UCN2

Summary

UCN2 (urocortin 2, HGNC:18414) is a protein-coding gene on chromosome 3p21.31, encoding Urocortin-2 (Q96RP3). Suppresses food intake, delays gastric emptying and decreases heat-induced edema.

This gene is a member of the sauvagine/corticotropin-releasing factor/urotensin I family. It is structurally related to the corticotropin-releasing factor (CRF) gene and the encoded product is an endogenous ligand for CRF type 2 receptors. In the brain it may be responsible for the effects of stress on appetite. In spite of the gene family name similarity, the product of this gene has no sequence similarity to urotensin II.

Source: NCBI Gene 90226 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 1 total
• MANE Select transcript: NM_033199

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18414
Approved symbol	UCN2
Name	urocortin 2
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	UCNI, SRP, URP, UCN-II
Ensembl gene	ENSG00000145040
Ensembl biotype	protein_coding
OMIM	605902
Entrez	90226

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000273610

RefSeq mRNA: 1 — MANE Select: NM_033199 NM_033199

CCDS: CCDS2772

Canonical transcript exons

ENST00000273610 — 2 exons

Exon	Start	End
ENSE00001080957	48561718	48563136
ENSE00001307195	48563703	48563781

Expression profiles

Bgee: expression breadth ubiquitous, 107 present calls, max score 85.39.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.2960 / max 253.2235, expressed in 122 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42146	1.2960	122

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	85.39	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.35	gold quality
skin of abdomen	UBERON:0001416	77.19	gold quality
zone of skin	UBERON:0000014	76.78	gold quality
skin of leg	UBERON:0001511	76.57	gold quality
lower esophagus mucosa	UBERON:0035834	69.80	gold quality
metanephros cortex	UBERON:0010533	68.72	gold quality
esophagus mucosa	UBERON:0002469	68.09	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	67.71	gold quality
vagina	UBERON:0000996	67.59	gold quality
prostate gland	UBERON:0002367	63.85	gold quality
minor salivary gland	UBERON:0001830	60.66	gold quality
saliva-secreting gland	UBERON:0001044	60.25	gold quality
ectocervix	UBERON:0012249	59.60	gold quality
uterine cervix	UBERON:0000002	56.90	gold quality
tibial nerve	UBERON:0001323	56.81	gold quality
endocervix	UBERON:0000458	56.20	gold quality
apex of heart	UBERON:0002098	55.25	gold quality
descending thoracic aorta	UBERON:0002345	54.97	gold quality
islet of Langerhans	UBERON:0000006	54.06	gold quality
esophagus	UBERON:0001043	53.98	gold quality
thoracic aorta	UBERON:0001515	53.94	gold quality
ascending aorta	UBERON:0001496	53.61	gold quality
popliteal artery	UBERON:0002250	50.75	gold quality
tibial artery	UBERON:0007610	50.69	gold quality
gall bladder	UBERON:0002110	50.40	gold quality
smooth muscle tissue	UBERON:0001135	49.57	gold quality
spleen	UBERON:0002106	49.39	gold quality
heart left ventricle	UBERON:0002084	48.71	gold quality
hypothalamus	UBERON:0001898	48.52	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.80

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

23 targeting UCN2, 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-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-4696	99.48	67.48	1040
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-3688-5P	99.12	69.67	1091
HSA-MIR-4716-5P	98.82	68.57	1168
HSA-MIR-198	98.70	67.32	920
HSA-MIR-31-5P	98.58	68.35	1239
HSA-MIR-4290	98.51	65.17	907
HSA-MIR-891A-3P	98.05	67.99	970
HSA-MIR-2467-5P	97.36	67.71	991
HSA-MIR-1233-3P	96.81	65.44	573
HSA-MIR-7973	96.48	65.54	502
HSA-MIR-6846-3P	94.80	65.19	389
HSA-MIR-4442	92.35	67.08	98
HSA-MIR-3181	88.42	63.57	25

Literature-anchored findings (GeneRIF, showing 25)

• 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)
• data suggest a distinctive role for corticotropin-releasing hormone receptor 2 specific agonists like urocortin II in the control of myometrial contractility during human pregnancy (PMID:14592950)
• data indicate that intracisternal Ucn 2 induced a central CRF(2)-mediated inhibition of gastric emptying involving sympathetic alpha(1)-adrenergic mechanisms independent from the vagus contrasting with the vagal-dependent inhibitory actions of CRF & Ucn 1 (PMID:16223946)
• the 38 amino acid urocortin 2 peptide is the minimal pharmacophore (PMID:16476507)
• 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)
• Urocortin 2 may play a role in the regulation of estradiol production throughout pregnancy, thereby contributing to the placental regulation of key reproductive events in pregnancy maintenance and parturition. (PMID:19417223)
• 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)
• Unlike urocortin-1 levels, higher levels of urocortin 2 are not associated with worse left ventricular diastolic performance in patients with chronic systolic heart failure. (PMID:20670842)
• 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. Ucn2 is proinflammatory. (PMID:22000474)
• Description of ucn2 posttranslational processing and peptide sequence. Hypoxia and glycosylation, paradigms that might influence secretion or processing of gene products, did not significantly impact hUcn 2 prohormone cleavage. (PMID:23493376)
• Stresscopin-related peptide induces a weaker enhancement of cardiovascular function through corticotropin-releasing factor receptorn 2 than that induced by stresscopin. (PMID:23850799)
• UCN2 is significantly associated with AAA and inhibits VSMC proliferation by inducing a G1 cell cycle arrest suggesting a plausible regulatory role in AAA pathogenesis (PMID:24107226)
• UCNII caused cell death via different membrane-disrupting mechanisms that involve aggregation & membrane depolarization in bacteria and pore formation in Leishmania even inside macrophages. Innate immune cells produce UCNII in response to infections. (PMID:24249730)
• Solubilized SUMO-eXact-preproUCN2 was used successfully to generate two high affinity mouse monoclonal antibodies specific to the pro-region of urocortin 2. (PMID:24291344)
• Corticotrophin-Releasing Factor (CRF) and the urocortins are potent regulators of the inflammatory phenotype of human and mouse white adipocytes. (PMID:24835211)
• up-regulated in placenta, fetal membranes, and myometrium in labor (PMID:25426872)
• The transcripts of TAS1R3 and UCN2 in peripheral blood cells may be considered potential biomarkers of consumption of sugary and fatty food, respectively, to complement data of food-intake questionnaires. (PMID:26168276)
• examination of the local and systemic cardiovascular effects of urocortin 2 and urocortin 3 in healthy subjects and patients with heart failure (PMID:27275843)
• Data show that corticotropin releasing hormone receptor 2 (Crhr2) protein is abundantly expressed in the heart, and plasma Ucn2 levels were higher in patients with heart failure compared to healthy controls, indicating that endogenous Crhr2 is associated with heart failure. (PMID:28550160)
• laryngeal cancer cells were enriched in the recurrent chimera COL7A1-UCN2, which potentially affected cancer stem cell transition (PMID:29499655)
• Ucn2 may be an important element in the mosaic of blood pressure-lowering factors in patients treated for essential hypertension. (PMID:31443094)
• Urocortin-2 levels were elevated in hypertensive patients and correlated with left ventricular mass index in those patients. (PMID:31925709)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	ucn3l	ENSDARG00000087241
mus_musculus	Ucn2	ENSMUSG00000049699

Paralogs (1): UCN3 (ENSG00000178473)

Protein

Protein identifiers

Urocortin-2 — Q96RP3 (reviewed: Q96RP3)

Alternative names: Stresscopin-related peptide, Urocortin II, Urocortin-related peptide

All UniProt accessions (1): Q96RP3

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.

Post-translational modifications. Glycosylated.

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

RefSeq proteins (1): NP_149976* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000187	CRF	Domain
IPR024270	Urocortin_II/III	Family

Pfam: PF00473

UniProt features (7 total): helix 2, signal peptide 1, propeptide 1, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3N95	X-RAY DIFFRACTION	2.72
2RMG	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96RP3-F1	69.60	0.32

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 69 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOBP_DIGESTION, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, AP1_Q4_01, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, TGCTGAY_UNKNOWN, BACH2_01, TGANTCA_AP1_C, GOBP_RESPONSE_TO_HORMONE, GATA1_03, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING, GOMF_SIGNALING_RECEPTOR_BINDING, AP1FJ_Q2, GOBP_ADENYLATE_CYCLASE_ACTIVATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (4): adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), digestion (GO:0007586), hormone-mediated signaling pathway (GO:0009755), cellular response to nutrient levels (GO:0031669)

GO Molecular Function (6): hormone activity (GO:0005179), hormone binding (GO:0042562), corticotropin-releasing hormone receptor binding (GO:0051429), corticotropin-releasing hormone receptor 2 binding (GO:0051431), G protein-coupled receptor binding (GO:0001664), signaling receptor binding (GO:0005102)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

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
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
multicellular organismal process	1
signal transduction	1
cellular response to hormone stimulus	1
response to nutrient levels	1
cellular response to stimulus	1
receptor ligand activity	1
binding	1
peptide hormone receptor binding	1
neuropeptide receptor binding	1
corticotropin-releasing hormone receptor binding	1
signaling receptor binding	1
protein binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

244 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UCN2	CRHR2	Q13324	999
UCN2	UCN3	Q969E3	987
UCN2	CRHR1	P34998	976
UCN2	UCN	P55089	971
UCN2	CRH	P06850	940
UCN2	CRHBP	P24387	716
UCN2	POMC	P01189	709
UCN2	DEFB133	Q30KQ1	419
UCN2	FOS	P01100	387
UCN2	NPY	P01303	377
UCN2	UTS2	O95399	374
UCN2	PNOC	Q13519	368
UCN2	TOR2A	Q5JU69	352
UCN2	GHRL	Q9UBU3	348
UCN2	UTS2B	Q765I0	336

IntAct

3 interactions, top by confidence:

A	B	Type	Score
CRH	CRHR2	psi-mi:“MI:0915”(physical association)	0.540
CRHR2	UCN2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (2): UCN2 (Reconstituted Complex), UCN2 (Reconstituted Complex)

ESM2 similar proteins: A0A1B0GUA5, A0A494C0Y3, A0JNN8, A2A9F4, A2ARS0, A2VDX9, A5A769, A5PJP1, A8MTW9, C9JTQ0, O54887, P0C171, P0DJK0, P0DPE3, P36343, P60531, P98162, Q13487, Q1HCM0, Q1LZC5, Q2TBK3, Q2VPJ9, Q566C8, Q5BLP8, Q5JTB6, Q5NRQ0, Q64322, Q68FX5, Q6F5E0, Q6QNY0, Q6VUP9, Q7TN12, Q7TPD7, Q867D0, Q8K025, Q8MJW9, Q8NAX2, Q8NG41, Q8TAP8, Q8TEF2

Diamond homologs: Q1RMJ9, Q91WW1, Q96RP3, Q99ML8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

696 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:48562871:A:G	I85T	0.891
3:48562811:A:G	I105T	0.877
3:48562857:C:G	A90P	0.841
3:48562868:A:G	L86S	0.806
3:48562895:T:A	D77V	0.794
3:48562819:G:C	N102K	0.793
3:48562819:G:T	N102K	0.793
3:48562892:A:T	V78D	0.791
3:48562894:A:C	D77E	0.779
3:48562894:A:T	D77E	0.779
3:48562820:T:A	N102I	0.775
3:48562871:A:C	I85S	0.768
3:48562889:G:A	P79L	0.756
3:48562877:A:G	L83S	0.751
3:48562811:A:C	I105S	0.732
3:48562889:G:T	P79H	0.731
3:48562896:C:G	D77H	0.726
3:48562892:A:G	V78A	0.714
3:48562904:A:T	L74Q	0.698
3:48562889:G:C	P79R	0.689
3:48562830:C:G	A99P	0.687
3:48562880:A:T	L82H	0.681
3:48562821:T:A	N102Y	0.669
3:48563041:G:C	F28L	0.666
3:48563041:G:T	F28L	0.666
3:48563043:A:G	F28L	0.666
3:48562858:T:A	Q89H	0.663
3:48562858:T:G	Q89H	0.663
3:48562796:C:A	G110V	0.662
3:48562895:T:G	D77A	0.646

dbSNP variants (sampled 300 via entrez): RS1001325189 (3:48565094 G>A), RS1001774733 (3:48565635 C>T), RS1002831952 (3:48564537 G>A,T), RS1003131154 (3:48562705 C>T), RS1003540361 (3:48563810 T>C), RS1003879036 (3:48565051 G>T), RS1007194016 (3:48564044 C>A,G), RS1007570429 (3:48563120 G>A), RS1007874067 (3:48564289 G>A), RS1007905377 (3:48564496 A>G), RS1009586175 (3:48564788 C>T), RS1010515761 (3:48561382 C>T), RS1010588872 (3:48563704 G>A), RS1011551431 (3:48561954 G>A), RS1011777076 (3:48562714 T>C)

Disease associations

OMIM: gene MIM:605902 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001725_77	Inflammatory bowel disease	1.000000e-47
GCST002548_9	Ulcerative colitis	8.000000e-07
GCST004131_23	Inflammatory bowel disease	1.000000e-33
GCST004132_17	Crohn’s disease	3.000000e-23
GCST004133_11	Ulcerative colitis	8.000000e-20
GCST010698_80	Subcortical volume (min-P)	3.000000e-24
GCST010699_110	Brain morphology (min-P)	4.000000e-08
GCST010701_52	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_36	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_262	Brain morphology (MOSTest)	2.000000e-13

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

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
propionaldehyde	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
sodium arsenite	decreases expression	1
polyhexamethyleneguanidine	affects expression	1
abrine	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Acetaminophen	increases expression	1
Estradiol	affects cotreatment, increases expression	1
Plant Extracts	decreases expression, affects cotreatment	1
Rotenone	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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