UPK2

Summary

UPK2 (uroplakin 2, HGNC:12579) is a protein-coding gene on chromosome 11q23.3, encoding Uroplakin-2 (O00526). Component of the asymmetric unit membrane (AUM); a highly specialized biomembrane elaborated by terminally differentiated urothelial cells.

This gene encodes one of the proteins of the highly conserved urothelium-specific integral membrane proteins of the asymmetric unit membrane which forms urothelium apical plaques in mammals. The asymmetric unit membrane is believed to strengthen the urothelium by preventing cell rupture during bladder distention. The encoded protein is expressed in the peripheral blood of bladder cancer patients with transitional cell carcinomas.

Source: NCBI Gene 7379 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 29 total
• MANE Select transcript: NM_006760

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12579
Approved symbol	UPK2
Name	uroplakin 2
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	UP2, UPII, MGC138598
Ensembl gene	ENSG00000110375
Ensembl biotype	protein_coding
OMIM	611558
Entrez	7379

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000264031, ENST00000534788

RefSeq mRNA: 1 — MANE Select: NM_006760 NM_006760

CCDS: CCDS8404

Canonical transcript exons

ENST00000264031 — 5 exons

Exon	Start	End
ENSE00000930812	118957208	118957346
ENSE00001276572	118956298	118956426
ENSE00002140609	118958097	118958559
ENSE00003549235	118956883	118957014
ENSE00003593556	118957598	118957668

Expression profiles

Bgee: expression breadth ubiquitous, 120 present calls, max score 92.58.

FANTOM5 (CAGE): breadth broad, TPM avg 3.7226 / max 667.1139, expressed in 264 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117073	3.6183	258
117074	0.0489	22
117075	0.0300	12
117076	0.0255	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	92.58	gold quality
urinary bladder	UBERON:0001255	80.50	gold quality
lower esophagus mucosa	UBERON:0035834	75.25	gold quality
frontal pole	UBERON:0002795	68.43	gold quality
paraflocculus	UBERON:0005351	68.11	gold quality
middle frontal gyrus	UBERON:0002702	68.00	gold quality
ganglionic eminence	UBERON:0004023	66.81	gold quality
cortical plate	UBERON:0005343	66.67	gold quality
esophagus mucosa	UBERON:0002469	63.55	gold quality
pancreatic ductal cell	CL:0002079	62.02	silver quality
tongue squamous epithelium	UBERON:0006919	61.44	gold quality
nucleus accumbens	UBERON:0001882	60.90	gold quality
epithelial cell of pancreas	CL:0000083	60.73	gold quality
mucosa of urinary bladder	UBERON:0001259	60.47	silver quality
embryo	UBERON:0000922	59.40	gold quality
Brodmann (1909) area 10	UBERON:0013541	59.40	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	59.11	gold quality
cingulate cortex	UBERON:0003027	58.34	gold quality
anterior cingulate cortex	UBERON:0009835	58.16	gold quality
ventricular zone	UBERON:0003053	58.07	gold quality
amniotic fluid	UBERON:0000173	57.52	gold quality
cerebellar vermis	UBERON:0004720	57.05	gold quality
cranial nerve II	UBERON:0000941	56.34	silver quality
stromal cell of endometrium	CL:0002255	56.19	gold quality
diaphragm	UBERON:0001103	56.14	gold quality
putamen	UBERON:0001874	56.05	gold quality
heart right ventricle	UBERON:0002080	55.82	gold quality
caudate nucleus	UBERON:0001873	55.69	gold quality
amygdala	UBERON:0001876	55.46	gold quality
hypothalamus	UBERON:0001898	55.11	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	13.94
E-ANND-3	no	1.90

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GRHL3, HNF4A, NR1I3, PPARG

miRNA regulators (miRDB)

38 targeting UPK2, 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-4487	99.96	64.58	1252
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-765	99.84	68.24	2442
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-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-4796-3P	99.08	68.38	1681
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-6827-5P	98.46	64.88	1256
HSA-MIR-6873-5P	98.45	66.14	1417
HSA-MIR-6819-5P	97.96	66.59	1071
HSA-MIR-4665-5P	97.91	67.69	1536
HSA-MIR-6737-5P	97.75	66.54	1044

Literature-anchored findings (GeneRIF, showing 11)

• study offers no definitive support for uroplakin II mutations causing human renal tract malformations (PMID:17012268)
• combination of prostate stem cell antigen enhancer and uroplakin II promoter is feasible in constructing bladder cancer-specific vectors (PMID:18440837)
• Uroplakin II antibody BC21 demonstrated superior sensitivity and specificity in urothelial carcinoma, compared with uroplakin III, suggesting an advantage in differential diagnosis of urothelial carcinoma and in the detection of tumors of unknown origin. (PMID:24978921)
• UPII demonstrates a significantly higher sensitivity than UPIII in conventional and variant urothelial carcinomas (PMID:25389341)
• UPII was highly specific/moderately sensitive for urothelial carcinoma. May be a potentially useful marker to identify urothelial lineage and help distinguish UC from prostate cancer or, in conjunction with GATA3, from metastatic breast cancer. (PMID:25449628)
• UPII, GATA3, and p40, when used in combination, are highly sensitive in the differential diagnosis of invasive urothelial carcinoma. (PMID:25611245)
• These results suggest that whereas GATA-3 and uroplakin II may be most useful in the diagnosis of urothelial carcinoma metastasis, p40 may be additionally suited as a prognostic marker. (PMID:27594510)
• Uroplakin II was immunopositive in 53% and 60% of urothelial carcinomas (UC) of the bladder and the ureter, respectively. (PMID:30061246)
• Expression of uroplakin II and GATA-3 in bladder cancer mimickers: caveats in the use of a limited panel to determine cell of origin in bladder lesions. (PMID:33887302)
• Uroplakin II as a single marker for luminal versus basal molecular subtypes in muscle invasive urothelial carcinoma. (PMID:35612672)
• Distinct Uroplakin II Staining Pattern in Apocrine Breast Carcinoma. (PMID:36227121)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Upk2	ENSMUSG00000041523
rattus_norvegicus	Upk2	ENSRNOG00000043324

Protein

Protein identifiers

Uroplakin-2 — O00526 (reviewed: O00526)

Alternative names: Uroplakin II

All UniProt accessions (1): O00526

UniProt curated annotations — full annotation on UniProt →

Function. Component of the asymmetric unit membrane (AUM); a highly specialized biomembrane elaborated by terminally differentiated urothelial cells. May play an important role in regulating the assembly of the AUM.

Subunit / interactions. Interacts with uroplakin-1a (UPK1A).

Subcellular location. Cell membrane.

Tissue specificity. Expressed in ureter.

Similarity. Belongs to the uroplakin-2 family.

RefSeq proteins (1): NP_006751* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009952	Uroplakin-2	Family

Pfam: PF07353

UniProt features (12 total): glycosylation site 3, sequence variant 2, topological domain 2, signal peptide 1, propeptide 1, sequence conflict 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00526-F1	77.04	0.16

Functional residue map

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

Glycosylation sites (3): 28, 57, 66

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 85 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, WANG_CLIM2_TARGETS_UP, CCANNAGRKGGC_UNKNOWN, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, GOCC_APICAL_PLASMA_MEMBRANE, TAL1BETAE47_01, SHEN_SMARCA2_TARGETS_DN, GOCC_APICAL_PART_OF_CELL, GOCC_PLASMA_MEMBRANE_REGION, ZHOU_INFLAMMATORY_RESPONSE_LIVE_UP, MIKKELSEN_MEF_ICP_WITH_H3K27ME3, MIKKELSEN_ES_ICP_WITH_H3K4ME3, E2F1_UP.V1_UP, ERBB2_UP.V1_UP

GO Biological Process (1): epithelial cell differentiation (GO:0030855)

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

GO Cellular Component (4): plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), extracellular exosome (GO:0070062), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell differentiation	1
epithelium development	1
binding	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
extracellular vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

584 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UPK2	UPK3A	O75631	999
UPK2	UPK1A	O00322	999
UPK2	UPK1B	O75841	999
UPK2	PMS2P11	Q13670	941
UPK2	KRT20	P35900	703
UPK2	LIAT1	Q6ZQX7	585
UPK2	KRT5	P13647	573
UPK2	GATA3	P23771	528
UPK2	KRT7	P08729	510
UPK2	KRT14	P02533	509
UPK2	FOXR1	Q6PIV2	465
UPK2	CD53	P19397	451
UPK2	FGFR3	P22607	451
UPK2	CD37	P11049	431
UPK2	FOXA1	P55317	429

IntAct

103 interactions, top by confidence:

A	B	Type	Score
UPK2	ATP6AP2	psi-mi:“MI:0915”(physical association)	0.670
UPK2	CD74	psi-mi:“MI:0915”(physical association)	0.600
UPK2	KASH5	psi-mi:“MI:0915”(physical association)	0.560
KASH5	UPK2	psi-mi:“MI:0915”(physical association)	0.560
UPK2	BTNL9	psi-mi:“MI:0915”(physical association)	0.560
UPK2	FNDC9	psi-mi:“MI:0915”(physical association)	0.560
UPK2	KIR3DL3	psi-mi:“MI:0915”(physical association)	0.560
PLP1	UPK2	psi-mi:“MI:0915”(physical association)	0.560
UPK2	SLC22A23	psi-mi:“MI:0915”(physical association)	0.560
UPK2	CLEC17A	psi-mi:“MI:0915”(physical association)	0.560
UPK2	CLEC7A	psi-mi:“MI:0915”(physical association)	0.560
UPK2	ITM2C	psi-mi:“MI:0915”(physical association)	0.560
UPK2	TNFSF11	psi-mi:“MI:0915”(physical association)	0.560
UPK2	STOML3	psi-mi:“MI:0915”(physical association)	0.560
UPK2	TMPRSS2	psi-mi:“MI:0915”(physical association)	0.560
UPK2	HPN	psi-mi:“MI:0915”(physical association)	0.560
UPK2	TNFSF14	psi-mi:“MI:0915”(physical association)	0.560
BSCL2	UPK2	psi-mi:“MI:0915”(physical association)	0.560
UPK2	TMEM106C	psi-mi:“MI:0915”(physical association)	0.560
UPK2	ASGR2	psi-mi:“MI:0915”(physical association)	0.560
UPK2	FCGR1A	psi-mi:“MI:0915”(physical association)	0.560
UPK2	PLP1	psi-mi:“MI:0915”(physical association)	0.560
UPK2	GPA33	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (142): CCDC155 (Two-hybrid), UPK2 (Two-hybrid), UPK2 (Two-hybrid), UPK2 (Two-hybrid), UPK2 (Two-hybrid), C3orf52 (Two-hybrid), TNFSF11 (Two-hybrid), RNF170 (Two-hybrid), PLP1 (Two-hybrid), TNFSF14 (Two-hybrid), STOML3 (Two-hybrid), TMEM106C (Two-hybrid), ITM2C (Two-hybrid), SLC22A23 (Two-hybrid), GPA33 (Two-hybrid)

ESM2 similar proteins: A2RU67, B1AUH1, B3DK56, D3ZWJ9, E2RK30, E9PZ36, E9Q612, O00526, O14522, O43278, O60486, P08571, P08F94, P09758, P10810, P35054, P38575, Q04912, Q08537, Q0VCT2, Q3TYX2, Q3U2C5, Q5XIL0, Q62190, Q63691, Q6DF55, Q6NXM3, Q6P9Z6, Q6PVW7, Q6UDI7, Q6YI48, Q6ZN44, Q7TNI2, Q86VZ4, Q8BGV3, Q8BYI8, Q8CB67, Q8K1S3, Q91XF4, Q91ZV7

Diamond homologs: O00526, P38575, Q08537, Q95L04

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 37 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.

GO biological processes:

GO term	Partners	Fold	FDR
cell surface receptor signaling pathway	6	12.0×	1e-03
immune response	7	10.3×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	25
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

731 predictions. Top by Δscore:

Variant	Effect	Δscore
11:118957586:A:AG	acceptor_gain	1.0000
11:118957587:A:G	acceptor_gain	1.0000
11:118957591:A:AG	acceptor_gain	1.0000
11:118956418:GGGC:G	donor_gain	0.9900
11:118957588:A:AG	acceptor_gain	0.9900
11:118957589:C:G	acceptor_gain	0.9900
11:118957592:C:G	acceptor_gain	0.9900
11:118957593:A:AG	acceptor_gain	0.9900
11:118957594:A:G	acceptor_gain	0.9900
11:118958092:GACA:G	acceptor_loss	0.9900
11:118958094:CAG:C	acceptor_loss	0.9900
11:118958095:A:T	acceptor_loss	0.9900
11:118958096:GGAA:G	acceptor_gain	0.9900
11:118957157:G:A	acceptor_gain	0.9800
11:118957596:A:G	acceptor_gain	0.9800
11:118957597:G:GG	acceptor_gain	0.9800
11:118958095:A:AG	acceptor_gain	0.9800
11:118958096:G:GG	acceptor_gain	0.9800
11:118958096:GGA:G	acceptor_gain	0.9800
11:118956419:G:T	donor_gain	0.9700
11:118957156:T:TA	acceptor_gain	0.9700
11:118957597:GC:G	acceptor_gain	0.9700
11:118958095:AG:A	acceptor_gain	0.9700
11:118958096:GG:G	acceptor_gain	0.9700
11:118957665:CCTC:C	donor_gain	0.9600
11:118957665:CCTCG:C	donor_loss	0.9600
11:118957666:CTC:C	donor_gain	0.9600
11:118957666:CTCGT:C	donor_loss	0.9600
11:118957667:TCGTA:T	donor_loss	0.9600
11:118957668:CGT:C	donor_loss	0.9600

AlphaMissense

1156 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:118957223:T:G	F75C	0.989
11:118957222:T:C	F75L	0.985
11:118957224:T:A	F75L	0.985
11:118957224:T:G	F75L	0.985
11:118957638:A:C	S130R	0.985
11:118957640:C:A	S130R	0.985
11:118957640:C:G	S130R	0.985
11:118956885:T:C	F27L	0.982
11:118956887:C:A	F27L	0.982
11:118956887:C:G	F27L	0.982
11:118957605:T:G	Y119D	0.982
11:118956979:C:A	A58D	0.980
11:118956886:T:G	F27C	0.976
11:118957223:T:C	F75S	0.976
11:118958166:T:A	L163H	0.975
11:118956943:T:A	V46D	0.974
11:118956985:T:C	L60P	0.973
11:118957285:T:C	F96L	0.973
11:118957287:C:A	F96L	0.973
11:118957287:C:G	F96L	0.973
11:118958157:C:A	T160K	0.973
11:118958178:T:A	M167K	0.973
11:118956933:A:C	S43R	0.972
11:118956935:C:A	S43R	0.972
11:118956935:C:G	S43R	0.972
11:118957237:T:C	C80R	0.969
11:118956957:T:C	C51R	0.967
11:118956978:G:C	A58P	0.964
11:118958151:T:A	V158D	0.963
11:118956958:G:A	C51Y	0.962

dbSNP variants (sampled 300 via entrez): RS1000392173 (11:118955449 A>C), RS1000903628 (11:118955502 C>T), RS1002093358 (11:118954811 C>T), RS1002160285 (11:118954397 C>A), RS1002445686 (11:118956138 T>A), RS1003771225 (11:118956070 G>A), RS1003896227 (11:118957767 C>G,T), RS1004369650 (11:118956386 G>A,T), RS1004405407 (11:118956676 A>T), RS1006078242 (11:118957997 T>A,C,G), RS1010159186 (11:118955673 G>A), RS1011618873 (11:118958599 C>T), RS1011883024 (11:118954938 A>G), RS1011886704 (11:118956923 G>A), RS1012591917 (11:118957402 A>C)

Disease associations

OMIM: gene MIM:611558 | disease phenotypes: MIM:611819

GenCC curated gene-disease

Mondo (1): long QT syndrome 10 (MONDO:0012737)

Orphanet (2): Romano-Ward syndrome (Orphanet:101016), Congenital long QT syndrome (Orphanet:768)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009798_24	Asthma	4.000000e-11

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567514	Long Qt Syndrome 10 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
sodium arsenite	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases expression	1
Diethylhexyl Phthalate	increases expression	1
Estradiol	affects cotreatment, increases expression	1
Lipopolysaccharides	affects cotreatment, increases expression, affects response to substance	1
Mustard Gas	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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