UCN3

Summary

UCN3 (urocortin 3, HGNC:17781) is a protein-coding gene on chromosome 10p15.1, encoding Urocortin-3 (Q969E3). Suppresses food intake, delays gastric emptying and decreases heat-induced edema.

This gene encodes a member of the sauvagine/corticotropin-releasing factor/urotensin I family of proteins. The encoded preproprotein is proteolytically processed to generate the mature peptide hormone, which is secreted by pancreatic beta and alpha cells. This hormone is an endogenous ligand for corticotropin-releasing factor receptor 2 and may regulate insulin secretion in response to plasma glucose levels. Patients with type 2 diabetes exhibit reduced levels of the encoded protein in beta cells. In the brain, the encoded protein may be responsible for the effects of stress on appetite.

Source: NCBI Gene 114131 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 40 total
• MANE Select transcript: NM_053049

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17781
Approved symbol	UCN3
Name	urocortin 3
Location	10p15.1
Locus type	gene with protein product
Status	Approved
Aliases	UCNIII, SPC
Ensembl gene	ENSG00000178473
Ensembl biotype	protein_coding
OMIM	605901
Entrez	114131

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000380433

RefSeq mRNA: 1 — MANE Select: NM_053049 NM_053049

CCDS: CCDS7065

Canonical transcript exons

ENST00000380433 — 2 exons

Exon	Start	End
ENSE00001484954	5373715	5374692
ENSE00001484959	5364966	5365230

Expression profiles

Bgee: expression breadth broad, 71 present calls, max score 91.11.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2293 / max 116.4285, expressed in 20 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
103630	0.0919	13
103629	0.0603	11
103632	0.0421	12
103631	0.0188	6
103633	0.0162	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	91.11	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	82.97	gold quality
pancreas	UBERON:0001264	72.48	gold quality
mucosa of transverse colon	UBERON:0004991	71.24	gold quality
rectum	UBERON:0001052	66.96	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	65.44	gold quality
body of pancreas	UBERON:0001150	64.56	gold quality
superficial temporal artery	UBERON:0001614	64.41	gold quality
nasal cavity mucosa	UBERON:0001826	63.76	gold quality
gingival epithelium	UBERON:0001949	62.81	gold quality
vastus lateralis	UBERON:0001379	62.80	gold quality
quadriceps femoris	UBERON:0001377	62.61	gold quality
transverse colon	UBERON:0001157	62.26	gold quality
germinal epithelium of ovary	UBERON:0001304	61.22	gold quality
mucosa of paranasal sinus	UBERON:0005030	61.22	gold quality
adenohypophysis	UBERON:0002196	61.11	gold quality
gingiva	UBERON:0001828	61.08	gold quality
amniotic fluid	UBERON:0000173	60.95	gold quality
nasal cavity epithelium	UBERON:0005384	60.48	gold quality
heart right ventricle	UBERON:0002080	60.08	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	59.77	gold quality
tendon of biceps brachii	UBERON:0008188	59.66	gold quality
gall bladder	UBERON:0002110	59.27	gold quality
small intestine Peyer’s patch	UBERON:0003454	59.22	gold quality
duodenum	UBERON:0002114	59.08	gold quality
small intestine	UBERON:0002108	59.03	gold quality
epithelium of nasopharynx	UBERON:0001951	58.88	gold quality
intestine	UBERON:0000160	57.98	gold quality
large intestine	UBERON:0000059	57.87	gold quality
colon	UBERON:0001155	57.72	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	7.01
E-ANND-3	no	2.32

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A

Literature-anchored findings (GeneRIF, showing 23)

• SCP and UCN are potent activators of the p42/44 MAPK pathway, with SRP able to induce phosphorylation of p42/44 MAPK as well, albeit not as pronounced (PMID:14519439)
• CRH-R1:CRH-R2 ratio varied according to fat-depot type; whereas CRH-R1 expression was higher in sc fat than in visceral fat, the opposite was true for CRH-R2. (PMID:14764822)
• Expression of Ucn III/SCP in the human heart and kidney as well as brain and pituitary tissues and its presence in plasma and urine. Ucn III/SCP may therefore regulate the cardiac and renal function as a local factor and a circulating hormone. (PMID:15070962)
• Ucn 3 plays some physiological or pathological roles in the modulation of gastrointestinal functions during stressful conditions. (PMID:15949638)
• Ucn3 is produced in the normal adrenal gland and in adrenal tumors (both adrenocortical tumors and pheochromocytomas) and acts as an autocrine or paracrine regulator in both the normal and cancerous adrenal gland tissue. (PMID:16095756)
• UCN2 and UCN3 are expressed in human placenta, decidua, and fetal membranes and may be proposed as regulators of placental vascular endothelial tone. (PMID:16626608)
• Both peptides were immunolocalized in epithelial, stromal, and endothelial cells. (PMID:17074339)
• the SCP/CRHR2 system is present in human ovaries and treatment with SCP/Ucn3 inhibits progesterone production by cultured granulosa-lutein cells through interaction with CRHR2 (PMID:19351656)
• Placental Ucn2 and Ucn3 expression is sensitive to O(2) tensions and mediated by HIF-1alpha. In preeclampsia, the increased expression of both peptides may reflect a response to the oxidative stress. (PMID:20616367)
• Confirm the anti-inflammatory function of VIP, through the modulation of the expression of CRF system that impacts in a reduction of mediators with inflammatory/destructive functions. (PMID:21360527)
• These data suggest a possible involvement of urocortin 2 and Ucn 3 in the mechanisms of endometriosis. (PMID:21454316)
• study showed that Ucn2 and Ucn3 differentially regulate the LPS-induced TNF-alpha and IL-10 expression and secretion in trophoblast explants acting through CRH-R2. Ucn3 has an anti-inflammatory effect. (PMID:22000474)
• SCP inhibits a subpopulation of PVN neurons, especially OTergic magnocellular neurons, by enhancing the activity of GIRK channels via CRF-R2 (PMID:23349753)
• Data suggest that UCN3 expression can serve as a late stage maturation/differentiation marker in beta-cells during pancreogenesis. [REVIEW] (PMID:25148370)
• The molecular modifications of urocortin 3[36-38] led to an improved understanding of the relationship between molecular structure and biological activity of this peptide, could be further tested for possible clinical treatment of depression (PMID:25304878)
• The paracrine actions of Ucn3 activate a negative feedback loop that promotes somatostatin release to ensure the timely reduction of insulin secretion upon normalization of plasma glucose. (PMID:26076035)
• results show that activation of CRH receptors by CRH ligands stimulates VEGF-A expression in intestinal epithelial cells through the cAMP/CREB pathway (PMID:26350463)
• circulating levels elevated and positively correlated with C-reactive protein in polycystic ovary syndrome (PMID:26488073)
• Antiamnesic properties of analogs and mimetics of the tripeptide human urocortin 3 (PMID:27262310)
• examination of the local and systemic cardiovascular effects of urocortin 2 and urocortin 3 in healthy subjects and patients with heart failure (PMID:27275843)
• In summary, cardiac expression of CRFR1, CRF, and Ucn3 genes is elevated in heart failure and may contribute to the activation of the CRF/Ucn system in these patients. (PMID:27754786)
• Increased urocortin 3 levels are associated with the risk of having type 2 diabetes mellitus. (PMID:31893569)
• Urocortin3: Local inducer of somatostatin release and bellwether of beta cell maturity. (PMID:35065098)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ucn3l	ENSDARG00000087241
mus_musculus	Ucn3	ENSMUSG00000044988
rattus_norvegicus	Ucn3	ENSRNOG00000017759

Paralogs (1): UCN2 (ENSG00000145040)

Protein

Protein identifiers

Urocortin-3 — Q969E3 (reviewed: Q969E3)

Alternative names: Stresscopin, Urocortin III

All UniProt accessions (1): Q969E3

UniProt curated annotations — full annotation on UniProt →

Function. Suppresses food intake, delays gastric emptying and decreases heat-induced edema. Might represent an endogenous ligand for maintaining homeostasis after stress.

Subunit / interactions. Binds with high affinity to CRF receptors 2-alpha and 2-beta.

Subcellular location. Secreted.

Similarity. Belongs to the sauvagine/corticotropin-releasing factor/urotensin I family.

RefSeq proteins (1): NP_444277* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000187	CRF	Domain
IPR024270	Urocortin_II/III	Family

Pfam: PF00473

UniProt features (9 total): sequence variant 2, helix 2, signal peptide 1, propeptide 1, chain 1, region of interest 1, modified residue 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3N93	X-RAY DIFFRACTION	2.5
2RMH	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q969E3-F1	65.44	0.12

Functional residue map

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

Post-translational modifications (1): 157

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-373080	Class B/2 (Secretin family receptors)

MSigDB gene sets: 95 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GOBP_DIGESTION, GOBP_RESPONSE_TO_IMMOBILIZATION_STRESS, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_INSULIN_SECRETION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_INSULIN_SECRETION, GOBP_REGULATION_OF_PROTEIN_SECRETION, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_LEVELS, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS

GO Biological Process (11): adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), digestion (GO:0007586), response to glucose (GO:0009749), hormone-mediated signaling pathway (GO:0009755), cellular response to nutrient levels (GO:0031669), positive regulation of insulin secretion (GO:0032024), response to immobilization stress (GO:0035902), response to starvation (GO:0042594), positive regulation of membrane potential (GO:0045838), response to corticosterone (GO:0051412), cellular response to hypoxia (GO:0071456)

GO Molecular Function (5): hormone activity (GO:0005179), corticotropin-releasing hormone receptor binding (GO:0051429), corticotropin-releasing hormone receptor 2 binding (GO:0051431), signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), varicosity (GO:0043196), axon terminus (GO:0043679), axon (GO:0030424)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
GPCR ligand binding	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to nutrient levels	2
response to stress	2
cellular anatomical structure	2
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
multicellular organismal process	1
response to hexose	1
signal transduction	1
cellular response to hormone stimulus	1
cellular response to stimulus	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
regulation of membrane potential	1
response to glucocorticoid	1
response to mineralocorticoid	1
response to alcohol	1
response to ketone	1
response to hypoxia	1
cellular response to stress	1
cellular response to decreased oxygen levels	1
receptor ligand activity	1
peptide hormone receptor binding	1
neuropeptide receptor binding	1
corticotropin-releasing hormone receptor binding	1
protein binding	1
binding	1
main axon	1
neuron projection terminus	1
presynapse	1
distal axon	1
neuron projection	1

Protein interactions and networks

STRING

596 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UCN3	CRHR2	Q13324	999
UCN3	CRHR1	P34998	990
UCN3	UCN2	Q96RP3	987
UCN3	CRH	P06850	963
UCN3	UCN	P55089	957
UCN3	CRHBP	P24387	839
UCN3	POMC	P01189	668
UCN3	NKX6-1	P78426	640
UCN3	SST	P01166	608
UCN3	NKX6-2	Q9C056	596
UCN3	CFAP126	Q5VTH2	592
UCN3	SLC2A2	P11168	585
UCN3	GLP1R	P43220	579
UCN3	GCG	P01275	562
UCN3	UMOD	P07911	539

IntAct

6 interactions, top by confidence:

A	B	Type	Score
CRHR2	UCN3	psi-mi:“MI:0407”(direct interaction)	0.560
CRH	CRHR2	psi-mi:“MI:0407”(direct interaction)	0.540
UCN3	PCDH7	psi-mi:“MI:0914”(association)	0.350
UCN3	VWA8	psi-mi:“MI:0914”(association)	0.350

BioGRID (24): HERC1 (Affinity Capture-MS), CD109 (Affinity Capture-MS), UCN3 (Reconstituted Complex), UCN3 (Reconstituted Complex), GOPC (Affinity Capture-MS), FAT1 (Affinity Capture-MS), BTD (Affinity Capture-MS), FREM2 (Affinity Capture-MS), RNF25 (Affinity Capture-MS), FAT3 (Affinity Capture-MS), PCDH7 (Affinity Capture-MS), FAT4 (Affinity Capture-MS), GPR98 (Affinity Capture-MS), PCDH20 (Affinity Capture-MS), SEC24A (Affinity Capture-MS)

ESM2 similar proteins: A0A679PF76, A5LHG2, D2HJ50, D5J9S0, F5CPE8, P01172, P01286, P02822, P07480, P09681, P09916, P0DJK0, P0DJK1, P0DW25, P10683, P11242, P13207, P16043, P17640, P20800, P22389, P22466, P23943, P33745, P45644, P47212, P48143, P48756, P51694, P58844, P79799, P83228, Q06145, Q1RMJ9, Q5NRP8, Q5NRQ0, Q60549, Q62949, Q6DJ00, Q765Z5

Diamond homologs: Q1RMJ9, Q91WW1, Q924A4, Q969E3, Q99ML8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

329 predictions. Top by Δscore:

Variant	Effect	Δscore
10:5365216:G:GT	donor_gain	1.0000
10:5365216:G:T	donor_gain	1.0000
10:5365229:GG:G	donor_gain	1.0000
10:5365230:GG:G	donor_gain	1.0000
10:5365231:G:C	donor_loss	0.9900
10:5365231:G:GG	donor_gain	0.9900
10:5365232:T:G	donor_loss	0.9900
10:5373707:T:TA	acceptor_gain	0.9900
10:5373709:CTGCA:C	acceptor_loss	0.9900
10:5373710:T:A	acceptor_gain	0.9900
10:5373710:TGCAG:T	acceptor_loss	0.9900
10:5373711:GCA:G	acceptor_loss	0.9900
10:5373712:CA:C	acceptor_loss	0.9900
10:5373712:CAGGG:C	acceptor_gain	0.9900
10:5373713:A:AC	acceptor_loss	0.9900
10:5373713:A:AG	acceptor_gain	0.9900
10:5373713:AG:A	acceptor_gain	0.9900
10:5373713:AGG:A	acceptor_gain	0.9900
10:5373713:AGGGA:A	acceptor_gain	0.9900
10:5373714:G:GG	acceptor_gain	0.9900
10:5373714:GG:G	acceptor_gain	0.9900
10:5373714:GGG:G	acceptor_gain	0.9900
10:5373714:GGGA:G	acceptor_gain	0.9900
10:5373714:GGGAG:G	acceptor_gain	0.9900
10:5374200:G:GT	donor_gain	0.9700
10:5374197:G:GT	donor_gain	0.9600
10:5365228:CGG:C	donor_gain	0.9400
10:5365229:GGG:G	donor_gain	0.9400
10:5372713:C:G	donor_gain	0.9400
10:5365227:TCGG:T	donor_gain	0.9300

AlphaMissense

1045 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:5374100:C:T	P127L	0.985
10:5374169:A:T	N150I	0.979
10:5374094:A:T	D125V	0.977
10:5374091:T:A	L124H	0.974
10:5374113:G:A	M131I	0.972
10:5374113:G:C	M131I	0.972
10:5374113:G:T	M131I	0.972
10:5374097:T:A	V126D	0.969
10:5374183:G:C	A155P	0.969
10:5374171:G:C	A151P	0.964
10:5374109:T:G	I130S	0.960
10:5374099:C:A	P127T	0.959
10:5374095:C:A	D125E	0.958
10:5374095:C:G	D125E	0.958
10:5374100:C:A	P127H	0.958
10:5374181:T:C	M154T	0.958
10:5374159:G:C	A147P	0.957
10:5374178:T:C	L153P	0.957
10:5374193:G:T	G158V	0.957
10:5374087:T:C	S123P	0.956
10:5374193:G:A	G158E	0.956
10:5374085:T:A	L122Q	0.954
10:5374100:C:G	P127R	0.954
10:5374121:T:A	L134H	0.952
10:5374182:G:A	M154I	0.952
10:5374182:G:C	M154I	0.952
10:5374182:G:T	M154I	0.952
10:5374103:C:T	T128I	0.948
10:5374132:G:C	A138P	0.948
10:5374099:C:T	P127S	0.946

dbSNP variants (sampled 300 via entrez): RS1000170377 (10:5374393 C>T), RS1000558689 (10:5363819 T>C), RS1000583272 (10:5363569 T>A), RS1000880185 (10:5369025 T>C), RS1001775347 (10:5373443 C>T), RS1001950033 (10:5368953 G>T), RS1002136014 (10:5363269 T>C), RS1002384046 (10:5368693 A>C,T), RS1002774860 (10:5372321 G>C), RS1002906055 (10:5367894 C>A), RS1002937140 (10:5367659 G>T), RS1004025057 (10:5374672 T>G), RS1004296092 (10:5369622 C>A), RS1004422049 (10:5364387 T>C,G), RS1004453979 (10:5364104 G>A)

Disease associations

OMIM: gene MIM:605901 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001428_8	Intelligence	9.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence

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
pirinixic acid	affects binding, decreases expression, increases activity	1
terbufos	increases methylation	1
arsenite	increases methylation	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	decreases methylation	1
imeglimin	increases expression	1
Air Pollutants	increases expression, increases abundance	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Fonofos	increases methylation	1
Parathion	increases methylation	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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