (Reconstituted Complex), SIAH2 (Two-hybrid), SIAH2 (Affinity Capture-Western), SIAH2 (Affinity Capture-Western), SIAH2 (Affinity Capture-Western), SIAH2 (Affinity Capture-MS), SIAH2 (Affinity Capture-MS), SIAH2 (Affinity Capture-Western)

ESM2 similar proteins: A2YX04, A8X679, F4IPE3, O02748, O43255, O60291, P21461, P27540, P29304, P41739, P53762, P61093, P79832, Q06986, Q09268, Q28CH2, Q297L2, Q5XIQ4, Q680Q4, Q6ASW7, Q6E3C9, Q6E3D0, Q6L4L4, Q6Z8M8, Q700C2, Q75LH6, Q7SYL3, Q7Z5Q1, Q7ZUL9, Q812E0, Q84JL3, Q86MW9, Q8BFX3, Q8I147, Q8R4T2, Q8RY95, Q8S3N1, Q8T3Y0, Q93WE4, Q965X6

Diamond homologs: A8X679, O43255, P21461, P29304, P61092, P61093, P93748, Q06985, Q06986, Q10L91, Q7SYL3, Q7ZVG6, Q84JL3, Q86MW9, Q8I147, Q8IUQ4, Q8IW03, Q8R4T2, Q8T3Y0, Q920M9, Q965X6, Q9FKD9, Q9I8X5, Q9M2P4, Q9STN8, Q84K34, Q8S3N1, Q9C6H2, Q9C6H4, Q9C9M0, Q9FKD5, Q9FKD6, Q9FKD7, Q9C6H3, P0DTL6, P0DW91, Q7XA77, Q93WE4, Q9FM14, P0DW87

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
SIAH2	down-regulates	SNCAIP	ubiquitination
MAPK14	up-regulates	SIAH2	phosphorylation
SIAH2	up-regulates	HIF1A
DYRK2	up-regulates	SIAH2	phosphorylation
Ub:E2	“up-regulates activity”	SIAH2	ubiquitination
SIAH2	“down-regulates quantity by destabilization”	AKAP1	polyubiquitination
SRC	“up-regulates activity”	SIAH2	phosphorylation
SIAH2	“down-regulates quantity by destabilization”	PSMD4	polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

430 predictions. Top by Δscore:

Variant	Effect	Δscore
3:150742694:GCATA:G	acceptor_gain	1.0000
3:150742695:CATA:C	acceptor_gain	1.0000
3:150742695:CATAC:C	acceptor_gain	1.0000
3:150742696:ATA:A	acceptor_gain	1.0000
3:150742696:ATACT:A	acceptor_loss	1.0000
3:150742697:TA:T	acceptor_gain	1.0000
3:150742698:ACTG:A	acceptor_loss	1.0000
3:150742699:C:CC	acceptor_gain	1.0000
3:150742700:T:C	acceptor_loss	1.0000
3:150761285:T:TA	donor_gain	0.9900
3:150762428:CTTA:C	donor_loss	0.9900
3:150762429:TTAC:T	donor_loss	0.9900
3:150762431:ACCT:A	donor_loss	0.9900
3:150742702:C:CT	acceptor_gain	0.9800
3:150759592:G:A	donor_gain	0.9800
3:150762432:CCTTA:C	donor_gain	0.9800
3:150759628:CTAG:C	donor_gain	0.9700
3:150763312:T:TA	donor_gain	0.9700
3:150742703:A:T	acceptor_gain	0.9600
3:150762431:A:AC	donor_gain	0.9400
3:150762432:C:CC	donor_gain	0.9400
3:150762459:C:CT	donor_gain	0.9300
3:150762460:C:CT	donor_gain	0.9300
3:150749781:T:TA	donor_gain	0.9200
3:150762431:AC:A	donor_gain	0.9100
3:150762432:CC:C	donor_gain	0.9100
3:150762436:A:AC	donor_gain	0.9100
3:150762437:C:CC	donor_gain	0.9100
3:150762571:C:CC	acceptor_gain	0.8900
3:150742696:A:C	acceptor_gain	0.8800

AlphaMissense

2118 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:150742160:A:C	I319S	1.000
3:150742160:A:G	I319T	1.000
3:150742160:A:T	I319N	1.000
3:150742166:A:T	V317D	1.000
3:150742172:A:C	I315S	1.000
3:150742172:A:G	I315T	1.000
3:150742172:A:T	I315N	1.000
3:150742178:A:G	L313P	1.000
3:150742178:A:T	L313H	1.000
3:150742195:A:C	F307L	1.000
3:150742195:A:T	F307L	1.000
3:150742196:A:G	F307S	1.000
3:150742197:A:G	F307L	1.000
3:150742197:A:T	F307I	1.000
3:150742220:A:G	F299S	1.000
3:150742226:A:G	L297P	1.000
3:150742226:A:T	L297H	1.000
3:150742228:G:C	C296W	1.000
3:150742230:A:G	C296R	1.000
3:150742277:G:C	P280R	1.000
3:150742277:G:T	P280H	1.000
3:150742284:C:G	A278P	1.000
3:150742288:C:A	W276C	1.000
3:150742288:C:G	W276C	1.000
3:150742290:A:G	W276R	1.000
3:150742290:A:T	W276R	1.000
3:150742316:A:G	L267S	1.000
3:150742322:A:G	L265P	1.000
3:150742322:A:T	L265Q	1.000
3:150742329:A:C	Y263D	1.000

dbSNP variants (sampled 300 via entrez): RS1000056691 (3:150752645 A>G,T), RS1000092748 (3:150742275 G>A,T), RS1000161728 (3:150743959 G>T), RS1000173373 (3:150762249 T>A,C), RS1000204677 (3:150762705 G>C), RS1000307205 (3:150746076 G>A,T), RS1000474234 (3:150764781 T>C), RS1000507537 (3:150760679 A>C), RS1000531268 (3:150759303 A>G), RS1001213614 (3:150748116 G>A), RS1001724389 (3:150761497 G>A), RS1001733653 (3:150751140 G>C), RS1001754456 (3:150741665 TTCAG>T), RS1001974170 (3:150749566 C>A,T), RS1002041517 (3:150756708 C>T)

Disease associations

OMIM: gene MIM:602213 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001667_1	Breast cancer	9.000000e-08
GCST006719_1	BRCA1/2-negative high-risk breast cancer	6.000000e-07
GCST006719_16	BRCA1/2-negative high-risk breast cancer	2.000000e-06
GCST009665_2	Breast cancer	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009443	BRCAX breast cancer

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	8
Estradiol	affects cotreatment, decreases reaction, increases expression, decreases expression	6
bisphenol A	increases expression	3
Cisplatin	increases expression	2
Diethylstilbestrol	increases expression	2
Genistein	increases expression	2
chloroacetaldehyde	increases expression	1
bis(tri-n-butyltin)oxide	increases expression	1
methylparaben	decreases expression	1
o,p’-DDT	increases expression	1
afimoxifene	decreases reaction, increases expression	1
perfluorooctanoic acid	affects cotreatment, decreases expression	1
butylparaben	decreases expression	1
indeno(1,2,3-cd)pyrene	decreases expression	1
ICI 164384	affects cotreatment, decreases reaction, increases expression, decreases expression, affects response to substance	1
picene	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
PCI 5002	increases expression, affects cotreatment	1
NSC668394	increases expression	1
Erlotinib Hydrochloride	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Fulvestrant	decreases expression	1

Clinical trials (associated diseases)

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