SHISA3

Summary

SHISA3 (shisa family member 3, HGNC:25159) is a protein-coding gene on chromosome 4p13, encoding Protein shisa-3 homolog (A0PJX4). Plays an essential role in the maturation of presomitic mesoderm cells by individual attenuation of both FGF and WNT signaling.

This gene encodes a single-transmembrane protein which is one of nine members of a family of transmembrane adaptors that modulate both WNT and FGF signaling by blocking the maturation and transport of their receptors to the cell surface. Members of this family contain an N-terminal cysteine-rich domain with a distinct cysteine pattern, a single transmembrane domain, and a C-terminal proline-rich, low complexity region. The encoded protein acts as a tumor suppressor by accelerating beta-catenin degradation.

Source: NCBI Gene 152573 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 44 total
• MANE Select transcript: NM_001080505

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25159
Approved symbol	SHISA3
Name	shisa family member 3
Location	4p13
Locus type	gene with protein product
Status	Approved
Aliases	hShisa3
Ensembl gene	ENSG00000178343
Ensembl biotype	protein_coding
OMIM	617325
Entrez	152573

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000319234, ENST00000909498

RefSeq mRNA: 1 — MANE Select: NM_001080505 NM_001080505

CCDS: CCDS33979

Canonical transcript exons

ENST00000319234 — 2 exons

Exon	Start	End
ENSE00001239890	42401012	42402487
ENSE00001489443	42397488	42398333

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 92.09.

FANTOM5 (CAGE): breadth broad, TPM avg 1.6969 / max 197.8994, expressed in 447 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47514	1.5636	424
47515	0.0773	33
47516	0.0385	12
47513	0.0175	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	92.09	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.84	gold quality
metanephros	UBERON:0000081	86.60	gold quality
metanephros cortex	UBERON:0010533	84.75	gold quality
heart right ventricle	UBERON:0002080	83.74	gold quality
adult mammalian kidney	UBERON:0000082	83.61	gold quality
kidney	UBERON:0002113	81.88	gold quality
epithelial cell of pancreas	CL:0000083	81.71	silver quality
tibial nerve	UBERON:0001323	81.46	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	80.32	gold quality
right atrium auricular region	UBERON:0006631	80.04	gold quality
lower esophagus muscularis layer	UBERON:0035833	79.87	gold quality
mucosa of stomach	UBERON:0001199	79.82	gold quality
cardiac atrium	UBERON:0002081	79.75	gold quality
apex of heart	UBERON:0002098	79.72	gold quality
lower esophagus	UBERON:0013473	79.70	gold quality
parietal pleura	UBERON:0002400	79.46	gold quality
heart left ventricle	UBERON:0002084	79.17	gold quality
cardiac ventricle	UBERON:0002082	78.99	gold quality
heart	UBERON:0000948	77.94	gold quality
descending thoracic aorta	UBERON:0002345	76.99	gold quality
thoracic aorta	UBERON:0001515	76.34	gold quality
ascending aorta	UBERON:0001496	76.14	gold quality
left coronary artery	UBERON:0001626	75.94	gold quality
renal medulla	UBERON:0000362	75.84	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.53	gold quality
coronary artery	UBERON:0001621	74.16	gold quality
kidney epithelium	UBERON:0004819	73.07	silver quality
lymph node	UBERON:0000029	72.92	gold quality
right coronary artery	UBERON:0001625	72.69	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9906	yes	2347.24
E-HCAD-10	yes	505.39
E-ANND-3	yes	4.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TBX2, TBX3

miRNA regulators (miRDB)

85 targeting SHISA3, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-4525	99.94	64.38	675

Literature-anchored findings (GeneRIF, showing 6)

• Down-regulation of SHISA3 expression was associated with colorectal cancer. (PMID:25968618)
• SHISA3 promoter hypermethylation might increase the risk of LSCC through regulation of gene expression and is a potential diagnostic and prognostic biomarker for laryngeal squamous cell carcinoma (PMID:28299336)
• SHISA3 is a candidate gene for the identification of CLL patients who will benefit of lenalidomide treatment as single agent. (PMID:28639485)
• Low Shisa3 expression is associated with Nasopharyngeal Carcinoma Metastasis. (PMID:30573520)
• For TKI-resistant PC9/ER tumors in nod-scid mice, overexpressed shisa3 had a significant inhibitory effect. In addition, we verified that shisa3 inhibited EGFR-TKI resistance by interacting with FGFR1/3 to regulate AKT/mTOR signaling. (PMID:31801598)
• SHISA3, an antagonist of the Wnt/beta-catenin signaling, is epigenetically silenced and its ectopic expression suppresses growth in breast cancer. (PMID:32692756)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	shisa3	ENSDARG00000075467
mus_musculus	Shisa3	ENSMUSG00000050010
rattus_norvegicus	Shisa3	ENSRNOG00000025670

Paralogs (5): SHISAL1 (ENSG00000138944), SHISAL2B (ENSG00000145642), SHISA2 (ENSG00000180730), SHISAL2A (ENSG00000182183), SHISA4 (ENSG00000198892)

Protein

Protein identifiers

Protein shisa-3 homolog — A0PJX4 (reviewed: A0PJX4)

All UniProt accessions (1): A0PJX4

UniProt curated annotations — full annotation on UniProt →

Function. Plays an essential role in the maturation of presomitic mesoderm cells by individual attenuation of both FGF and WNT signaling.

Subcellular location. Endoplasmic reticulum membrane.

Similarity. Belongs to the shisa family.

RefSeq proteins (1): NP_001073974* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026910	Shisa	Family
IPR053891	Shisa_N	Domain

Pfam: PF13908

UniProt features (9 total): topological domain 2, signal peptide 1, chain 1, transmembrane region 1, region of interest 1, compositionally biased region 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A0PJX4-F1	67.16	0.32

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 68 (showing top): GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, FOSTER_TOLERANT_MACROPHAGE_UP, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, CUI_TCF21_TARGETS_2_DN, VECCHI_GASTRIC_CANCER_EARLY_DN, MODULE_95, RIGGI_EWING_SARCOMA_PROGENITOR_UP, GOBP_NEGATIVE_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOCC_NUCLEAR_OUTER_MEMBRANE_ENDOPLASMIC_RETICULUM_MEMBRANE_NETWORK, GOCC_ORGANELLE_SUBCOMPARTMENT, MEISSNER_BRAIN_HCP_WITH_H3K4ME2_AND_H3K27ME3, MARTENS_TRETINOIN_RESPONSE_UP, LEE_BMP2_TARGETS_DN, ZWANG_CLASS_1_TRANSIENTLY_INDUCED_BY_EGF

GO Biological Process (1): negative regulation of canonical Wnt signaling pathway (GO:0090090)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): endoplasmic reticulum membrane (GO:0005789), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

532 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SHISA3	GSG1L2	A8MUP6	611
SHISA3	CFAP299	Q6V702	483
SHISA3	ZNF549	Q6P9A3	481
SHISA3	GAS2L2	Q8NHY3	468
SHISA3	RGS22	Q8NE09	458
SHISA3	EEPD1	Q7L9B9	453
SHISA3	BEND4	Q6ZU67	448
SHISA3	LRRC66	Q68CR7	441
SHISA3	SHISAL1	Q3SXP7	427
SHISA3	VOPP1	Q96AW1	426
SHISA3	TRABD2B	A6NFA1	418
SHISA3	TMEM33	P57088	405
SHISA3	ATP8A1	Q9Y2Q0	401
SHISA3	SYNDIG1	Q9H7V2	396
SHISA3	PDCL2	Q8N4E4	394
SHISA3	SGSM1	Q2NKQ1	394

IntAct

26 interactions, top by confidence:

A	B	Type	Score
SHISA3	PNMA1	psi-mi:“MI:0915”(physical association)	0.560
PNMA1	SHISA3	psi-mi:“MI:0915”(physical association)	0.560
CLDN11	SHISA3	psi-mi:“MI:0915”(physical association)	0.560
MAL	SHISA3	psi-mi:“MI:0915”(physical association)	0.560
ANKRD46	SHISA3	psi-mi:“MI:0915”(physical association)	0.560
TMEM147	SHISA3	psi-mi:“MI:0915”(physical association)	0.560
CMTM7	SHISA3	psi-mi:“MI:0915”(physical association)	0.560
SHISA3	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
SHISA3	CLDN11	psi-mi:“MI:0915”(physical association)	0.560
SHISA3	MAL	psi-mi:“MI:0915”(physical association)	0.560
SHISA3	ANKRD46	psi-mi:“MI:0915”(physical association)	0.560
SHISA3	TMEM147	psi-mi:“MI:0915”(physical association)	0.560
SHISA3	CMTM7	psi-mi:“MI:0915”(physical association)	0.560
BMP2K	SHISA3	psi-mi:“MI:0915”(physical association)	0.370
SHISA3	ZNF316	psi-mi:“MI:0914”(association)	0.350
SHISA3		psi-mi:“MI:0914”(association)	0.350
SHISA3	SCAP	psi-mi:“MI:0914”(association)	0.350
SHISA3	MEOX2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (32): SHISA3 (Two-hybrid), SHISA3 (Two-hybrid), SHISA3 (Two-hybrid), SHISA3 (Two-hybrid), SHISA3 (Two-hybrid), SHISA3 (Two-hybrid), ANKRD46 (Two-hybrid), RPUSD2 (Affinity Capture-MS), TRIP6 (Affinity Capture-MS), PTGES2 (Affinity Capture-MS), SARM1 (Affinity Capture-MS), TRMT61B (Affinity Capture-MS), ZNF316 (Affinity Capture-MS), TGFBR3 (Affinity Capture-MS), ZNF852 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GW64, A0A5F4BST2, A0PJX4, A8MVS5, A8MWV9, B0FP48, E5RIL1, E9PGG2, O14836, O60320, O95998, P09564, Q01113, Q01114, Q13477, Q2KI80, Q2T9R2, Q3TS39, Q3UPR0, Q3URD2, Q4V9L6, Q5FVJ4, Q5M869, Q6A044, Q6UWJ8, Q75VT8, Q864V4, Q8BRJ3, Q8BX43, Q8C503, Q8IVY1, Q8K5A9, Q8N112, Q8NC24, Q8NDY8, Q8QZT4, Q8R138, Q969Z4, Q9BUF7, Q9CQM1

Diamond homologs: A0PJX4, A2RV66, A6QPA0, A7MC48, Q2WFL8, Q3UPR0, Q5BLC7, Q6UWI4, Q7T0Z7, Q8QZV2, B3DHW5, B4DS77, J3QNX5, Q9CZN4, Q9D7I0, A6NL88, B8ZZ34, Q3UH99, Q6ZSJ9, Q9D1Y9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	41
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

220 predictions. Top by Δscore:

Variant	Effect	Δscore
4:42398330:GCGC:G	donor_gain	1.0000
4:42398332:GC:G	donor_gain	1.0000
4:42398332:GCGT:G	donor_loss	1.0000
4:42398334:G:GG	donor_gain	1.0000
4:42398334:GT:G	donor_loss	1.0000
4:42398335:T:G	donor_loss	1.0000
4:42398329:TGCGC:T	donor_gain	0.9900
4:42398330:GCGCG:G	donor_gain	0.9900
4:42398331:CGC:C	donor_gain	0.9900
4:42398332:GCG:G	donor_gain	0.9900
4:42398336:AAGT:A	donor_loss	0.9900
4:42401010:A:AG	acceptor_gain	0.9900
4:42401011:G:GG	acceptor_gain	0.9900
4:42398323:C:T	donor_gain	0.9700
4:42401011:GA:G	acceptor_gain	0.9700
4:42401011:GAGC:G	acceptor_gain	0.9600
4:42401006:TTTTA:T	acceptor_loss	0.9500
4:42401007:TTTA:T	acceptor_loss	0.9500
4:42401008:TTA:T	acceptor_loss	0.9500
4:42401009:TAGAG:T	acceptor_loss	0.9500
4:42401010:A:T	acceptor_loss	0.9500
4:42401011:G:C	acceptor_gain	0.9500
4:42401011:G:GA	acceptor_loss	0.9500
4:42401011:GAGCC:G	acceptor_gain	0.9400
4:42398338:G:GG	donor_gain	0.9300
4:42399264:G:T	donor_gain	0.9300
4:42398337:A:AG	donor_gain	0.9200
4:42398337:AGTG:A	donor_loss	0.9100
4:42399128:G:T	donor_gain	0.8900
4:42401002:T:TA	acceptor_gain	0.8900

AlphaMissense

1529 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:42398149:G:C	W31C	0.998
4:42398149:G:T	W31C	0.998
4:42398181:T:G	F42C	0.998
4:42398228:G:T	G58C	0.998
4:42398180:T:C	F42L	0.997
4:42398182:C:A	F42L	0.997
4:42398182:C:G	F42L	0.997
4:42398251:T:G	C65W	0.997
4:42398181:T:C	F42S	0.996
4:42398224:C:G	C56W	0.996
4:42401041:G:C	G103R	0.996
4:42398186:T:A	C44S	0.995
4:42398187:G:C	C44S	0.995
4:42398222:T:C	C56R	0.995
4:42398223:G:A	C56Y	0.995
4:42398226:G:A	C57Y	0.995
4:42398229:G:T	G58V	0.995
4:42398254:C:G	C66W	0.995
4:42401042:G:A	G103D	0.995
4:42401059:T:C	F109L	0.995
4:42401061:C:A	F109L	0.995
4:42401061:C:G	F109L	0.995
4:42401071:G:C	G113R	0.995
4:42401072:G:A	G113D	0.995
4:42398222:T:A	C56S	0.994
4:42398223:G:C	C56S	0.994
4:42398227:C:G	C57W	0.994
4:42398247:A:G	Y64C	0.994
4:42398253:G:A	C66Y	0.994
4:42401039:T:A	V102D	0.994

dbSNP variants (sampled 300 via entrez): RS1000204885 (4:42399222 A>G), RS1001160939 (4:42396745 C>A,T), RS1001445144 (4:42396961 G>A,C), RS1001827016 (4:42398683 T>A,G), RS1003237587 (4:42397679 C>A), RS1003556159 (4:42401983 A>C), RS1003621232 (4:42401618 A>C,G), RS1003836767 (4:42396487 T>C), RS1003899367 (4:42398992 G>C), RS1004096878 (4:42399568 A>C), RS1004232400 (4:42399948 C>T), RS1005103937 (4:42398464 C>A), RS1005902355 (4:42395875 T>C), RS1005921497 (4:42402247 T>C), RS1005948190 (4:42402744 G>A)

Disease associations

OMIM: gene MIM:617325 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004125_6	Type 2 diabetes (age of onset)	2.000000e-06
GCST007627_5	Impulsivity (attentional)	4.000000e-06
GCST010456_1	Anthracycline-induced cardiotoxicity in early breast cancer	4.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006946	behavioural disinhibition measurement
EFO:0005257	response to anthracycline-based chemotherapy
EFO:1001482	cardiotoxicity

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	3
bisphenol F	increases expression	1
propionaldehyde	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
pentanal	decreases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
NSC 689534	affects binding, decreases expression	1
Decitabine	affects expression	1
Zoledronic Acid	decreases expression	1
Fulvestrant	decreases methylation, affects cotreatment	1
Ethanol	affects cotreatment, increases expression	1
Aldehydes	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation, affects methylation, decreases methylation	1
Cisplatin	affects expression	1
Citrulline	decreases expression	1
Copper	affects binding, decreases expression	1
Folic Acid	affects cotreatment, increases expression	1
Lipopolysaccharides	increases expression, decreases reaction	1
Malathion	increases expression	1
Nickel	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tretinoin	decreases expression	1
Triclosan	increases expression	1

Clinical trials (associated diseases)

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