ECRG4

Summary

ECRG4 (ECRG4 augurin precursor, HGNC:24642) is a protein-coding gene on chromosome 2q12.2, encoding Augurin (Q9H1Z8). Probable hormone that may attenuate cell proliferation and induce senescence of oligodendrocyte and neural precursor cells in the central nervous system.

Enables neuropeptide hormone activity. Involved in neuropeptide signaling pathway; positive regulation of hormone secretion; and vasopressin secretion. Located in apical plasma membrane; dense core granule; and extracellular space.

Source: NCBI Gene 84417 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 5 total
• MANE Select transcript: NM_032411

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24642
Approved symbol	ECRG4
Name	ECRG4 augurin precursor
Location	2q12.2
Locus type	gene with protein product
Status	Approved
Aliases	augurin
Ensembl gene	ENSG00000119147
Ensembl biotype	protein_coding
OMIM	611752
Entrez	84417

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000238044, ENST00000409944, ENST00000437659, ENST00000479337, ENST00000489174, ENST00000493478

RefSeq mRNA: 1 — MANE Select: NM_032411 NM_032411

CCDS: CCDS2072

Canonical transcript exons

ENST00000238044 — 4 exons

Exon	Start	End
ENSE00000804392	106073886	106074043
ENSE00001159980	106065688	106065843
ENSE00003475302	106071844	106071891
ENSE00003670380	106077765	106078155

Expression profiles

Bgee: expression breadth ubiquitous, 230 present calls, max score 99.48.

FANTOM5 (CAGE): breadth broad, TPM avg 4.2339 / max 235.4510, expressed in 313 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21826	3.2608	287
21825	0.9422	180
21824	0.0309	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	99.48	gold quality
mucosa of stomach	UBERON:0001199	99.48	gold quality
bronchus	UBERON:0002185	99.42	gold quality
layer of synovial tissue	UBERON:0007616	99.29	gold quality
cartilage tissue	UBERON:0002418	99.11	gold quality
right coronary artery	UBERON:0001625	99.05	gold quality
tibia	UBERON:0000979	98.86	gold quality
synovial joint	UBERON:0002217	98.80	gold quality
trachea	UBERON:0003126	98.48	gold quality
coronary artery	UBERON:0001621	97.87	gold quality
left coronary artery	UBERON:0001626	97.75	gold quality
dorsal root ganglion	UBERON:0000044	97.51	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.50	gold quality
fundus of stomach	UBERON:0001160	97.39	gold quality
adenohypophysis	UBERON:0002196	97.17	gold quality
pituitary gland	UBERON:0000007	96.92	gold quality
left lobe of thyroid gland	UBERON:0001120	96.85	gold quality
descending thoracic aorta	UBERON:0002345	96.66	gold quality
tibial nerve	UBERON:0001323	96.54	gold quality
thyroid gland	UBERON:0002046	96.49	gold quality
ascending aorta	UBERON:0001496	96.46	gold quality
thoracic aorta	UBERON:0001515	96.39	gold quality
vena cava	UBERON:0004087	96.09	gold quality
aorta	UBERON:0000947	96.01	gold quality
tibial artery	UBERON:0007610	95.81	gold quality
popliteal artery	UBERON:0002250	95.77	gold quality
right lobe of thyroid gland	UBERON:0001119	95.69	gold quality
urethra	UBERON:0000057	95.63	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.47	gold quality
lower esophagus	UBERON:0013473	95.38	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	1696.87
E-MTAB-10885	yes	1493.34
E-MTAB-8221	yes	1478.64
E-MTAB-6701	yes	57.56
E-MTAB-10287	yes	49.65
E-GEOD-130148	yes	11.55
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB

miRNA regulators (miRDB)

19 targeting ECRG4, 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-4482-3P	99.98	72.50	3147
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-4650-3P	99.01	68.39	1062
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-6831-5P	98.26	67.20	990
HSA-MIR-93-3P	98.15	66.65	1309
HSA-MIR-3927-3P	97.68	66.76	892
HSA-MIR-6888-5P	95.89	63.78	831

Literature-anchored findings (GeneRIF, showing 40)

• Inactivation of ECRG 4 gene by hypermethylation is a frequent molecular event in esophageal squamous cell carcinoma and may be involved in the carcinogenesis of this cancer. (PMID:12800218)
• Significantly lower expression of esophageal cancer-related gene 4 is associated with esophageal squamous cell carcinoma (PMID:17786363)
• The restoration of ECRG4 expression in ESCC cells inhibited cell proliferation, colony formation, cell cycle progression and tumor growth in vivo. ECRG4 is a novel candidate tumor suppressor gene in ESCC. (PMID:19521989)
• ECRG4 is silenced via promoter hypermethylation in different types of human cancer cells. (PMID:20017917)
• Loss of ECRG4 is associated with glioma. (PMID:20598162)
• Data show that ECRG4 interacts directly with ECRG1 to upregulate p21 protein expression, induce cell cycle G1 phase block and inhibit cancer cells proliferation in ESCC. (PMID:21288367)
• Augurin would play a constitutive inhibitory function in normal CNS while down regulation of Ecrg4 gene expression in injury, like in cancer, dysinhibits proliferation. (PMID:21935431)
• ECRG4 is a candidate tumor suppressor gene in breast cancer (PMID:22110708)
• DNA methylation of the ECRG4 promoter causes loss of ECRG4 gene expression in the esophageal squamous cell carcinoma cell line EC9706. (PMID:22325214)
• Tumor necrosis factor-alpha-induced apoptosis was also suppressed in ECRG4-overexpressing Jurkat cells. (PMID:22411956)
• kDa Ecrg4 localizes to the cell surface of prostate (PC3) or kidney (HEK) epithelial cells after transfection. (PMID:22526622)
• Aberrant ECRG4 promoter methylation may be used to monitor early gastric cancer and predict pathological staging. (PMID:22626786)
• Aberrant DNA methylation of ECRG4 gene is associated with colorectal cancer. (PMID:22901147)
• overexpression of ECRG4 enhanced the chemosensitivity of gastric cancer SGC-7901 cells to 5-FU through induction of apoptosis. (PMID:23553029)
• results suggest that C2ORF40 acts as a tumor suppressor gene in breast cancer pathogenesis and progression and is a candidate prognostic marker for this disease (PMID:23770814)
• ECRG4 is a candidate tumor suppressor gene that might be involved in the proliferation of esophageal squamous cell carcinoma (PMID:23957914)
• The expression of ECRG4 is frequently upregulated in a papillary thyroid carcinoma through the demethylation mechanism of CpG islands in the gene promoter region, and the ECRG4 has a tumor-promoting function through inducing the cell cycle transition (PMID:25326809)
• Results identify Ecrg4 as a paracrine factor that activates microglia and is chemotactic for monocytes, with potential as an antitumor therapeutic. (PMID:25378632)
• ECRG4 is present on the surface of human monocytes and granulocytes and its interaction with the innate immunity receptor complex supports a role for cell surface activation of ECRG4 during inflammation (PMID:25511108)
• Our data suggest that methylation-mediated suppression of the ECRG4 gene occurs frequently in nasopharyngeal carcinoma (PMID:25707757)
• Overexpression of ECRG4 inhibited laryngeal cancer cell proliferation and induced cancer cell apoptosis. (PMID:26165988)
• ECRG4 may be a tumor suppressor in renal cancer and serve as a prognostic marker (PMID:26276361)
• loss of ECRG4 protein expression may be involved in tumor progression and may serve as a prognostic biomarker for breast cancer. (PMID:26631111)
• The overexpression of ECRG4 inhibited tumorigenesis. (PMID:26762416)
• low expression or no expression of ECRG4 in esophageal cancer tissues was closely related to the degree of tumor invasion level, TNM staging, lymph node metastasis and recurrence and survival after surgery. (PMID:26823803)
• Downregulated ECRG4 is correlated with lymph node metastasis in nasopharyngeal carcinoma (PMID:27119734)
• the overexpression of Beclin 1 promoted apoptosis and decreased invasion by upregulating the expression of ECRG4 in A549 lung adenocarcinoma cells. Therefore, the selection of Beclin l as a target for gene therapy represents a more effective method for the treatment of lung cancer. (PMID:27175789)
• we have provided evidence to show that Ecrg4 is constitutively expressed in atria and the conduction systems and is down-regulated in AF. (PMID:28578429)
• UBR5 directly binds to the tumor suppressor esophageal cancer-related gene 4, increasing its ubiquitination to reducing the protein stability of ECRG4 to promote colorectal cancer progression. (PMID:28856538)
• positive and negative regulatory elements controlling ECRG4 expression include a counter regulation between promoter methylation and Sp1 activation. (PMID:28870864)
• Results from many studies support the discovery that ECRG4 plays a critical role in the pathogenesis of atrial fibrillation. [review] (PMID:29126922)
• ECRG4 down-regulates UBE2C expression in esophageal squamous cell carcinoma cells. (PMID:29268240)
• mutations in Pakistani patients with dilated cardiomyopathy rs375563861 (C2orf40), rs143187236 (MYOM3), and rs564181443 (RTKN2) have 3 fold or higher allele frequency in South Asians than in the global populations (PMID:29886034)
• ECRG4 is unique in its cytokine-like functional pattern and epigenetically-regulated gene expression pattern. The gene can be released from the cell membrane upon activation and detected in liquid biopsy, thus offering considerable potential in precision medicine. [review] (PMID:30003403)
• ECRG4 may act as a tumor suppressor, inhibiting proliferation and migration, inducing G0/G1 phase arrest and apoptosis via the mitochondrial apoptotic pathway. (PMID:30918105)
• Esophageal cancer related gene-4 inhibits the migration and proliferation of oral squamous cell carcinoma through BC200 lncRNA/MMP-9 and -13 signaling pathway. (PMID:31152845)
• the results help establish that phage display can be used to identify cryptic domains within ORFs of the human secretome and identify a novel TLR4-targeted internalization domain in the amino terminus of ECRG4 that may contribute to its effects on cell migration, immune cell activation and tumor suppression. (PMID:31190084)
• role of Ecrg4 in the cardiovascular system [review] (PMID:31468282)
• ECRG4 regulates neutrophil recruitment and CD44 expression during the inflammatory response to injury. (PMID:32195341)
• MicroRNA-196b promotes gastric cancer progression by targeting ECRG4. (PMID:33417325)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ecrg4a	ENSDARG00000056087
danio_rerio	ecrg4b	ENSDARG00000088717
mus_musculus	Ecrg4	ENSMUSG00000026051
rattus_norvegicus	Ecrg4	ENSRNOG00000023576

Protein

Protein identifiers

Augurin — Q9H1Z8 (reviewed: Q9H1Z8)

Alternative names: Esophageal cancer-related gene 4 protein

All UniProt accessions (3): Q9H1Z8, B8ZZE5, C9JRR0

UniProt curated annotations — full annotation on UniProt →

Function. Probable hormone that may attenuate cell proliferation and induce senescence of oligodendrocyte and neural precursor cells in the central nervous system. ECRG4-induced senescence is characterized by G1 arrest, RB1 dephosphorylation and accelerated CCND1 and CCND3 proteasomal degradation.

Subcellular location. Secreted. Cytoplasm. Apical cell membrane.

Tissue specificity. Expressed in the brain, with expression in the epithelial cell layer of the choroid plexus (at protein level).

Similarity. Belongs to the augurin family.

RefSeq proteins (1): NP_115787* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR028173	Augurin	Family

Pfam: PF15187

UniProt features (5 total): propeptide 2, signal peptide 1, peptide 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H1Z8-F1	66.76	0.05

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 145 (showing top): GOCC_SECRETORY_GRANULE, GOBP_ANAPHASE_PROMOTING_COMPLEX_DEPENDENT_CATABOLIC_PROCESS, chr2q12, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, GOBP_CELLULAR_SENESCENCE, CHANDRAN_METASTASIS_DN, GOBP_POSITIVE_REGULATION_OF_LIPID_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, MARTINEZ_RB1_TARGETS_DN, GOBP_REGULATION_OF_ENDOCRINE_PROCESS

GO Biological Process (5): central nervous system development (GO:0007417), anaphase-promoting complex-dependent catabolic process (GO:0031145), regulation of cell population proliferation (GO:0042127), G1 to G0 transition (GO:0070314), cellular senescence (GO:0090398)

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

GO Cellular Component (6): obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), apical plasma membrane (GO:0016324), extracellular region (GO:0005576), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
nervous system development	1
system development	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
cell population proliferation	1
regulation of cellular process	1
cell cycle process	1
cellular process	1
cellular response to stress	1
binding	1
intracellular anatomical structure	1
apical part of cell	1
plasma membrane region	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

540 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ECRG4	SPX	Q9BT56	572
ECRG4	TMPRSS11A	Q6ZMR5	399
ECRG4	PDLIM4	P50479	375
ECRG4	SCG2	P13521	355
ECRG4	MAMDC2	Q7Z304	348
ECRG4	CPNE4	Q96A23	347
ECRG4	ZNF169	Q14929	335
ECRG4	C11orf58	O00193	330
ECRG4	ANGPTL7	O43827	321
ECRG4	ATP13A4	Q4VNC1	316
ECRG4	NMU	P48645	305
ECRG4	KLHL8	Q9P2G9	305
ECRG4	UXS1	Q8NBZ7	301
ECRG4	FHAD1	B1AJZ9	299
ECRG4	FIGN	Q5HY92	297

IntAct

7 interactions, top by confidence:

A	B	Type	Score
ECRG4	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
ECRG4	WFS1	psi-mi:“MI:0915”(physical association)	0.560
ECRG4	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (4): C2orf40 (Affinity Capture-Western), UBR5 (Affinity Capture-Western), UBQLN2 (Two-hybrid), C2orf40 (Affinity Capture-RNA)

ESM2 similar proteins: A0JMK6, A5A6J6, B9WZ56, C0HKY1, C0HM54, E1ZXU8, O12956, O35314, O35417, O70176, P01165, P01282, P01362, P05060, P05408, P06300, P06308, P10362, P12285, P12961, P13521, P13589, P16014, P16613, P17685, P17686, P18509, P18844, P20616, P23389, P27682, P30945, P41534, P41535, P41585, P45644, P48143, P48144, P81401, P85799

Diamond homologs: D4A540, P0CAX4, Q32KM8, Q566V9, Q5FVX5, Q7ZXZ6, Q99LS0, Q9H1Z8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	4
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

800 predictions. Top by Δscore:

Variant	Effect	Δscore
2:106077761:CCA:C	acceptor_loss	1.0000
2:106077763:A:AG	acceptor_gain	1.0000
2:106077763:A:C	acceptor_loss	1.0000
2:106077764:G:GA	acceptor_gain	1.0000
2:106077764:GA:G	acceptor_gain	1.0000
2:106077764:GAA:G	acceptor_gain	1.0000
2:106077764:GAAA:G	acceptor_gain	1.0000
2:106077764:GAAAT:G	acceptor_gain	1.0000
2:106065839:CCCAG:C	donor_loss	0.9900
2:106065843:GGTGA:G	donor_loss	0.9900
2:106065845:T:G	donor_loss	0.9900
2:106072261:T:TA	donor_gain	0.9900
2:106072262:A:AA	donor_gain	0.9900
2:106072306:A:T	donor_gain	0.9900
2:106074041:GCG:G	donor_gain	0.9900
2:106077761:CCAGA:C	acceptor_gain	0.9900
2:106077762:CAGAA:C	acceptor_gain	0.9900
2:106077763:A:AT	acceptor_gain	0.9900
2:106071838:CTTTA:C	acceptor_loss	0.9800
2:106071839:TTTA:T	acceptor_loss	0.9800
2:106071840:TTAGG:T	acceptor_loss	0.9800
2:106071841:TAGGT:T	acceptor_loss	0.9800
2:106071842:AGG:A	acceptor_loss	0.9800
2:106071843:G:A	acceptor_loss	0.9800
2:106072305:G:GT	donor_gain	0.9800
2:106077759:CTCCA:C	acceptor_gain	0.9800
2:106077760:TCCAG:T	acceptor_gain	0.9800
2:106077764:G:A	acceptor_gain	0.9800
2:106071889:AAGGT:A	donor_loss	0.9700
2:106071890:AGGT:A	donor_loss	0.9700

AlphaMissense

958 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:106073977:G:C	W73C	0.997
2:106073977:G:T	W73C	0.997
2:106073975:T:A	W73R	0.996
2:106073975:T:C	W73R	0.996
2:106074005:T:A	W83R	0.995
2:106074005:T:C	W83R	0.995
2:106074018:T:C	F87S	0.993
2:106074032:T:C	F92L	0.993
2:106074034:T:A	F92L	0.993
2:106074034:T:G	F92L	0.993
2:106074007:G:C	W83C	0.992
2:106074007:G:T	W83C	0.992
2:106074008:T:G	Y84D	0.987
2:106074033:T:C	F92S	0.985
2:106077769:T:C	F97S	0.983
2:106073939:T:C	F61L	0.982
2:106073941:C:A	F61L	0.982
2:106073941:C:G	F61L	0.982
2:106074017:T:C	F87L	0.982
2:106074018:T:G	F87C	0.982
2:106074019:T:A	F87L	0.982
2:106074019:T:G	F87L	0.982
2:106073976:G:C	W73S	0.980
2:106077791:G:C	W104C	0.979
2:106077791:G:T	W104C	0.979
2:106077911:C:A	N144K	0.977
2:106077911:C:G	N144K	0.977
2:106074033:T:G	F92C	0.974
2:106077769:T:G	F97C	0.974
2:106077789:T:A	W104R	0.968

dbSNP variants (sampled 300 via entrez): RS1000145015 (2:106067632 G>C,T), RS1000176925 (2:106067232 C>A,T), RS1000226135 (2:106072871 A>C), RS1000557381 (2:106071612 T>C), RS1000568952 (2:106078392 G>A,T), RS1000931383 (2:106061449 TTCCCACAATTA>T), RS1001091859 (2:106072366 A>G), RS1001209117 (2:106076748 C>A), RS1001423637 (2:106070686 A>C,G), RS1001486953 (2:106062559 A>G), RS1001492617 (2:106065655 A>G), RS1001557498 (2:106067727 C>T), RS1001578431 (2:106073770 G>A,T), RS1001877574 (2:106072639 A>G), RS1001956424 (2:106066580 A>G)

Disease associations

OMIM: gene MIM:611752 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002187_1	Systolic blood pressure in sickle cell anemia	1.000000e-06
GCST005514_1	Neuritic plaques or neurofibrillary tangles or cerebral amyloid angiopathy (pleiotropy)	2.000000e-07
GCST005515_2	Neuritic plaques or cerebral amyloid angiopathy (pleiotropy)	3.000000e-06
GCST005516_4	Neuritic plaques or neurofibrillary tangles (pleiotropy)	2.000000e-08
GCST012227_1204	Hip circumference adjusted for BMI	5.000000e-09
GCST90020028_68	Hip circumference adjusted for BMI	2.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0006797	neurofibrillary tangles measurement
EFO:0006798	neuritic plaque measurement
EFO:0008039	BMI-adjusted hip circumference

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
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	6
entinostat	increases expression, affects cotreatment	2
Nickel	decreases expression	2
methylmercuric chloride	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases methylation, affects cotreatment	1
Arsenic Trioxide	decreases methylation, increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	increases methylation	1
Rotenone	increases expression	1
Silicon Dioxide	affects expression	1
Thimerosal	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Cyclosporine	decreases expression	1

Clinical trials (associated diseases)

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