UPK1A

Summary

UPK1A (uroplakin 1A, HGNC:12577) is a protein-coding gene on chromosome 19q13.12, encoding Uroplakin-1a (O00322). Component of the asymmetric unit membrane (AUM); a highly specialized biomembrane elaborated by terminally differentiated urothelial cells.

The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is found in the asymmetrical unit membrane (AUM) where it can complex with other transmembrane 4 superfamily proteins. It may play a role in normal bladder epithelial physiology, possibly in regulating membrane permeability of superficial umbrella cells or in stabilizing the apical membrane through AUM/cytoskeletal interactions. The protein may also play a role in tumor suppression. Alternative splicing results in multiple transcript variants of this gene.

Source: NCBI Gene 11045 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 63 total
• MANE Select transcript: NM_007000

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12577
Approved symbol	UPK1A
Name	uroplakin 1A
Location	19q13.12
Locus type	gene with protein product
Status	Approved
Aliases	TSPAN21
Ensembl gene	ENSG00000105668
Ensembl biotype	protein_coding
OMIM	611557
Entrez	11045

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000222275, ENST00000379013

RefSeq mRNA: 2 — MANE Select: NM_007000 NM_001281443, NM_007000

CCDS: CCDS12470, CCDS62640

Canonical transcript exons

ENST00000222275 — 8 exons

Exon	Start	End
ENSE00000699918	35675840	35676019
ENSE00000699922	35673438	35673545
ENSE00000699925	35673232	35673306
ENSE00000699928	35668454	35668654
ENSE00000699930	35666809	35666896
ENSE00002830255	35677975	35678481
ENSE00003573727	35677812	35677895
ENSE00003964220	35666517	35666538

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 98.31.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0320 / max 11.4272, expressed in 13 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175363	0.0320	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	98.31	gold quality
cervix squamous epithelium	UBERON:0006922	90.78	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.29	gold quality
urinary bladder	UBERON:0001255	89.86	gold quality
esophagus squamous epithelium	UBERON:0006920	85.64	gold quality
epithelium of esophagus	UBERON:0001976	85.40	gold quality
cervix epithelium	UBERON:0004801	85.08	gold quality
mucosa of urinary bladder	UBERON:0001259	83.06	gold quality
vagina	UBERON:0000996	81.48	gold quality
esophagus mucosa	UBERON:0002469	80.46	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.85	gold quality
skin of leg	UBERON:0001511	77.84	gold quality
skin of abdomen	UBERON:0001416	76.86	gold quality
squamous epithelium	UBERON:0006914	76.58	gold quality
zone of skin	UBERON:0000014	74.01	gold quality
urethra	UBERON:0000057	73.10	gold quality
prostate gland	UBERON:0002367	70.19	gold quality
oral cavity	UBERON:0000167	68.75	gold quality
oviduct epithelium	UBERON:0004804	68.44	gold quality
Brodmann (1909) area 10	UBERON:0013541	67.36	gold quality
uterine cervix	UBERON:0000002	65.97	gold quality
amniotic fluid	UBERON:0000173	65.57	silver quality
mammalian vulva	UBERON:0000997	65.21	silver quality
ectocervix	UBERON:0012249	64.71	gold quality
endometrium epithelium	UBERON:0004811	64.68	gold quality
sperm	CL:0000019	64.19	silver quality
tongue squamous epithelium	UBERON:0006919	63.46	gold quality
esophagus	UBERON:0001043	63.42	gold quality
male germ cell	CL:0000015	63.18	silver quality
hair follicle	UBERON:0002073	57.98	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	15.72
E-ANND-3	yes	11.17

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARG

miRNA regulators (miRDB)

32 targeting UPK1A, 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-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-623	99.76	68.16	1170
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-5197-5P	99.64	69.08	1494
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-6799-5P	99.14	65.72	2093
HSA-MIR-942-3P	98.81	69.04	876
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-4780	98.57	64.75	611
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-4722-5P	98.46	66.34	1611
HSA-MIR-619-3P	98.38	65.58	693
HSA-MIR-5589-5P	98.34	64.82	1148
HSA-MIR-3670	97.88	64.39	763
HSA-MIR-450B-3P	97.56	66.12	512
HSA-MIR-769-3P	97.06	64.83	464
HSA-MIR-3156-5P	96.93	67.36	800
HSA-MIR-664B-5P	96.74	67.50	509

Literature-anchored findings (GeneRIF, showing 10)

• uroplakin Ia is expressed in urinary bladder transitional cell carcinoma (PMID:12036448)
• determined the genomic structure of the uroplakin Ia gene and defined the position of a transcriptional start site (PMID:15913809)
• The authors show by cryo-electron microscopy that FimH binding to the extracellular domain of UP Ia induces global conformational changes in the entire UP receptor complex, including a coordinated movement of the tightly bundled transmembrane helices. (PMID:19577575)
• Loss of UPK1A is associated with esophageal squamous cell carcinoma. (PMID:20978196)
• Reduced expression of uroplakin 1A is associated with gastric adenocarcinoma. (PMID:24698999)
• expression of UPKIa was a promising predictor for poor outcome of colorectal cancer patients (PMID:25197375)
• Down-regulation of UPK1A suppresses proliferation and enhances apoptosis of bladder transitional cell carcinoma cells. (PMID:25701463)
• Long Noncoding RNA Expression Profiling Reveals Upregulation of Uroplakin 1A and Uroplakin 1A Antisense RNA 1 under Hypoxic Conditions in Lung Cancer Cells. (PMID:33273139)
• Large-scale human tissue analysis identifies Uroplakin 1a as a putative diagnostic marker for urothelial cancer. (PMID:35872365)
• Uroplakin 1a Interacts with Regucalcin and Proteasome Subunit Beta 1. (PMID:37468792)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	upk1a	ENSDARG00000021866
mus_musculus	Upk1a	ENSMUSG00000006313
rattus_norvegicus	Upk1a	ENSRNOG00000024331

Paralogs (32): TSPAN6 (ENSG00000000003), CD9 (ENSG00000010278), TSPAN9 (ENSG00000011105), TSPAN17 (ENSG00000048140), TSPAN32 (ENSG00000064201), CD82 (ENSG00000085117), TSPAN15 (ENSG00000099282), CD37 (ENSG00000104894), TSPAN12 (ENSG00000106025), TSPAN13 (ENSG00000106537), TSPAN14 (ENSG00000108219), CD81 (ENSG00000110651), TSPAN11 (ENSG00000110900), PRPH2 (ENSG00000112619), UPK1B (ENSG00000114638), TSPAN1 (ENSG00000117472), TSPAN8 (ENSG00000127324), TSPAN16 (ENSG00000130167), TSPAN2 (ENSG00000134198), CD63 (ENSG00000135404), TSPAN31 (ENSG00000135452), TSPAN3 (ENSG00000140391), CD53 (ENSG00000143119), ROM1 (ENSG00000149489), TSPAN7 (ENSG00000156298), TSPAN18 (ENSG00000157570), TSPAN33 (ENSG00000158457), TSPAN5 (ENSG00000168785), CD151 (ENSG00000177697), TSPAN10 (ENSG00000182612), TSPAN4 (ENSG00000214063), TSPAN19 (ENSG00000231738)

Protein

Protein identifiers

Uroplakin-1a — O00322 (reviewed: O00322)

Alternative names: Tetraspanin-21, Uroplakin Ia

All UniProt accessions (1): O00322

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 normal bladder epithelial physiology, possibly in regulating membrane permeability of superficial umbrella cells or in stabilizing the apical membrane through AUM/cytoskeletal interactions.

Subunit / interactions. Homodimer; disulfide-linked. Interacts with uroplakin-2 (UPK2).

Subcellular location. Membrane.

Tissue specificity. High expression restricted to ureteric urothelium (most superficial cells); low expression in prostate. Expression in normal urothelial cells is lost in culture. Some expression in tumor cell lines derived from urothelial malignancies.

Similarity. Belongs to the tetraspanin (TM4SF) family.

Isoforms (2)

UniProt ID	Names	Canonical?
O00322-1	1	yes
O00322-2	2

RefSeq proteins (2): NP_001268372, NP_008931* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000301	Tetraspanin_animals	Family
IPR008952	Tetraspanin_EC2_sf	Homologous_superfamily
IPR018499	Tetraspanin/Peripherin	Family

Pfam: PF00335

UniProt features (14 total): topological domain 5, transmembrane region 4, sequence variant 2, chain 1, glycosylation site 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00322-F1	86.71	0.43

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 (1): 170

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9638630	Attachment of bacteria to epithelial cells

MSigDB gene sets: 75 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, MORF_BRCA1, GOCC_CELL_SURFACE, GOCC_APICAL_PLASMA_MEMBRANE, SCHLOSSER_SERUM_RESPONSE_UP, GOCC_APICAL_PART_OF_CELL, GOCC_PLASMA_MEMBRANE_REGION, RAY_TUMORIGENESIS_BY_ERBB2_CDC25A_UP, TGATTTRY_GFI1_01, MORF_ERCC4, DUTERTRE_ESTRADIOL_RESPONSE_24HR_DN, WIERENGA_STAT5A_TARGETS_UP, WIERENGA_STAT5A_TARGETS_GROUP1, YANG_BCL3_TARGETS_UP, ELVIDGE_HIF1A_TARGETS_DN

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

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

GO Cellular Component (8): endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), protein-containing complex (GO:0032991), extracellular exosome (GO:0070062), apical plasma membrane urothelial plaque (GO:0120001), apical plasma membrane (GO:0016324)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Biofilm formation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
plasma membrane region	2
cell differentiation	1
epithelium development	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
cellular_component	1
extracellular vesicle	1
plasma membrane	1
apical plasma membrane	1
apical part of cell	1

Protein interactions and networks

STRING

628 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UPK1A	UPK3A	O75631	999
UPK1A	UPK2	O00526	999
UPK1A	PMS2P11	Q13670	943
UPK1A	UPK1B	O75841	939
UPK1A	CD53	P19397	760
UPK1A	CD37	P11049	725
UPK1A	CD63	P08962	655
UPK1A	KRT20	P35900	621
UPK1A	TSPAN31	Q12999	555
UPK1A	B4E171	B4E171	544
UPK1A	KRT13	P13646	511
UPK1A	SFTPD	P35247	489
UPK1A	DHRS2	Q13268	462
UPK1A	KRT5	P13647	422
UPK1A	KRT6A	P02538	422

IntAct

8 interactions, top by confidence:

A	B	Type	Score
SFTPD	UPK1A	psi-mi:“MI:0407”(direct interaction)	0.540
UPK1A	SFTPD	psi-mi:“MI:0915”(physical association)	0.540
fimH	UPK1A	psi-mi:“MI:0915”(physical association)	0.400
UPK1A	fimH	psi-mi:“MI:0915”(physical association)	0.400
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
UPK1A	MFSD12	psi-mi:“MI:0914”(association)	0.350
UPK1A	A2ML1	psi-mi:“MI:0914”(association)	0.350

BioGRID (151): TMEM62 (Affinity Capture-MS), SLC44A1 (Affinity Capture-MS), TUSC3 (Affinity Capture-MS), FZD7 (Affinity Capture-MS), FZD3 (Affinity Capture-MS), FZD2 (Affinity Capture-MS), FZD8 (Affinity Capture-MS), CIB1 (Affinity Capture-MS), DPY19L4 (Affinity Capture-MS), DPY19L1 (Affinity Capture-MS), SLC15A4 (Affinity Capture-MS), TRPM4 (Affinity Capture-MS), SELT (Affinity Capture-MS), MFSD5 (Affinity Capture-MS), SLC6A9 (Affinity Capture-MS)

ESM2 similar proteins: A0A8M2B5N2, A0A8V0ZLT4, A1L157, O00322, O60637, O75841, P11049, P19075, P21926, P30409, P30413, P30932, P31053, P38572, P38573, P40239, P40240, P40241, Q0D289, Q2KHY8, Q2MJQ7, Q3SZR9, Q4R4Z3, Q4R7W6, Q566D0, Q568Y5, Q58CY8, Q5RDV7, Q5RE11, Q5RH71, Q61470, Q6AYR9, Q6GQF5, Q6P0C6, Q6ZUX7, Q80WR1, Q8WMQ3, Q91Y55, Q925N4, Q96FX8

Diamond homologs: O00322, O75841, P30413, P38572, P38573, Q566D0, Q9D132, Q9Z2C6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	59
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1222 predictions. Top by Δscore:

Variant	Effect	Δscore
19:35673301:GAC:G	donor_gain	1.0000
19:35673303:C:CG	donor_gain	1.0000
19:35673307:G:GG	donor_gain	1.0000
19:35673434:TCAGA:T	acceptor_loss	1.0000
19:35673435:CAGAT:C	acceptor_loss	1.0000
19:35673436:AGA:A	acceptor_loss	1.0000
19:35673436:AGAT:A	acceptor_gain	1.0000
19:35673437:GATG:G	acceptor_gain	1.0000
19:35675838:A:AG	acceptor_gain	1.0000
19:35675839:G:GG	acceptor_gain	1.0000
19:35675839:GCAA:G	acceptor_gain	1.0000
19:35676015:CCAAG:C	donor_loss	1.0000
19:35676016:CAAG:C	donor_loss	1.0000
19:35676017:AAGGT:A	donor_loss	1.0000
19:35676018:AGGTG:A	donor_loss	1.0000
19:35676019:GGTG:G	donor_loss	1.0000
19:35676020:G:T	donor_loss	1.0000
19:35676021:T:G	donor_loss	1.0000
19:35668452:AGCT:A	acceptor_gain	0.9900
19:35668453:GCT:G	acceptor_gain	0.9900
19:35668453:GCTG:G	acceptor_gain	0.9900
19:35668599:T:TA	donor_gain	0.9900
19:35668600:A:AA	donor_gain	0.9900
19:35668653:CGGT:C	donor_loss	0.9900
19:35668654:GGTGA:G	donor_loss	0.9900
19:35668655:G:GA	donor_loss	0.9900
19:35668656:T:C	donor_loss	0.9900
19:35673299:GTGAC:G	donor_gain	0.9900
19:35673300:TGACT:T	donor_gain	0.9900
19:35673302:ACTAC:A	donor_gain	0.9900

AlphaMissense

1687 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:35675875:G:C	W168C	1.000
19:35675875:G:T	W168C	1.000
19:35675873:T:A	W168R	0.999
19:35675873:T:C	W168R	0.999
19:35673525:T:A	W150R	0.998
19:35673525:T:C	W150R	0.998
19:35673527:G:C	W150C	0.998
19:35673527:G:T	W150C	0.998
19:35675849:T:A	C160S	0.997
19:35675850:G:A	C160Y	0.997
19:35675850:G:C	C160S	0.997
19:35675852:G:T	G161C	0.997
19:35675941:C:G	C190W	0.997
19:35675942:T:A	C191S	0.997
19:35675943:G:C	C191S	0.997
19:35675984:T:A	C205S	0.997
19:35675985:G:C	C205S	0.997
19:35677816:G:A	C218Y	0.997
19:35673268:T:C	C108R	0.996
19:35675846:T:A	C159S	0.996
19:35675846:T:C	C159R	0.996
19:35675847:G:C	C159S	0.996
19:35675851:T:G	C160W	0.996
19:35675853:G:A	G161D	0.996
19:35675853:G:T	G161V	0.996
19:35675927:T:A	W186R	0.996
19:35675927:T:C	W186R	0.996
19:35675939:T:A	C190S	0.996
19:35675939:T:C	C190R	0.996
19:35675940:G:A	C190Y	0.996

dbSNP variants (sampled 300 via entrez): RS1000093320 (19:35669797 C>T), RS1000579510 (19:35675570 C>T), RS1001045741 (19:35669281 G>A,C), RS1001322872 (19:35669163 C>T), RS1001456717 (19:35668317 A>C,G), RS1001628471 (19:35668867 A>G), RS1001658137 (19:35673715 G>A), RS1002496030 (19:35675605 G>A), RS1002559116 (19:35667173 G>A,C), RS1002771094 (19:35678671 G>T), RS1002923763 (19:35678681 G>A), RS1003152423 (19:35672514 C>A,T), RS1003212059 (19:35678432 G>A), RS1003596260 (19:35670749 C>G), RS1004063349 (19:35667783 C>T)

Disease associations

OMIM: gene MIM:611557 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010002_54	Refractive error	1.000000e-10
GCST010703_277	Brain morphology (MOSTest)	2.000000e-15

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

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
mercuric bromide	decreases expression, affects cotreatment	2
Resveratrol	affects cotreatment, decreases expression, increases expression	2
Cisplatin	affects expression, affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
1-cyclopropyl-4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)piperazine	decreases reaction, increases expression	1
fluorene-9-bisphenol	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
methylmercuric chloride	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
sodium arsenate	decreases expression, increases abundance	1
ethyl-p-hydroxybenzoate	decreases expression	1
dimethylselenide	increases expression, increases oxidation	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
jinfukang	affects cotreatment, decreases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Decitabine	affects expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Estradiol	affects cotreatment, increases expression	1
Oxygen	decreases reaction, increases expression	1
Ozone	increases expression, increases oxidation	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Urethane	decreases expression	1

Clinical trials (associated diseases)

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